Liquid preparation for treating xerophthalmia and preparation process

Abstract

The invention relates to a liquid preparation for treating xerophthalmia. Every 1000 ml of the liquid preparation is prepared from 45 g to 55 g of honeysuckle flower extracting solution, 28 g to 32 g of herba houttuyniae extracting solution, 28 g to 32 g of wild chrysanthemum flower extracting solution by weight, 20 g to 30 g of grape skin extracting solution, 5 g to 10 g of silybum marianum extracting solution by weight, 45 g to 55 g of butterflybush flower extracting solution by weight, 28 g to 32 g of radix salviae miltiorrhizae extracting solution by weight, 9 g to 12 g of pearl powder extracting solution, 1.8 g to 2.2 g of borneol, 95 g to 100 g of sodium chloride, 2.8 g to 3.2 g of sodium benzoate and 0.6 g to 1 g of vitamin E; the balance is sterile water; the relative density of each extracting solution at 25 DEG C is 1.05-1.1. In order to solve the problem of xerophthalmia, the invention develops a liquid preparation of pure traditional Chinese medicines, preferably an atomized spray, and a novel treatment scheme with a remarkable curative effect is provided for the treatment of xerophthalmia through the optimized combination of the formula.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine preparations, and in particular to a liquid preparation for treating dry eye and a preparation process thereof. Background Art

[0002] Dry eye (DE) is a chronic ocular surface disease that generally affects people's vision and quality of life. According to the definition of the Chinese Chapter of the Asian Dry Eye Association in 2020, dry eye is caused by abnormalities in the quality, quantity and dynamics of tears, resulting in tear film instability or imbalance of the ocular surface microenvironment, often accompanied by ocular surface inflammatory response, tissue damage and nerve abnormalities, causing a variety of ocular discomfort symptoms and (or) visual dysfunction. Dry eye can be classified in various ways, including aqueous deficiency type, lipid abnormality type, mucin abnormality type, tear dynamics abnormality type and mixed type, of which lipid abnormality type dry eye accounts for 60-90%, and meibomian gland dysfunction (MGD) is its most common cause.

[0003] The prevalence and high incidence of dry eyes bring obvious discomfort to patients, such as dryness, burning sensation, foreign body sensation and pain, which seriously affect the patient's visual function, daily activities and work, and may even cause depression and / or anxiety. According to statistics, dry eyes affect tens of millions of people worldwide, with an incidence rate of 5-50%. In China, the incidence of dry eyes has reached 21-30%, with the number of patients approaching 300 million, and the demand for diagnosis and treatment is increasing year by year. Western medicine mainly treats dry eyes by lubricating the ocular surface with artificial tears, promoting repair drugs, anti-inflammatory treatment, antibacterial treatment and other means to reduce inflammatory response and improve symptoms, but there are potential risks of complications, such as hormones and immunosuppressants may cause increased intraocular pressure and cataracts. Traditional Chinese medicine provides a new perspective for the treatment of dry eyes. In traditional Chinese medicine theory, dry eyes are related to liver and kidney deficiency, which leads to malnutrition of the eyes. Treatment should follow the principle of nourishing the liver and kidney, promoting fluid and nourishing yin, so as to achieve the effect of clearing the liver and improving eyes. However, there are some limitations in traditional Chinese medicine treatment methods, such as insufficient efficacy, inconvenience in use, unreasonable formulation, and the effect needs to be further improved. Summary of the invention

[0004] 1. Technical issues to be resolved

[0005] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a liquid preparation and a preparation process for treating dry eye, which optimizes the traditional Chinese medicine formula and uses vitamin E as a preservative ingredient to prepare the liquid preparation, providing a new and effective treatment scheme for the treatment of dry eye.

[0006] (II) Technical solution

[0007] In a first aspect, the present invention provides a liquid preparation for treating dry eye, wherein each 1000 ml of the liquid preparation is composed of the following components: 45-55 g of honeysuckle extract, 28-32 g of houttuynia cordata extract, 28-32 g of wild chrysanthemum extract, 20-30 g of grape skin extract, 5-10 g of milk thistle extract, 45-55 g of buddlejac extract, 28-32 g of salvia miltiorrhiza extract, 9-12 g of pearl powder extract, 1.8-2.2 g of borneol, 95-100 g of sodium chloride, 2.8-3.2 g of sodium benzoate, and 0.6-1 g of vitamin E; the remainder is sterile water; and the relative density of the aforementioned extracts at 25°C is 1.05-1.1.

[0008] According to a preferred embodiment of the present invention, every 1000 ml of liquid preparation comprises: 50 g of honeysuckle extract, 30 g of houttuynia cordata extract, 30 g by weight of wild chrysanthemum extract, 25 g of grape skin extract, 8 g of milk thistle extract, 50 g of buddlejac extract, 30 g by weight of salvia miltiorrhiza extract, 10 g of pearl powder extract, 2 g of borneol, 100 g of sodium chloride, 3 g of sodium benzoate, and 1 g of vitamin E; the balance is sterile water.

[0009] According to a preferred embodiment of the present invention, the honeysuckle extract, houttuynia cordata extract, salvia miltiorrhiza extract, wild chrysanthemum extract and buddleja buddleja extract are respectively obtained by extracting with water to obtain a water extract, then subjecting the extract to alcohol precipitation, taking the supernatant, evaporating the ethanol from the supernatant, and then dissolving the extract in sterile water.

[0010] According to a preferred embodiment of the present invention, the preparation process of the grape skin extract is as follows: fresh red grape skin is freeze-dried and ground into 80-100 mesh powder, and then pressure-extracted with 2-3 times the volume of anhydrous ethanol at 35-45°C for 12-24h, and vacuum rotary evaporation is performed at 10-20°C. After freeze-drying, sterile water is added to dissolve, and precision filtration is performed to obtain an extract with a relative density of 1.05-1.1 at 25°C.

[0011] According to a preferred embodiment of the present invention, the preparation process of milk thistle extract is as follows: cold-pressing milk thistle fruit or seeds to obtain oil cakes, crushing the oil cakes into 80-100 mesh powders, adding 3-5 times the volume of the powder to 85-95% ethanol, and extracting at 50-60°C for 8-12h; filtering and retaining the filter residue and the extract, repeating the above process 2-3 times, combining the extracts each time, and after vacuum rotary evaporation at 5-25°C, freeze-drying, adding sterile water to dissolve, and fine filtering to obtain an extract with a relative density of 1.05-1.1 at 25°C.

[0012] Preferably, the liquid preparation is an atomized liquid, eye drops or a fumigant.

[0013] In a second aspect, the present invention provides a process for preparing a liquid preparation for treating dry eye, comprising:

[0014] S1. Preparation of Chinese herbal medicine raw materials

[0015] The raw materials include honeysuckle, houttuynia, wild chrysanthemum, buddleja, pearl powder, salvia miltiorrhiza, and borneol, and the raw materials are cleaned and selected; fresh red grape skins are freeze-dried, and milk thistle fruits or seeds are cold-pressed to obtain oil cakes; borneol, freeze-dried grape skins, oil cakes, and pearls are respectively ground into 80-100 mesh powders for standby use;

[0016] S2, honeysuckle, houttuynia, wild chrysanthemum, pearl powder, buddleja buddleja and salvia miltiorrhiza were decocted with water twice, the first time, 7.5-8.5 times the volume of water was added and decocted for 1.5-2h, the first filtrate was filtered and retained to obtain the residue; the second time, the residue was decocted with 5.5-6.5 times the volume of water for 0.8-1.2h, and the second filtrate was filtered and retained; the first filtrate and the second filtrate were combined, decocted and concentrated to an extract with a relative density of 1.15-1.20 at 60°C, 1-1.5 times the ethanol was added to the extract to make the ethanol concentration reach between 60-70%, after stirring evenly, it was allowed to stand for 20-26h, and the supernatant was taken; the supernatants of honeysuckle, houttuynia, wild chrysanthemum, pearl powder, buddleja buddleja and salvia miltiorrhiza were obtained according to the above method;

[0017] The grape skin powder is extracted with 2-3 times the volume of anhydrous ethanol at 35-45° C. for 12-24 hours under pressure, concentrated by vacuum rotary evaporation at 10-20° C., and freeze-dried to obtain freeze-dried grape skin extract powder;

[0018] Add 3-5 times the volume of 85-95% ethanol to the powder of the oil cake, and extract at 50-60°C for 8-12h; filter and retain the filter residue and extract, repeat the above process 2-3 times, combine the extracts each time, evaporate under reduced pressure at 5-25°C, and freeze-dry to obtain freeze-dried powder of milk thistle extract;

[0019] S3, volatilize the ethanol in the supernatant of each medicinal material until the supernatant has no ethanol smell, dilute with pure water, and accurately filter to obtain the filtrate of each medicinal material; dissolve the freeze-dried powder of grape skin extract and the freeze-dried powder of milk thistle extract with sterile water, and accurately filter to obtain grape skin extract and milk thistle extract respectively; the relative density of the above-mentioned filtrate and extract at 25°C is 1.05-1.1; dissolve borneol, sodium benzoate, and vitamin E with a small amount of ethanol for later use;

[0020] S4. Mix the ethanol solution containing borneol, sodium benzoate and vitamin E with the filtrate of each medicinal material, grape skin extract and milk thistle extract in a predetermined proportion, and allow the ethanol to evaporate until there is no ethanol smell. Add pure water to make up to the sufficient amount, stir evenly, and fill.

[0021] In order to reduce the irritation of the liquid preparation to the eyes, the ethanol content in the product is less than 0.01%. The ethanol used to dissolve borneol, sodium benzoate and vitamin E should be in an amount that is just enough to dissolve these ingredients.

[0022] According to a preferred embodiment of the present invention, in S3, the pore size of the filter membrane for precision filtration is 0.22 μm.

[0023] According to a preferred embodiment of the present invention, the method further includes step S5: sterilizing with gamma rays at a temperature of 2-10°C and an irradiation dose of 9-15Gy; the sterilized drug solution is stored at 2-8°C to maintain the stability and effectiveness of the drug solution.

[0024] (III) Beneficial effects

[0025] The innovation and technical effects of the present invention mainly include:

[0026] Improvement of Chinese medicine formula: The Chinese medicinal materials of the liquid preparation of the present invention include honeysuckle, houttuynia, salvia miltiorrhiza, wild chrysanthemum, red grape skin, milk thistle, buddleja, pearl powder and borneol, etc.; the active ingredients of these Chinese medicinal materials are mild and non-irritating to the mucosa, and the combination has a good therapeutic and alleviating effect on dry eye. Among them, honeysuckle can clear away heat and detoxify, and clear and disperse. Modern pharmacological studies have shown that honeysuckle has multiple pharmacological effects such as anti-inflammatory, antioxidant, immunomodulatory and liver protection. When buddleja and honeysuckle are used in combination, they can work synergistically to clear liver and lung heat toxins, remove cataracts, relieve itching and improve eyesight. Pharmacological experiments further confirmed that buddleja can prevent and treat acute and chronic liver damage, significantly inhibit lipid peroxidation reactions in normal and damaged liver cells, promote the synthesis of cytochrome P450, prevent the reduction of protein, DNA, RNA, urea and ceruloplasmin in damaged cells, and reduce the damage of liver toxins to the ultrastructure of cells cultured in vitro.

[0027] Wild chrysanthemum has the effect of relieving eye redness and itching. Modern pharmacological experiments show that wild chrysanthemum has the effect of relieving eye redness and itching. - ) and hydroxyl radicals (OH), and its scavenging ability increases with the increase of dosage, and the effect is better than vitamin C.

[0028] Danshen has the effects of promoting blood circulation and removing blood stasis, anti-oxidation, anti-inflammatory and improving microcirculation. Modern pharmacological experiments have shown that Danshen also has the effects of anti-inflammatory, anti-liver cell damage and promoting DIA synthesis in rat liver cells.

[0029] Red grape skin extract is rich in resveratrol and proanthocyanidins, which can resist free radicals and maintain the health of cells. Silymarin, with its strong antioxidant, anti-inflammatory and cell protection functions, can prevent eye diseases and has a certain preventive effect on cataracts.

[0030] Houttuynia cordata can reduce swelling and inflammation, reduce the production of inflammatory mediators, has obvious anti-inflammatory and antioxidant effects, can scavenge free radicals and protect cells from oxidative damage.

[0031] Pearl powder has the effects of clearing the lungs and removing cataracts, calming the heart fire, nourishing yin and improving eyesight. Modern pharmacological experiments have shown that pearl powder has a certain inhibitory effect on the central nervous system and has a central sedative effect; at the same time, it can regulate the endocrine system of the human body, enhance immunity, and has anti-inflammatory effects.

[0032] Borneol is used as a drug to guide other drugs to pass through the eyes and synergistically treat ophthalmic diseases. Modern pharmacological experiments have shown that borneol has anti-inflammatory effects, can promote the transdermal absorption of other drugs, and promote the division and growth of glial cells.

[0033] The dosage ratio of each component is improved: each 1000 ml of the liquid preparation contains 45-55g of honeysuckle extract, 28-32g of houttuynia extract, 28-32g of wild chrysanthemum extract, 20-30g of grape skin extract, 5-10g of milk thistle extract, 45-55g of buddlejac extract, 28-32g of salvia extract, 9-12g of pearl powder extract, 1.8-2.2g of borneol, 95-100g of sodium chloride, 2.8-3.2g of sodium benzoate, 0.6-1g of vitamin E and other ingredients. This group distribution ratio has been proven by clinical trials to have a good therapeutic effect on dry eye, but the therapeutic effect of the atomized liquid on dry eye becomes worse after changing the group distribution ratio.

[0034] Improved extraction method: Honeysuckle, Houttuynia cordata, Salvia miltiorrhiza, Chrysanthemum indica, Buddleja buddha and pearl powder in the medicinal materials are first decocted with water and then precipitated with alcohol. The precipitate insoluble in water and alcohol is removed by standing and separation. Impurities in the water extract can be effectively removed, such as tannins, resins, starch, protein and other macromolecular substances and some impurities with low polarity. These impurities have low solubility in ethanol and are easy to precipitate, thereby achieving the effect of purifying the medicinal solution and improving the purity and clarity. After alcohol precipitation, precise filtration is combined to achieve the refining of high-clarity medicinal solution, and the supernatant of alcohol precipitation is evaporated to no ethanol odor for drug preparation. The process is relatively simple to operate, low cost, and suitable for large-scale production.

[0035] Grape skin extract is freeze-dried from fresh red grape skins, which can retain the most active ingredients such as resveratrol. Milk thistle extract is made from milk thistle fruit or seeds, which are cold-pressed to obtain oil cakes. Squeezing out the oil can prevent the oil from affecting subsequent extraction and product stability; freeze-drying removes ethanol to avoid irritation to the eyes caused by ethanol residues.

[0036] Improved antiseptic properties: A small amount of vitamin E is added to enhance the stability of the liquid medicine and maintain its natural properties, thereby improving the stability of the liquid medicine, reducing the use of chemical preservatives, and making the product safer and milder.

[0037] Improvement of liquid medicine dosage form: The present invention combines the principle of TCM syndrome differentiation and treatment with modern atomization technology, and uses atomization technology to make the drug act directly on the ocular surface, which has the advantages of rapid onset of action, easy use, and few side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 Comparison of the stained area of ​​mouse eyes before and after modeling.

[0039] Figure 2 The changes of cGMP content in the ciliary body of each group of experimental mice before and after administration. DETAILED DESCRIPTION

[0040] In order to better explain the present invention and facilitate understanding, the present invention is described in detail below in conjunction with specific implementation methods.

[0041] The present invention provides a process for preparing a liquid preparation for treating dry eye, which comprises:

[0042] S1. Preparation of Chinese herbal medicine raw materials

[0043] The raw materials include honeysuckle, houttuynia cordata, wild chrysanthemum, buddleja buddleja, pearl powder, salvia miltiorrhiza, and borneol, and the raw materials are cleaned and selected;

[0044] Freeze-dry fresh red grape skins, and cold-press milk thistle fruits or seeds to obtain oil cakes; grind borneol, freeze-dried grape skins, oil cakes, and pearls into 80-100 mesh powders respectively for later use;

[0045] S2, honeysuckle, houttuynia, wild chrysanthemum, pearl powder, buddleja and salvia miltiorrhiza are decocted with water for 2 times, the first time, 7.5-8.5 times the volume of water is added and decocted for 1.5-2h, the first filtrate is filtered and retained to obtain the residue; the second time, the residue is decocted with 5.5-6.5 times the volume of water for 0.8-1.2h, and the second filtrate is filtered and retained; the first filtrate and the second filtrate are combined, decocted and concentrated to an extract with a relative density of 1.15-1.20 at 60°C, 1-1.5 times the ethanol is added to the extract to make the concentration of ethanol reach between 60-70%, after stirring evenly, let it stand for 20-26h, and take the supernatant;

[0046] According to the above method, the supernatants of honeysuckle, houttuynia cordata, wild chrysanthemum, pearl powder, buddlejac and salvia miltiorrhiza were obtained respectively;

[0047] The grape skin powder is extracted with 2-3 times the volume of anhydrous ethanol at 35-45° C. for 12-24 hours under pressure, concentrated by vacuum rotary evaporation at 10-20° C., and freeze-dried to obtain freeze-dried grape skin extract powder;

[0048] Add 3-5 times the volume of 85-95% ethanol to the powder of the oil cake, and extract at 50-60°C for 8-12h; filter and retain the filter residue and extract, repeat the above process 2-3 times, combine the extracts each time, evaporate under reduced pressure at 5-25°C, and freeze-dry to obtain freeze-dried powder of milk thistle extract;

[0049] S3, volatilize the ethanol in the supernatant of each medicinal material until the supernatant has no ethanol smell, dilute with pure water, and accurately filter to obtain the filtrate of each medicinal material; dissolve the freeze-dried powder of grape skin extract and the freeze-dried powder of milk thistle extract with sterile water, and accurately filter to obtain grape skin extract and milk thistle extract respectively; the relative density of the above-mentioned filtrate and extract at 25°C is 1.05-1.1; dissolve borneol, sodium benzoate, and vitamin E with a small amount of ethanol for later use;

[0050] S4. Mix the ethanol solution containing borneol, sodium benzoate and vitamin E with the filtrate of each medicinal material, grape skin extract and milk thistle extract in a predetermined proportion, and allow the ethanol to evaporate until there is no ethanol smell. Add pure water to make up to the sufficient amount, stir evenly, and fill.

[0051] In order to reduce the irritation of liquid preparations to the eyes, the ethanol content in the product needs to be controlled below 0.01%. The amount of ethanol used to dissolve borneol, sodium benzoate and vitamin E should be just enough to dissolve these ingredients. Among them, the pore size of the filter membrane for precision filtration is 0.22μm. Finally, gamma ray sterilization can also be used to ensure the sterility of the drug solution; the sterilized drug solution is stored at 2-8°C to maintain the stability and effectiveness of the drug solution. Sterilization is carried out at a temperature of 2-10°C and an irradiation dose of 9-15Gy, which can minimize the denaturation of antioxidant, anti-inflammatory and other components in the atomized liquid caused by the sterilization process.

[0052] Dry eyes are a multifactorial chronic functional ocular surface disease, which is caused by decreased tear film stability and eye discomfort and ocular surface tissue lesions. Dry eyes are similar to the "white and astringent syndrome" in traditional Chinese medicine. According to medical theory, the causes of white and astringent syndrome are liver and kidney deficiency syndrome, qi stagnation and blood stasis syndrome, spleen and kidney deficiency syndrome, and yin deficiency and dampness-heat syndrome. Visual fatigue is a group of syndromes caused by various causes that make the human eye exceed the load that its visual function can bear when viewing objects, resulting in visual impairment, eye discomfort or accompanied by systemic symptoms after using the eyes, so that normal visual work cannot be performed. According to medical theory, its causes are caused by liver and kidney deficiency, spleen deficiency and weak qi, heart blood deficiency, liver depression and qi stagnation, and insufficient qi and blood. It can be seen that the causes of dry eyes and visual fatigue are closely related.

[0053] The Chinese medicine composition of the present invention comprehensively dialectically treats dry eyes and visual fatigue, and through the reasonable combination of monarch, minister, assistant and guiding ingredients, takes clearing away heat and detoxifying, promoting blood circulation and removing blood stasis, anti-inflammatory and detumescent, and calming and tranquilizing the mind as the treatment principles, has the functions of improving eyesight and refreshing, promoting tear secretion, stabilizing tear film, and relieving the symptoms of dry eyes and visual fatigue.

[0054] In the liquid preparation of the present invention, honeysuckle and buddlejac are the main drugs, houttuynia cordata, wild chrysanthemum and salvia miltiorrhiza are the assistant drugs, grape skin extract, milk thistle and pearl powder are the adjuvant drugs, and borneol is the guiding drug.

[0055] Honeysuckle is cold in nature and sweet in taste. It enters the lung, heart and stomach meridians. It has the effects of clearing away heat and detoxifying, and evacuating wind-heat. Its cold nature can clear away heat and toxins in the eyes and relieve redness, swelling and pain. Buddleja buddha is cold in nature and enters the liver meridian. It is combined with honeysuckle to clear away heat and purge fire, clear the liver and lungs, nourish the liver and improve eyesight, improve red and swollen eyes, photophobia and excessive tears, liver deficiency and dark eyes, reduce eye inflammation, and relieve dry eyes and visual fatigue symptoms.

[0056] Houttuynia cordata is slightly cold in nature and enters the lung meridian, assisting honeysuckle in strengthening its ability to clear heat and detoxify; wild chrysanthemum is cold in nature and bitter in taste, and enters the liver and heart meridians, clears heat and detoxifies, purges fire and calms the liver, assists honeysuckle in clearing the liver and improving eyesight, and relieves symptoms of eye discomfort; Salvia miltiorrhiza is slightly cold in nature and enters the heart and liver meridians, promotes blood circulation and removes blood stasis, dredges and relieves pain, clears the heart and relieves restlessness, cools blood and eliminates carbuncles, assists honeysuckle in evacuating wind-heat, improves blood circulation in the eyes, cools blood and relieves pain, relieves symptoms of dry eyes and visual fatigue, dredges and increases the efficacy of the prescription, and at the same time better relieves eye congestion caused by excessive use of the eyes.

[0057] Grape peel extract is neutral in nature and rich in antioxidants, which can protect the eyes from free radical damage and relieve symptoms of dry eyes and visual fatigue; milk thistle is cold in nature and enters the liver meridian, protecting the liver and improving eyesight, and the liver opens the eyes, which helps improve vision. Pearl powder is cold in nature and enters the heart and liver meridians, calming the mind, soothing the liver and relieving depression, and relieving symptoms of dry eyes and visual fatigue caused by long-term illness, long-term depression, and mental stress.

[0058] Borneol is pungent and bitter, slightly cold in nature, and enters the heart, spleen, and lung meridians. It can invigorate the mind, clear away heat and relieve pain, harmonize various medicines, guide the medicines upward, reach the lesions of the eye, enhance the efficacy of the medicines, and promote drug penetration.

[0059] Sodium chloride, sodium benzoate and vitamin E are other auxiliary ingredients. Sodium chloride is neutral in nature and can replenish electrolytes, maintain the osmotic pressure balance of the eyes, and relieve dry eye symptoms; sodium benzoate is neutral in nature and acts as a preservative to ensure the safety and stability of the prescription; vitamin E is warm in nature, enters the liver meridian, has antioxidant properties, protects eye cells, and relieves visual fatigue.

[0060] Modern pharmacology research:

[0061] Honeysuckle: Modern pharmacological experiments have shown that honeysuckle has anti-inflammatory, antioxidant, immunomodulatory, and liver-protective pharmacological effects.

[0062] Houttuynia cordata: Modern pharmacological experiments have shown that pearl powder has a certain inhibitory effect on the central nervous system and has a central sedative effect; it can also regulate the human endocrine system, enhance immunity, and has anti-inflammatory effects.

[0063] Wild chrysanthemum: Modern pharmacological experiments have shown that wild chrysanthemum has a strong anti-2,2-biphenyl-1-picrylhydrazyl free radical (DPPH), superoxide anion free radical (O 2- ) and hydroxyl radicals (OH) have strong scavenging effects, the scavenging ability increases with the increase of added amount, and the scavenging effect is better than that of vitamin C.

[0064] Red grape skin extract: rich in resveratrol and proanthocyanidins, which can resist free radicals and maintain the health of cells;

[0065] Silymarin: It has strong antioxidant, anti-inflammatory and cell protection functions, can prevent eye diseases, and has a certain preventive effect on cataracts.

[0066] Buddleja: Modern pharmacological experiments have shown that Buddleja can prevent and treat acute and chronic liver damage, significantly inhibit lipid peroxidation in normal and damaged liver cells, induce the synthesis of cytochrome c50, prevent the reduction of protein, DNA, RNA, urea and ceruloplasmin in damaged cells, and reduce the damage of liver toxins to the ultrastructure of cells cultured in vitro;

[0067] Salvia miltiorrhiza: Modern pharmacological experiments have shown that Salvia miltiorrhiza also has anti-inflammatory, anti-hepatocellular damage and promotion effects of DIA synthesis in rat hepatocytes.

[0068] Pearl powder: Modern pharmacological experiments have shown that pearl powder has a certain inhibitory effect on the central nervous system and has a central sedative effect; it can also regulate the human endocrine system, enhance immunity, and has anti-inflammatory effects.

[0069] Borneol: Modern pharmacological experiments have shown that borneol has anti-inflammatory effects, can promote the transdermal absorption of other drugs, and promote the division and growth of glial cells.

[0070] The Chinese medicine composition of the present invention has sufficient theoretical support in terms of both traditional Chinese medicine theory and modern pharmacology research, and can have good therapeutic and alleviating effects on dry eye and visual fatigue.

[0071] In order to verify the technical effect of the present invention, a description is given below in conjunction with specific embodiments.

[0072] Example 1

[0073] The preparation process of an atomized liquid for treating dry eye in this embodiment is as follows:

[0074] S1. Preparation of Chinese herbal medicine raw materials

[0075] The raw materials include honeysuckle, houttuynia cordata, wild chrysanthemum, buddleja bud, pearl powder, salvia miltiorrhiza, and borneol, which are cleaned and selected; fresh red grape skins are freeze-dried, and milk thistle seeds are cold-pressed to obtain oil cakes; borneol, freeze-dried grape skins, oil cakes, and pearls are respectively ground into 100-mesh powders for standby use.

[0076] S2, honeysuckle, houttuynia, wild chrysanthemum, pearl powder, buddleja buddleja and salvia miltiorrhiza were decocted with water twice, the first time 8 times the volume of water was added for 1.5 hours, the first filtrate was filtered and retained to obtain the residue; the second time, the residue was decocted with 6 times the volume of water for 1 hour, and the second filtrate was filtered and retained; the first filtrate and the second filtrate were combined, decocted and concentrated to an extract with a relative density of 1.15 at 60°C, anhydrous ethanol was added to the extract to make the ethanol concentration reach 65% (volume concentration), after stirring evenly, it was allowed to stand for 24 hours, and the supernatant was taken; the supernatants of honeysuckle, houttuynia, wild chrysanthemum, pearl powder, buddleja buddleja and salvia miltiorrhiza were obtained according to the above method;

[0077] The grape skin powder is pressurized and extracted with 3 times the volume of anhydrous ethanol at 42°C and 1.5 atmospheres for 24 hours, concentrated by vacuum rotary evaporation at 20°C, and freeze-dried to obtain freeze-dried powder of grape skin extract; the powder of the oil cake is extracted with 3 times the volume of 90% ethanol at 55°C for 8 hours, the residue and the extract are retained after filtration, and the above process is repeated twice, the three extracts are combined, and after reduced pressure rotary evaporation at 25°C, freeze-dried to obtain freeze-dried powder of milk thistle extract.

[0078] S3. The ethanol in the supernatant of each medicinal material is evaporated until the supernatant has no ethanol smell, diluted with pure water, and finely filtered with a 0.22μm filter membrane to obtain the filtrate of each medicinal material; borneol, sodium benzoate, and vitamin E are dissolved in a small amount of ethanol for later use. The freeze-dried powder of grape skin extract and the freeze-dried powder of milk thistle extract are dissolved in pure water, and finely filtered with a 0.22μm filter membrane to obtain grape skin extract and milk thistle extract. The relative density of the filtrate of the above medicinal materials, the grape skin extract, and the milk thistle extract is controlled at 1.08 (25°C).

[0079] S4. Mix the ethanol solution containing borneol, sodium benzoate and vitamin E with the filtrate of each medicinal material, grape skin extract, milk thistle extract, etc. in a predetermined proportion, let it stand until the ethanol evaporates until there is no ethanol smell, then add pure water to make up to the sufficient amount, stir evenly, sterilize with gamma rays at a temperature of 6-10°C (atomized liquid temperature) and an irradiation dose of 9Gy, fill, inspect, and store to obtain the product.

[0080] The mixing ratio of each component in the prepared atomized liquid product is as follows: 50g of honeysuckle extract, 30g of houttuynia extract, 30g by weight of wild chrysanthemum extract, 25g of grape skin extract, 7g of milk thistle extract, 50g of buddlejac extract, 30g by weight of salvia miltiorrhiza extract, 10g of pearl powder extract, 2g of borneol, 100g of sodium chloride, 3g of sodium benzoate, and 1g of vitamin E are mixed and supplemented with sterile water to 1000ml.

[0081] Example 2

[0082] The mixing ratio of each component in the atomized liquid product of this embodiment is as follows: 53g of honeysuckle extract, 32g of houttuynia extract, 32g of wild chrysanthemum extract, 20g of grape skin extract, 10g of milk thistle extract, 52g of buddleja extract, 29g of salvia extract, 11g of pearl powder extract, 2g of borneol, 98g of sodium chloride, 2.8g of sodium benzoate, 1g of vitamin E, and sterile water is added to make up to 1000ml. The relative density of the atomized liquid at 25°C is 1.09. The rest is the same as in Example 1 to obtain an atomized liquid.

[0083] Comparative Example 1

[0084] This comparative example is based on Example 1, except that milk thistle extract is not added when preparing the atomized liquid; the mass of the original milk thistle extract is replaced and supplemented by wild chrysanthemum extract; the other preparation processes are shown in Example 1.

[0085] Comparative Example 2

[0086] This comparative example is based on Example 1, but no red grape skin and milk thistle extracts were added when preparing the atomized liquid; and the quality of the original red grape skin and milk thistle extracts was replaced and supplemented by honeysuckle extract; other preparation processes refer to Example 1.

[0087] Animal experiments

[0088] 1. Experimental grouping and treatment

[0089] (1) Experimental animals and reagents

[0090] Animal selection: The mice used to construct dry eye were C57BL / 6 mice, half female and half male, 8 weeks old. They were healthy and had no eye abnormalities. They were given appropriate water and food, and maintained in good feeding conditions with appropriate temperature and humidity.

[0091] (2) Animal grouping and drug administration

[0092] 42 mice were modeled for dry eye disease. The modeling method was as follows: the mice were placed in an experimental environment and raised for 1 week to make preliminary preparations for modeling. Male and female mice of similar weight were selected and separated into cages. A blank control group (6 mice) was set aside, and the remaining mice were subjected to experimental modeling. After the mice were separated into cages, a 2 mg / ml benzalkonium chloride (BAC) solution was prepared and used to drop into the mice's eyes. Each eye was given 5 μl of the prepared benzalkonium chloride each time, and the eye drops were given 3 times a day for 10 consecutive days. After the modeling begins, pay attention to keeping the living environment of the mice dry to a certain extent, and the mice eat and drink normally. The success of the modeling was confirmed based on the staining area. Figure 1 The figure shows the comparison of the stained area of ​​the mouse eyes before and after modeling. The comparison can confirm that the modeling is successful.

[0093] The mice were evenly divided into 7 groups, including blank control group, negative control group, positive control group, experimental group 1, experimental group 2, comparison group 1 and comparison group 2, with 6 mice in each group and 12 eyes in each group. The negative control group did not establish a model, but only dripped with normal saline. The negative control group did not receive medication after modeling. The positive control group was dripped with a commercially available eye drop. Dosage time: 2 drops (about 5 μL) per eye, twice a day, for 14 consecutive days.

[0094] The experimental group 1, experimental group 2, comparative group 1 and comparative group 2 were respectively given the atomized liquid of Example 1, Example 2, comparative example 1 and comparative example 2 after modeling (no additional drugs were given). The method of administering the atomized liquid: Use a nozzle atomizing bottle to spray the atomized liquid into micron-sized droplets, aim the spray at a distance of 35-40 cm from the mouse eyes, spray 10 μL each time, twice a day. The dosing method of each group of mice is shown in Table 1:

[0095] Table 1: Grouping and administration method (quantity is calculated based on the number of eyes)

[0096]

[0097]

[0098] 2. Changes in tear secretion before and after administration

[0099] On the 0th day after the dry eye model was successfully established, the tears of mice in each group were collected, and the tear secretion was measured by phenol red cotton thread, and then the tear secretion of mice in each group was measured 14 days after administration. The specific operation of phenol red cotton thread detection of mouse tears is to grab the mouse, clamp the phenol red cotton thread with ophthalmic forceps and place the cotton thread on the conjunctiva of the lower eyelid of the mouse at one-third of the distance from the outer corner of the eye, and then take it out and fix it after 60 seconds. Immediately use a millimeter ruler to measure the length (mm) of the wet stained part of the phenol red cotton thread and record it. The test results are shown in Table 2. The tear secretion in Table 2 is the mean ± standard deviation.

[0100] Table 2: Tear secretion of mice before and after administration

[0101]

[0102] It can be seen from Table 2 that the tear secretion of mice without modeling always remains at a normal level. After modeling, the tear secretion of mice in the negative control group, positive control group, experimental group 1, experimental group 2, comparison group 1 and comparison group 2 was significantly reduced. Among them, the negative control group was only given normal saline. After 14 days of administration, the tear secretion of mice in the negative control group was further reduced. It can be seen that the use of normal saline for supplementation cannot eliminate and relieve dry eyes and promote tear secretion. After 14 days of administration, the tear secretion of mice in the positive control group, experimental group 1 and experimental group 2 returned to a normal level, and the tear secretion of mice in the experimental group 2 was slightly better than that in the positive control group. After 14 days of administration, the tear secretion of mice in the comparison group 1 and comparison group 2 also increased, but the degree of increase was not obvious. This shows that after reducing the milk thistle extract in the atomized liquid formula of Comparative Example 1, the effect of the atomized liquid on improving dry eye syndrome in mice and promoting tear secretion will be weakened, and after reducing the grape skin and milk thistle extracts in the atomized liquid formula of Comparative Example 2, the effect of the atomized liquid on improving dry eye syndrome in mice and promoting tear secretion will be further weakened.

[0103] 3. Fluorescein sodium staining score before and after administration

[0104] On the 0th day after the successful establishment of the dry eye model and 14 days after administration, the eye was stained with 0.25% sodium fluorescein solution. After staying on the ocular surface for 10 seconds, the excess dye was rinsed with 0.9% sodium chloride, and the ocular surface was wiped dry with a cotton swab; the slit lamp light source was adjusted to cobalt blue light, and the mouse eyeballs were exposed to the slit lamp for observation. After adjusting the magnification, photos were taken to record the corneal staining of sodium fluorescein in different groups of mice. The cornea was divided into four quadrants: superior temporal, inferior temporal, superior nasal, and inferior nasal. Each quadrant was scored according to 0-3 points. The scoring criteria were: no staining was 0 points; 1-30 punctate staining (mild) was 1 point; more than 30 punctate staining but staining was not fused (moderate) was 2 points; corneal punctate staining fusion, filaments and ulcers (severe) were 3 points. Each corneal score was the sum of the scores of the four quadrants. The test results are shown in Table 3.

[0105] Table 3: Statistics of corneal staining scores of mice before and after drug administration

[0106]

[0107]

[0108] The lower the corneal score, the higher the degree of corneal epithelial repair in the mouse and the better the eye recovery. Conversely, the higher the score, the more severe the corneal damage and the worse the recovery.

[0109] As shown in Table 3, the tear secretion of mice without modeling is always maintained at a normal level. After modeling, the corneal epithelial staining area of ​​the negative control group, the positive control group, the experimental group 1, the experimental group 2, the contrast group 1 and the contrast group 2 mice increased significantly, and the corneal score increased. Among them, since the negative control group only dripped normal saline, the corneal epithelial staining area and score of the mice in the negative control group increased further after 14 days of administration, and the dripping of normal saline did not reduce corneal inflammation. After 14 days of administration, the corneal epithelial staining area and score of the positive control group, the experimental group 1 and the experimental group 2 were significantly reduced, and the corneal improvement of the mice in the experimental group 1-experimental group 2 was slightly better than that of the positive control group. After 14 days of administration of the contrast group 1 and the contrast group 2, the corneal epithelial staining area and score of the mice also decreased to a certain extent, but compared with the atomized liquid of the embodiment 1-2 of the present invention, the score of the contrast group 1 and the contrast group 2 decreased less, which shows that the Chinese medicine spray liquid formula of the comparative example 1-2 is not as effective as the Chinese medicine spray liquid of the embodiment 1-2 for the treatment of dry eyes.

[0110] 4. Changes of cGMP content in mouse ciliary body before and after administration

[0111] Dry eye is often accompanied by an inflammatory response, and the release of inflammatory factors may lead to changes in intracellular signaling pathways. As an important second messenger, cGMP plays a certain regulatory role in the inflammatory response. The lacrimal gland function of patients with dry eye is impaired, which may lead to changes in the cGMP signaling pathway. Excessive GMP levels can lead to excessive signal transduction, which can aggravate the inflammatory response.

[0112] In order to study the recovery effect of the traditional Chinese medicine spray liquid prepared by the present invention on dry eye in mice, the mice were killed after completing the sodium fluorescein staining scoring in the experiment, the bilateral eyeballs were removed, and the ciliary bodies were separated under a surgical microscope. Subsequently, rinse with physiological saline and dry with filter paper, weigh and use an internal tissue homogenizer to prepare a 10% homogenate in ice water (homogenization time 10 seconds / time, interval 30 seconds, continuous 3 to 5 times). The prepared homogenate was centrifuged at a speed of 2000 rpm for 15 minutes in a low-temperature low-speed centrifuge, and the supernatant was taken for ELISA measurement. The measurement results are as follows Figure 2 In the figure, compared with the blank control group, P < 0.05 is indicated by "*"; compared with the negative control group, P < 0.05 is indicated by "#"; compared with the positive control group, P < 0.05 is indicated by "&"; compared with the experimental group 1, P < 0.05 is indicated by "%".

[0113] Compared with the blank control group, the cGMP content in the ciliary body of the model group was significantly increased (P<0.05), verifying the successful construction of the dry eye model. After 14 days of drug treatment, the cGMP content of the positive control group, experimental group 1 and experimental group 2 all decreased significantly (P<0.05), and the expression level was close to that of the blank control group. This shows that the atomized liquid prepared in Example 1-2 can effectively inhibit the expression of cGMP in the ciliary body of dry eye mice. Compared with commercially available eye drop products, the atomized liquid of Example 1-2 of the present invention shows a better cGMP expression inhibitory effect. Although the comparison group 1 and the comparison group 2 also showed a certain cGMP inhibitory effect, the effect was still not as good as the atomized liquid prepared in Example 1-2.

[0114] According to the above two animal experimental results, it can be known that the atomized liquid prepared by the present invention has a good therapeutic effect on dry eye.

[0115] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A liquid preparation for treating dry eye, characterized in that: Each 1000 ml of liquid preparation consists of the following components: 45-55 g of honeysuckle extract, 28-32 g of houttuynia cordata extract, 28-32 g of wild chrysanthemum extract, 20-30 g of grape skin extract, 5-10 g of milk thistle extract, 45-55 g of buddlejac extract, 28-32 g of salvia miltiorrhiza extract, 9-12 g of pearl powder extract, 1.8-2.2 g of borneol, 95-100 g of sodium chloride, 2.8-3.2 g of sodium benzoate, and 0.6-1 g of vitamin E; the balance is sterile water; the relative density of the above-mentioned extracts at 25°C is 1.05-1.

1.

2. The liquid preparation for treating dry eye according to claim 1, characterized in that: Each 1000 ml of liquid preparation contains: 50 g of honeysuckle extract, 30 g of houttuynia cordata extract, 30 g of wild chrysanthemum extract, 25 g of grape skin extract, 8 g of milk thistle extract, 50 g of buddlejac extract, 30 g of salvia miltiorrhiza extract, 10 g of pearl powder extract, 2 g of borneol, 100 g of sodium chloride, 3 g of sodium benzoate, and 1 g of vitamin E; the balance is sterile water.

3. The liquid preparation for treating dry eye according to claim 1, characterized in that: The honeysuckle extract, houttuynia cordata extract, salvia miltiorrhiza extract, chrysanthemum wilde extract and buddleja buddleja extract are obtained by extracting with water to obtain a water extract, then precipitating with alcohol, taking the supernatant, evaporating the ethanol from the supernatant, and then dissolving it with sterile water.

4. The liquid preparation for treating dry eye according to claim 1, characterized in that: The preparation process of the grape skin extract is as follows: fresh red grape skin is freeze-dried and ground into 80-100 mesh powder, then pressure-extracted with 2-3 times the volume of anhydrous ethanol at 35-45° C. for 12-24 hours, vacuum rotary evaporation concentrated at 10-20° C., freeze-dried, dissolved with sterile water, and precisely filtered to obtain an extract with a relative density of 1.05-1.1 at 25° C.

5. The liquid preparation for treating dry eye according to claim 1, characterized in that: The preparation process of milk thistle extract is as follows: cold-pressing milk thistle fruit or seeds to obtain oil cakes, crushing the oil cakes into 80-100 mesh powders, adding 3-5 times the volume of the powder to 85-95% ethanol, and extracting at 50-60°C for 8-12 hours; filtering and retaining the filter residue and extract, repeating the above process 2-3 times, combining the extracts each time, vacuum-evaporating at 5-25°C, freeze-drying, dissolving with sterile water, and accurately filtering to obtain an extract with a relative density of 1.05-1.1 at 25°C.

6. The liquid preparation for treating dry eye according to claim 1, characterized in that: The liquid preparation is an atomized liquid, eye drops or a fumigant.

7. A process for preparing a liquid preparation for treating dry eye according to any one of claims 1 to 6, characterized in that: It includes: S1. Preparation of Chinese herbal medicine raw materials The raw materials include honeysuckle, houttuynia, wild chrysanthemum, buddleja, pearl powder, salvia miltiorrhiza, and borneol, and the raw materials are cleaned and selected; fresh red grape skins are freeze-dried, and milk thistle fruits or seeds are cold-pressed to obtain oil cakes; borneol, freeze-dried grape skins, oil cakes, and pearls are respectively ground into 80-100 mesh powders for standby use; S2, honeysuckle, houttuynia, wild chrysanthemum, pearl powder, buddleja buddleja and salvia miltiorrhiza were decocted with water twice, the first time, 7.5-8.5 times the volume of water was added and decocted for 1.5-2h, the first filtrate was filtered and retained to obtain the residue; the second time, the residue was decocted with 5.5-6.5 times the volume of water for 0.8-1.2h, and the second filtrate was filtered and retained; the first filtrate and the second filtrate were combined, decocted and concentrated to an extract with a relative density of 1.15-1.20 at 60°C, 1-1.5 times the ethanol was added to the extract to make the ethanol concentration reach between 60-70%, after stirring evenly, it was allowed to stand for 20-26h, and the supernatant was taken; the supernatants of honeysuckle, houttuynia, wild chrysanthemum, pearl powder, buddleja buddleja and salvia miltiorrhiza were obtained according to the above method; The grape skin powder is extracted with 2-3 times the volume of anhydrous ethanol at 35-45° C. for 12-24 hours under pressure, concentrated by vacuum rotary evaporation at 10-20° C., and freeze-dried to obtain freeze-dried grape skin extract powder; Add 3-5 times the volume of 85-95% ethanol to the powder of the oil cake, and extract at 50-60°C for 8-12h; filter and retain the filter residue and extract, repeat the above process 2-3 times, combine the extracts each time, evaporate under reduced pressure at 5-25°C, and freeze-dry to obtain freeze-dried powder of milk thistle extract; S3, volatilize the ethanol in the supernatant of each medicinal material until the supernatant has no ethanol smell, dilute with pure water, and accurately filter to obtain the filtrate of each medicinal material; dissolve the freeze-dried powder of grape skin extract and the freeze-dried powder of milk thistle extract with sterile water, and accurately filter to obtain grape skin extract and milk thistle extract respectively; the relative density of the above-mentioned filtrate and extract at 25°C is 1.05-1.1; dissolve borneol, sodium benzoate, and vitamin E with a small amount of ethanol for later use; S4. Mix the ethanol solution containing borneol, sodium benzoate and vitamin E with the filtrate of each medicinal material, grape skin extract and milk thistle extract in a predetermined proportion, and allow the ethanol to evaporate until there is no ethanol smell. Add pure water to make up to the sufficient amount, stir evenly, and fill.

8. The preparation process according to claim 7, characterized in that: In step S3, the amount of ethanol used to dissolve borneol, sodium benzoate and vitamin E should be just enough to dissolve these ingredients, and the ethanol content in the product should be less than 0.01%.

9. The preparation process according to claim 7, characterized in that: In step S3, the pore size of the filter membrane for precision filtration is 0.22 μm.

10. The preparation process according to claim 7, characterized in that: The method further comprises step S5, i.e. sterilizing by gamma rays at a temperature of 2-10° C. and an irradiation dose of 9-15 Gy; the sterilized drug solution is stored at 2-8° C.

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