Externally applied medicine for thyroid nodules and preparation method thereof

Abstract

The invention provides an external application medicine for thyroid nodules and a preparation method thereof, the medicine is composed of a traditional Chinese medicine compound extract, a targeting active component, a transdermal promotion system and a medicinal matrix, the traditional Chinese medicine compound extract contains multiple medicinal materials such as prunella vulgaris, the targeting component comprises selenium yeast and tetrahydrocurcumin, and the transdermal system is composed of azone and the like. The preparation method comprises the steps of raw material pretreatment, step-by-step extraction, purification and inclusion, and matrix forming. The traditional Chinese medicine composition is scientific in compatibility, high in transdermal absorption efficiency, stable in drug effect, high in safety and convenient to use, can effectively inhibit thyroid nodule hyperplasia and reduce the nodule volume, and is suitable for clinical adjuvant therapy of thyroid nodules.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a topical medicine for thyroid nodules and its preparation method. Background Technology

[0002] Thyroid nodules are common benign endocrine system lesions with an increasing incidence rate. Clinical manifestations often include a neck mass and a foreign body sensation; some patients may also experience swallowing discomfort and dull pain. Without intervention, nodules may enlarge, increasing the risk of malignancy. Currently, clinical treatments for thyroid nodules mainly include oral medication, surgery, and topical adjuvant therapy. Oral medications have drawbacks such as poor targeted efficacy after systemic absorption, significant gastrointestinal irritation, and the potential for drug resistance with long-term use. Surgical treatment is highly invasive, has a long recovery period, and carries a risk of recurrence, placing a significant physical and psychological burden on patients.

[0003] Topical medications, as an adjunct treatment for thyroid nodules, have advantages such as targeted action on the lesion site, minimal systemic side effects, and ease of use, making them a hot topic in clinical research. However, existing topical medications for thyroid nodules have several shortcomings: First, the formulation of traditional Chinese medicine is often unreasonable, mainly consisting of single nodule-dispersing components, lacking synergistic effects from multiple components, resulting in limited efficacy; second, they lack targeted active ingredients, making it difficult to effectively regulate thyroid function and inhibit nodule proliferation; third, transdermal absorption is poor, with active ingredients unable to penetrate the skin barrier to reach the lesion site, resulting in low bioavailability; and fourth, the preparation process is crude, leading to insufficient extraction of active ingredients and poor stability, resulting in a short shelf life and large fluctuations in efficacy.

[0004] Therefore, developing a topical thyroid nodule medication with scientific formulation, clear efficacy, good transdermal absorption, and stable preparation process to overcome the shortcomings of existing technologies has significant clinical application value and market prospects. Summary of the Invention

[0005] In view of this, the present invention proposes a topical medicine for thyroid nodules and its preparation method, thereby solving the above problems.

[0006] The technical solution of this invention is implemented as follows: A topical medicine for thyroid nodules, composed of a traditional Chinese medicine compound extract, a targeted active ingredient, a transdermal enhancement system, and a medicinal matrix; the traditional Chinese medicine compound extract is calculated by weight of the following raw materials: Prunella vulgaris 20-28 parts, Fritillaria thunbergii 14-22 parts, Gleditsia sinensis thorns 10-18 parts, Bupleurum chinense 8-16 parts, Scrophularia ningpoensis 12-20 parts, Scutellaria baicalensis 9-17 parts, Mentha haplocalyx 6-12 parts, Gardenia jasminoides 7-15 parts, Rheum palmatum 5-13 parts, Sparganium stoloniferum 9-16 parts, Curcuma zedoaria 9-16 parts, raw oyster shell 22-32 parts, Uncaria rhynchophylla 14-22 parts, Curcuma longa 7-13 parts, Dioscorea bulbifera 5-10 parts, dried alum 3-8 parts, and Glycyrrhiza uralensis 4-9 parts.

[0007] Furthermore, the targeted active ingredients include 0.1-0.2 parts of selenium yeast and 0.4-0.9 parts of curcumin derivative.

[0008] Furthermore, the transdermal enhancement system is composed of 1.2-2.2 parts azone, 0.8-1.6 parts menthol, and 1.0-1.7 parts sodium hyaluronate.

[0009] Furthermore, the pharmaceutical matrix comprises 1.3-1.9 parts of carbomer 941, 11-16 parts of glycerol, 5-10 parts of propylene glycol, and purified water to a total of 100 parts.

[0010] Furthermore, the curcumin derivative is tetrahydrocurcumin.

[0011] Furthermore, the selenium yeast contains 100-200 μg / g of selenium and is microencapsulated with microcapsule particles of 50-100 nm in diameter.

[0012] Furthermore, a method for preparing a topical medication for thyroid nodules includes the following steps:

[0013] S1. Raw material pretreatment: Prunella vulgaris, Fritillaria thunbergii, Uncaria rhynchophylla, Dioscorea bulbifera, Scutellaria baicalensis, Gardenia jasminoides, and Rheum palmatum are pulverized to 80-100 mesh; Sparganium stoloniferum, Curcuma zedoaria, Curcuma longa, Bupleurum chinense, and Scrophularia ningpoensis are pulverized to 60-80 mesh; raw oyster shell is pulverized to 40-60 mesh; licorice and calcined alum are pulverized to 100-120 mesh; and peppermint is pulverized to 100-120 mesh. These are then sealed separately for later use. All raw materials are sieved separately before use.

[0014] S2. Step-by-step extraction:

[0015] (1) Take Prunella vulgaris, Fritillaria thunbergii, Uncaria rhynchophylla, Dioscorea bulbifera, Scutellaria baicalensis, Gardenia jasminoides, and Rheum palmatum coarse powder, add 75-85% v / v ethanol solution, material-liquid ratio 1:8-12 (g / mL), ultrasonically reflux extract 1-3 times, each time for 2-2.5 hours, ultrasonic power 200-300W, temperature 65-75℃, combine the extracts, concentrate under reduced pressure to a relative density of 1.16-1.21 (60℃) to obtain extract I.

[0016] (2) Take the crude powders of Sparganium rhizome, Curcuma rhizome, Curcuma longa, Bupleurum root, and Scrophularia root. First, reflux extract once with petroleum ether at 60-90℃ at a material-to-liquid ratio of 1:7-10 (g / mL) for 1-2 hours. Filter out the residue. Then, reflux extract the residue with 55-65% v / v ethanol solution at a material-to-liquid ratio of 1:10-15 (g / mL) 1-3 times for 1-2 hours each time. Combine the extracts and concentrate under reduced pressure to a relative density of 1.16-1.21 (60℃) to obtain extract II.

[0017] (3) Take raw oyster, licorice, and coarse powder of alum, add purified water at a ratio of 1:15-20 (g / mL), decoct and extract 2-4 times, each time for 2-3 hours, combine the decoctions, and concentrate under reduced pressure to a relative density of 1.12-1.17 (60℃) to obtain extract III.

[0018] (4) Take coarse peppermint powder, add purified water at a ratio of 1:5-10 (g / mL), distill for 0.5-1.5 hours, collect the volatile oil for later use, filter the residue, concentrate the filtrate to a relative density of 1.10-1.15 (60℃), and obtain extract IV.

[0019] S3. Purification and Inclusion: Combine extracts I, II, III, and IV, and purify them using an AB-8 macroporous adsorption resin column. First, elute with purified water for 3 BV to remove impurities, then elute with 35%-55% v / v ethanol solution at a flow rate of 2.5 BV / h for 5 BV. Collect the eluent and vacuum dry to constant weight to obtain the total extract of the traditional Chinese medicine compound. Mix the total extract of the traditional Chinese medicine compound, selenium yeast, curcumin derivative, and peppermint volatile oil collected in step S2, and add 2-3 times the total mass of β-cyclodextrin to the mixture. Include using the saturated aqueous solution method at an inclusion temperature of 42-48℃ and a stirring time of 2-3 hours. Freeze-dry to obtain the inclusion powder.

[0020] S4. Matrix Preparation and Molding: Take Carbomer 941, add purified water to swell it until there are no particles, add glycerin and propylene glycol, stir evenly, then add azone, menthol and sodium hyaluronate, and ultrasonically disperse for 15-20 minutes to obtain a gel matrix; add the inclusion powder to the gel matrix, stir evenly, adjust the pH to 6.2-6.8 with 1mol / L sodium hydroxide solution, coat it on a non-woven fabric backing with a thickness of 0.3-0.5mm, dry at 55-60℃ for 2.5-3.5 hours, cut, cover and package to obtain the topical drug for thyroid nodules (sustain-release gel patch dosage form).

[0021] Furthermore, in step S2, the vacuum degree of the reduced pressure concentration is 0.06-0.08 MPa, and the temperature is 55-65℃.

[0022] Further, in step S3, the vacuum drying temperature is 45-55℃ and the vacuum degree is 0.07-0.09MPa; the freeze-drying temperature is -40 to -30℃ and the vacuum degree is 10-20Pa; in step S3, the diameter-to-height ratio of the AB-8 type macroporous adsorption resin column is 1:8-1:12; the inclusion aqueous solution method includes heating purified water to 42-48℃, adding β-cyclodextrin while stirring until the β-cyclodextrin no longer dissolves, obtaining a saturated aqueous solution of β-cyclodextrin, slowly adding the mixture dropwise to the saturated aqueous solution of β-cyclodextrin, maintaining a constant temperature of 42-48℃ while stirring for 2.5 hours, freeze-drying, pulverizing and sieving to obtain the inclusion powder.

[0023] Furthermore, in step S4, the ultrasonic dispersion power is 150-250W, the stirring speed is 300-500r / min, the coating is done using a precision coating machine, and the coating speed is 1-2m / min; after drying, low-temperature film coating is used, and the film coating temperature is 30-35℃.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows.

[0025] This invention utilizes a compound extract of 17 traditional Chinese medicinal herbs, including Prunella vulgaris, Fritillaria thunbergii, and Gleditsia sinensis thorns. These herbs work synergistically to dissipate nodules, regulate qi, promote blood circulation, nourish yin, and clear heat, specifically targeting thyroid nodules and inhibiting nodule proliferation. Simultaneously, the addition of selenium-enriched yeast and tetrahydrocurcumin, among other targeted active ingredients, helps regulate thyroid function and enhances anti-inflammatory and anti-proliferative effects, overcoming the limitations of existing topical medications in terms of single efficacy and poor targeting. A transdermal absorption enhancement system composed of azone, menthol, and sodium hyaluronate significantly promotes the penetration of the compound extract and targeted active ingredients into the skin barrier, improving transdermal absorption efficiency and bioavailability. This ensures rapid and sustained action of the active ingredients on the lesion site, effectively enhancing transdermal absorption efficiency compared to existing topical medications.

[0026] This invention employs a combined process of stepwise extraction, macroporous adsorption resin purification, and β-cyclodextrin inclusion. Stepwise extraction allows for the targeted extraction of effective components from different medicinal materials, purification removes impurities and improves the purity of effective components, and inclusion enhances the stability of the active ingredients and reduces volatilization loss. Simultaneously, precise limits are placed on process parameters such as extraction, concentration, and drying to ensure a stable and repeatable preparation process, resulting in a drug shelf life of over 24 months with minimal fluctuations in efficacy.

[0027] The drug of this invention is a sustained-release gel patch formulation with strong adhesion and long retention time. It can be directly applied to the lesion site, which is convenient to use and avoids the gastrointestinal irritation and systemic side effects of oral drugs. All drug components are pharmaceutical grade raw materials, and safety tests have verified that they are non-irritating to the skin, do not cause allergic reactions, have high safety, and are suitable for long-term use. Detailed Implementation

[0028] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0029] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0030] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0031] Skin irritation tests were conducted on the embodiments and comparative examples of the present invention, and the results showed that the prepared topical patch was non-irritating to intact skin.

[0032] The properties, flavors, meridian tropisms, functions, and indications of each medicinal herb are as follows:

[0033] Prunella vulgaris: It has a pungent and bitter taste and is cold in nature; it enters the liver and gallbladder meridians; its functions and indications are: clearing liver fire, improving eyesight, dispersing nodules and reducing swelling. It is used for red and swollen eyes, night pain in the eyeballs, scrofula, goiter, and mastitis, which meets the needs of dispersing nodules (goiter) in thyroid nodules.

[0034] Fritillaria thunbergii: bitter in taste and cold in nature; enters the lung and heart meridians; functions and indications: clears heat and resolves phlegm, disperses nodules and eliminates carbuncles, used for wind-heat cough, phlegm-fire cough, scrofula, goiter, sores, mastitis, and precisely targets thyroid nodules to disperse nodules.

[0035] Gleditsia sinensis thorns: pungent in taste and warm in nature; enters the liver and stomach meridians; functions and indications: reduces swelling and promotes detoxification, drains pus, kills parasites, used for carbuncles in their early stages or when pus has formed but not yet ruptured, externally used for scabies and leprosy, assists in dispersing nodules and reducing swelling, and improves local swelling of nodules.

[0036] Bupleurum chinense: bitter and pungent in taste, slightly cold in nature; enters the liver and gallbladder meridians; functions and indications: harmonizes the lesser yang, soothes the liver and raises yang, used for colds with fever, alternating chills and fever, chest and rib pain, irregular menstruation, and thyroid nodules caused by liver qi stagnation accompanied by emotional distress.

[0037] Scrophularia: Sweet, bitter, and salty in taste, slightly cold in nature; enters the lung, stomach, and kidney meridians; functions and indications: clears heat and cools blood, nourishes yin and reduces fire, detoxifies and dissipates nodules, used for heat entering the blood, febrile diseases causing rashes, febrile diseases damaging yin, red tongue with thirst, sore throat, scrofula, goiter, taking into account both nourishing yin and dissipating nodules.

[0038] Scutellaria baicalensis tablets: bitter in taste and cold in nature; enters the lung, gallbladder, spleen, large intestine, and small intestine meridians; functions and indications: clears heat and dries dampness, drains fire and detoxifies, stops bleeding, calms the fetus, used for damp-heat syndrome, summer-heat syndrome, chest tightness and nausea, damp-heat fullness, diarrhea, jaundice, lung-heat cough, high fever and thirst, carbuncles and boils, and helps clear local damp-heat in nodules.

[0039] Peppermint: pungent in taste and cool in nature; enters the lung and liver meridians; functions and indications: dispels wind-heat, clears the head and eyes, soothes the throat, promotes rash eruption, soothes the liver and regulates qi; used for wind-heat cold, early stage of wind-heat syndrome, headache, red eyes, sore throat, mouth sores, urticaria, measles, chest and rib distension, and relieves neck discomfort and emotional distress associated with thyroid nodules.

[0040] Gardenia: Bitter in taste and cold in nature; enters the heart, liver, lung, stomach, and triple burner meridians; functions and indications: clears heat and relieves irritability, clears heat and promotes diuresis, cools blood and detoxifies, externally reduces swelling and relieves pain, used for fever with irritability, damp-heat jaundice, painful urination, hematemesis and epistaxis due to blood heat, red and swollen eyes, and carbuncles due to fire toxins, and assists in clearing heat and dissipating nodules.

[0041] Rhubarb: Bitter in taste and cold in nature; enters the spleen, stomach, large intestine, liver, and pericardium meridians; functions and indications: purgative, clears heat and fire, cools blood and detoxifies, removes blood stasis and unblocks menstruation, promotes diuresis and relieves jaundice; used for constipation due to heat accumulation, hematemesis and epistaxis due to blood heat, red eyes and sore throat, carbuncles and boils, amenorrhea due to blood stasis, abdominal pain due to blood stasis, and assists in dispersing nodules and blood stasis.

[0042] Sparganium rhizome: pungent and bitter in taste, neutral in nature; enters the liver and spleen meridians; functions and indications: breaks up blood stasis and promotes qi circulation, eliminates stagnation and relieves pain, used for abdominal masses, amenorrhea due to blood stasis, chest pain, abdominal distension and pain due to food stagnation, and enhances the effect of dispersing nodules for thyroid nodules with blood stasis.

[0043] Curcuma zedoaria: pungent and bitter in taste, warm in nature; enters the liver and spleen meridians; functions and indications: breaks up blood stasis and promotes qi circulation, eliminates stagnation and relieves pain. It is used for abdominal masses, amenorrhea due to blood stasis, chest pain, and abdominal distension due to food stagnation. When combined with Sparganium rhizome, it enhances the effects of promoting qi circulation, activating blood circulation, dispersing nodules and eliminating masses.

[0044] Raw oyster: Salty in taste and slightly cold in nature; enters the liver, gallbladder and kidney meridians; functions and indications: calms the mind and spirit, nourishes yin and yang, softens and disperses nodules, astringes and consolidates; used for palpitations and insomnia, dizziness and tinnitus, scrofula and phlegm nodules, abdominal masses; it is the core medicinal material for softening and dispersing nodules in thyroid nodules.

[0045] Cat's Claw Herb: Sweet and pungent in taste, warm in nature; enters the liver and lung meridians; functions and indications: resolves phlegm and dissipates nodules, detoxifies and reduces swelling, used for scrofula, boils and carbuncles, snake and insect bites, specifically dissipates nodules, and helps shrink thyroid nodules.

[0046] Turmeric: It is pungent and bitter in taste and cold in nature; it enters the liver, heart and lung meridians; its functions and indications are: to promote blood circulation and relieve pain, to regulate qi and relieve depression, to clear the heart and cool the blood, to promote bile secretion and reduce jaundice. It is used for chest and rib pain, chest pain, amenorrhea and dysmenorrhea, breast distension and pain, delirium due to febrile diseases, epilepsy and mania, and to relieve neck pain and depression associated with nodules.

[0047] Dioscorea bulbifera: bitter in taste and cold in nature; enters the lung and liver meridians; functions and indications: resolves phlegm, dissipates nodules and eliminates goiter, clears heat and detoxifies, used for goiter, scrofula, sore throat, and snake bites, and is a commonly used medicinal material for treating goiter (thyroid nodules).

[0048] Alum: It tastes sour and astringent, and is cold in nature; it enters the lung, spleen, liver, and large intestine meridians; its functions and indications are: external use to detoxify and kill parasites, dry dampness and relieve itching; internal use to stop bleeding and diarrhea, and dispel wind and phlegm; external use to assist in dispersing nodules and astringing, and reduce local exudation of nodules.

[0049] Licorice: Sweet in taste and neutral in nature; enters the heart, lung, spleen and stomach meridians; functions and indications: invigorates qi and replenishes the middle jiao, clears heat and detoxifies, harmonizes the effects of various medicines, alleviates the irritation of bitter and cold herbs in the formula, harmonizes the properties of 16 herbs, and enhances the synergistic effect of dispersing nodules.

[0050] Example 1

[0051] A topical medication for thyroid nodules, the components of which are, by weight:

[0052] Traditional Chinese medicine compound extract: 20 parts of Prunella vulgaris, 14 parts of Fritillaria thunbergii, 10 parts of Gleditsia sinensis thorns, 8 parts of Bupleurum chinense, 12 parts of Scrophularia ningpoensis, 9 parts of Scutellaria baicalensis, 6 parts of Mentha haplocalyx, 7 parts of Gardenia jasminoides, 5 parts of Rheum palmatum, 9 parts of Sparganium stoloniferum, 9 parts of Curcuma zedoaria, 22 parts of raw oyster shell, 14 parts of Uncaria rhynchophylla, 7 parts of Curcuma longa, 5 parts of Dioscorea bulbifera, 3 parts of dried alum, and 4 parts of Glycyrrhiza uralensis.

[0053] Targeted active ingredients: 0.1 parts of selenium yeast (Se content 100μg / g, particle size 50nm), 0.4 parts of tetrahydrocurcumin (purity 98%);

[0054] Transdermal transdermal enhancement system: azone 1.2 parts, menthol 0.8 parts, sodium hyaluronate 1.0 part;

[0055] Pharmaceutical matrix: 1.3 parts carbomer 941, 11 parts glycerin, 5 parts propylene glycol, and purified water to 100 parts.

[0056] Example 2

[0057] A topical medication for thyroid nodules, the components of which are, by weight:

[0058] Traditional Chinese medicine compound extract: 28 parts of Prunella vulgaris, 22 parts of Fritillaria thunbergii, 18 parts of Gleditsia sinensis thorns, 16 parts of Bupleurum chinense, 20 parts of Scrophularia ningpoensis, 17 parts of Scutellaria baicalensis, 12 parts of Mentha haplocalyx, 15 parts of Gardenia jasminoides, 13 parts of Rheum palmatum, 16 parts of Sparganium stoloniferum, 16 parts of Curcuma zedoaria, 32 parts of raw oyster shell, 22 parts of Uncaria rhynchophylla, 13 parts of Curcuma longa, 10 parts of Dioscorea bulbifera, 8 parts of dried alum, and 9 parts of Glycyrrhiza uralensis.

[0059] Targeted active ingredients: 0.2 parts of selenium yeast (Se content 200μg / g, particle size 100nm), 0.9 parts of tetrahydrocurcumin (purity 98%);

[0060] Transdermal transdermal enhancement system: azone 2.2 parts, menthol 1.6 parts, sodium hyaluronate 1.7 parts;

[0061] Pharmaceutical matrix: 1.9 parts carbomer 941, 16 parts glycerin, 10 parts propylene glycol, and purified water to 100 parts.

[0062] Example 3

[0063] Traditional Chinese medicine compound extract: 24 parts of Prunella vulgaris, 18 parts of Fritillaria thunbergii, 14 parts of Gleditsia sinensis thorns, 12 parts of Bupleurum chinense, 16 parts of Scrophularia ningpoensis, 13 parts of Scutellaria baicalensis, 9 parts of Mentha haplocalyx, 11 parts of Gardenia jasminoides, 9 parts of Rheum palmatum, 12 parts of Sparganium stoloniferum, 12 parts of Curcuma zedoaria, 27 parts of raw Ostrea gigas, 18 parts of Uncaria rhynchophylla, 10 parts of Curcuma longa, 7 parts of Dioscorea bulbifera, 5 parts of dried alum, and 6 parts of Glycyrrhiza uralensis.

[0064] Targeted active ingredients: 0.15 parts selenium yeast, 0.6 parts tetrahydrocurcumin (98% purity);

[0065] Transdermal transdermal enhancement system: azone 1.7 parts, menthol 1.2 parts, sodium hyaluronate 1.3 parts;

[0066] Pharmaceutical matrix: 1.5 parts carbomer 941, 13 parts glycerin, 7 parts propylene glycol, and purified water to 100 parts.

[0067] The above Examples 1-3 were prepared using the following methods:

[0068] S1. Raw material pretreatment: Prunella vulgaris, Fritillaria thunbergii, Uncaria rhynchophylla, Dioscorea bulbifera, Scutellaria baicalensis, Gardenia jasminoides, and Rheum palmatum are pulverized to 90 mesh to obtain coarse powder A; Sparganium stoloniferum, Curcuma zedoaria, Curcuma longa, Bupleurum chinense, and Scrophularia ningpoensis are pulverized to 70 mesh to obtain coarse powder B; raw oyster shell is pulverized to 50 mesh to obtain coarse powder C; licorice and calcined alum (calcined at 320℃ for 1.2 hours) are pulverized to 110 mesh to obtain coarse powder D; peppermint is pulverized to 110 mesh to obtain coarse powder E; each is sealed separately for later use; all raw materials are sieved separately for later use.

[0069] S2. Step-by-step extraction:

[0070] (1) Take crude powder A, add 80% v / v ethanol solution, material-liquid ratio 1:10 (g / mL), extract twice by ultrasonic reflux, each time for 2.2 hours, ultrasonic power 250W, temperature 70℃, combine the extracts, concentrate under reduced pressure (vacuum degree 0.07MPa, temperature 60℃) to relative density 1.18 (measured at 60℃), to obtain extract I.

[0071] (2) Take crude powder B, add 8 times (w / v) of petroleum ether (70℃), reflux extract once for 1.5 hours, filter out the residue; the residue is then refluxed twice with 60% v / v ethanol solution at a material-to-liquid ratio of 1:12 (g / mL) for 1.5 hours each time, combine the extracts, concentrate under reduced pressure (vacuum degree 0.07MPa, temperature 60℃) to a relative density of 1.18 (60℃) to obtain extract II.

[0072] (3) Take coarse powder C and coarse powder D, add purified water at a ratio of 1:18 (g / mL), decoct and extract 3 times, each time for 2.5 hours, combine the decoctions, concentrate under reduced pressure (vacuum degree 0.07MPa, temperature 60℃) to a relative density of 1.15 (60℃) to obtain extract III.

[0073] (4) Take crude powder E, add purified water at a ratio of 1:8 (g / mL), distill for 1 hour, and collect the volatile oil for later use; after filtering the residue, concentrate the filtrate to a relative density of 1.12 (60℃) to obtain extract IV.

[0074] S3. Purification and Inclusion:

[0075] Combine extracts I, II, III, and IV, and stir them thoroughly to obtain a combined extract;

[0076] The combined extract was loaded onto a pretreated AB-8 macroporous adsorption resin column (column diameter to height ratio 1:10); eluted first with 3 column volumes (BV) of purified water at a flow rate of 2 BV / h, and the water wash was discarded. Then eluted with 5 column volumes of 45% v / v ethanol solution at a flow rate of 2.5 BV / h, and the eluent was collected;

[0077] The eluent was concentrated under reduced pressure at 50°C and 0.08 MPa and vacuum dried to constant weight. It was then pulverized to obtain the total extract powder of the traditional Chinese medicine compound.

[0078] Weigh out the total extract powder of the above-mentioned Chinese herbal compound, microencapsulated selenium yeast, tetrahydrocurcumin and peppermint volatile oil collected in step S2, and mix them evenly.

[0079] Add β-cyclodextrin equivalent to 2.5 times the total mass of the above mixture, and encapsulate using a saturated aqueous solution method: Heat purified water to 45°C, add β-cyclodextrin while stirring until no more dissolves, to prepare a saturated solution. Slowly add the above mixture solution dropwise to the saturated solution, and stir at a constant temperature of 45°C for 2.5 hours. Then place it in a freeze dryer and freeze-dry to dryness at -35°C and 15 Pa. Remove, pulverize, and pass through a 100-mesh sieve to obtain the encapsulated powder.

[0080] S4. Matrix preparation and molding: Take carbomer 941, add purified water to swell until there are no particles, add glycerol and propylene glycol, stir evenly, then add azone, menthol and sodium hyaluronate, and ultrasonically disperse for 18 minutes (power 200W, stirring speed 400r / min) to obtain the gel matrix.

[0081] Under continuous stirring, the inclusion powder is added to the gel matrix and stirred evenly. The pH is adjusted to 6.5 with 1 mol / L sodium hydroxide solution. The mixture is then coated onto a non-woven fabric backing with a precision coating machine (coating speed 1.5 m / min) to a thickness of 0.4 mm. It is dried at 58°C for 3 hours, then laminated at 32°C. The resulting product is cut into 5 cm × 5 cm sheets and packaged to obtain the external patch of this invention.

[0082] Comparative Example 1

[0083] The difference between this comparative example and Example 3 is that no targeted active ingredient is added, while the remaining components and preparation process are the same as in Example 3.

[0084] Comparative Example 2

[0085] The difference between this comparative example and Example 3 is that no transdermal enhancement system was added, while the remaining components and preparation process are the same as in Example 3.

[0086] Comparative Example 3

[0087] The difference between this comparative example and Example 3 is that step S3 does not involve β-cyclodextrin inclusion. Instead, the total extract of the traditional Chinese medicine compound, selenium yeast, tetrahydrocurcumin, and peppermint volatile oil are directly mixed and dried to obtain a mixed powder, which replaces the inclusion powder. The remaining steps and components are the same as in Example 3.

[0088] Comparative Example 4

[0089] The traditional decoction method is used: all the raw materials of the Chinese herbal compound (except peppermint) are mixed, decocted three times with water, and the decoctions are combined and concentrated into an extract. This extract is then directly mixed with a matrix such as carbomer, without stepwise extraction, resin purification, or inclusion processes. Peppermint is added at the end in the form of volatile oil.

[0090] Experimental Example: Effect Verification

[0091] I. In vitro transdermal absorption test:

[0092] 1. Methods: A Franz diffusion cell was used, with fresh isolated mouse abdominal skin as a barrier. Drug-containing gels (calculated at the same dose of the indicator component geniposide) prepared in Examples 1, 2, 3, and Comparative Examples 1, 2, 3, and 4 were placed in the supply cell. The receiving solution was a phosphate buffer-ethanol (7:3) mixture at pH 7.4. Samples were taken at set time points (2, 4, 6, 8, 12, 24 h), and an equal volume of receiving solution was added. The concentration of geniposide in the receiving solution was determined by HPLC, and the cumulative permeation (Q_n, μg / cm³) was calculated. 2 ).

[0093]

[0094] 2. Results Analysis: As shown in Table 1 above, Example 3 exhibited the highest cumulative penetration over 24 hours, indicating optimal transdermal performance within the scope of the claims. Comparative Example 1 showed a slight decrease in penetration, suggesting that the targeting component may have a positive impact on drug dispersion in the matrix or skin affinity. Comparative Example 2 showed a significant decrease in penetration, directly demonstrating the crucial role of the transdermal enhancement system of this invention. The penetration of Comparative Examples 3 and 4 was also significantly lower than that of the other examples, indicating that the β-cyclodextrin inclusion process and stepwise extraction and purification process are essential for improving the transdermal efficiency of the active ingredient.

[0095] II. Pharmacodynamic Tests (Rat Thyroid Nodule Model):

[0096] 1. Methods: SD rats were used to induce a thyroid hyperplasia nodule model through subcutaneous injection of thyroid-stimulating hormone (TSH) combined with a high-iodine drinking water method. After successful model establishment, rats were randomly divided into: normal control group, model group, positive control group (orally administered levothyroxine sodium tablets), Example 1 group, Example 2 group, Example 3 group, Comparative Example 1 group, Comparative Example 2 group, Comparative Example 3 group, and Comparative Example 4 group. In each treatment group, a corresponding drug patch was applied externally to the thyroid region of the rat's neck (applied for 8 hours daily, with a new patch applied afterward), for 4 consecutive weeks.

[0097] 2. After treatment, the following tests were performed: ① Thyroid volume was measured by ultrasound; ② Serum was collected and the levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were detected by chemiluminescence immunoassay; ③ Thyroid tissue was collected, and hematoxylin-eosin (HE) staining was performed to observe the pathological morphology, and the positive rate of proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry.

[0098]

[0099] 3. The data in the table above show that the topical medicine of the present invention (especially Example 3) not only effectively inhibits the hyperplasia of thyroid nodules, but also helps to restore or protect the normal endocrine function of the thyroid gland, without causing hypothyroidism or hyperthyroidism. This further proves its comprehensive advantages and safety in treatment from a functional perspective.

[0100] III. Stability Test

[0101] 1. Method: The finished patches prepared in Example 3, Comparative Examples 3 and 4 were placed in a drug stability test chamber and placed under accelerated conditions (temperature 40℃±2℃, relative humidity 75%±5%) for 6 months. Samples were taken at the end of 0, 1, 2, 3 and 6 months.

[0102] 2. Detection indicators: ① Appearance; ② pH value; ③ Gel adhesion; ④ The content of the main active ingredients, prunella vulgarisin and geniposide, was determined by HPLC.

[0103]

[0104] 3. Results and Analysis: As shown in Table 3, after 6 months of accelerated testing, the key quality attributes of Example 3 showed minimal changes, with the main active ingredient content retention rate exceeding 96%, and stable appearance, pH, and adhesion. In contrast, Comparative Example 3 showed slight discoloration and odor changes after 3 months, and a significant decrease in active ingredient content after 6 months. Comparative Example 4 exhibited the worst stability, with the most significant content decrease, and slight oil seepage from the ointment. These results strongly demonstrate the crucial role of the β-cyclodextrin inclusion process and stepwise extraction and purification process of this invention in ensuring product quality stability and efficacy during storage.

[0105] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A topical medication for thyroid nodules, characterized in that, It is composed of traditional Chinese medicine compound extracts, targeted active ingredients, transdermal transdermal enhancement system and pharmaceutical matrix; the traditional Chinese medicine compound extracts are calculated by weight of the following raw materials: Prunella vulgaris 20-28 parts, Fritillaria thunbergii 14-22 parts, Gleditsia sinensis thorns 10-18 parts, Bupleurum chinense 8-16 parts, Scrophularia ningpoensis 12-20 parts, Scutellaria baicalensis 9-17 parts, Mentha haplocalyx 6-12 parts, Gardenia jasminoides 7-15 parts, Rheum palmatum 5-13 parts, Sparganium stoloniferum 9-16 parts, Curcuma zedoaria 9-16 parts, raw oyster shell 22-32 parts, Uncaria rhynchophylla 14-22 parts, Curcuma longa 7-13 parts, Dioscorea bulbifera 5-10 parts, dried alum 3-8 parts, Glycyrrhiza uralensis 4-9 parts.

2. The topical medication for thyroid nodules as described in claim 1, characterized in that, The targeted active ingredients include 0.1-0.2 parts of selenium yeast and 0.4-0.9 parts of curcumin derivative.

3. The topical medication for thyroid nodules as described in claim 1, characterized in that, The transdermal penetration enhancement system consists of 1.2-2.2 parts azone, 0.8-1.6 parts menthol, and 1.0-1.7 parts sodium hyaluronate.

4. The topical medication for thyroid nodules as described in claim 1, characterized in that, The pharmaceutical matrix comprises 1.3-1.9 parts of carbomer 941, 11-16 parts of glycerol, 5-10 parts of propylene glycol, and purified water to a total of 100 parts.

5. A topical medication for thyroid nodules as described in claim 2, characterized in that, The curcumin derivative is tetrahydrocurcumin.

6. A topical medication for thyroid nodules as described in claim 2, characterized in that, The selenium yeast contains 100-200 μg / g of selenium and is microencapsulated with microcapsule particles of 50-100 nm in diameter.

7. A method for preparing a topical medication for thyroid nodules as described in any one of claims 1-6, characterized in that, Includes the following steps: S1. Raw material pretreatment: Prunella vulgaris, Fritillaria thunbergii, Uncaria rhynchophylla, Dioscorea bulbifera, Scutellaria baicalensis, Gardenia jasminoides, and Rheum palmatum are pulverized to 80-100 mesh; Sparganium stoloniferum, Curcuma zedoaria, Curcuma longa, Bupleurum chinense, and Scrophularia ningpoensis are pulverized to 60-80 mesh; raw oyster shell is pulverized to 40-60 mesh; licorice and calcined alum are pulverized to 100-120 mesh; and peppermint is pulverized to 100-120 mesh. These are then sealed separately for later use. All raw materials are sieved separately before use. S2. Step-by-step extraction: (1) Take Prunella vulgaris, Fritillaria thunbergii, Uncaria rhynchophylla, Dioscorea bulbifera, Scutellaria baicalensis, Gardenia jasminoides, and Rheum palmatum (coarse powder), add 75-85% v / v ethanol solution, with a material-to-liquid ratio of 1:8-12 (g / mL), and extract by ultrasonic reflux 1-3 times, each time for 2-2.5 hours, with an ultrasonic power of 200-300W and a temperature of 65-75℃. Combine the extracts and concentrate under reduced pressure to a relative density of 1.16-1.21 (60℃) to obtain extract I; (2) Take coarse powders of Sparganium rhizome, Curcuma rhizome, Curcuma longa, Bupleurum root, and Scrophularia root. First, extract once with petroleum ether at 60-90℃ at a material-to-liquid ratio of 1:7-10 (g / mL) for 1-2 hours. Filter out the residue. Then, extract the residue again with 55-65% v / v ethanol solution at a material-to-liquid ratio of 1:10-15 (g / mL) 1-3 times, 1-2 hours each time. Combine the extracts and concentrate under reduced pressure to a relative density of 1.16-1.21 (60℃) to obtain extract II; (3) Take raw oyster, licorice, and coarse powder of alum, add purified water at a ratio of 1:15-20 (g / mL), decoct and extract 2-4 times, each time for 2-3 hours, combine the decoctions, and concentrate under reduced pressure to a relative density of 1.12-1.17 (60℃) to obtain extract III; (4) Take coarse peppermint powder, add purified water at a ratio of 1:5-10 (g / mL), distill for 0.5-1.5 hours, collect the volatile oil for later use, filter the residue, concentrate the filtrate to a relative density of 1.10-1.15 (60℃), and obtain extract IV; S3. Purification and Inclusion: Combine extracts I, II, III, and IV, and purify them using an AB-8 macroporous adsorption resin column. First, elute with purified water for 3 BV to remove impurities, then elute with 35%-55% v / v ethanol solution at a flow rate of 2.5 BV / h for 5 BV. Collect the eluent and vacuum dry to constant weight to obtain the total extract of the traditional Chinese medicine compound. Mix the total extract of the traditional Chinese medicine compound, selenium yeast, curcumin derivative, and peppermint volatile oil collected in step S2. Add 2-3 times the total mass of the mixture of β-cyclodextrin, and use the saturated aqueous solution method for inclusion at an inclusion temperature of 42-48℃ and a stirring time of 2-3 hours. Freeze-dry to obtain the inclusion powder. S4. Matrix Preparation and Molding: Take Carbomer 941, add purified water to swell until no particles are present, add glycerol and propylene glycol, stir evenly, then add azone, menthol, and sodium hyaluronate, and ultrasonically disperse for 15-20 minutes to obtain a gel matrix; add the inclusion powder to the gel matrix, stir evenly, adjust the pH to 6.2-6.8 with 1mol / L sodium hydroxide solution, coat it on a non-woven fabric backing with a thickness of 0.3-0.5mm, dry at 55-60℃ for 2.5-3.5 hours, cut, coat, and package to obtain the final product.

8. The preparation method according to claim 7, characterized in that, In step S2, the vacuum degree of the reduced pressure concentration is 0.06-0.08 MPa, and the temperature is 55-65℃.

9. The preparation method according to claim 7, characterized in that, In step S3, the vacuum drying temperature is 45-55℃ and the vacuum degree is 0.07-0.09MPa; the freeze-drying temperature is -40 to -30℃ and the vacuum degree is 10-20Pa; in step S3, the diameter-to-height ratio of the AB-8 type macroporous adsorption resin column is 1:8-1:12; the inclusion aqueous solution method includes heating purified water to 42-48℃, adding β-cyclodextrin while stirring until the β-cyclodextrin no longer dissolves, obtaining a saturated β-cyclodextrin aqueous solution, slowly adding the mixture dropwise to the saturated β-cyclodextrin aqueous solution, maintaining a constant temperature of 42-48℃ while stirring for 2.5 hours, freeze-drying, pulverizing and sieving to obtain the inclusion powder.

10. The preparation method according to claim 7, characterized in that, In step S4, the ultrasonic dispersion power is 150-250W, the stirring speed is 300-500r / min, the coating is done with a precision coating machine, and the coating speed is 1-2m / min; after drying, low-temperature film coating is used, and the film coating temperature is 30-35℃.

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