Preparation method of compound preparation applied to eye diseases

Abstract

The invention discloses a preparation method of a compound preparation applied to eye diseases, which comprises the following steps: S1, mixing cleaned, dried and crushed chrysanthemum powder, erigeron breviscapus powder and pseudo-ginseng root powder according to a weight ratio of 10: (3-8): (1-5) to obtain compound powder, sieving with a 60-100-mesh sieve, adding deionized water according to a weight ratio of 1: (10-20), soaking in a water bath oscillator, and filtering with a filter screen to obtain filtrate; and then slightly boiling and decocting. The ophthalmic compound preparation prepared by the invention comprises basic components including a free amino acid extract, vitamin A ester, glycosaminoglycan, carboxymethyl chitosan and aminoethanesulfonic acid which are included by a compound hydrophilic polymer, and a gel matrix component consisting of polyglutamic acid and polygonatum polysaccharide, when the compound preparation is used, a specific buffer solution or an isotonic solution does not need to be adopted for dissolution, meanwhile, the prepared compound preparation for the eyes can improve the low adhesiveness of traditional eye washing liquid components, especially small molecule components, and the defects that traditional eye washing liquid is large in size, inconvenient to carry and poor in solution storage stability are overcome.

Description

Technical Field

[0001] The present invention relates to the technical field of compound preparation, and specifically to a preparation method of a compound preparation for ophthalmic diseases. Background Art

[0002] Ophthalmic diseases are often the result of the combined action of multiple factors. For example, in infectious ophthalmic inflammation, there is not only the infection of pathogens such as bacteria, but also an inflammatory response. Taking the compound preparation of tobramycin dexamethasone eye drops as an example, the tobramycin in it can inhibit the synthesis of bacterial proteins and play an antibacterial role against Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli, effectively clearing the source of infection. As a glucocorticoid, dexamethasone can inhibit the inflammatory response, reduce the release of inflammatory mediators, and reduce the infiltration of inflammatory cells, thereby alleviating symptoms such as eye redness, pain, and itching. The synergistic effect of the two components can combat diseases more comprehensively, effectively control infection and inflammation, which is better than using antibiotics alone to treat infections or anti-inflammatory drugs alone to treat inflammation.

[0003] A compound preparation for ophthalmic diseases is a drug that combines two or more drug components with different pharmacological effects in the same preparation and is used for the treatment or diagnosis of ophthalmic diseases. These preparations can be in various dosage forms such as eye drops, eye ointments, and ophthalmic gels. Their design purpose is to integrate the advantages of multiple drugs and more effectively address complex ophthalmic problems. In the market, for products that relieve eye fatigue and improve the symptoms of dry eye (dry eye, especially lacrimal fluid deficiency type dry eye, usually has symptoms of dry eye surface), in addition to droppable eye drops, instruments, and eye patches, there are also eye washes. In the field of ophthalmology, eye washing is an effective means to relieve dry eye. However, current eye washes are usually in liquid form preparations or include liquid components, which are not only inconvenient to carry around, but also lack effective eye nutrition components, unable to nourish the eyes and improve eye fatigue, and can only relieve the dryness sensation. Summary of the Invention

[0004] Based on the technical problems existing in the background art, the present invention proposes a preparation method of a compound preparation for ophthalmic diseases, including the following steps: S1: Mix three powders of chrysanthemum, erigeron breviscapus, and notoginseng root that have been cleaned, dried, crushed, and processed according to a weight ratio of 10:3 - 8:1 - 5 to obtain a compound powder. Pass through a 60 - 100 mesh sieve, add deionized water according to a weight ratio of 1:10 - 20, soak it in a water bath oscillator, and then decoct it with gentle boiling. S2: After the decoction is cooled, place it in an ultrasonic extractor for ultrasonic extraction, filter it while it is hot and concentrate the filtrate. After removing impurities and decolorizing with activated carbon, centrifuge it at high speed. The supernatant passes through a 0.22 μm microporous filter membrane to obtain a concentrated extract of the water-soluble component. S3: Pour the water-soluble component concentrate obtained in S2 into a macroporous silica gel resin column for adsorption. After 0.5 - 1 h of adsorption, elute successively with deionized water and ethanol with a volume fraction of 50% at a rate of 5 - 10 ml / min. Collect the eluate containing amino acid components according to the amino acid ultraviolet signal monitor, evaporate and concentrate, and then dry in vacuum to obtain a composite extract powder mainly composed of free amino acids. The obtained extract powder is sterilized by dry heat for standby; S4: Weigh 10 - 15 parts of a composite hydrophilic polymer composed of sulfobutyl ether-β-cyclodextrin and polyvinyl alcohol (mass ratio 10:1 - 3) by weight, add it to 100 parts of sterile deionized water, and stir well until dissolved uniformly to obtain a polymer solution; S5: Take another 1 - 1.5 parts of the extract powder obtained in S3 and dissolve it in 10 - 20 parts of sterile water, and appropriately heat and stir to completely dissolve it to obtain a free amino acid solution; S6: Under ultrasonic conditions, drop the free amino acid solution obtained in S5 into the polymer solution obtained in S4 for inclusion. After dropping, continue ultrasonic treatment for 5 - 10 min to make the two solutions fully mixed evenly, and slowly stir for 10 - 15 min for full inclusion to obtain a composite micelle solution of polymer inclusion of free amino acids; S7: Weigh 0.5 - 1 part of vitamin A ester by weight, appropriately heat it to just dissolve it in ethanol, and drop it into 100 parts of 10 - 30 wt% hydroxypropyl-β-cyclodextrin solution under water bath and rapid stirring conditions for inclusion. After dropping, ultrasonic treatment for 5 - 10 min to make the solution fully mixed, and then heat and stir well to volatilize the residual organic solvent, so as to obtain a polymer-included vitamin A ester solution; S8: Add the artificial tear base liquid component into sterile water according to a mass fraction ratio of 0.1 - 0.5 wt% and mix evenly to obtain the artificial tear base liquid; S9: Mix the vitamin A ester solution obtained in S7 and the artificial tear base liquid obtained in S8 according to a weight ratio of 1:1 - 1.5 and stir evenly to obtain a mixed solution. Then, based on the weight of the mixed solution, add 0.1 - 0.5 wt% of glycosaminoglycan and stir and dissolve it well under appropriate heating conditions to obtain artificial tears; S10: At room temperature, weigh 0.5 - 1 part of polyglutamic acid and 1 - 2 parts of polygonatum polysaccharide by weight, add them to 100 parts of sterilized deionized water, heat and keep warm for full swelling. After full swelling, add 0.05 - 0.1 part of polyethylene glycol ester and stir and dissolve it evenly to obtain a gel matrix solution; S11: In a homogenizing emulsifying kettle heated in a water bath to 50 - 60 °C, drop the composite micelle solution of polymer inclusion of free amino acids obtained in S6 into the artificial tears obtained in S9 according to a mass ratio of 1:1 - 5, and homogenize until evenly mixed to obtain solution C; S12: Under stirring conditions, slowly add solution C obtained in S11 to the gel matrix solution obtained in S10 that has been preheated, at a mass ratio of 1:2 - 5, stir until substantially uniform, then successively perform ultrasonic treatment and vortex treatment to fully mix evenly, obtaining a gel solution; S13: Quantitatively fill the gel solution obtained in S12 into sterile dispensing containers, wait for it to naturally cool to room temperature, then place it in an ice bath and let it stand to obtain an in-situ gel. Put the dispensing containers into a vacuum freeze dryer for freeze-drying to obtain a freeze-dried ophthalmic solid preparation. The obtained ophthalmic solid preparation is successively subjected to dry heat sterilization and irradiation sterilization, and then packaged and stored; S14: At room temperature or not exceeding 40 °C, dissolve the ophthalmic solid preparation obtained in S13 in sterile water at a weight ratio of 1:100 - 1000, and mix until uniform to obtain an ophthalmic preparation solution.

[0005] Preferably, in step S1, the soaking temperature is 80 - 90 °C, the soaking time is 2 - 3 h, and the decocting time is 0.5 - 1 h.

[0006] Preferably, in step S2, the ultrasonic extraction temperature is 50 - 60 °C, and the ultrasonic extraction time is 15 - 30 min.

[0007] Preferably, in step S6, the ultrasonic power is set to 200 - 300 W.

[0008] Preferably, in step S7, the water bath temperature is 50 - 60 °C, and the heating temperature is 65 - 70 °C.

[0009] Preferably, in step S8, the artificial tear base liquid component is composed of a mixture of carboxymethyl chitosan and aminoethanesulfonic acid.

[0010] Preferably, in step S10, the heating temperature is 60 - 80 °C, and the heat preservation time is 15 - 30 min.

[0011] Preferably, in step S12, the preheating treatment temperature is 40 - 50 °C, the ultrasonic treatment time is 3 - 5 min, and the vortex treatment time is 30 - 60 s.

[0012] Preferably, in step S13, the standing time is 6 - 12 h.

[0013] Compared with the prior art, the present invention has the following beneficial effects: the ophthalmic composite preparation prepared by the present invention comprises free amino acid extracts, vitamin A esters, glycosaminoglycans, carboxymethyl chitosan and aminoethanesulfonic acid basic components encapsulated by a composite hydrophilic polymer, and a gel matrix component composed of polyglutamic acid and polygonatum polysaccharide, and does not require the use of a specific buffer or isotonic solution for dissolution during use. At the same time, the ophthalmic composite preparation prepared by the present invention can improve the low adhesion of traditional eyewash components, especially small molecule components, and overcome the defects of traditional eyewashes that are large in volume, inconvenient to carry, and poor storage stability of the solution. It can not only relieve dry eye syndrome and improve visual fatigue, but also relieve dryness, and has a better use effect. DETAILED DESCRIPTION

[0014] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0015] The present invention provides a technical solution: a method for preparing a composite preparation for eye diseases, comprising the following steps: S1: Mix the washed, dried and crushed chrysanthemum, breviscapus breviscapus and notoginseng root powders in a weight ratio of 10:3-8:1-5 to obtain a composite powder, pass through a 60-100 mesh sieve, add deionized water in a weight ratio of 1:10-20, soak in a water bath oscillator, and then boil slightly; S2: After the boiled liquid is cooled, it is placed in an ultrasonic extractor for ultrasonic extraction, the filtrate is filtered and concentrated while hot, the filtrate is decolorized by activated carbon and then centrifuged at high speed, the supernatant is filtered through a 0.22 μm microporous filter membrane to obtain a concentrated extract of the water-soluble component; S3: pour the concentrated water-soluble component obtained in S2 into a macroporous silica resin column for adsorption. After adsorption for 0.5-1h, elute with deionized water and 50% volume fraction ethanol at a rate of 5-10ml / min in sequence. Collect the eluate containing amino acid components according to the amino acid ultraviolet signal monitor, evaporate and concentrate, and then vacuum dry to obtain a composite extract powder mainly composed of free amino acids. The obtained extract powder is sterilized by dry heat and then used for later use; S4: 10-15 parts by weight of a composite hydrophilic polymer composed of sulfobutyl ether-β-cyclodextrin and polyvinyl alcohol (mass ratio 10:1-3) are weighed and added to 100 parts of sterile deionized water, and stirred until dissolved uniformly to obtain a polymer solution; S5: Dissolve 1-1.5 parts of the extract powder obtained in S3 in 10-20 parts of sterile water, and heat and stir appropriately to completely dissolve it to obtain a free amino acid solution; S6: Under ultrasonic conditions, the free amino acid solution obtained in S5 is dropped into the polymer solution obtained in S4 for inclusion. After the dropping is completed, ultrasonic treatment is continued for 5 - 10 min to fully mix the two solutions evenly, and then slow stirring is carried out for 10 - 15 min for full inclusion to obtain a composite micelle solution of polymer - included free amino acids; S7: By weight, 0.5 - 1 part of vitamin A ester is appropriately heated to just dissolve in ethanol, and then dropped into 100 parts of 10 - 30 wt% hydroxypropyl - β - cyclodextrin solution under water bath and rapid stirring conditions for inclusion. After the dropping is completed, ultrasonic treatment is carried out for 5 - 10 min to fully mix the solution, and then heating and full stirring are carried out to volatilize the residual organic solvent, thereby obtaining a vitamin A ester solution included by the polymer; S8: The components of the artificial tear base solution are added to sterile water according to a mass fraction ratio of 0.1 - 0.5 wt% and mixed evenly to obtain the artificial tear base solution; S9: The vitamin A ester solution obtained in S7 and the artificial tear base solution obtained in S8 are mixed according to a weight ratio of 1:1 - 1.5 and stirred evenly to obtain a mixed solution. Then, based on the weight of the mixed solution, 0.1 - 0.5 wt% of glycosaminoglycan is added and fully stirred and dissolved under appropriate heating conditions to obtain the artificial tear solution; S10: At room temperature, by weight, 0.5 - 1 part of polyglutamic acid and 1 - 2 parts of polygonatum polysaccharide are added to 100 parts of sterilized deionized water, heated and kept warm for full swelling. After full swelling, 0.05 - 0.1 part of polyethylene glycol ester is added and stirred and dissolved evenly to obtain a gel matrix solution; S11: In a homogenizing emulsifying kettle heated in a water bath to 50 - 60 °C, the composite micelle solution of polymer - included free amino acids obtained in S6 is dropped into the artificial tear solution obtained in S9 according to a mass ratio of 1:1 - 5, and homogenized until evenly mixed to obtain solution C; S12: Under stirring conditions, solution C obtained in S11 is slowly added to the gel matrix solution obtained in S10 after pre - heating treatment according to a mass ratio of 1:2 - 5, stirred until basically uniform, and then ultrasonic treatment and vortex treatment are carried out in turn to fully mix evenly to obtain a gel solution; S13: The gel solution obtained in S12 is quantitatively filled into sterile dispensing containers, allowed to naturally cool to room temperature, then placed in an ice bath and left to stand to obtain an in - situ gel. The dispensing containers are put into a vacuum freeze - dryer for freeze - drying to obtain a freeze - dried ophthalmic composite preparation. The obtained ophthalmic composite preparation is successively subjected to dry heat sterilization and irradiation sterilization and then sealed and stored; S14: At room temperature or not exceeding 40 °C, the ophthalmic composite preparation obtained in S13 is dissolved in sterile water according to a weight ratio of 1:100 - 1000 and mixed until uniform to obtain the ophthalmic preparation solution.

[0016] In this embodiment, in step S1, the soaking temperature is 80 - 90°C, the soaking time is 2 - 3 h, and the decocting time is 0.5 - 1 h.

[0017] In this embodiment, in step S2, the ultrasonic extraction temperature is 50 - 60°C, and the ultrasonic extraction time is 15 - 30 min.

[0018] In this embodiment, in step S6, the ultrasonic power is set to 200 - 300 W.

[0019] In this embodiment, in step S7, the water bath temperature is 50 - 60°C, and the heating temperature is 65 - 70°C.

[0020] In this embodiment, in step S8, the artificial tear base liquid component is composed of a mixture of carboxymethyl chitosan and aminoethanesulfonic acid.

[0021] In this embodiment, in step S10, the heating temperature is 60 - 80°C, and the heat preservation time is 15 - 30 min.

[0022] In this embodiment, in step S12, the preheating treatment temperature is 40 - 50°C, the ultrasonic treatment time is 3 - 5 min, and the vortex treatment time is 30 - 60 s.

[0023] In this embodiment, in step S13, the standing time is 6 - 12 h.

[0024] Example Two: The difference from Example One lies in: S1: Mix the three powders of chrysanthemum, erigeron breviscapus, and notoginseng root that have been cleaned, dried, and pulverized according to a weight ratio of 10:3 - 8:1 - 5 to obtain a composite powder. Pass through a 60 - 100 mesh sieve, add deionized water according to a weight ratio of 1:10 - 20, soak in a water bath shaker, and then decoct with gentle boiling. S2: After the decoction is cooled, place it in an ultrasonic extractor for ultrasonic extraction, filter while it is hot and concentrate the filtrate. After removing impurities and decolorizing with activated carbon, centrifuge at high speed. The supernatant passes through a 0.22 μm microporous filter membrane to obtain a concentrated extract of the water-soluble component. S3: Pour the concentrated water-soluble component solution obtained in S2 into a macroporous silica gel resin column for adsorption. After 0.5 - 1 h of adsorption, elute successively with deionized water and 50% (v / v) ethanol at a rate of 5 - 10 ml / min. Collect the eluate containing amino acid components according to an amino acid ultraviolet signal monitor, evaporate and concentrate, and then dry in vacuo to obtain a composite extract powder mainly composed of free amino acids. The obtained extract powder is sterilized by dry heat for later use. S4: Weigh 10 - 15 parts of a composite hydrophilic polymer composed of sulfobutyl ether - β - cyclodextrin and polyvinyl alcohol (mass ratio 10:1 - 3) by weight, add them to 100 parts of sterile deionized water, and stir well until dissolved uniformly to obtain a polymer solution; S5: Take another 1 - 1.5 parts of the extract powder obtained in S3 and dissolve it in 10 - 20 parts of sterile water, and appropriately heat and stir to completely dissolve it to obtain a free amino acid solution; S6: Under ultrasonic conditions, drop the free amino acid solution obtained in S5 into the polymer solution obtained in S4 for inclusion. After dropping, continue ultrasonic treatment for 5 - 10 min to make the two solutions fully mixed uniformly, and then slowly stir for 10 - 15 min for full inclusion to obtain a composite micelle solution of polymer - encapsulated free amino acids; S7: By weight, appropriately heat 0.5 - 1 part of vitamin A ester until it just dissolves in ethanol, and drop it into 100 parts of a 10 - 30 wt% hydroxypropyl - β - cyclodextrin solution under water bath and rapid stirring conditions for inclusion. After dropping, perform ultrasonic treatment for 5 - 10 min to make the solution fully mixed, and then heat and stir well to volatilize the residual organic solvent, thereby obtaining a vitamin A ester solution encapsulated by the polymer; S8: Add the components of the artificial tear base solution according to a mass fraction ratio of 0.1 - 0.5 wt% to sterile water and mix well to obtain the artificial tear base solution; S9: Mix the vitamin A ester solution obtained in S7 and the artificial tear base solution obtained in S8 according to a weight ratio of 1:1 - 1.5 and stir well to obtain a mixed solution, and then add 0.1 - 0.5 wt% of glycosaminoglycan based on the weight of the mixed solution and stir well to dissolve under appropriate heating conditions to obtain artificial tears; S10: At room temperature, by weight, add 0.5 - 1 part of polyglutamic acid and 1 - 2 parts of polygonatum polysaccharide to 100 parts of sterilized deionized water, heat and keep warm for full swelling, and after full swelling, add 0.05 - 0.1 part of polyethylene glycol ester and stir to dissolve uniformly to obtain a gel matrix solution; S11: In a homogenizing emulsifying kettle heated to 50 - 60 °C in a water bath, drop the composite micelle solution of polymer - encapsulated free amino acids obtained in S6 into the artificial tears obtained in S9 according to a mass ratio of 1:1 - 5, and perform homogenization treatment until evenly mixed to obtain solution C; S12: Under stirring conditions, slowly add solution C obtained in S11 to the gel matrix solution obtained in S10 after pre - heating treatment according to a mass ratio of 1:2 - 5, stir until basically uniform, and then perform ultrasonic treatment and vortex treatment in sequence to fully mix uniformly to obtain a gel solution; S13: Quantitatively fill the gel solution obtained in S12 into sterile dispensing containers. After naturally cooling to room temperature, place it in an ice bath and let it stand to obtain an in-situ gel. Then put the dispensing containers into a vacuum freeze dryer for freeze-drying to obtain a freeze-dried ophthalmic composite preparation. The obtained ophthalmic composite preparation is sequentially subjected to dry heat sterilization, irradiation sterilization, and then packaged and stored. S14: At room temperature or not exceeding 40 °C, dissolve the ophthalmic composite preparation obtained in S13 in sterile water at a weight ratio of 1:100 - 1000, and mix until uniform to obtain an ophthalmic preparation solution.

[0025] In this example, in step S1, the soaking temperature is 80 - 90 °C, the soaking time is 2 - 3 h, and the decocting time is 0.5 - 1 h.

[0026] In this example, in step S2, the ultrasonic extraction temperature is 50 - 60 °C, and the ultrasonic extraction time is 15 - 30 min.

[0027] In this example, in step S6, the ultrasonic power is set to 200 - 300 W.

[0028] In this example, in step S7, the water bath temperature is 50 - 60 °C, and the heating temperature is 65 - 70 °C.

[0029] In this example, in step S8, the artificial tear base liquid component is composed of a mixture of carboxymethyl chitosan and aminoethanesulfonic acid.

[0030] In this example, in step S10, the heating temperature is 100 - 120 °C, and the heat preservation time is 45 - 60 min.

[0031] In this example, in step S12, the preheating treatment temperature is 40 - 50 °C, the ultrasonic treatment time is 3 - 5 min, and the vortex treatment time is 30 - 60 s.

[0032] In this example, in step S13, the standing time is 6 - 12 h.

[0033] Example Three: The difference features from Example One and Example Two are as follows: S1: Mix the powders of chrysanthemum, erigeron breviscapus, and notoginseng root that have been cleaned, dried, and pulverized according to a weight ratio of 10:3 - 8:1 - 5 to obtain a composite powder. Pass it through a 60 - 100 - mesh sieve, add deionized water at a weight ratio of 1:10 - 20, soak it in a water bath oscillator, and then decoct it over low heat. S2: After the decoction is cooled, place it in an ultrasonic extractor for ultrasonic extraction, filter it while it is hot and concentrate the filtrate. Remove impurities and decolorize with activated carbon, then centrifuge at high speed. The supernatant passes through a 0.22 - μm microporous filter membrane to obtain a concentrated extract of the water-soluble component. S3: pour the concentrated water-soluble component obtained in S2 into a macroporous silica resin column for adsorption. After adsorption for 0.5-1h, elute with deionized water and 50% volume fraction ethanol at a rate of 5-10ml / min in sequence. Collect the eluate containing amino acid components according to the amino acid ultraviolet signal monitor, evaporate and concentrate, and then vacuum dry to obtain a composite extract powder mainly composed of free amino acids. The obtained extract powder is sterilized by dry heat and then used for later use; S4: 10-15 parts by weight of a composite hydrophilic polymer composed of sulfobutyl ether-β-cyclodextrin and polyvinyl alcohol (mass ratio 10:1-3) are weighed and added to 100 parts of sterile deionized water, and stirred until dissolved uniformly to obtain a polymer solution; S5: Dissolve 1-1.5 parts of the extract powder obtained in S3 in 10-20 parts of sterile water, and heat and stir appropriately to completely dissolve it to obtain a free amino acid solution; S6: under ultrasonic conditions, the free amino acid solution obtained in S5 is added dropwise to the polymer solution obtained in S4 for inclusion, and after the addition is completed, ultrasonication is continued for 5-10 minutes to allow the two solutions to be fully mixed, and the two solutions are slowly stirred for 10-15 minutes for full inclusion to obtain a composite micelle solution of free amino acids included in the polymer; S7: By weight, 0.5-1 part of vitamin A ester is heated appropriately to make it just dissolved in ethanol, and then added dropwise to 100 parts of 10-30wt% hydroxypropyl-β-cyclodextrin solution in a water bath with rapid stirring for inclusion, and after the addition is completed, the solution is ultrasonicated for 5-10 minutes to fully mix, and then heated and stirred to volatilize the residual organic solvent, thereby obtaining a polymer-included vitamin A ester solution; S8: adding the tear-simulating base solution components into sterile water at a mass fraction ratio of 0.1-0.5 wt % and mixing well to obtain a tear-simulating base solution; S9: mixing the vitamin A ester solution obtained in S7 and the simulated tear base solution obtained in S8 at a weight ratio of 1:1-1.5 and stirring to obtain a mixed solution, then adding 0.1-0.5wt% of glycosaminoglycan based on the weight of the mixed solution and stirring to dissolve under appropriate heating conditions to obtain a simulated tear solution; S10: at room temperature, 0.5-1 parts of polyglutamic acid and 1-2 parts of polygonatum polysaccharide are added to 100 parts of sterilized deionized water by weight, and the mixture is heated and kept warm for full swelling. After full swelling, 0.05-0.1 parts of polyethylene glycol are added and stirred to be uniformly dissolved to obtain a gel matrix solution; S11: In a homogenizing emulsifier heated to 50-60° C. in a water bath, the composite micelle solution of free amino acids included in the polymer obtained in S6 is added dropwise to the pseudo-tear solution obtained in S9 at a mass ratio of 1:1-5, and the mixture is homogenized until uniformly mixed to obtain a solution C; S12: Under stirring conditions, slowly add the solution C obtained in S11 to the gel matrix solution obtained in S10 that has been preheated, at a mass ratio of 1:2 - 5, and stir until it is basically uniform. Then, perform ultrasonic treatment and vortex treatment in sequence to mix thoroughly and obtain a gel solution; S13: Quantitatively fill the gel solution obtained in S12 into sterile dispensing containers. After naturally cooling to room temperature, place it in an ice bath and let it stand to obtain an in-situ gel. Put the dispensing containers into a vacuum freeze dryer for freeze-drying to obtain a freeze-dried ophthalmic composite preparation. The obtained ophthalmic composite preparation is sequentially subjected to dry heat sterilization and irradiation sterilization and then sealed and stored; S14: At room temperature or not exceeding 40 °C, dissolve the ophthalmic composite preparation obtained in S13 in sterile water at a weight ratio of 1:100 - 1000, and mix until uniform to obtain an ophthalmic preparation solution.

[0034] In this embodiment, in step S1, the soaking temperature is 80 - 90 °C, the soaking time is 2 - 3 h, and the decocting time is 0.5 - 1 h.

[0035] In this embodiment, in step S2, the ultrasonic extraction temperature is 50 - 60 °C, and the ultrasonic extraction time is 15 - 30 min.

[0036] In this embodiment, in step S6, the ultrasonic power is set to 200 - 300 W.

[0037] In this embodiment, in step S7, the water bath temperature is 50 - 60 °C, and the heating temperature is 65 - 70 °C.

[0038] In this embodiment, in step S8, the artificial tear base liquid component is composed of a mixture of carboxymethyl chitosan and aminoethanesulfonic acid.

[0039] In this embodiment, in step S10, the heating temperature is 30 - 60 °C, and the heat preservation time is 5 - 10 min.

[0040] In this embodiment, in step S12, the preheating treatment temperature is 40 - 50 °C, the ultrasonic treatment time is 3 - 5 min, and the vortex treatment time is 30 - 60 s.

[0041] In this embodiment, in step S13, the standing time is 6 - 12 h.

[0042] Example Four: The difference features from Example One, Example Two, and Example Three are as follows: S1: Mix the washed, dried and crushed chrysanthemum, breviscapus breviscapus and notoginseng root powders in a weight ratio of 10:3-8:1-5 to obtain a composite powder, pass through a 60-100 mesh sieve, add deionized water in a weight ratio of 1:10-20, soak in a water bath oscillator, and then boil slightly; S2: After the boiled liquid is cooled, it is placed in an ultrasonic extractor for ultrasonic extraction, the filtrate is filtered and concentrated while hot, the filtrate is decolorized by activated carbon and then centrifuged at high speed, the supernatant is filtered through a 0.22 μm microporous filter membrane to obtain a concentrated extract of the water-soluble component; S3: pour the concentrated water-soluble component obtained in S2 into a macroporous silica resin column for adsorption. After adsorption for 0.5-1h, elute with deionized water and 50% volume fraction ethanol at a rate of 5-10ml / min in sequence. Collect the eluate containing amino acid components according to the amino acid ultraviolet signal monitor, evaporate and concentrate, and then vacuum dry to obtain a composite extract powder mainly composed of free amino acids. The obtained extract powder is sterilized by dry heat and then used for later use; S4: 10-15 parts by weight of a composite hydrophilic polymer composed of sulfobutyl ether-β-cyclodextrin and polyvinyl alcohol (mass ratio 10:1-3) are weighed and added to 100 parts of sterile deionized water, and stirred until dissolved uniformly to obtain a polymer solution; S5: Dissolve 1-1.5 parts of the extract powder obtained in S3 in 10-20 parts of sterile water, and heat and stir appropriately to completely dissolve it to obtain a free amino acid solution; S6: under ultrasonic conditions, the free amino acid solution obtained in S5 is added dropwise to the polymer solution obtained in S4 for inclusion, and after the addition is completed, ultrasonication is continued for 5-10 minutes to allow the two solutions to be fully mixed, and the two solutions are slowly stirred for 10-15 minutes for full inclusion to obtain a composite micelle solution of free amino acids included in the polymer; S7: By weight, 0.5-1 part of vitamin A ester is heated appropriately to make it just dissolved in ethanol, and then added dropwise to 100 parts of 10-30wt% hydroxypropyl-β-cyclodextrin solution in a water bath with rapid stirring for inclusion, and after the addition is completed, the solution is ultrasonicated for 5-10 minutes to fully mix, and then heated and stirred to volatilize the residual organic solvent, thereby obtaining a polymer-included vitamin A ester solution; S8: adding the tear-simulating base solution components into sterile water at a mass fraction ratio of 0.1-0.5 wt % and mixing well to obtain a tear-simulating base solution; S9: mixing the vitamin A ester solution obtained in S7 and the simulated tear base solution obtained in S8 at a weight ratio of 1:1-1.5 and stirring to obtain a mixed solution, then adding 0.1-0.5wt% of glycosaminoglycan based on the weight of the mixed solution and stirring to dissolve under appropriate heating conditions to obtain a simulated tear solution; S10: At room temperature, by weight, add 0.5 - 1 part of polyglutamic acid and 1 - 2 parts of polygonatum polysaccharide to 100 parts of sterilized deionized water, heat and keep warm for sufficient swelling. After sufficient swelling, add 0.05 - 0.1 part of polyethylene glycol ester and stir to dissolve evenly to obtain a gel matrix solution; S11: In a homogenizing emulsifying kettle heated in a water bath to 50 - 60 °C, dropwise add the composite micelle solution of the polymer encapsulating free amino acids obtained in S6 into the artificial tear fluid obtained in S9 according to a mass ratio of 1:1 - 5, and perform homogenization treatment until evenly mixed to obtain solution C; S12: Under stirring conditions, slowly add solution C obtained in S11 to the gel matrix solution obtained in S10 after preheating treatment according to a mass ratio of 1:2 - 5, stir until basically uniform, and then perform ultrasonic treatment and vortex treatment in sequence to mix evenly to obtain a gel solution; S13: Quantitatively fill the gel solution obtained in S12 into sterile dispensing containers, wait for it to naturally cool to room temperature, then place it in an ice bath and let it stand to obtain an in-situ gel. Put the dispensing containers into a vacuum freeze dryer for freeze drying to obtain a freeze-dried ophthalmic composite preparation. The obtained ophthalmic composite preparation is sequentially subjected to dry heat sterilization and irradiation sterilization and then packaged and stored; S14: At room temperature or not exceeding 40 °C, dissolve the ophthalmic composite preparation obtained in S13 in sterile water according to a weight ratio of 1:100 - 1000, and mix until uniform to obtain an ophthalmic preparation solution.

[0043] In this embodiment, in step S1, the soaking temperature is 80 - 90 °C, the soaking time is 2 - 3 h, and the decocting time is 0.5 - 1 h.

[0044] In this embodiment, in step S2, the ultrasonic extraction temperature is 50 - 60 °C, and the ultrasonic extraction time is 15 - 30 min.

[0045] In this embodiment, in step S6, the ultrasonic power is set to 200 - 300 W.

[0046] In this embodiment, in step S7, the water bath temperature is 50 - 60 °C, and the heating temperature is 65 - 70 °C.

[0047] In this embodiment, in step S8, the artificial tear base liquid component is composed of a mixture of carboxymethyl chitosan and aminoethanesulfonic acid.

[0048] In this embodiment, in step S10, the heating temperature is 60 - 80 °C, and the heat preservation time is 15 - 30 min.

[0049] In this embodiment, in step S12, the preheating treatment temperature is 40 - 50 °C, the ultrasonic treatment time is 8 - 10 min, and the vortex treatment time is 90 - 120 s.

[0050] In this embodiment, in step S13, the standing time is 6-12 hours.

[0051] Embodiment five: The difference between the first embodiment, the second embodiment, the third embodiment and the fourth embodiment is that: S1: Mix the washed, dried and crushed chrysanthemum, breviscapus breviscapus and notoginseng root powders in a weight ratio of 10:3-8:1-5 to obtain a composite powder, pass through a 60-100 mesh sieve, add deionized water in a weight ratio of 1:10-20, soak in a water bath oscillator, and then boil slightly; S2: After the boiled liquid is cooled, it is placed in an ultrasonic extractor for ultrasonic extraction, the filtrate is filtered and concentrated while hot, the filtrate is decolorized by activated carbon and then centrifuged at high speed, the supernatant is filtered through a 0.22 μm microporous filter membrane to obtain a concentrated extract of the water-soluble component; S3: pour the concentrated water-soluble component obtained in S2 into a macroporous silica resin column for adsorption. After adsorption for 0.5-1h, elute with deionized water and 50% volume fraction ethanol at a rate of 5-10ml / min in sequence. Collect the eluate containing amino acid components according to the amino acid ultraviolet signal monitor, evaporate and concentrate, and then vacuum dry to obtain a composite extract powder mainly composed of free amino acids. The obtained extract powder is sterilized by dry heat and then used for later use; S4: 10-15 parts by weight of a composite hydrophilic polymer composed of sulfobutyl ether-β-cyclodextrin and polyvinyl alcohol (mass ratio 10:1-3) are weighed and added to 100 parts of sterile deionized water, and stirred until dissolved uniformly to obtain a polymer solution; S5: Dissolve 1-1.5 parts of the extract powder obtained in S3 in 10-20 parts of sterile water, and heat and stir appropriately to completely dissolve it to obtain a free amino acid solution; S6: under ultrasonic conditions, the free amino acid solution obtained in S5 is added dropwise to the polymer solution obtained in S4 for inclusion, and after the addition is completed, ultrasonication is continued for 5-10 minutes to allow the two solutions to be fully mixed, and the two solutions are slowly stirred for 10-15 minutes for full inclusion to obtain a composite micelle solution of free amino acids included in the polymer; S7: By weight, 0.5-1 part of vitamin A ester is heated appropriately to make it just dissolved in ethanol, and then added dropwise to 100 parts of 10-30wt% hydroxypropyl-β-cyclodextrin solution in a water bath with rapid stirring for inclusion, and after the addition is completed, the solution is ultrasonicated for 5-10 minutes to fully mix, and then heated and stirred to volatilize the residual organic solvent, thereby obtaining a polymer-included vitamin A ester solution; S8: adding the tear-simulating base solution components into sterile water at a mass fraction ratio of 0.1-0.5 wt % and mixing well to obtain a tear-simulating base solution; S9: Mix the vitamin A ester solution obtained in S7 and the artificial tear base solution obtained in S8 at a weight ratio of 1:1 - 1.5 and stir evenly to obtain a mixed solution. Then, based on the weight of the mixed solution, add 0.1 - 0.5 wt% of glycosaminoglycan and stir and dissolve it fully under appropriate heating conditions to obtain artificial tears; S10: At room temperature, by weight, add 0.5 - 1 part of polyglutamic acid and 1 - 2 parts of polygonatum polysaccharide to 100 parts of sterilized deionized water, heat and keep warm for sufficient swelling. After sufficient swelling, add 0.05 - 0.1 part of polyethylene glycol ester and stir and dissolve it evenly to obtain a gel matrix solution; S11: In a homogenizing emulsifying kettle heated in a water bath to 50 - 60 °C, dropwise add the composite micelle solution of polymer - encapsulated free amino acids obtained in S6 into the artificial tears obtained in S9 at a mass ratio of 1:1 - 5, and perform homogenization treatment until evenly mixed to obtain solution C; S12: Under stirring conditions, slowly add solution C obtained in S11 to the gel matrix solution obtained in S10 after pre - heating treatment at a mass ratio of 1:2 - 5, stir until basically uniform, and then perform ultrasonic treatment and vortex treatment in sequence to mix evenly to obtain a gel solution; S13: Quantitatively fill the gel solution obtained in S12 into sterile dispensing containers, wait for it to naturally cool to room temperature, then place it in an ice - bath condition and let it stand to obtain an in - situ gel. Put the dispensing containers into a vacuum freeze - dryer for freeze - drying to obtain a freeze - dried ophthalmic composite preparation. The obtained ophthalmic composite preparation is sequentially sterilized by dry heat and irradiation and then sealed for storage; S14: At room temperature or not exceeding 40 °C, dissolve the ophthalmic composite preparation obtained in S13 in sterile water at a weight ratio of 1:100 - 1000, and mix until uniform to obtain an ophthalmic preparation solution.

[0052] In this embodiment, in step S1, the soaking temperature is 80 - 90 °C, the soaking time is 2 - 3 h, and the decocting time is 0.5 - 1 h.

[0053] In this embodiment, in step S2, the ultrasonic extraction temperature is 50 - 60 °C, and the ultrasonic extraction time is 15 - 30 min.

[0054] In this embodiment, in step S6, the ultrasonic power is set to 200 - 300 W.

[0055] In this embodiment, in step S7, the water - bath temperature is 50 - 60 °C, and the heating temperature is 65 - 70 °C.

[0056] In this embodiment, in step S8, the artificial tear base solution component is composed of a mixture of carboxymethyl chitosan and aminoethanesulfonic acid.

[0057] In this embodiment, in step S10, the heating temperature is 60 - 80°C, and the heat preservation time is 15 - 30 min.

[0058] In this embodiment, in step S12, the preheating treatment temperature is 40 - 50°C, the ultrasonic treatment time is 0.5 - 1 min, and the vortex treatment time is 10 - 15 s.

[0059] In this embodiment, in step S13, the standing time is 6 - 12 h.

[0060] In summary: The present invention provides a preparation method for a compound preparation for ophthalmic diseases. The ophthalmic compound preparation obtained by the formulation method according to Example 1 has high adhesiveness, small volume, is convenient to carry and store, and has good stability. The ophthalmic compound preparation obtained by the formulation method according to Example 2 may have low adhesiveness and poor stability of the ophthalmic compound preparation because in step S10, the heating temperature is increased to 100 - 120°C and at the same time the heat preservation time is extended to 45 - 60 min. The ophthalmic compound preparation obtained by the formulation method according to Example 3 may have too high adhesiveness of the ophthalmic compound preparation, which is not conducive to dripping out from the bottle and affects the use of the user because in step S10, the heating temperature is reduced to 30 - 60°C and at the same time the heat preservation time is shortened to 5 - 10 min. The ophthalmic compound preparation obtained by the formulation method according to Example 4 may cause the polymer network structure in the gel solution, resulting in the loss of the original elasticity and toughness of the gel solution and affecting the efficacy of the later ophthalmic compound preparation because in step S12, the ultrasonic treatment time is increased to 8 - 10 min and at the same time the vortex treatment time is extended to 90 - 120 s. The ophthalmic compound preparation obtained by the formulation method according to Example 5 may cause the polymer molecular chains in the gel solution to not be fully unraveled and mixed, resulting in a lower crosslinking degree of the gel solution and unable to form a gel solution with the expected strength and stability, and further affecting the viscosity of the later ophthalmic compound preparation.

[0061] It should be noted that in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variant thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements not only includes those elements, but also includes other elements not expressly listed, or elements inherent to such process, method, article or device.

[0062] Although embodiments of the present invention have been shown and described, those of ordinary skill in the art will appreciate that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a composite preparation for eye diseases, characterized in that: The following steps are involved: S1: Mix the washed, dried and crushed chrysanthemum, breviscapus breviscapus and notoginseng root powders in a weight ratio of 10:3-8:1-5 to obtain a composite powder, pass through a 60-100 mesh sieve, add deionized water in a weight ratio of 1:10-20, soak in a water bath oscillator, and then boil slightly; S2: After the boiled liquid is cooled, it is placed in an ultrasonic extractor for ultrasonic extraction, the filtrate is filtered and concentrated while hot, the filtrate is decolorized by activated carbon and then centrifuged at high speed, the supernatant is filtered through a 0.22 μm microporous filter membrane to obtain a concentrated extract of the water-soluble component; S3: pour the concentrated water-soluble component obtained in S2 into a macroporous silica resin column for adsorption. After adsorption for 0.5-1h, elute with deionized water and 50% volume fraction ethanol at a rate of 5-10ml / min in sequence. Collect the eluate containing amino acid components according to the amino acid ultraviolet signal monitor, evaporate and concentrate, and then vacuum dry to obtain a composite extract powder mainly composed of free amino acids. The obtained extract powder is sterilized by dry heat and then used for later use; S4: 10-15 parts by weight of a composite hydrophilic polymer composed of sulfobutyl ether-β-cyclodextrin and polyvinyl alcohol (mass ratio 10:1-3) are weighed and added to 100 parts of sterile deionized water, and stirred until dissolved uniformly to obtain a polymer solution; S5: Dissolve 1-1.5 parts of the extract powder obtained in S3 in 10-20 parts of sterile water, and heat and stir appropriately to completely dissolve it to obtain a free amino acid solution; S6: under ultrasonic conditions, the free amino acid solution obtained in S5 is added dropwise to the polymer solution obtained in S4 for inclusion, and after the addition is completed, ultrasonication is continued for 5-10 minutes to allow the two solutions to be fully mixed, and the two solutions are slowly stirred for 10-15 minutes for full inclusion to obtain a composite micelle solution of free amino acids included in the polymer; S7: By weight, 0.5-1 part of vitamin A ester is heated appropriately to make it just dissolved in ethanol, and then added dropwise to 100 parts of 10-30wt% hydroxypropyl-β-cyclodextrin solution in a water bath with rapid stirring for inclusion, and after the addition is completed, the solution is ultrasonicated for 5-10 minutes to fully mix, and then heated and stirred to volatilize the residual organic solvent, thereby obtaining a polymer-included vitamin A ester solution; S8: adding the tear-simulating base solution components into sterile water at a mass fraction ratio of 0.1-0.5 wt % and mixing well to obtain a tear-simulating base solution; S9: mixing the vitamin A ester solution obtained in S7 and the simulated tear base solution obtained in S8 at a weight ratio of 1:1-1.5 and stirring to obtain a mixed solution, then adding 0.1-0.5wt% of glycosaminoglycan based on the weight of the mixed solution and stirring to dissolve under appropriate heating conditions to obtain a simulated tear solution; S10: at room temperature, 0.5-1 parts of polyglutamic acid and 1-2 parts of polygonatum polysaccharide are added to 100 parts of sterilized deionized water by weight, and the mixture is heated and kept warm for full swelling. After full swelling, 0.05-0.1 parts of polyethylene glycol are added and stirred to be uniformly dissolved to obtain a gel matrix solution; S11: In a homogenizing emulsifier heated to 50-60° C. in a water bath, the composite micelle solution of free amino acids included in the polymer obtained in S6 is added dropwise to the pseudo-tear solution obtained in S9 at a mass ratio of 1:1-5, and the mixture is homogenized until uniformly mixed to obtain a solution C; S12: under stirring conditions, slowly adding the solution C obtained in S11 to the gel matrix solution obtained in S10 after preheating in a mass ratio of 1:2-5, stirring until it is basically uniform, and then sequentially performing ultrasonic treatment and vortex treatment to fully mix and obtain a gel solution; S13: quantitatively filling the gel solution obtained in S12 into sterile sub-filling containers, and after the solution naturally cools to room temperature, placing it in an ice bath to obtain an in-situ gel, placing the sub-filling container in a vacuum freeze dryer for freeze drying to obtain a freeze-dried ophthalmic composite preparation, and the obtained ophthalmic composite preparation is successively sterilized by dry heat and irradiation, and then packaged and stored; S14: At room temperature or not more than 40° C., dissolve the ophthalmic composite preparation obtained in S13 in sterile water at a weight ratio of 1:100-1000, and mix until uniform to obtain an ophthalmic preparation liquid.

2. The method for preparing a composite preparation for eye diseases according to claim 1, characterized in that: In step S1, the soaking temperature is 80-90°C, the soaking time is 2-3h, and the boiling time is 0.5-1h.

3. The method for preparing a composite preparation for eye diseases according to claim 1, characterized in that: In step S2, the ultrasonic extraction temperature is 50-60°C, and the ultrasonic extraction time is 15-30 minutes.

4. The method for preparing a composite preparation for eye diseases according to claim 1, characterized in that: In step S6, the ultrasonic power is set to 200-300W.

5. The method for preparing a composite preparation for eye diseases according to claim 1, characterized in that: In step S7, the water bath temperature is 50-60°C, and the heating temperature is 65-70°C.

6. The method for preparing a composite preparation for eye diseases according to claim 1, characterized in that: In step S8, the tear-simulating base solution component is composed of a mixture of carboxymethyl chitosan and aminoethanesulfonic acid.

7. The method for preparing a composite preparation for eye diseases according to claim 1, characterized in that: In step S10, the heating temperature is 60-80° C., and the insulation time is 15-30 min.

8. The method for preparing a composite preparation for eye diseases according to claim 1, characterized in that: In step S12, the preheating treatment temperature is 40-50°C, the ultrasonic treatment time is 3-5 minutes, and the vortex treatment time is 30-60 seconds.

9. The method for preparing a composite preparation for eye diseases according to claim 1, characterized in that: In step S13, the standing time is 6-12 hours.