Transdermal absorption ointment for treating stomach illness and preparation method of transdermal absorption ointment

Abstract

The invention provides a transdermal absorption ointment for treating stomach diseases and a preparation method thereof, and belongs to the technical field of medicines. The preparation method comprises the following steps: modifying n-docosyl-coated calcium carbonate phase change microspheres through polydopamine, coupling the modified microspheres to arginine nonamer modified chitosan, reacting with chlorinated beta-cyclodextrin for grafting, adding enzyme extracts of cinnamon, cardamom, fennel, rhizoma zingiberis and fructus evodiae, stirring for inclusion, and adding genipin for crosslinking to prepare the percutaneous absorption ointment for treating stomach diseases. The percutaneous absorption ointment for treating stomach diseases prepared by the invention is well attached to the skin, a patient feels comfortable after being attached, the compliance is high, the percutaneous absorption ointment is superior to the traditional Chinese medicine glue ointment, the percutaneous absorption ointment directly enters systemic circulation through percutaneous absorption, gastric acid damage and liver metabolism are avoided, and the bioavailability is better.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a transdermal absorption ointment for treating gastric diseases and its preparation method. Background Technology

[0002] Currently, the main treatments for stomach pain include Western medicine, acupuncture, and oral Chinese herbal medicine. Western medicine primarily uses proton pump inhibitors and H2-receptor blockers, which offer good short-term effects but are prone to relapse. Long-term use of these medications can cause adverse reactions such as headaches, thirst, and sluggishness. Excessive suppression of gastric acid can lead to upper abdominal pain, bloating, diarrhea, nausea, vomiting, and other gastrointestinal dysfunction symptoms. Acupuncture treatment requires a visit to a specialized hospital and is performed by a qualified Chinese medicine practitioner, demanding significant time and medical expertise. Oral Chinese herbal medicine requires daily decoction and administration, which can be quite painful and requires a highly skilled physician to prescribe it.

[0003] Chinese invention patent CN105250586A discloses a traditional Chinese medicine plaster for preventing stomach ailments and its preparation method. It is prepared using the following raw materials in parts by weight: 3-10 parts Atractylodes macrocephala, 11-22 parts Citrus reticulata peel, 8-15 parts Crataegus pinnatifida, 6-9 parts Paeonia lactiflora, 12-20 parts Dioscorea opposita, 2-6 parts Codonopsis pilosula, 1-5 parts Astragalus membranaceus, 2-6 parts Poria cocos, and 15-30 parts water. The process includes the following steps: A. Drying the raw materials; B. Grinding Atractylodes macrocephala, Citrus reticulata peel, Crataegus pinnatifida, Dioscorea opposita, Codonopsis pilosula, Astragalus membranaceus, and Poria cocos into powder; stir-frying Paeonia lactiflora with alcohol, then grinding it into powder; mixing the powders of the raw materials evenly to obtain a mixed powder; C. Adding water to the mixed powder to obtain a mixture, heating and stirring the mixture until it becomes thick; D. Cooling the thick mixture. This patent uses a traditional Chinese medicine plaster for transdermal drug delivery, which avoids the toxic side effects of oral administration and is convenient to use. However, it is mainly used for the prevention of stomach diseases and has a low efficacy in the treatment of stomach diseases. It cannot achieve good drug release penetration and sustained-release therapy.

[0004] Chinese invention patent CN116036189A discloses a transdermal-enhancing traditional Chinese medicine patch for treating stomach ailments and its preparation method. The patch comprises, from bottom to top, a backing layer, a heating layer, an adhesive layer, and a protective layer. The adhesive layer consists of traditional Chinese medicine, pressure-sensitive adhesive, and a penetration enhancer in a weight ratio of 20-25:65:10-15. The penetration enhancer is transdermal-enhancing microcapsule-modified sepiolite. This treatment is effective for patients with chest fullness, rib distension, and stomach pain due to indigestion. Transdermal administration avoids the toxic side effects of oral medication, has fewer side effects, and higher bioavailability. However, the limited effectiveness of the penetration enhancer prevents sustained-release and effective long-term transdermal drug delivery, necessitates frequent patch changes, is complex to operate, and results in low patient compliance. Summary of the Invention

[0005] The purpose of this invention is to propose a transdermal absorption ointment for treating gastric diseases and its preparation method. It has good skin adhesion, releases the drug with heat, and regulates the qi and blood of the spleen and stomach. Thus, it can significantly improve the superficial symptoms of gastric diseases and regulate the disease itself, thereby eliminating the lesions. Patients feel comfortable after applying it and have high compliance. It is superior to traditional Chinese medicine ointments. It is absorbed directly into the systemic circulation through the skin, avoiding destruction by gastric acid and liver metabolism, and has better bioavailability.

[0006] The technical solution of this invention is implemented as follows: This invention provides a method for preparing a transdermal absorption ointment for treating gastric diseases. The method involves modifying n-dodecane@calcium carbonate phase change microspheres with polydopamine, coupling them to arginine nonamer-modified chitosan, then grafting them with β-cyclodextrin chloride. Enzyme extracts of cinnamon, cardamom, fennel, dried ginger, and evodia are added, and the mixture is stirred to encapsulate the microspheres. Genipin is then added for cross-linking, resulting in the transdermal absorption ointment for treating gastric diseases.

[0007] As a further improvement to the present invention, the following steps are included: S1. Dissolve the emulsifier in water, adjust the pH value to obtain an aqueous phase; heat and melt n-dopene, keep warm to obtain an oil phase; add the oil phase to the aqueous phase, heat and stir to mix evenly, shear emulsify to obtain an emulsion; add calcium-containing aqueous solution dropwise to the emulsion, stir to mix evenly, add sodium carbonate or potassium carbonate solution dropwise, stir to react, centrifuge, collect the precipitate, wash, dry, and obtain n-dopene@calcium carbonate phase change microspheres; S2. Add n-docosane@calcium carbonate phase change microspheres to Tris-HCl solution, add dopamine hydrochloride, heat and stir the reaction, centrifuge, collect the precipitate, wash, dry, and obtain modified n-docosane@calcium carbonate phase change microspheres; S3. Dissolve β-cyclodextrin in dimethylformamide, add dimethylformamide solution of thionyl chloride dropwise, stir the reaction, remove the solvent under reduced pressure, and obtain chloro-β-cyclodextrin; S4. Arginine nonmer was dissolved in water, and a tetrahydrofuran solution of di-tert-butyl dicarbonate was added. The pH of the solution was adjusted, and the mixture was stirred to obtain a reaction solution. Chitosan was added to an acidic solution, and N-hydroxythiosuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The pH was adjusted to acidic to obtain a chitosan solution. The reaction solution was added, and the mixture was stirred at room temperature. Trifluoroacetic acid was added and stirred. Then hydroxylamine was added, and the pH was adjusted to alkaline to obtain an arginine nonmer modified chitosan solution. S5. Add N-hydroxythiosuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the arginine nonmer modified chitosan solution, stir to activate, add modified n-dodecane@calcium carbonate phase change microspheres, stir to react, dialyze, and dry to obtain phase change microspheres / arginine nonmer modified chitosan. S6. Phase change microspheres / arginine nonamer modified chitosan was added to dimethylformamide, β-cyclodextrin chloride and triethylamine were added, the mixture was stirred and reacted, dialyzed and dried to obtain cyclodextrin / phase change microspheres / arginine nonamer modified chitosan. S7. Crush cinnamon, cardamom, fennel, dried ginger, and evodia into powder, add to the extract, heat and stir to extract, filter, inactivate enzymes, dry, and obtain the extract; S8. Add cyclodextrin / phase change microspheres / arginine nonamer modified chitosan to water, add extract, stir and mix evenly, add genipin for cross-linking, and obtain a transdermal absorption ointment for treating gastric diseases.

[0008] As a further improvement of the present invention, the emulsifier in step S1 is selected from at least one of Tween-20, Tween-40, Tween-60, Tween-80, and Tween-85, the calcium-containing aqueous solution is a calcium chloride solution, the mass ratio of the emulsifier, n-dodecane, calcium chloride, sodium carbonate, or potassium carbonate is 2-4:10-15:10-20:10-15, the pH value is adjusted to 7-10, the rotation speed of the shear emulsification is 8000-10000 r / min, the time is 5-10 min, and the stirring reaction time is 3-5 h.

[0009] As a further improvement of the present invention, in step S2, the mass ratio of n-dodecane@calcium carbonate phase change microspheres to dopamine hydrochloride is 10:3-5, the heating and stirring reaction temperature is 45-55℃, the time is 3-5h, and the pH value of the Tris-HCl solution is 9-10; in step S3, the mass ratio of β-cyclodextrin to sulfoxide is 10:1-2, and the stirring reaction time is 2-4h.

[0010] As a further improvement of the present invention, the mass ratio of arginine nonamer, ditert-butyl dicarbonate, chitosan, N-hydroxythiosuccinimide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in step S4 is 15-25:12-18:270-290:5-6:20-30, the pH value of the adjusted solution is 9-10, the acid solution is 1-2 wt% acetic acid solution, and the stirring reaction time at room temperature is 44-52 h.

[0011] As a further improvement of the present invention, the mass ratio of the arginine nonamer modified chitosan solution, N-hydroxythiosuccinimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and modified n-dodecane@calcium carbonate phase change microspheres in step S5 is 500:0.5-0.6:2-3:8-10.

[0012] As a further improvement of the present invention, the mass ratio of the microspheres / arginine nonamer modified chitosan, chloroβ-cyclodextrin and triethylamine in step S6 is 10-15:3-4:1-2.

[0013] As a further improvement of the present invention, the mass ratio of cinnamon, cardamom, fennel, dried ginger and evodia in step S7 is 2-4:1-2:1-3:4-6:3-5, the extract is an acetate solution with pH 5-6 containing 1-3wt% cellulase, 0.5-1wt% pectinase and 1-2wt% bromelain, and the heating and stirring extraction temperature is 40-45℃ and the time is 2-3h.

[0014] As a further improvement of the present invention, the mass ratio of cyclodextrin / phase change microspheres / arginine nonamer modified chitosan and extract in step S8 is 10:3-5.

[0015] This invention further protects a transdermal absorption ointment for treating gastric diseases prepared by the above-described preparation method.

[0016] The present invention has the following beneficial effects: In the n-docosane@calcium carbonate phase change microspheres prepared in this invention, the phase change temperature of the n-docosane phase change material is approximately 42-46℃. Before use, the ointment is heated until the phase change material becomes liquid. After application, the body surface temperature is lower than the phase change temperature, allowing for continuous heat release on the body surface, simulating a gentle moxibustion effect, dilating capillaries, and promoting drug penetration. The latent heat absorption characteristics of the phase change material avoid the drawbacks of traditional hot compresses, such as large temperature fluctuations and the risk of burns. The inorganic calcium carbonate shell provides rigid support, preventing leakage of the phase change material. Dopamine modification enhances the interfacial bonding between the microspheres and the chitosan matrix through mussel-inspired biochemistry. It can also couple with arginine nonamers modified on chitosan, thereby reducing the risk of phase separation. Simultaneously, the rigid calcium carbonate microspheres create microscopic roughness in the ointment, generating a slight mechanical massage during application and promoting local microcirculation.

[0017] In chitosan modified with arginine nonamer, the arginine nonamer is rich in guanidine groups and exhibits strong positive charge at physiological pH. It can form hydrogen bonds with negatively charged salts in cells, thereby adsorbing onto the membrane surface, breaking the tight bonds between epithelial cells, lowering the membrane potential, and promoting the intercellular or intracellular transport of carriers. This allows for efficient cell penetration, with a transmembrane efficiency higher than that of pure chitosan, making it a novel carrier that does not cause permanent damage to the cell membrane. Chitosan modified with arginine nonamer not only improves the water solubility of chitosan but also enhances the transdermal absorption performance of the material, thus promoting drug absorption through the skin, significantly improving efficacy, and solving the problem of low bioavailability in traditional plasters.

[0018] β-Cyclodextrin encapsulates volatile oil molecules and active components of traditional Chinese medicine (TCM) within a hollow cavity, enhancing the water solubility and chemical stability (such as antioxidant properties) of the volatile oils. This solves the problems of easy volatility and light-induced decomposition of volatile oils such as cinnamon and cardamom. The increased local temperature accelerates drug release, achieving highly efficient drug delivery. Simultaneously, the hydrophilic outer wall of cyclodextrin can adsorb moisture from the stratum corneum, increasing the hydration level of the stratum corneum and thus the drug diffusion coefficient.

[0019] The skin at the Shenque acupoint (navel) is thinner and has a higher microvascular density than the surrounding skin. Compared to oral administration, the first-pass effect of absorption through the Shenque acupoint is reduced. Warming herbs such as dried ginger and cinnamon enter the spleen and stomach meridians, and through the Ren meridian (Shenque is an important acupoint on the Ren meridian), they regulate the Qi and blood of the spleen and stomach. This can significantly improve the superficial symptoms of stomach diseases and also regulate the disease itself, thereby eliminating the lesions. The thermal effect of phase change microspheres lasts for a long time, synergistically enhancing the transdermal absorption of the drug and improving its efficacy.

[0020] For patients with gastric motility disorders, warming and dispelling cold medications can regulate the secretion of gastrointestinal hormones (motilin and gastrin), and when combined with the thermal stimulation of phase change materials, promote gastric emptying and improve symptoms of functional dyspepsia.

[0021] In addition, the hydrogel ointment formed by chitosan cross-linking has an elastic modulus similar to that of the skin, good skin adhesion, and a comfortable feel for patients after application, resulting in high compliance. It is superior to traditional Chinese medicine ointments, as it is absorbed directly into the systemic circulation through the skin, avoiding destruction by gastric acid and liver metabolism, and has better bioavailability. Detailed Implementation

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] Arginine nonamer, purity >95%; chitosan, MW=5.9×10⁵, degree of deacetylation >95. Example 1

[0024] This embodiment provides a method for preparing a transdermal absorption ointment for treating gastric diseases, comprising the following steps: S1. Dissolve 2g Tween-20 in 100mL of water, adjust the pH to 7, and obtain an aqueous phase; heat 10g of n-docosane to 60℃, stir to melt, and keep warm to obtain an oil phase; add the oil phase to the aqueous phase, heat to 60℃, stir to mix evenly, and shear emulsify at 8000r / min for 10min to obtain an emulsion; add 70mL of an aqueous solution containing 10g of calcium chloride to the emulsion, stir and mix for 3h, then add 70mL of an aqueous solution containing 10g of sodium carbonate, stir and react for 3h, centrifuge, collect the precipitate, wash, and dry to obtain n-docosane@calcium carbonate phase change microspheres; S2. Add 10g of n-docosane@calcium carbonate phase change microspheres to 200mL of Tris-HCl solution with pH 9, add 3g of dopamine hydrochloride, heat to 45℃, stir for 3h, centrifuge, collect the precipitate, wash, dry, and obtain modified n-docosane@calcium carbonate phase change microspheres. S3. Dissolve 1g of β-cyclodextrin in 80mL of dimethylformamide, add 20mL of dimethylformamide solution containing 0.1g of sulfoxide, stir for 2h, remove the solvent under reduced pressure to obtain chloro-β-cyclodextrin; S4. Dissolve 0.15g of arginine nonamer in 100mL of water, add 100mL of tetrahydrofuran solution containing 0.12g of di-tert-butyl dicarbonate, adjust the pH of the solution to 9, stir the reaction to obtain a reaction solution; add 2.7g of chitosan to 300mL of 1wt% acetic acid solution, add 50mg of N-hydroxythiosuccinimide and 0.2g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, adjust the pH to 6 to obtain a chitosan solution, add the reaction solution, stir the reaction at room temperature for 44h, add 1wt% trifluoroacetic acid and stir to eliminate di-tert-butyl dicarbonate, then add 50wt% hydroxylamine to make the final concentration 10mmol / L, adjust the pH to 8, and obtain arginine nonamer modified chitosan solution; S5. Add 0.5g N-hydroxythiosuccinimide and 2g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to 500g arginine nonmer modified chitosan solution, stir and activate for 30min, add 8g modified n-docosane@calcium carbonate phase change microspheres, stir and react for 10h, add to dialysis bag with MW=8000, immerse in deionized water, dialyze for 48h, dry to obtain phase change microspheres / arginine nonmer modified chitosan; S6. Add 1g of phase change microspheres / arginine nonamer modified chitosan to 100mL of dimethylformamide, add 0.3g of β-cyclodextrin chloride and 0.1g of triethylamine, stir and react at 55℃ for 5h, add to a dialysis bag with MW=8000, immerse in deionized water, dialyze for 24h, dry, and obtain cyclodextrin / phase change microspheres / arginine nonamer modified chitosan; S7. Crush 2g of cinnamon, 1g of cardamom, 1g of fennel, 4g of dried ginger, and 3g of Evodia rutaecarpa, add them to 100mL of extract, heat to 40℃, stir and extract for 2h, filter, inactivate enzymes, and dry to obtain the extract; the extract is an acetate solution with pH 5 containing 1wt% cellulase, 0.5wt% pectinase, and 1wt% bromelain. S8. Add 1g of cyclodextrin / phase change microspheres / arginine nonamer modified chitosan to 100mL of water, add 0.3g of extract, stir and mix for 30min, add genipin to the final concentration of 1wt%, crosslink for 10min, and obtain a transdermal absorption ointment for treating gastric diseases. Example 2

[0025] This embodiment provides a method for preparing a transdermal absorption ointment for treating gastric diseases, comprising the following steps: S1. Dissolve 4g Tween-80 in 100mL of water, adjust the pH to 10, and obtain an aqueous phase; heat 15g of n-docosane to 60℃, stir to melt, and keep warm to obtain an oil phase; add the oil phase to the aqueous phase, heat to 60℃, stir to mix evenly, and shear emulsify at 10000r / min for 10min to obtain an emulsion; add 70mL of an aqueous solution containing 20g of calcium chloride to the emulsion, stir and mix for 3h, then add 70mL of an aqueous solution containing 15g of potassium carbonate, stir and react for 5h, centrifuge, collect the precipitate, wash, and dry to obtain n-docosane@calcium carbonate phase change microspheres; S2. Add 10g of n-docosane@calcium carbonate phase change microspheres to 200mL of Tris-HCl solution with pH 10, add 5g of dopamine hydrochloride, heat to 55℃, stir for 5h, centrifuge, collect the precipitate, wash, dry, and obtain modified n-docosane@calcium carbonate phase change microspheres. S3. Dissolve 1g of β-cyclodextrin in 80mL of dimethylformamide, add 20mL of dimethylformamide solution containing 0.2g of sulfoxide, stir and react for 4h, remove the solvent under reduced pressure to obtain chloroβ-cyclodextrin; S4. Dissolve 0.25g of arginine nonamer in 100mL of water, add 100mL of tetrahydrofuran solution containing 0.18g of di-tert-butyl dicarbonate, adjust the pH of the solution to 10, stir the reaction to obtain a reaction solution; add 2.9g of chitosan to 300mL of 2wt% acetic acid solution, add 60mg of N-hydroxythiosuccinimide and 0.3g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, adjust the pH to 6 to obtain a chitosan solution, add the reaction solution, stir the reaction at room temperature for 52h, add 1wt% trifluoroacetic acid and stir to eliminate di-tert-butyl dicarbonate, then add 50wt% hydroxylamine to make the final concentration 10mmol / L, adjust the pH to 8, and obtain arginine nonamer modified chitosan solution; S5. Add 0.6g N-hydroxythiosuccinimide and 3g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to 500g arginine nonmer modified chitosan solution, stir and activate for 30min, add 10g modified n-docosane@calcium carbonate phase change microspheres, stir and react for 12h, add to a dialysis bag with MW=12000, immerse in deionized water, dialyze for 48h, dry, and obtain phase change microspheres / arginine nonmer modified chitosan; S6. Add 1.5g of phase change microspheres / arginine nonamer modified chitosan to 100mL of dimethylformamide, add 0.4g of β-cyclodextrin chloride and 0.2g of triethylamine, stir and react at 55℃ for 5h, add to a dialysis bag with MW=12000, immerse in deionized water, dialyze for 24h, dry, and obtain cyclodextrin / phase change microspheres / arginine nonamer modified chitosan; S7. Crush 4g cinnamon, 2g cardamom, 3g fennel, 6g dried ginger, and 5g evodia rutaecarpa, add them to 100mL of extract, heat to 45℃, stir and extract for 3h, filter, inactivate enzymes, and dry to obtain the extract; the extract is an acetate solution with pH 6 containing 3wt% cellulase, 1wt% pectinase, and 2wt% bromelain. S8. Add 1g of cyclodextrin / phase change microspheres / arginine nonamer modified chitosan to 100mL of water, add 0.5g of extract, stir and mix for 30min, add genipin to the final concentration of 1wt%, crosslink for 20min, and obtain a transdermal absorption ointment for treating gastric diseases. Example 3

[0026] This embodiment provides a method for preparing a transdermal absorption ointment for treating gastric diseases, comprising the following steps: S1. Dissolve 3g Tween-85 in 100mL of water, adjust the pH to 8.5, and obtain an aqueous phase; heat 12g of n-docosane to 60℃, stir to melt, and keep warm to obtain an oil phase; add the oil phase to the aqueous phase, heat to 60℃, stir to mix evenly, and shear emulsify at 9000r / min for 7min to obtain an emulsion; add 70mL of an aqueous solution containing 15g of calcium chloride to the emulsion, stir and mix for 3h, then add 70mL of an aqueous solution containing 12g of sodium carbonate, stir and react for 4h, centrifuge, collect the precipitate, wash, and dry to obtain n-docosane@calcium carbonate phase change microspheres; S2. Add 10g of n-docosane@calcium carbonate phase change microspheres to 200mL of Tris-HCl solution with pH 9.5, add 4g of dopamine hydrochloride, heat to 50℃, stir for 4h, centrifuge, collect the precipitate, wash, dry, and obtain modified n-docosane@calcium carbonate phase change microspheres. S3. Dissolve 1g of β-cyclodextrin in 80mL of dimethylformamide, add 20mL of dimethylformamide solution containing 0.15g of sulfoxide, stir for 3h, remove the solvent under reduced pressure to obtain chloro-β-cyclodextrin; S4. Dissolve 0.2g of arginine nonamer in 100mL of water, add 100mL of tetrahydrofuran solution containing 0.15g of di-tert-butyl dicarbonate, adjust the pH of the solution to 9.5, stir the reaction to obtain a reaction solution; add 2.8g of chitosan to 300mL of 1.5wt% acetic acid solution, add 55mg of N-hydroxythiosuccinimide and 0.25g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, adjust the pH to 6 to obtain a chitosan solution, add the reaction solution, stir the reaction at room temperature for 48h, add 1wt% trifluoroacetic acid and stir to eliminate di-tert-butyl dicarbonate, then add 50wt% hydroxylamine to make the final concentration 10mmol / L, adjust the pH to 8, and obtain arginine nonamer modified chitosan solution; S5. Add 0.55g N-hydroxythiosuccinimide and 2.5g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to 500g arginine nonmer modified chitosan solution, stir and activate for 30min, add 9g modified n-docosane@calcium carbonate phase change microspheres, stir and react for 11h, add to dialysis bag with MW=10000, immerse in deionized water, dialyze for 48h, dry to obtain phase change microspheres / arginine nonmer modified chitosan; S6. 1.2 g of phase change microspheres / arginine nonamer modified chitosan was added to 100 mL of dimethylformamide, 0.35 g of β-cyclodextrin chloride and 0.15 g of triethylamine were added, and the mixture was stirred at 55 °C for 5 h. The mixture was then added to a dialysis bag with MW=10000, immersed in deionized water, dialyzed for 24 h, and dried to obtain cyclodextrin / phase change microspheres / arginine nonamer modified chitosan. S7. Crush 3g cinnamon, 1.5g cardamom, 2g fennel, 5g dried ginger, and 4g evodia rutaecarpa into powder, add to 100mL of extract, heat to 42℃, stir and extract for 2.5h, filter, inactivate enzymes, and dry to obtain the extract; the extract is an acetate solution with pH 5.5 containing 2wt% cellulase, 0.7wt% pectinase, and 1.5wt% bromelain; S8. Add 1g of cyclodextrin / phase change microspheres / arginine nonamer modified chitosan to 100mL of water, add 0.4g of extract, stir and mix for 30min, add genipin to the final concentration of 1wt%, crosslink for 15min, and obtain a transdermal absorption ointment for treating gastric diseases.

[0027] Comparative Example 1 The difference from Example 3 is that step S2 was not performed.

[0028] Includes the following steps: S1. Dissolve 3g Tween-85 in 100mL of water, adjust the pH to 8.5, and obtain an aqueous phase; heat 12g of n-docosane to 60℃, stir to melt, and keep warm to obtain an oil phase; add the oil phase to the aqueous phase, heat to 60℃, stir to mix evenly, and shear emulsify at 9000r / min for 7min to obtain an emulsion; add 70mL of an aqueous solution containing 15g of calcium chloride to the emulsion, stir and mix for 3h, then add 70mL of an aqueous solution containing 12g of sodium carbonate, stir and react for 4h, centrifuge, collect the precipitate, wash, and dry to obtain n-docosane@calcium carbonate phase change microspheres; S2. Dissolve 1g of β-cyclodextrin in 80mL of dimethylformamide, add 20mL of dimethylformamide solution containing 0.15g of sulfoxide, stir and react for 3h, remove the solvent under reduced pressure to obtain chloro-β-cyclodextrin; S3. Dissolve 0.2g of arginine nonamer in 100mL of water, add 100mL of tetrahydrofuran solution containing 0.15g of di-tert-butyl dicarbonate, adjust the pH of the solution to 9.5, stir the reaction to obtain a reaction solution; add 2.8g of chitosan to 300mL of 1.5wt% acetic acid solution, add 55mg of N-hydroxythiosuccinimide and 0.25g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, adjust the pH to 6 to obtain a chitosan solution, add the reaction solution, stir the reaction at room temperature for 48h, add 1wt% trifluoroacetic acid and stir to eliminate di-tert-butyl dicarbonate, then add 50wt% hydroxylamine to make the final concentration 10mmol / L, adjust the pH to 8, and obtain arginine nonamer modified chitosan solution; S4. Add 9g of n-docosane@calcium carbonate phase change microspheres to 500g of arginine nonmer modified chitosan solution, stir and mix for 1h, add to a dialysis bag with MW=10000, immerse in deionized water, dialyze for 48h, and dry to obtain phase change microspheres / arginine nonmer modified chitosan. S5. 1.2 g of phase change microspheres / arginine nonamer modified chitosan was added to 100 mL of dimethylformamide, along with 0.35 g of β-cyclodextrin chloride and 0.15 g of triethylamine. The mixture was stirred at 55 °C for 5 h, then added to a dialysis bag with MW=10000 and immersed in deionized water. Dialysis was performed for 24 h, and the mixture was dried to obtain cyclodextrin / phase change microspheres / arginine nonamer modified chitosan. S6. Crush 3g cinnamon, 1.5g cardamom, 2g fennel, 5g dried ginger, and 4g evodia rutaecarpa into powder, add to 100mL of extract, heat to 42℃, stir and extract for 2.5h, filter, inactivate enzymes, and dry to obtain the extract; the extract is an acetate solution with pH 5.5 containing 2wt% cellulase, 0.7wt% pectinase, and 1.5wt% bromelain; S7. Add 1g of cyclodextrin / phase change microspheres / arginine nonamer modified chitosan to 100mL of water, add 0.4g of extract, stir and mix for 30min, add genipin to the final concentration of 1wt%, crosslink for 15min, and obtain a transdermal absorption ointment for treating gastric diseases.

[0029] Comparative Example 2 The difference from Example 3 is that step S4 was not performed.

[0030] Includes the following steps: S1. Dissolve 3g Tween-85 in 100mL of water, adjust the pH to 8.5, and obtain an aqueous phase; heat 12g of n-docosane to 60℃, stir to melt, and keep warm to obtain an oil phase; add the oil phase to the aqueous phase, heat to 60℃, stir to mix evenly, and shear emulsify at 9000r / min for 7min to obtain an emulsion; add 70mL of an aqueous solution containing 15g of calcium chloride to the emulsion, stir and mix for 3h, then add 70mL of an aqueous solution containing 12g of sodium carbonate, stir and react for 4h, centrifuge, collect the precipitate, wash, and dry to obtain n-docosane@calcium carbonate phase change microspheres; S2. Add 10g of n-docosane@calcium carbonate phase change microspheres to 200mL of Tris-HCl solution with pH 9.5, add 4g of dopamine hydrochloride, heat to 50℃, stir for 4h, centrifuge, collect the precipitate, wash, dry, and obtain modified n-docosane@calcium carbonate phase change microspheres. S3. Dissolve 1g of β-cyclodextrin in 80mL of dimethylformamide, add 20mL of dimethylformamide solution containing 0.15g of sulfoxide, stir for 3h, remove the solvent under reduced pressure to obtain chloro-β-cyclodextrin; S4. Add 2.8g of chitosan to 300mL of 1.5wt% acetic acid solution to obtain chitosan solution; S5. Add 9g of modified n-docosane@calcium carbonate phase change microspheres to 500g of chitosan solution, stir and react for 11h, add to a dialysis bag with MW=10000, immerse in deionized water, dialyze for 48h, dry, and obtain phase change microsphere modified chitosan. S6. Add 1.2g of phase change microsphere modified chitosan to 100mL of dimethylformamide, add 0.35g of chloro-β-cyclodextrin and 0.15g of triethylamine, stir and react at 55℃ for 5h, add to a dialysis bag with MW=10000, immerse in deionized water, dialyze for 24h, dry, and obtain cyclodextrin / phase change microsphere modified chitosan; S7. Crush 3g cinnamon, 1.5g cardamom, 2g fennel, 5g dried ginger, and 4g evodia rutaecarpa into powder, add to 100mL of extract, heat to 42℃, stir and extract for 2.5h, filter, inactivate enzymes, and dry to obtain the extract; the extract is an acetate solution with pH 5.5 containing 2wt% cellulase, 0.7wt% pectinase, and 1.5wt% bromelain; S8. Add 1g of cyclodextrin / phase change microsphere modified chitosan to 100mL of water, add 0.4g of extract, stir and mix for 30min, add genipin to the final concentration of 1wt%, crosslink for 15min, and obtain a transdermal absorption ointment for treating gastric diseases.

[0031] Comparative Example 3 The difference from Example 3 is that steps S3 and S6 were not performed.

[0032] Includes the following steps: S1. Dissolve 3g Tween-85 in 100mL of water, adjust the pH to 8.5, and obtain an aqueous phase; heat 12g of n-docosane to 60℃, stir to melt, and keep warm to obtain an oil phase; add the oil phase to the aqueous phase, heat to 60℃, stir to mix evenly, and shear emulsify at 9000r / min for 7min to obtain an emulsion; add 70mL of an aqueous solution containing 15g of calcium chloride to the emulsion, stir and mix for 3h, then add 70mL of an aqueous solution containing 12g of sodium carbonate, stir and react for 4h, centrifuge, collect the precipitate, wash, and dry to obtain n-docosane@calcium carbonate phase change microspheres; S2. Add 10g of n-docosane@calcium carbonate phase change microspheres to 200mL of Tris-HCl solution with pH 9.5, add 4g of dopamine hydrochloride, heat to 50℃, stir for 4h, centrifuge, collect the precipitate, wash, dry, and obtain modified n-docosane@calcium carbonate phase change microspheres. S3. Dissolve 0.2g of arginine nonamer in 100mL of water, add 100mL of tetrahydrofuran solution containing 0.15g of di-tert-butyl dicarbonate, adjust the pH of the solution to 9.5, stir the reaction to obtain a reaction solution; add 2.8g of chitosan to 300mL of 1.5wt% acetic acid solution, add 55mg of N-hydroxythiosuccinimide and 0.25g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, adjust the pH to 6 to obtain a chitosan solution, add the reaction solution, stir the reaction at room temperature for 48h, add 1wt% trifluoroacetic acid and stir to eliminate di-tert-butyl dicarbonate, then add 50wt% hydroxylamine to make the final concentration 10mmol / L, adjust the pH to 8, and obtain arginine nonamer modified chitosan solution; S4. Add 0.55g N-hydroxythiosuccinimide and 2.5g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to 500g arginine nonmer modified chitosan solution, stir and activate for 30min, add 9g modified n-docosahexadecane@calcium carbonate phase change microspheres, stir and react for 11h, add to a dialysis bag with MW=10000, immerse in deionized water, dialyze for 48h, dry, and obtain phase change microspheres / arginine nonmer modified chitosan; S5. Crush 3g cinnamon, 1.5g cardamom, 2g fennel, 5g dried ginger, and 4g evodia rutaecarpa into powder, add to 100mL of extract, heat to 42℃, stir and extract for 2.5h, filter, inactivate enzymes, and dry to obtain the extract; the extract is an acetate solution with pH 5.5 containing 2wt% cellulase, 0.7wt% pectinase, and 1.5wt% bromelain; S6. Add 1g of phase change microspheres / arginine nonamer modified chitosan to 100mL of water, add 0.4g of extract, stir and mix for 30min, add genipin to the final concentration of 1wt%, crosslink for 15min, and obtain a transdermal absorption ointment for treating gastric diseases.

[0033] Comparative Example 4 The difference from Example 3 is that steps S1, S2 and S5 were not performed.

[0034] Includes the following steps: S1. Dissolve 1g of β-cyclodextrin in 80mL of dimethylformamide, add 20mL of dimethylformamide solution containing 0.15g of sulfoxide, stir and react for 3h, remove the solvent under reduced pressure to obtain chloro-β-cyclodextrin; S2. Dissolve 0.2g of arginine nonamer in 100mL of water, add 100mL of tetrahydrofuran solution containing 0.15g of di-tert-butyl dicarbonate, adjust the pH of the solution to 9.5, stir the reaction to obtain a reaction solution; add 2.8g of chitosan to 300mL of 1.5wt% acetic acid solution, add 55mg of N-hydroxythiosuccinimide and 0.25g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, adjust the pH to 6 to obtain a chitosan solution, add the reaction solution, stir the reaction at room temperature for 48h, add 1wt% trifluoroacetic acid and stir to eliminate di-tert-butyl dicarbonate, then add 50wt% hydroxylamine to make the final concentration 10mmol / L, adjust the pH to 8 to obtain arginine nonamer modified chitosan solution, add to a dialysis bag with MW=10000, immerse in deionized water, dialyze for 48h, dry to obtain arginine nonamer modified chitosan; S3. Add 1.2g of arginine nonamer modified chitosan to 100mL of dimethylformamide, add 0.35g of chloro-β-cyclodextrin and 0.15g of triethylamine, stir and react at 55℃ for 5h, add to a dialysis bag with MW=10000, immerse in deionized water, dialyze for 24h, dry, and obtain cyclodextrin / arginine nonamer modified chitosan; S4. Crush 3g cinnamon, 1.5g cardamom, 2g fennel, 5g dried ginger, and 4g evodia fruit, add them to 100mL of extract, heat to 42℃, stir and extract for 2.5h, filter, inactivate enzymes, and dry to obtain the extract; the extract is an acetate solution with pH 5.5 containing 2wt% cellulase, 0.7wt% pectinase, and 1.5wt% bromelain; S5. Add 1g of cyclodextrin / arginine nonamer modified chitosan to 100mL of water, add 0.4g of extract, stir and mix for 30min, add genipin to a final concentration of 1wt%, crosslink for 15min, and obtain a transdermal absorption ointment for treating gastric diseases.

[0035] Comparative Example 5 The difference from Example 3 is that the extract in step S7 is replaced with water.

[0036] Includes the following steps: S1. Dissolve 3g Tween-85 in 100mL of water, adjust the pH to 8.5, and obtain an aqueous phase; heat 12g of n-docosane to 60℃, stir to melt, and keep warm to obtain an oil phase; add the oil phase to the aqueous phase, heat to 60℃, stir to mix evenly, and shear emulsify at 9000r / min for 7min to obtain an emulsion; add 70mL of an aqueous solution containing 15g of calcium chloride to the emulsion, stir and mix for 3h, then add 70mL of an aqueous solution containing 12g of sodium carbonate, stir and react for 4h, centrifuge, collect the precipitate, wash, and dry to obtain n-docosane@calcium carbonate phase change microspheres; S2. Add 10g of n-docosane@calcium carbonate phase change microspheres to 200mL of Tris-HCl solution with pH 9.5, add 4g of dopamine hydrochloride, heat to 50℃, stir for 4h, centrifuge, collect the precipitate, wash, dry, and obtain modified n-docosane@calcium carbonate phase change microspheres. S3. Dissolve 1g of β-cyclodextrin in 80mL of dimethylformamide, add 20mL of dimethylformamide solution containing 0.15g of sulfoxide, stir for 3h, remove the solvent under reduced pressure to obtain chloro-β-cyclodextrin; S4. Dissolve 0.2g of arginine nonamer in 100mL of water, add 100mL of tetrahydrofuran solution containing 0.15g of di-tert-butyl dicarbonate, adjust the pH of the solution to 9.5, stir the reaction to obtain a reaction solution; add 2.8g of chitosan to 300mL of 1.5wt% acetic acid solution, add 55mg of N-hydroxythiosuccinimide and 0.25g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, adjust the pH to 6 to obtain a chitosan solution, add the reaction solution, stir the reaction at room temperature for 48h, add 1wt% trifluoroacetic acid and stir to eliminate di-tert-butyl dicarbonate, then add 50wt% hydroxylamine to make the final concentration 10mmol / L, adjust the pH to 8, and obtain arginine nonamer modified chitosan solution; S5. Add 0.55g N-hydroxythiosuccinimide and 2.5g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to 500g arginine nonmer modified chitosan solution, stir and activate for 30min, add 9g modified n-docosane@calcium carbonate phase change microspheres, stir and react for 11h, add to dialysis bag with MW=10000, immerse in deionized water, dialyze for 48h, dry to obtain phase change microspheres / arginine nonmer modified chitosan; S6. 1.2 g of phase change microspheres / arginine nonamer modified chitosan was added to 100 mL of dimethylformamide, 0.35 g of β-cyclodextrin chloride and 0.15 g of triethylamine were added, and the mixture was stirred at 55 °C for 5 h. The mixture was then added to a dialysis bag with MW=10000, immersed in deionized water, dialyzed for 24 h, and dried to obtain cyclodextrin / phase change microspheres / arginine nonamer modified chitosan. S7. Crush 3g cinnamon, 1.5g cardamom, 2g fennel, 5g dried ginger and 4g evodia, add to 100mL water, heat under reflux for 2.5h, filter, dry the filtrate to obtain the extract; S8. Add 1g of cyclodextrin / phase change microspheres / arginine nonamer modified chitosan to 100mL of water, add 0.4g of extract, stir and mix for 30min, add genipin to the final concentration of 1wt%, crosslink for 15min, and obtain a transdermal absorption ointment for treating gastric diseases.

[0037] Test Example 1: Heat Dissipation Performance Test Male SD rats weighing 200-250g were randomly divided into a blank control group, Example 1-3 groups, and Comparative Examples 1-5 groups, with 6 rats in each group. They were housed in a dedicated animal facility for one week to acclimatize. The drug was loaded into a delivery device, sealed with a sealing film, and heated in a 50℃ constant temperature water bath for 10 minutes. The drug was then administered via the umbilicus. ① The blank control group received no treatment; ② Example 1-3 groups and Comparative Examples 1-5 groups received 1.0 mL of a transdermal absorption gel for treating gastric diseases. The rats were fasted for 24 hours prior to administration, but water was allowed. They were anesthetized with ether and fixed prone on a worktable equipped with a constant temperature heating pad. The temperature probe of a temperature measuring instrument was disinfected with 75% medical alcohol and then moistened with a suitable amount of glycerin. The probe was slowly inserted 2cm into the rat's umbilicus. Once the temperature stabilized, the drug was administered immediately, and the temperature was recorded every 2 seconds using data acquisition software. The results are shown in Table 1.

[0038] Among them, the platform temperature is the temperature after the temperature rises and stabilizes; the heating duration is the duration during which the temperature is higher than the base temperature.

[0039] Table 1

[0040] As shown in the table above, the transdermal absorption ointments for treating gastric diseases prepared in Examples 1-3 of this invention can rapidly heat up and have a relatively long heating time. In Comparative Example 1, the n-dodecane@calcium carbonate phase change microspheres were not modified with polydopamine, and after the addition of chitosan gel, they were prone to agglomeration, causing local overheating and shortening the heating time. In Comparative Example 3, the microspheres were modified with cyclodextrin, which reduced the inclusion amount of gingerol and shogaol in ginger. Gingerol and shogaol can stimulate heating, thus reducing the heating time. In Comparative Example 4, no n-dodecane@calcium carbonate phase change microspheres were added, but its plateau temperature was still higher than that of the blank group. This is because the gingerol and shogaol in the extract exerted a heating effect and had a certain heating time (2 min), but the effect was short-lived. In Comparative Example 5, the water extraction method was used, and the extraction rate of effective substances was not high, thus reducing the heating time.

[0041] Test Example 2 The transdermal absorption ointments for treating gastric diseases prepared in Examples 1-3 and Comparative Examples 1-5 were subjected to performance tests, and the results are shown in Table 2.

[0042] Gel adhesion force determination: Take an appropriate amount of sample on the Anton Paar rheometer sample stage, use a 25mm flat plate rotor, and record the maximum normal force during the peeling process under the conditions of 42℃, 100μm gap, and 5μm / s speed. This is the adhesion force of the sample.

[0043] Gel yield strength determination: Take an appropriate amount of sample on the Anton Paar rheometer sample stage, use a 25 mm flat plate rotor, and under the conditions of 42℃, 1 mm gap and 0.01 l / s shear rate, record the maximum shear stress during the 300s scanning test, which is the yield strength of the sample.

[0044] In vitro cytotoxicity: The samples were tested according to the ISO 10993-5 standard test method.

[0045] Table 2

[0046] As can be seen from the table above, the transdermal absorption ointments for treating gastric diseases prepared in Examples 1-3 of this invention have good adhesion and yield strength, and low cytotoxicity.

[0047] Test Example 3 The average release amount of the transdermal absorption ointments for treating gastric diseases prepared in Examples 1-3 and Comparative Examples 1-5 was tested.

[0048] Using gingerol, the active component of dried ginger, as the test component, a model was established using pigskin. The drug release properties were determined using a modified Franz diffusion cell. The receiving solution was physiological saline, the cell temperature was 37℃, and the sample mass was 2g with a thickness of 2mm. Samples were taken from the receiving chamber at 1, 3, 6, and 12 hours, filtered, and analyzed. The gingerol content in the samples was determined using high-performance liquid chromatography (HPLC). The results are shown in Table 3.

[0049] Table 3

[0050] As can be seen from the table above, the transdermal absorption ointments for treating gastric diseases prepared in Examples 1-3 of this invention have a good transdermal absorption promoting effect.

[0051] 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 method for preparing a transdermal absorption ointment for treating gastric diseases, characterized in that, After being modified with polydopamine, docosane@calcium carbonate phase change microspheres were coupled onto arginine nonamer-modified chitosan, and then grafted with β-cyclodextrin chloride. Enzyme extracts of cinnamon, cardamom, fennel, dried ginger, and evodia were added, stirred and encapsulated, and then genipin was added for cross-linking to obtain a transdermal absorption ointment for treating gastric diseases.

2. The preparation method according to claim 1, characterized in that, Includes the following steps: S1. Dissolve the emulsifier in water, adjust the pH value to obtain an aqueous phase; heat and melt n-dopene, keep warm to obtain an oil phase; add the oil phase to the aqueous phase, heat and stir to mix evenly, shear emulsify to obtain an emulsion; add calcium-containing aqueous solution dropwise to the emulsion, stir to mix evenly, add sodium carbonate or potassium carbonate solution dropwise, stir to react, centrifuge, collect the precipitate, wash, dry, and obtain n-dopene@calcium carbonate phase change microspheres; S2. Add n-docosane@calcium carbonate phase change microspheres to Tris-HCl solution, add dopamine hydrochloride, heat and stir the reaction, centrifuge, collect the precipitate, wash, dry, and obtain modified n-docosane@calcium carbonate phase change microspheres; S3. Dissolve β-cyclodextrin in dimethylformamide, add dimethylformamide solution of thionyl chloride dropwise, stir the reaction, remove the solvent under reduced pressure, and obtain chloro-β-cyclodextrin; S4. Arginine nonmer was dissolved in water, and a tetrahydrofuran solution of di-tert-butyl dicarbonate was added. The pH of the solution was adjusted, and the mixture was stirred to obtain a reaction solution. Chitosan was added to an acidic solution, and N-hydroxythiosuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The pH was adjusted to acidic to obtain a chitosan solution. The reaction solution was added, and the mixture was stirred at room temperature. Trifluoroacetic acid was added and stirred. Then hydroxylamine was added, and the pH was adjusted to alkaline to obtain an arginine nonmer modified chitosan solution. S5. Add N-hydroxythiosuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the arginine nonmer modified chitosan solution, stir to activate, add modified n-dodecane@calcium carbonate phase change microspheres, stir to react, dialyze, and dry to obtain phase change microspheres / arginine nonmer modified chitosan. S6. Phase change microspheres / arginine nonamer modified chitosan was added to dimethylformamide, β-cyclodextrin chloride and triethylamine were added, the mixture was stirred and reacted, dialyzed and dried to obtain cyclodextrin / phase change microspheres / arginine nonamer modified chitosan. S7. Crush cinnamon, cardamom, fennel, dried ginger, and evodia into powder, add to the extract, heat and stir to extract, filter, inactivate enzymes, dry, and obtain the extract; S8. Add cyclodextrin / phase change microspheres / arginine nonamer modified chitosan to water, add extract, stir and mix evenly, add genipin for cross-linking, and obtain a transdermal absorption ointment for treating gastric diseases.

3. The preparation method according to claim 2, characterized in that, The emulsifier in step S1 is selected from at least one of Tween-20, Tween-40, Tween-60, Tween-80, and Tween-85. The calcium-containing aqueous solution is a calcium chloride solution. The mass ratio of the emulsifier, n-dodecane, calcium chloride, sodium carbonate, or potassium carbonate is 2-4:10-15:10-20:10-15. The pH value is adjusted to 7-10. The rotation speed of the shear emulsification is 8000-10000 r / min, and the time is 5-10 min. The stirring reaction time is 3-5 h.

4. The preparation method according to claim 2, characterized in that, In step S2, the mass ratio of n-dodecane@calcium carbonate phase change microspheres to dopamine hydrochloride is 10:3-5, the heating and stirring reaction temperature is 45-55℃, the time is 3-5h, and the pH value of the Tris-HCl solution is 9-10; in step S3, the mass ratio of β-cyclodextrin to sulfoxide is 10:1-2, and the stirring reaction time is 2-4h.

5. The preparation method according to claim 2, characterized in that, In step S4, the mass ratio of arginine nonamer, ditert-butyl dicarbonate, chitosan, N-hydroxythiosuccinimide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 15-25:12-18:270-290:5-6:20-30. The pH of the adjusted solution is 9-10, the acid solution is 1-2 wt% acetic acid solution, and the stirring reaction at room temperature lasts for 44-52 hours.

6. The preparation method according to claim 2, characterized in that, In step S5, the mass ratio of the arginine nonamer modified chitosan solution, N-hydroxythiosuccinimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and modified n-dodecane@calcium carbonate phase change microspheres is 500:0.5-0.6:2-3:8-10.

7. The preparation method according to claim 2, characterized in that, In step S6, the mass ratio of the microspheres / arginine nonamic modified chitosan, chloro-β-cyclodextrin, and triethylamine is 10-15:3-4:1-2.

8. The preparation method according to claim 2, characterized in that, In step S7, the mass ratio of cinnamon, cardamom, fennel, dried ginger, and evodia is 2-4:1-2:1-3:4-6:3-5. The extract is an acetate solution with a pH of 5-6 containing 1-3 wt% cellulase, 0.5-1 wt% pectinase, and 1-2 wt% bromelain. The heating and stirring extraction temperature is 40-45℃, and the time is 2-3 hours.

9. The preparation method according to claim 2, characterized in that, The mass ratio of cyclodextrin / phase change microspheres / arginine nonamer modified chitosan and extract in step S8 is 10:3-5.

10. A transdermal absorption ointment for treating gastric diseases, prepared by the method according to any one of claims 1-9.

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