External application medicine for acute stage of subacute thyroiditis and preparation method of external application medicine

Abstract

The invention provides an external application medicine for acute stage of subacute thyroiditis and a preparation method of the external application medicine. The external application medicine comprises an active component, a percutaneous absorption enhancer, an antioxidant and a gel matrix, the active ingredients comprise a traditional Chinese medicine compound extract, a non-steroidal anti-inflammatory drug and an immunomodulator in a specific weight ratio, the percutaneous absorption enhancer is a compound system of paeoniflorin oleate, camellia saponin and menthol, resveratrol and curcumin are added as antioxidants, and the gel matrix is a compound system of carboxymethyl chitosan and sodium alginate. The thyroid gland anti-inflammatory drug has the advantages of high transdermal efficiency and good biocompatibility, can act on thyroid lesions in a targeting manner, quickly relieves neck swelling and pain in the acute stage of subacute thyroiditis, reduces inflammation indexes, and is high in safety, and three-in-one synergistic treatment of anti-inflammatory, immunoregulation, stagnation eliminating and pain relieving is achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a topical patch for the acute phase of subacute thyroiditis and its preparation method. Background Technology

[0002] Subacute thyroiditis, also known as subacute granulomatous thyroiditis, (pseudo)giant cell thyroiditis, non-infectious thyroiditis, migratory thyroiditis, viral thyroiditis, DeQuervain's thyroiditis, granulomatous thyroiditis, or giant cell thyroiditis, is a common inflammatory disease of the thyroid gland. It is often associated with upper respiratory tract viral infections such as Coxsackievirus, influenza virus, and Epstein-Barr virus. Its course is mainly divided into the acute phase (thyrotoxicosis phase), the remission phase (hypothyroidism phase), and the recovery phase. The acute phase is the stage with the most severe symptoms and the highest rate of patient visits. The core clinical manifestations are severe pain in the thyroid region, diffuse / nodular enlargement, and significant tenderness. The pain can radiate to the jaw, behind the ear, and throat. It is accompanied by systemic inflammatory reactions such as fever and fatigue, as well as transient thyrotoxicosis symptoms such as palpitations, tremors, and excessive sweating caused by the massive release of thyroid hormones, severely impacting the patient's quality of life.

[0003] Currently, first-line clinical treatment mainly relies on oral nonsteroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids. Although these drugs can effectively control symptoms, long-term or high-dose use is often accompanied by systemic side effects such as gastrointestinal damage, water and sodium retention, and elevated blood sugar. Furthermore, there is a risk of relapse after discontinuation of the drugs, resulting in poor patient compliance. These treatments cannot fundamentally stop the progression of the disease, and some patients develop permanent hypothyroidism.

[0004] In recent years, topical therapy has shown advantages in treating soft tissue inflammatory diseases as a strategy that can reduce systemic exposure and increase drug concentration at the target site. However, it still has many drawbacks: the active ingredients are often singular, containing only traditional Chinese medicine components or single chemical drug components, failing to achieve the synergistic effects of anti-inflammatory and analgesic, immunomodulatory, and swelling-reducing effects simultaneously, resulting in limited therapeutic efficacy. In particular, the large number of reactive oxygen free radicals generated during acute inflammatory outbreaks can lead to oxidative stress damage to thyroid follicular cells, a key pathological link often overlooked in current topical treatments. Furthermore, while traditional Chinese medicine topical preparations have a theoretical basis of "clearing heat and detoxifying, dispersing nodules and relieving pain" in treating "goiter" (subacute thyroiditis), they often suffer from low transdermal efficiency of active ingredients, short local retention time at the lesion, and single therapeutic target, making it difficult to quickly relieve severe pain and inflammation in the acute phase. The compatibility of the preparation matrix is ​​poor; existing topical gels and ointments often have problems such as poor adhesion, easy migration, poor breathability, and easy staining of clothing, resulting in poor patient compliance.

[0005] Therefore, there is an urgent need to develop a topical compound preparation that can penetrate the skin barrier, achieve high-efficiency enrichment in the thyroid lesion area, and simultaneously exert multiple synergistic effects of anti-inflammatory, immunomodulatory, antioxidant and direct analgesic effects, in order to overcome the shortcomings of existing oral treatments with large systemic side effects and the insufficient efficacy of traditional topical drugs. Summary of the Invention

[0006] In view of this, the present invention proposes a topical patch for the acute phase of subacute thyroiditis and its preparation method, thereby solving the above problems.

[0007] The technical solution of the present invention is implemented as follows: a topical patch for the acute phase of subacute thyroiditis, comprising active ingredients, transdermal absorption enhancers, antioxidants, and a gel matrix; the active ingredients are traditional Chinese medicine compound extracts, nonsteroidal anti-inflammatory drugs, and immunomodulators in a weight ratio of (1-3):(0.5-2):(0.2-1); the antioxidants are resveratrol and curcumin in a weight ratio of (3-8):1, with a total addition amount of 0.8-1.2% of the total weight of the active ingredients; the gel matrix is ​​prepared by compounding carboxymethyl chitosan and sodium alginate in a mass ratio of (1-3):1.

[0008] Preferably, the traditional Chinese medicine compound extract comprises the following raw materials in parts by weight: 30-40 parts of Prunella vulgaris, 25-35 parts of Taraxacum mongolicum, 20-30 parts of Paeonia lactiflora, 15-25 parts of Scrophularia ningpoensis, 25-35 parts of Uncaria rhynchophylla, and 10-20 parts of Boswellia carterii.

[0009] Preferably, the nonsteroidal anti-inflammatory drug is any one of diclofenac sodium, ketoprofen, or flurbiprofen ester, and the nonsteroidal anti-inflammatory drug is micronized to a particle size of 1-5 μm, which can improve skin penetration efficiency.

[0010] Preferably, the immunomodulator is one or more of the following: total glucosides of paeony, tripterygium wilfordii lactone, and dipotassium glycyrrhizate. The immunomodulator is encapsulated in nanoliposomes with an average particle size of 50-200 nm and an encapsulation rate of ≥85%.

[0011] Preferably, the transdermal absorption enhancer is composed of paeoniflorin oleate, camellia saponin, and menthol in a weight ratio of (3-5):(2-3):1, and the total amount added is 3-8% of the total weight of the active components; the paeoniflorin oleate is a lipophilic modified product of paeoniflorin, and the camellia saponin is obtained by desaccharification and purification of camellia seed extract.

[0012] Preferably, the paeoniflorin oleate is prepared by esterification reaction of paeoniflorin and oleic acid. The specific modification method is as follows: paeoniflorin and oleic acid are mixed in a molar ratio of 1:(1-1.5), solvent and catalyst are added, and the mixture is stirred at a constant temperature of 60-80℃ for 4-6 hours. After the reaction is completed, the mixture is washed with water, distilled under reduced pressure and purified by column chromatography to obtain paeoniflorin oleate with a purity of ≥90%.

[0013] Preferably, after pulverizing the camellia seed extract, add 5-8 times its weight of deionized water, stir to dissolve, adjust the pH to 4.5-5.5, add 2-5% of β-glucosidase by weight of the extract, and enzymatically hydrolyze at 45-55℃ for 2-3 hours to inactivate the enzyme. Centrifuge and collect the supernatant. Add 3-5 times the volume of anhydrous ethanol to the supernatant, let it stand to precipitate for 2-4 hours, filter to remove polysaccharide precipitate, concentrate the filtrate under reduced pressure until there is no alcohol odor, and purify by silica gel column chromatography (eluent is chloroform-methanol, volume ratio 8:2-7:3). Collect the target eluent fraction, freeze-dry it, and obtain camellia saponin with a purity ≥95%.

[0014] The present invention also provides a method for preparing the above-mentioned topical patch for the acute phase of subacute thyroiditis, comprising the following steps:

[0015] S1. Preprocessing:

[0016] a) Preparation of compound extract of traditional Chinese medicine: Prunella vulgaris, dandelion, red peony root, scrophularia ningpoensis, cat's claw grass and vinegar-processed frankincense were weighed according to the weight parts. After pretreatment, they were extracted by supercritical CO2 extraction. The extract was collected, concentrated under reduced pressure and freeze-dried to obtain dry powder of compound extract of traditional Chinese medicine.

[0017] b) Immunomodulator pretreatment: Immunomodulators were prepared into nanoliposomes using a thin-film dispersion-ultrasound method, and then homogenized under high pressure and freeze-dried to obtain nanoliposome-encapsulated immunomodulator dry powder.

[0018] S2. Preparation of active component premix: The dry powder of Chinese herbal compound extract, the micronized non-steroidal anti-inflammatory drug, and the dry powder of immunomodulatory agent encapsulated in nanoliposomes are mixed evenly according to the weight ratio described above. A transdermal absorption promoter is added, and the mixture is stirred at a constant temperature until it is completely dispersed to obtain the active component premix.

[0019] S3. Preparation of composite gel matrix: Carboxymethyl chitosan and sodium alginate were weighed according to the mass ratio, and purified water was added separately to fully swell them. The two swollen solutions were mixed evenly, and a crosslinking agent was added and stirred at a constant temperature to prepare a uniform and transparent composite gel matrix sol.

[0020] S4. Forming of the patch: Add the active component premix and antioxidant to the composite gel matrix sol, stir evenly after vacuum degassing, coat it on the medical non-woven fabric backing layer, cover it with a polyethylene anti-adhesive layer, and after constant temperature shaping, slicing and aseptic packaging, the external patch is obtained.

[0021] Preferably, in step S1 a), the pretreatment involves pulverizing the raw material and passing it through an 80-100 mesh sieve; supercritical CO2 extraction uses anhydrous ethanol as an entrainer, with the weight ratio of anhydrous ethanol to the Chinese herbal raw material being 1:1-2, an extraction pressure of 20-30 MPa, an extraction temperature of 40-50℃, and an extraction time of 1.5-2.5 h; the vacuum degree of the reduced pressure concentration is 0.06-0.08 MPa, the temperature is 45-55℃, and the concentration is carried out until the extract has no alcohol odor.

[0022] Preferably, in step S1 b), the preparation of the nanoliposomes specifically involves: dissolving lecithin and cholesterol in anhydrous ethanol at a mass ratio of 4-6:1, adding an immunomodulator, stirring until completely dissolved, removing the organic solvent by rotary evaporation under reduced pressure to form a uniform lipid film, hydrating it with phosphate buffer after vacuum drying, homogenizing it under high pressure after ultrasonic treatment (ultrasonic frequency 30-50kHz, power 150-300W, temperature 35-45℃, ultrasonic duration 15-25min, homogenization pressure 60-90MPa, homogenization temperature controlled at 30-40℃, homogenizing 2-4 times, filtering through a 0.22μm microporous membrane to obtain a nanoliposome suspension, and then freeze-drying it to obtain a dry powder.

[0023] Preferably, in step S2, the temperature of the constant temperature stirring is 35-45℃, the stirring speed is 30-50 r / min, and the stirring time is 20-30 min.

[0024] Preferably, in step S3, the swelling temperature of the carboxymethyl chitosan and sodium alginate is 40-50℃, and the swelling time is 2-4h; the crosslinking agent is calcium gluconate, and the amount added is 0.5-2% of the total mass of carboxymethyl chitosan and sodium alginate; the constant temperature reaction temperature is 35-45℃, and the reaction time is 15-30min.

[0025] Preferably, in step S4, the coating thickness is 0.3-0.5 mm, the constant temperature setting temperature is 40-50℃, and the setting time is 30-60 min.

[0026] The present invention also provides the use of the above-mentioned topical patch for the acute phase of subacute thyroiditis in the preparation of a drug for treating neck swelling, pain and fever caused by subacute thyroiditis.

[0027] Compared with the prior art, the beneficial effects of the present invention are:

[0028] In view of the core pathogenesis and pathological characteristics of "heat-toxin stasis, phlegm-blood stasis, and overactivation of autoimmunity" in the acute stage of subacute thyroiditis, a proprietary traditional Chinese medicine compound is formulated: Prunella vulgaris clears the liver and purges fire, dissipates nodules and relieves swelling as the monarch drug; Taraxacum mongolicum clears heat and detoxifies, dissipates nodules and relieves swelling as the minister drug; Paeonia lactiflora clears heat and cools blood, dispels stasis and relieves pain, Scrophularia ningpoensis nourishes yin and reduces fire, detoxifies and dissipates nodules, Nepeta cataria dispels phlegm and dissipates nodules, detoxifies and relieves swelling, Olibanum activates blood circulation to stop pain, promotes tissue regeneration and relieves swelling. The six herbs are used together to directly address the core symptoms of thyroid swelling and pain, achieving radical intervention in dissipating nodules, relieving pain, and clearing heat and detoxifying; in combination with non-steroidal anti-inflammatory drugs, it rapidly inhibits local inflammatory responses and relieves pain and fever symptoms; at the same time, an immunomodulator is added, which is delivered by targeted encapsulation in nanoliposomes, competitively inhibits inflammatory factors, regulates the overactivated autoimmune response of the body, reduces the damage of thyroid follicular epithelial cells, blocks the progression of the disease from the pathological root, and avoids the recurrence of the disease. The three are compounded in a specific ratio and work synergistically to not only rapidly relieve the symptoms in the acute stage but also complete the targeted intervention of the core pathological mechanism, treating both the symptoms and the root cause, and making up for the defect of existing drugs that only treat the symptoms.

[0029] The present invention uses a combination of paeoniflorin oleate, camellia saponin yuan, and menthol to form a synergistic penetration-enhancing system. Among them, paeoniflorin oleate has both therapeutic activity and lipophilicity, and can reversibly open the intercellular spaces of stratum corneum cells; camellia saponin yuan can loosen cutin lipids and inhibit the efflux function of P-glycoprotein, reduce drug loss, and increase local retention; menthol rapidly dilates pores, assists in enhancing penetration, and relieves surface pain. The three work synergistically to bidirectionally improve the transdermal efficiency of active ingredients and the local retention amount at the lesion site.

[0030] The present invention uses a specific ratio of resveratrol and curcumin as antioxidants. This compound combination can synergistically and efficiently scavenge a large number of reactive oxygen free radicals generated at the lesion site in the acute stage of subacute thyroiditis, directly reducing the damage of oxidative stress to thyroid follicular cells. This not only helps to interrupt the "oxidation-inflammation" vicious cycle from the root, enhancing the overall anti-inflammatory effect, but also can produce a rapid analgesic effect by inhibiting the direct activation of pain receptors by free radicals.

[0031] The present invention is for topical application to the neck. The active ingredients can be directly targeted and enriched in the thyroid lesion through percutaneous absorption. The local drug concentration is high and the onset is fast, avoiding the drug loss of oral administration through gastrointestinal absorption and liver metabolism. At the same time, it completely avoids the gastrointestinal irritation, liver and kidney function damage of oral non-steroidal anti-inflammatory drugs, as well as the various adverse reactions of systemic glucocorticoid therapy. It has excellent safety and a wide range of applicable populations, especially suitable for patients with gastrointestinal diseases, liver and kidney insufficiency, diabetes, etc. who cannot tolerate oral or systemic hormone therapy, and has broad clinical application prospects. Detailed implementation manners

[0032] To better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0033] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0034] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0035] Preparation Example 1: Preparation of Paeoniflorin Oleate

[0036] Paeoniflorin and oleic acid were mixed at a molar ratio of 1:1.2, and toluene (3 times the total mass of the reactants) was added as a solvent. 1% p-toluenesulfonic acid (1% of the total mass of the reaction system) was added as a catalyst. The mixture was stirred at 70°C for 5 hours. After the reaction was completed, the mixture was washed three times with an equal amount of deionized water to separate the organic phase. The organic phase was then distilled under reduced pressure at 45°C and -0.098 MPa to remove toluene, yielding the crude product.

[0037] 200-300 mesh silica gel was used as the stationary phase, and the amount of silica gel was 20 times the weight of the sample to be purified. Wet packing was used, and the column diameter to height ratio was 1:10. After packing, the two column volumes were equilibrated with eluent. The crude product was dissolved in eluent and then loaded onto the silica gel bed at a volume of 4%. A gradient elution was performed using a chloroform-methanol mixture as the eluent. First, three column volumes of chloroform-methanol (9:1 v / v) were eluted to remove impurities. Then, the chloroform-methanol v / v ratio was adjusted to 7.5:2.5, and five column volumes were eluted to collect the target component. The elution flow rate was controlled at 1 column volume / hour. Thin-layer chromatography (TLC) was used to monitor the elution process. Single-component eluates with an Rf value of 0.5 were combined, concentrated under reduced pressure to remove the eluent, and freeze-dried at -40°C to obtain purified paeoniflorin oleate, with a purity of 92.5% as determined by HPLC.

[0038] Preparation Example 2: Preparation of Camellia oleifera saponins

[0039] Take crude saponin powder from camellia seeds with a total saponin content of 55% (obtained from defatted camellia seed meal through extraction with 70% ethanol), pulverize it, add 6 times its weight of deionized water, stir to dissolve, adjust the pH to 5.0, add 3% of the extract weight of β-glucosidase, enzymatically hydrolyze at 50℃ for 2.5h, boil for 12min to inactivate the enzyme, centrifuge (8000rpm, 15min) and collect the supernatant; add 4 times the volume of anhydrous ethanol to the supernatant, let it stand to precipitate for 3h, filter to remove polysaccharide precipitate; concentrate the filtrate under reduced pressure until there is no alcohol odor to obtain the concentrate.

[0040] The concentrate was purified by silica gel column chromatography (200-300 mesh) using chloroform-methanol (7.5:2.5 v / v) as the eluent at a flow rate of approximately 1.5 mL / min, with each fraction collected in 10 mL increments. Thin-layer chromatography (TLC) was used to monitor the fractions, and fractions with Rf values ​​consistent with the camellia saponin standard were collected. The target eluates were combined, pre-frozen at -50°C, and then freeze-dried for 24 h to obtain camellia saponin with a purity of 96.2% (as determined by HPLC).

[0041] Example 1

[0042] This embodiment provides a topical patch for use in the acute phase of subacute thyroiditis, which consists of the following components:

[0043] 1. Active ingredients: a compound extract of traditional Chinese medicine in a weight ratio of 2:1:0.5, diclofenac sodium, and total glycosides of paeony; wherein, the raw materials of the compound extract of traditional Chinese medicine are: 35 parts of Prunella vulgaris, 30 parts of Taraxacum mongolicum, 25 parts of Paeonia lactiflora, 20 parts of Scrophularia ningpoensis, 30 parts of Uncaria rhynchophylla, and 15 parts of Boswellia carterii.

[0044] Sodium diclofenac is micronized to a particle size of 2-3 μm;

[0045] Paeonia lactiflora total glycosides were encapsulated in nanoliposomes with an average particle size of 100-150 nm and an encapsulation efficiency of 88.2%.

[0046] 2. Transdermal absorption enhancer: composed of paeoniflorin oleate obtained in Preparation Example 1, camellia saponin obtained in Preparation Example 2, and menthol in a weight ratio of 4:2.5:1, with the total amount added being 5% of the total weight of the active ingredients;

[0047] 3. Antioxidants: Resveratrol and curcumin in a weight ratio of 5:1, with a total addition amount of 1% of the total weight of active ingredients;

[0048] 4. Gel matrix: Carboxymethyl chitosan and sodium alginate are compounded in a mass ratio of 2:1, and the total weight of the gel matrix is ​​80% of the total weight of the applied drug.

[0049] The preparation method of the topical patch drug in this embodiment includes the following steps:

[0050] S1. Preprocessing:

[0051] a) Preparation of compound extract of traditional Chinese medicine: Prunella vulgaris, dandelion, Paeonia lactiflora, Scrophularia ningpoensis, Uncaria rhynchophylla, and frankincense were weighed according to the specified weight proportions, pulverized and passed through a 100-mesh sieve, and added to a supercritical CO2 extraction device. Anhydrous ethanol was added as an entrainer, with a weight ratio of anhydrous ethanol to the raw materials of traditional Chinese medicine of 1:1.5. The extraction pressure was 25 MPa, the extraction temperature was 45℃, and the extraction time was 2 h. The extract was collected. The extract was concentrated under reduced pressure at a vacuum of 0.07 MPa and a temperature of 50℃ until the extract had no alcohol odor. Then it was freeze-dried (pre-freezing temperature -35℃, pre-freezing time 3 h; sublimation drying temperature -20℃, desorption drying temperature 25℃, vacuum degree 0.02 MPa throughout, total drying time 15 h) to obtain the dry powder of compound extract of traditional Chinese medicine.

[0052] b) Immunomodulator pretreatment: Lecithin and cholesterol were dissolved in anhydrous ethanol at a mass ratio of 5:1. Total paeoniflorin was added and stirred until completely dissolved. The organic solvent was removed by rotary evaporation under reduced pressure to form a uniform lipid film. After vacuum drying, the film was hydrated with phosphate buffer solution at pH 6.8. After ultrasonic treatment, the film was homogenized under high pressure. Ultrasonic treatment process parameters: ultrasonic frequency 40kHz, power 200W, temperature 40℃, ultrasonic duration 20min, intermittent ultrasonication, working interval ratio 2s:3s. High pressure homogenization process parameters: homogenization pressure 75MPa, homogenization temperature 35℃, homogenization cycle 3 times. After homogenization, the film was filtered through a 0.22μm microporous membrane to obtain a nanoliposome suspension. Then, it was freeze-dried (pre-freezing temperature -45℃, pre-freezing time 4h; sublimation drying temperature -25℃, desorption drying temperature 20℃, vacuum degree 0.01MPa, total drying time 18h) to obtain nanoliposome-encapsulated total paeoniflorin powder.

[0053] S2. Preparation of active component premix: The dry powder of Chinese herbal compound extract, the micronized diclofenac sodium, and the dry powder of total paeoniflorin encapsulated in nanoliposomes are mixed evenly at a weight ratio of 2:1:0.5. A transdermal absorption promoter is added, and the mixture is stirred at a constant temperature of 40℃ and 40r / min for 25min until it is completely dispersed to obtain the active component premix.

[0054] S3. Preparation of composite gel matrix: Carboxymethyl chitosan and sodium alginate were weighed at a mass ratio of 2:1, and purified water was added separately. The mixture was swollen at 45℃ for 3 hours until it was completely swollen. The two swollen solutions were mixed evenly, and calcium gluconate (1% of the total mass of carboxymethyl chitosan and sodium alginate) was added. The mixture was stirred at 40℃ for 20 minutes to obtain a uniform and transparent composite gel matrix sol.

[0055] S4. Forming of the patch: Add the active component premix and antioxidant to the composite gel matrix sol, stir evenly after vacuum degassing, coat it on the medical non-woven fabric backing layer with a coating thickness of 0.4 mm, cover it with a polyethylene anti-adhesive layer, and fix it at a constant temperature of 45°C for 45 min. Cut it into pieces and aseptically package it to obtain the topical patch.

[0056] Example 2

[0057] This embodiment provides a topical patch for use in the acute phase of subacute thyroiditis, which consists of the following components:

[0058] 1. Active ingredients: a traditional Chinese medicine compound extract in a weight ratio of 1:0.5:0.2, ketoprofen, and dipotassium glycyrrhizate; wherein the raw materials of the traditional Chinese medicine compound extract are: 30 parts of Prunella vulgaris, 25 parts of Taraxacum mongolicum, 20 parts of Paeonia lactiflora, 15 parts of Scrophularia ningpoensis, 25 parts of Uncaria rhynchophylla, and 10 parts of Boswellia carterii; ketoprofen is micronized to a particle size of 1-3 μm; dipotassium glycyrrhizate is encapsulated in nanoliposomes to an average particle size of 50-100 nm and an encapsulation rate of 86.7%;

[0059] 2. Transdermal absorption enhancer: composed of paeoniflorin oleate obtained in Preparation Example 1, camellia saponin obtained in Preparation Example 2, and menthol in a weight ratio of 3:2:1, with the total amount added being 3% of the total weight of the active ingredients;

[0060] 3. Antioxidants: Resveratrol and curcumin in a weight ratio of 3:1, with a total addition amount of 0.8% of the total weight of active ingredients;

[0061] 4. Gel matrix: Carboxymethyl chitosan and sodium alginate are compounded in a mass ratio of 1:1, and the total weight of the gel matrix is ​​85% of the total weight of the applied drug.

[0062] The preparation method of the topical patch drug in this embodiment is the same as that in Embodiment 1.

[0063] Example 3

[0064] This embodiment provides a topical patch for use in the acute phase of subacute thyroiditis, which consists of the following components:

[0065] 1. Active ingredients: a compound extract of traditional Chinese medicine in a weight ratio of 3:2:1, flurbiprofen ester, and triptolide; wherein, the raw materials of the compound extract of traditional Chinese medicine are: 40 parts of Prunella vulgaris, 35 parts of Taraxacum mongolicum, 30 parts of Paeonia lactiflora, 25 parts of Scrophularia ningpoensis, 35 parts of Uncaria rhynchophylla, and 20 parts of Boswellia carterii (vinegar-processed); flurbiprofen ester is micronized to a particle size of 3-5 μm; triptolide is encapsulated in nanoliposomes to an average particle size of 150-200 nm with an encapsulation rate of 89.1%;

[0066] 2. Transdermal absorption enhancer: composed of paeoniflorin oleate obtained in Preparation Example 1, camellia saponin obtained in Preparation Example 2, and menthol in a weight ratio of 5:3:1, with the total amount added being 8% of the total weight of the active ingredients;

[0067] 3. Antioxidants: Resveratrol and curcumin in a weight ratio of 8:1, with a total addition amount of 1.2% of the total weight of active ingredients;

[0068] 4. Gel matrix: Carboxymethyl chitosan and sodium alginate are compounded in a mass ratio of 3:1, and the total weight of the gel matrix is ​​75% of the total weight of the applied drug.

[0069] The preparation method of the topical patch drug in this embodiment is the same as that in Embodiment 1.

[0070] Comparative Example 1

[0071] The only difference between this comparative example and Example 1 is that the active ingredients do not contain the immunomodulatory total paeoniflorin; the other components, proportions, and preparation methods are the same as in Example 1.

[0072] Comparative Example 2

[0073] The only difference between this comparative example and Example 1 is that the transdermal absorption enhancer is replaced with an equal weight of the traditional penetration enhancer azone; the other components, proportions, and preparation methods are the same as in Example 1.

[0074] Comparative Example 3

[0075] The only difference between this comparative example and Example 1 is that the gel matrix is ​​replaced with an equal weight of a single sodium alginate gel matrix, while the other components, ratios, and preparation methods are the same as in Example 1.

[0076] Comparative Example 4

[0077] The only difference between this comparative example and Example 1 is that it does not contain antioxidants, the missing component gel matrix is ​​made up, and the other components, proportions and preparation methods are the same as in Example 1.

[0078] Comparative Example 5

[0079] The comparative example is commercially available diclofenac sodium gel (specification: 1%), which serves as a positive control.

[0080] Experimental Example 1: In vitro transdermal performance test

[0081] In vitro transdermal assays were performed using a modified Franz diffusion cell, with isolated rat abdominal skin as the transdermal barrier. The receiving solution was phosphate buffer-anhydrous ethanol (7:3, volume ratio) at pH 7.4. The volume of the receiving cell was 15 mL, the diffusion area was 2.8 cm², the experimental temperature was 37 °C, and the stirring speed was 300 r / min.

[0082] Take the patch medications from Examples 1-3, Comparative Examples 1-3, and Comparative Example 5, cut them to a uniform diffusion area, and fix them between the supply and receiving pools of the diffusion pool, with the patch surface facing the stratum corneum of the skin. Take samples at 1h, 2h, 4h, 6h, 8h, and 12h after the start of the experiment, with 0.5mL of sample taken each time. At the same time, replenish an equal volume of fresh receiving liquid at the same temperature. Use high performance liquid chromatography (HPLC) to determine the content of diclofenac sodium in the receiving liquid and calculate the cumulative permeation.

[0083] After the experiment, the skin was peeled off, and the amount of drug retained in the skin and subcutaneous tissue was measured after treatment. The results are shown in Tables 1 and 2.

[0084]

[0085]

[0086] As shown in Tables 1 and 2, the cumulative drug penetration and subcutaneous drug retention in Examples 1-3 were significantly higher than those in Comparative Examples 2-3 (P<0.05), indicating that the composite transdermal absorption enhancer of the present invention can significantly improve the transdermal efficiency of the active ingredient and the local retention in the lesion, achieving highly efficient targeted drug delivery; there was no significant difference between Comparative Example 1 and Example 1, indicating that the immunomodulator had no significant effect on the transdermal performance of the drug.

[0087] Test Example 2: Anti-inflammatory Activity Test

[0088] The anti-inflammatory activity of the drug was evaluated using a rat paw edema model. Fifty male SPF-grade SD rats, weighing 180-220g, were randomly divided into five groups: blank control group, Example 1 group, Comparative Example 1 group, Comparative Example 2 group, Comparative Example 4 group, and Comparative Example 5 group, with 10 rats in each group.

[0089] Except for the blank control group, rats in all other groups were subcutaneously injected with 0.1 mL of 1% carrageenan saline solution into the right hind paw to induce inflammation. Immediately after inflammation, the following drugs were administered to the right hind paw: Group 1, Comparative Example 1, and Comparative Example 2 received the corresponding patch (cut into 1 cm × 1 cm pieces), Comparative Example 4 received 0.1 g of commercially available diclofenac sodium gel, and the blank control group received a blank gel matrix patch of equal area. The volume of the right hind paw was measured at 1 h, 2 h, 4 h, 6 h, and 8 h after inflammation, and the paw swelling rate was calculated. The results are shown in Table 3.

[0090]

[0091] As shown in Table 3, the foot swelling rate in Example 1 group was significantly lower than that in the other groups (P<0.05), indicating that the drug of the present invention has excellent anti-inflammatory activity, significantly superior to commercially available diclofenac sodium gel; the anti-inflammatory activity of Comparative Example 1 group was significantly lower than that of Example 1 group, indicating that the addition of immunomodulators can significantly enhance the anti-inflammatory effect of the drug and achieve synergistic effect; the anti-inflammatory activity of Comparative Example 2 group was significantly lower than that of Example 1 group, indicating that the composite permeation-enhancing system of the present invention can enhance the anti-inflammatory effect of the drug by improving transdermal efficiency; the anti-inflammatory activity of Comparative Example 4 was significantly lower than that of Example 1 group, indicating that antioxidants can scavenge a large number of reactive oxygen free radicals and reduce the direct inflammatory stimulation caused by oxidative damage.

[0092] Test Example 3: Analgesic Activity Test

[0093] The analgesic activity of the drug was evaluated using the acetic acid writhing test in mice. Sixty SPF-grade Kunming mice, half male and half female, weighing 18-22g, were randomly divided into 6 groups: blank control group, Example 1 group, comparative example 1 group, comparative example 3 group, comparative example 2 group, and comparative example 4 group, with 10 mice in each group.

[0094] Before drug administration, the abdomen of mice was shaved, covering an area of ​​approximately 2cm × 2cm. Drug administration was performed 24 hours after shaving: Groups 1, 2, and 4 received the corresponding drug patches (cut to 2cm × 2cm), while Group 5 received 0.2g of commercially available diclofenac sodium gel. The blank control group received a blank gel patch of equal area. Thirty minutes after drug administration, each mouse was intraperitoneally injected with 0.2mL of 0.6% acetic acid saline solution. The number of writhing movements of the mice within 15 minutes was observed and recorded, and the analgesic inhibition rate was calculated. The results are shown in Table 4.

[0095]

[0096] As shown in Table 4, the number of writhing movements in the Example 1 group was significantly less than that in the other groups (P<0.05), and the analgesic inhibition rate was as high as 75.95%, indicating that the drug of the present invention has excellent analgesic activity, which is significantly better than that of commercially available diclofenac sodium gel. The analgesic activity of the Comparative Example 1 group was significantly lower than that of the Example 1 group, indicating that the immunomodulator, traditional Chinese medicine compound, and non-steroidal anti-inflammatory drug have a synergistic effect, which can significantly improve the analgesic effect. The analgesic activity of the Comparative Example 2 group was significantly lower than that of the Example 1 group, indicating that the composite permeation-enhancing system of the present invention can enhance the analgesic effect of the drug by improving the transdermal efficiency. The results of Comparative Example 4 show that by scavenging reactive oxygen free radicals, the activation of TRPV1 / A1 channels by reactive oxygen free radicals is directly inhibited, which can quickly relieve pain directly caused by oxidative stress.

[0097] Trial Example 4: Preliminary Clinical Efficacy Trial

[0098] Sixty patients in the acute phase of subacute thyroiditis were randomly divided into a treatment group and a control group, with 30 patients in each group. The treatment group received the topical patch medication of Example 1 of this invention, applied to the skin of the neck corresponding to the thyroid gland, one patch per application, each patch left on for 8 hours, once daily for 2 weeks. The control group received oral diclofenac sodium sustained-release tablets, 75 mg once daily for 2 weeks.

[0099] The pain VAS score, degree of thyroid enlargement, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels of the two groups of patients before and after treatment were observed. The results are shown in Table 5.

[0100] A linear scoring system of 0-10 points is used, with the following scoring criteria:

[0101] 0 points: No pain, no discomfort in the thyroid area, and no abnormalities in neck movements such as swallowing and turning the head.

[0102] 1-3 points: Mild pain, slight dull pain or throbbing pain in the thyroid area, which is tolerable and does not affect neck movement, eating or sleeping.

[0103] 4-6 points: Moderate pain, with significant throbbing or stabbing pain in the thyroid area. The pain worsens with neck movements (swallowing, turning the head), and slightly affects sleep. No pain medication is required.

[0104] 7-10 points: Severe pain, intense swelling and stabbing pain in the thyroid area, persistent pain, severely limited neck movement, inability to eat or sleep normally, and the need to take painkillers for relief.

[0105]

[0106] As shown in Table 5, after treatment, the VAS score for pain, the diameter of thyroid enlargement, ESR, and CRP levels in the treatment group were significantly lower than those in the control group (P<0.05), and the incidence of adverse reactions was significantly lower in the treatment group (P<0.05). This indicates that the clinical efficacy of the topical patch drug of the present invention in treating the acute phase of subacute thyroiditis is significantly better than that of oral diclofenac sodium sustained-release tablets. It can quickly relieve neck swelling and pain, reduce inflammatory markers, and has excellent safety with no systemic adverse reactions like those of oral drugs.

[0107] Test Example 5: Skin Irritation Test

[0108] Twelve healthy rabbits, half male and half female, weighing 2.0-2.5 kg, were randomly divided into an intact skin group and a damaged skin group, with six rabbits in each group. 24 hours before administration, the hair on both sides of the spine on the back of the rabbits was removed, covering an area of ​​approximately 3cm × 3cm. In the damaged skin group, a "#" mark was made in the hair removal area with a sterile needle, to the point of bleeding, without damaging the dermis.

[0109] During administration, the drug of Example 1 was applied to the left hair removal area, and a blank gel matrix was applied to the right side as a control. The application time was 8 hours. After administration, residual drug was washed off with warm water. Erythema and edema of the hair removal area were observed at 1 hour, 24 hours, 48 ​​hours and 72 hours after drug removal. Skin irritation was scored according to the "Cosmetic Safety Technical Specifications".

[0110] The results showed that neither the intact skin group nor the damaged skin group had any irritation reactions such as erythema or edema at any time point, and the skin irritation score was 0 for both groups. This indicates that the topical patch of the present invention is non-irritating to the skin and has excellent safety.

[0111] 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 patch for use in the acute phase of subacute thyroiditis, characterized in that, It comprises active ingredients, transdermal absorption enhancers, antioxidants, and a gel matrix; the active ingredients are traditional Chinese medicine compound extracts, nonsteroidal anti-inflammatory drugs, and immunomodulators in a weight ratio of (1-3):(0.5-2):(0.2-1); the antioxidants are resveratrol and curcumin in a weight ratio of (3-8):1, with the total amount added being 0.8-1.2% of the total weight of the active ingredients; the gel matrix is ​​prepared by compounding carboxymethyl chitosan and sodium alginate in a mass ratio of (1-3):

1.

2. The topical patch medicine as described in claim 1, characterized in that, The herbal compound extract comprises the following raw materials in parts by weight: 30-40 parts of Prunella vulgaris, 25-35 parts of Taraxacum mongolicum, 20-30 parts of Paeonia lactiflora, 15-25 parts of Scrophularia ningpoensis, 25-35 parts of Uncaria rhynchophylla, and 10-20 parts of Boswellia carterii.

3. The topical patch medicine as described in claim 1, characterized in that, The nonsteroidal anti-inflammatory drug is any one of diclofenac sodium, ketoprofen, or flurbiprofen ester, and the nonsteroidal anti-inflammatory drug is micronized to a particle size of 1-5 μm.

4. The topical patch medicine as described in claim 1, characterized in that, The immunomodulator is one or more of the following: total glucosides of paeony, tripterygium lactone, and dipotassium glycyrrhizate. The immunomodulator is encapsulated in nanoliposomes with an average particle size of 50-200 nm and an encapsulation rate of ≥85%.

5. The topical patch medicine as described in claim 1, characterized in that, The transdermal absorption enhancer is composed of paeoniflorin oleate, camellia saponin, and menthol in a weight ratio of (3-5):(2-3):1, with the total addition amount being 3-8% of the total weight of the active components; the paeoniflorin oleate is a lipophilic modified product of paeoniflorin, and the camellia saponin is obtained by desaccharification and purification of camellia seed extract.

6. The topical patch medicine as described in claim 5, characterized in that, The paeoniflorin oleate was prepared by esterification reaction of paeoniflorin and oleic acid. The specific modification method is as follows: paeoniflorin and oleic acid are mixed in a molar ratio of 1:(1-1.5), solvent and catalyst are added, and the mixture is stirred at a constant temperature of 60-80℃ for 4-6 hours. After the reaction is completed, the mixture is washed with water, distilled under reduced pressure and purified by column chromatography to obtain paeoniflorin oleate.

7. The topical patch medicine as described in claim 5, characterized in that, The desugar purification method is as follows: After pulverizing the camellia seed extract, add 5-8 times its weight of deionized water, stir to dissolve, adjust the pH value to 4.5-5.5, add 2-5% of β-glucosidase by weight of the extract, and enzymatically hydrolyze at 45-55℃ for 2-3 hours to inactivate the enzyme. Centrifuge and collect the supernatant. Add 3-5 times the volume of anhydrous ethanol to the supernatant, let it stand to precipitate for 2-4 hours, filter and concentrate, purify, collect the target eluent, and freeze-dry to obtain camellia saponin.

8. A method for preparing a topical patch medicament as described in any one of claims 1-7, characterized in that, Includes the following steps: S1. Preprocessing: a) Preparation of compound extract of traditional Chinese medicine: Prunella vulgaris, dandelion, red peony root, scrophularia ningpoensis, cat's claw grass and vinegar-processed frankincense were weighed according to the weight parts. After pretreatment, they were extracted by supercritical CO2 extraction. The extract was collected, concentrated under reduced pressure and freeze-dried to obtain dry powder of compound extract of traditional Chinese medicine. b) Immunomodulator pretreatment: Immunomodulators were prepared into nanoliposomes using a thin-film dispersion-ultrasound method, and then homogenized under high pressure and freeze-dried to obtain nanoliposome-encapsulated immunomodulator dry powder. S2. Preparation of active component premix: The dry powder of Chinese herbal compound extract, the micronized non-steroidal anti-inflammatory drug, and the dry powder of immunomodulatory agent encapsulated in nanoliposomes are mixed evenly according to the weight ratio described above. A transdermal absorption promoter is added, and the mixture is stirred at a constant temperature until it is completely dispersed to obtain the active component premix. S3. Preparation of composite gel matrix: Carboxymethyl chitosan and sodium alginate were weighed according to the mass ratio, and purified water was added separately to fully swell them. The two swollen solutions were mixed evenly, and a crosslinking agent was added and stirred at a constant temperature to prepare a uniform and transparent composite gel matrix sol. S4. Forming of the patch: Add the active component premix and antioxidant to the composite gel matrix sol, stir evenly after vacuum degassing, coat it on the medical non-woven fabric backing layer, cover it with a polyethylene anti-adhesive layer, and after constant temperature shaping, slicing and aseptic packaging, the external patch is obtained.

9. The preparation method according to claim 8, characterized in that, In step S1 a), the pretreatment involves pulverizing the raw material and passing it through an 80-100 mesh sieve; supercritical CO2 extraction uses anhydrous ethanol as an entrainer, with the weight ratio of anhydrous ethanol to the Chinese herbal raw material being 1:1-2, an extraction pressure of 20-30 MPa, an extraction temperature of 40-50℃, and an extraction time of 1.5-2.5 h; the vacuum degree of the reduced pressure concentration is 0.06-0.08 MPa, the temperature is 45-55℃, and the concentration is carried out until the extract has no alcohol odor. In step S1 b), the preparation of the nanoliposomes is specifically as follows: lecithin and cholesterol are dissolved in anhydrous ethanol at a mass ratio of 4-6:1, an immunomodulator is added, and the mixture is stirred until completely dissolved. The organic solvent is removed by rotary evaporation under reduced pressure to form a uniform lipid film. After vacuum drying, phosphate buffer is added for hydration. The mixture is then subjected to ultrasonic treatment and high-pressure homogenization. The ultrasonic frequency is 30-50 kHz, the power is 150-300 W, the temperature is 35-45 ℃, the ultrasonic duration is 15-25 min, the homogenization pressure is 60-90 MPa, and the homogenization temperature is controlled at 30-40 ℃. The homogenization is repeated 2-4 times. The mixture is then filtered through a 0.22 μm microporous membrane to obtain a nanoliposome suspension, which is then freeze-dried to obtain a dry powder. In step S2, the temperature of the constant temperature stirring is 35-45℃, the stirring speed is 30-50 r / min, and the stirring time is 20-30 min; In step S3, the swelling temperature of the carboxymethyl chitosan and sodium alginate is 40-50℃, and the swelling time is 2-4h; the crosslinking agent is calcium gluconate, and the amount added is 0.5-2% of the total mass of carboxymethyl chitosan and sodium alginate; the constant temperature reaction temperature is 35-45℃, and the reaction time is 15-30min. In step S4, the coating thickness is 0.3-0.5 mm, the constant temperature setting temperature is 40-50℃, and the setting time is 30-60 min.

10. Use of a topical patch medicament as described in any one of claims 1-7 in the preparation of a medicament for treating neck swelling, pain, and fever caused by subacute thyroiditis.

Images