Traditional Chinese medicine composition for treating age-related macular degeneration and preparation method thereof

Abstract

The invention provides a traditional Chinese medicine composition for treating age-related macular degeneration, which comprises the following components in parts by weight: 10-20 parts of radix rehmanniae preparata; 6-15 parts of poria cocos; 6-15 parts of codonopsis pilosula; 6-15 parts of bighead atractylodes rhizome; 6 to 20 parts of pulp of dogwood fruit; 6-20 parts of Chinese yam; 6-15 parts of rhizoma alismatis; 6-15 parts of cortex moutan; 6-20 parts of pericarpium citri reticulatae; 6-20 parts of fructus lycii; 6 to 15 parts of chrysanthemum; 6-20 parts of angelica sinensis; 6-20 parts of radix paeoniae alba; 6 to 15 parts of tribulus terrestris; 6 to 15 parts of concha haliotidis; 10 to 20 parts of spica prunellae; 3-9 parts of liquorice; and 1-5 parts of pseudo-ginseng. The whole formula treats both symptoms and root causes, combines purgation and tonification, tonifies the liver and kidney, and also has the effects of tonifying spleen and promoting diuresis, promoting blood circulation to remove blood stasis, clearing heat and improving eyesight; according to the traditional Chinese medicine composition, scientific proportioning is adopted, and all the components can coordinate with one another and promote one another, so that the synergistic interaction effect is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine, and particularly to a traditional Chinese medicine composition for treating age-related macular degeneration and a preparation method thereof. Background Art

[0002] Age-related macular degeneration (AMD) is a severe blinding retinal disease with the main clinical manifestations of blurred vision, distorted vision, decreased visual acuity, and a dark shadow blocking the central visual field. In the early and middle stages, it may not attract attention, but late-stage AMD can cause severe visual impairment and is the main cause of vision loss among the total income population over 55 years old in various countries, accounting for 6% to 9% of the total global blindness. According to pathological changes, AMD can be divided into two categories: "dry" and "wet". Although wet AMD (wAMD) accounts for only 10%-20% of cases, it causes a sharp decline in vision in 90% of patients. Subretinal fluid leakage triggers fibro-vascular tissue proliferative edema, damage to the RPE layer and photoreceptors, resulting in subretinal hemorrhage and retinal choroid fibrosis. Therefore, wAMD has become the focus of current clinical diagnosis and treatment.

[0003] Traditional clinical treatment methods for wAMD mainly include photodynamic therapy and laser photocoagulation. Krypton ion laser treatment is used for small classic CNV outside the fovea centralis of the macula, and photodynamic therapy is used for CNV located in the fovea centralis of the macula. Although the disease progression can be slowed down in some patients, most patients still face irreversible visual impairment. Since 2006, the emergence of anti-vascular endothelial growth factor (VEGF) drugs has truly realized the wish of vision recovery and improvement for most wAMD patients. It can inhibit the expression of VEGF, a factor that promotes angiogenesis, increases vascular permeability, and accelerates the extravasation of plasma fibrinogen and other pathological phenomena, and is currently the first-line drug for wAMD. It cannot be ignored that although anti-VEGF drugs have revolutionized the treatment of wAMD, there are still certain limitations. First, anti-VEGF drugs require frequent intravitreal injections, generally once every 4-8 weeks, which brings many inconveniences and great psychological and economic pressures to patients. At the same time, anti-VEGF drugs mainly save vision by inhibiting the development of CNV and reducing exudation, and have poor efficacy for late-stage wAMD patients with already existing RPE atrophy and irreversible damage to photoreceptors. Long-term multiple injections may also increase the risk of complications such as endophthalmitis and subretinal hemorrhage. Although it is a local injection, there is still a certain amount of systemic absorption, which may increase the risk of cardiovascular and other events, especially in elderly patients with underlying diseases. Therefore, it is very necessary to find a treatment method that is effective and long-lasting or can supplement the deficiencies of anti-VEGF drugs, extend the injection interval, reduce the number of injections, reduce the drug risk, and improve the visual quality of patients. Summary of the Invention

[0004] In view of the above-mentioned disadvantages of the prior art, the purpose of the present invention is to provide a traditional Chinese medicine composition for treating age-related macular degeneration and its preparation method, so as to solve the problems in the prior art.

[0005] To achieve the above purpose and other related purposes, the present invention first provides a traditional Chinese medicine composition for treating age-related macular degeneration, which includes the following components by weight:

[0006] 10-20 parts of Rehmannia glutinosa; 6-15 parts of Poria cocos; 6-15 parts of Codonopsis pilosula; 6-15 parts of Atractylodes macrocephala; 6-20 parts of Cornus officinalis; 6-20 parts of Dioscorea opposita; 6-15 parts of Alisma orientale; 6-15 parts of Cortex Moutan; 6-20 parts of Citrus reticulata Blanco; 6-20 parts of Lycium barbarum; 6-15 parts of Chrysanthemum morifolium; 6-20 parts of Angelica sinensis; 6-20 parts of Paeonia lactiflora; 6-15 parts of Tribulus terrestris; 6-15 parts of Haliotis diversicolor Reeve; 10-20 parts of Prunella vulgaris; 3-9 parts of Glycyrrhiza uralensis Fisch.; 1-5 parts of Panax notoginseng.

[0007] In a preferred embodiment of the present invention, the traditional Chinese medicine composition includes the following formula by weight:

[0008] 13-17 parts of Rehmannia glutinosa; 7-11 parts of Poria cocos; 8-11 parts of Codonopsis pilosula; 7-11 parts of Atractylodes macrocephala; 9-15 parts of Cornus officinalis; 9-14 parts of Dioscorea opposita; 8-12 parts of Alisma orientale; 8-12 parts of Cortex Moutan; 12-18 parts of Citrus reticulata Blanco; 9-13 parts of Lycium barbarum; 7-12 parts of Chrysanthemum morifolium; 8-14 parts of Angelica sinensis; 8-15 parts of Paeonia lactiflora; 7-10 parts of Tribulus terrestris; 7-11 parts of Haliotis diversicolor Reeve; 13-18 parts of Prunella vulgaris; 5-8 parts of Glycyrrhiza uralensis Fisch.; 1-3 parts of Panax notoginseng.

[0009] The present invention also provides a preparation method of the above traditional Chinese medicine composition, including: fully mixing each component.

[0010] The present invention also provides a traditional Chinese medicine extract for treating age-related macular degeneration, which is obtained by extracting the above traditional Chinese medicine composition.

[0011] The present invention also provides a preparation method of a traditional Chinese medicine extract for treating age-related macular degeneration, and the preparation method includes:

[0012] 1) Extracting the traditional Chinese medicine composition composed of components other than Panax notoginseng to obtain an extraction solution;

[0013] 2) Making Panax notoginseng into Panax notoginseng powder;

[0014] 3) Mixing the extraction solution with Panax notoginseng powder to obtain the traditional Chinese medicine extract.

[0015] The present invention also provides a traditional Chinese medicine preparation for treating age-related macular degeneration, and the traditional Chinese medicine preparation comprises the above-mentioned traditional Chinese medicine composition and / or the above-mentioned traditional Chinese medicine extract.

[0016] The present invention also provides the use of the above-mentioned traditional Chinese medicine composition, the above-mentioned traditional Chinese medicine extract or the above-mentioned traditional Chinese medicine preparation in the preparation of a drug for treating age-related macular degeneration.

[0017] As described above, a traditional Chinese medicine composition for treating age-related macular degeneration and a preparation method thereof according to the present invention have the following beneficial effects:

[0018] 1) The whole prescription treats both the symptoms and root causes, combines attacking and tonifying, tonifies the liver and kidney, strengthens the spleen, promotes diuresis, activates blood circulation to remove stasis, and clears heat to improve eyesight;

[0019] 2) The traditional Chinese medicine composition adopts a scientific ratio, and each component can coordinate and promote each other, playing a role of synergistic enhancement;

[0020] 3) It has various effects, including improving retinal leakage, inhibiting the formation of choroidal neovascularization (CNV), reducing retinal damage, improving eyesight, reducing the thickness of the central macular subregion, reducing the superficial retinal vascular density, reducing the superficial retinal perfusion density, enhancing the average visual sensitivity, etc.;

[0021] 4) Compared with chemically synthesized drugs, the traditional Chinese medicine composition usually has better safety and lower side effects;

[0022] 5) The traditional Chinese medicine composition can be used as a supplement to existing treatment methods (such as anti-VEGF drugs), which may help to extend the injection interval, reduce the number of injections, reduce the drug risk, and improve the visual quality of patients;

[0023] 6) Promote the recovery of lesions, and promote the recovery of retinal CNV lesions in CNV rats by reducing the laser spot area. Description of the Drawings

[0024] Figure 1 It shows a schematic diagram of the body weight changes of rats in each group on D0, D2, D9, D16 and D23 in Example 4 of the present invention.

[0025] Figure 2 It shows the OCT (a) and fundus fluorescein angiography image (b) of CNV rats in Example 4 of the present invention; the white △ is a schematic diagram of the RPE laser injury lesion.

[0026] Figure 3 It shows a schematic diagram of the comparison of the retinal laser spot areas of rats in each group on the 9th day after modeling in Example 4 of the present invention; compared with the model group, *P<0.05.

[0027] Figure 4It shows a schematic diagram of the comparison of the laser spot area of the retina of rats in each group on the 23rd day after modeling in Example 4 of the present invention; compared with the model group, *P<0.05.

[0028] Figure 5 It shows a schematic diagram of the comparison of the laser spot scores of the retina of rats in each group on the 9th day after modeling in Example 4 of the present invention; compared with the model group, *P<0.05.

[0029] Figure 6 It shows a schematic diagram of the comparison of the laser spot scores of the retina of rats in each group on the 23rd day after modeling in Example 4 of the present invention; compared with the model group, **P<0.01; ***P<0.001.

[0030] Figure 7 It shows the fundus fluorescein angiography images of the rats in the combined treatment group and the model group on the 2nd, 9th, and 23rd days after modeling in Example 4 of the present invention.

[0031] Figure 8 It shows the stained images of the retinal tissue sections of rats in each group in Example 4 of the present invention (H&E staining, ×20).

[0032] Figure 9 It shows the changes in BCVA (LogMAR) of the two groups of patients before and after treatment in Example 5 of the present invention; *P<0.05.

[0033] Figure 10 It shows the CST of the two groups of patients before and after treatment in Example 5 of the present invention; *P<0.05.

[0034] Figure 11 It shows the superficial retinal vascular density (mm-) of the two groups of patients before and after treatment in Example 5 of the present invention; **P<0.01.

[0035] Figure 12 It shows the superficial retinal perfusion density of the two groups of patients before and after treatment in Example 5 of the present invention; *P<0.05.

[0036] Figure 13 It shows the average visual sensitivity (dB) of the two groups of patients before and after treatment in Example 5 of the present invention; *P<0.05.

[0037] Figure 14 It shows the fixation characteristics (P2) (%) of the two groups of patients before and after treatment in Example 5 of the present invention; *P<0.05.

[0038] Figure 15 It shows the scores of the macular quality of life scale of the two groups of patients before and after treatment in Example 5 of the present invention; *P<0.05.

[0039] Figure 16 Shown are the TCM syndrome scores of two groups of patients before and after treatment in Example 5 of the present invention. *P < 0.05, **P < 0.01. Detailed implementation manners

[0040] The present invention first provides a traditional Chinese medicine composition for treating age-related macular degeneration, which, by weight parts, comprises the following components:

[0041] 10 - 20 parts of Rehmannia glutinosa; 6 - 15 parts of Poria cocos; 6 - 15 parts of Codonopsis pilosula; 6 - 15 parts of Atractylodes macrocephala; 6 - 20 parts of Cornus officinalis; 6 - 20 parts of Dioscorea opposita; 6 - 15 parts of Alisma orientale; 6 - 15 parts of Cortex Moutan; 6 - 20 parts of Citrus reticulata Blanco; 6 - 20 parts of Lycium barbarum; 6 - 15 parts of Chrysanthemi Flos; 6 - 20 parts of Angelica sinensis; 6 - 20 parts of Paeonia lactiflora; 6 - 15 parts of Tribulus terrestris; 6 - 15 parts of Haliotidis; 10 - 20 parts of Prunella vulgaris; 3 - 9 parts of Glycyrrhiza uralensis; 1 - 5 parts of Panax notoginseng.

[0042] In certain embodiments of the present invention, the Rehmannia glutinosa in the traditional Chinese medicine composition, by weight parts, is selected from any one of the following ranges: 10 - 12 parts, 12 - 14 parts, 14 - 16 parts, 16 - 18 parts, 18 - 20 parts.

[0043] In certain embodiments of the present invention, the Poria cocos in the traditional Chinese medicine composition, by weight parts, is selected from any one of the following ranges: 6 - 8 parts, 8 - 10 parts, 10 - 12 parts, 12 - 14 parts, 14 - 15 parts.

[0044] In certain embodiments of the present invention, the Codonopsis pilosula in the traditional Chinese medicine composition, by weight parts, is selected from any one of the following ranges: 6 - 8 parts, 8 - 10 parts, 10 - 12 parts, 12 - 14 parts, 14 - 15 parts.

[0045] In certain embodiments of the present invention, the Atractylodes macrocephala in the traditional Chinese medicine composition, by weight parts, is selected from any one of the following ranges: 6 - 8 parts, 8 - 10 parts, 10 - 12 parts, 12 - 14 parts, 14 - 15 parts.

[0046] In certain embodiments of the present invention, the Cornus officinalis in the traditional Chinese medicine composition, by weight parts, is selected from any one of the following ranges: 6 - 8 parts, 8 - 10 parts, 10 - 12 parts, 12 - 14 parts, 14 - 16 parts, 16 - 18 parts, 18 - 20 parts.

[0047] In certain embodiments of the present invention, the Dioscorea opposita in the traditional Chinese medicine composition, by weight parts, is selected from any one of the following ranges: 6 - 8 parts, 8 - 10 parts, 10 - 12 parts, 12 - 14 parts, 14 - 16 parts, 16 - 18 parts, 18 - 20 parts.

[0048] In certain embodiments of the present invention, the Rhizoma Alismatis in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 6 to 8 parts, 8 to 10 parts, 10 to 12 parts, 12 to 14 parts, and 14 to 15 parts.

[0049] In certain embodiments of the present invention, the Cortex Moutan in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 6 to 8 parts, 8 to 10 parts, 10 to 12 parts, 12 to 14 parts, 14 to 15 parts.

[0050] In certain embodiments of the present invention, the tangerine peel in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 6 to 8 parts, 8 to 10 parts, 10 to 12 parts, 12 to 14 parts, 14 to 16 parts, 16 to 18 parts, and 18 to 20 parts.

[0051] In certain embodiments of the present invention, the amount of wolfberry in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 6 to 8 parts, 8 to 10 parts, 10 to 12 parts, 12 to 14 parts, 14 to 16 parts, 16 to 18 parts, and 18 to 20 parts.

[0052] In certain embodiments of the present invention, the amount of chrysanthemum in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 6 to 8 parts, 8 to 10 parts, 10 to 12 parts, 12 to 14 parts, and 14 to 15 parts.

[0053] In certain embodiments of the present invention, the amount of Angelica sinensis in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 6 to 8 parts, 8 to 10 parts, 10 to 12 parts, 12 to 14 parts, 14 to 16 parts, 16 to 18 parts, and 18 to 20 parts.

[0054] In certain embodiments of the present invention, the white peony root in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 6 to 8 parts, 8 to 10 parts, 10 to 12 parts, 12 to 14 parts, 14 to 16 parts, 16 to 18 parts, and 18 to 20 parts.

[0055] In certain embodiments of the present invention, the amount of Tribulus terrestris in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 6 to 8 parts, 8 to 10 parts, 10 to 12 parts, 12 to 14 parts, and 14 to 15 parts.

[0056] In certain embodiments of the present invention, the amount of Semen Cassiae in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 6 to 8 parts, 8 to 10 parts, 10 to 12 parts, 12 to 14 parts, and 14 to 15 parts.

[0057] In certain embodiments of the present invention, the amount of Prunella Vulgaris in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 10 to 12 parts, 12 to 14 parts, 14 to 16 parts, 16 to 18 parts, and 18 to 20 parts.

[0058] In certain embodiments of the present invention, the amount of licorice in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 3 to 4 parts, 4 to 5 parts, 5 to 6 parts, 6 to 7 parts, 7 to 8 parts, and 8 to 9 parts.

[0059] In certain embodiments of the present invention, the notoginseng in the traditional Chinese medicine composition is selected from any of the following ranges by weight: 1 to 2 parts, 2 to 3 parts, 3 to 4 parts, 4 to 5 parts.

[0060] In a preferred embodiment of the present invention, the Chinese medicine composition comprises the following composition by weight:

[0061] 13-17 parts of Rehmannia glutinosa; 7-11 parts of Poria cocos; 8-11 parts of Codonopsis pilosula; 7-11 parts of Atractylodes macrocephala; 9-15 parts of Cornus officinalis; 9-14 parts of Dioscorea opposita; 8-12 parts of Alisma orientalis; 8-12 parts of Moutan bark; 12-18 parts of Tangerine peel; 9-13 parts of Lycium barbarum; 7-12 parts of Chrysanthemum; 8-14 parts of Angelica sinensis; 8-15 parts of White Peony Root; 7-10 parts of Tribulus terrestris; 7-11 parts of Semen Cassiae; 13-18 parts of Prunella Vulgaris; 5-8 parts of Licorice; 1-3 parts of Panax notoginseng.

[0062] In an optimal embodiment of the present invention, the Chinese medicine composition comprises the following ingredients by weight: 15 parts of Rehmannia glutinosa; 9 parts of Poria cocos; 9 parts of Codonopsis pilosula; 9 parts of Atractylodes macrocephala; 12 parts of Cornus officinalis; 12 parts of Dioscorea batatas; 9 parts of Alisma orientalis; 9 parts of Moutan bark; 15 parts of Tangerine peel; 12 parts of Lycium barbarum; 9 parts of Chrysanthemum; 12 parts of Angelica sinensis; 2 parts of White Peony Root; 9 parts of Tribulus terrestris; 9 parts of Semen Cassiae; 15 parts of Prunella Vulgaris; 6 parts of Licorice; and 2 parts of Panax notoginseng.

[0063] In the present invention, the age-related macular degeneration is wet age-related macular degeneration.

[0064] In the present invention, the wet age-related macular degeneration is "liver and kidney yin deficiency" type wet age-related macular degeneration.

[0065] Furthermore, the patients with "liver and kidney yin deficiency" are often accompanied by symptoms such as dizziness, tinnitus, forgetfulness, insomnia, soreness of waist and knees, distension and pain in the ribs, dry mouth and throat, fever in the five parts of the body, red cheeks and night sweats, red tongue with little coating, and thin pulse.

[0066] Macular degeneration is closely related to liver, spleen and kidney insufficiency. The relationship between early lesions and drusen in traditional Chinese medicine has been studied. Most cases are caused by spleen deficiency, which results in poor spleen function and inability to transport and transform water and dampness, causing accumulation of dampness and phlegm, and turbid qi rising up, or spleen weakness, qi deficiency and blood stasis, and blurred vision. In the middle and late stages, kidney qi deficiency is the main cause. Old age leads to kidney essence deficiency, liver and spleen insufficiency, and lack of qi, blood and body fluids, which results in lack of nourishment for the eyes and weakened vision. At the same time, this disease is a degenerative fundus lesion, and blood stasis often occurs, so blood circulation and blood stasis, as well as orifice opening and blockage, should also be added or subtracted. Therefore, for patients with wet age-related macular degeneration, the treatment is mainly to tonify the liver and kidney, supplemented by strengthening the spleen, removing dampness and removing blood stasis.

[0067] In the Chinese medicine composition, Rehmannia glutinosa, Fructus Corni, Fructus Lycii, and Rhizoma Dioscoreae nourish the liver and kidney, replenish essence and benefit the marrow, consolidate the innate foundation to nourish the eyes; Codonopsis pilosula, Atractylodes macrocephala, Poria cocos, Rhizoma Alismatis, and Pericarpium Citri Reticulatae invigorate the spleen and replenish qi, eliminate dampness and resolve phlegm, and strengthen the middle jiao to eliminate the source of dampness and turbidity; Angelica sinensis and White Peony Root nourish blood and soften the liver; Cortex Moutan and Radix Notoginseng remove blood stasis and dredge the meridians; Chrysanthemum, Tribulus terrestris, Semen Cassiae, and Herba Prunellae clear the liver and purge fire, disperse knots and eliminate exudation, and jointly treat the symptoms of phlegm and blood stasis and liver fire disturbance; Licorice harmonizes all the medicines and protects the spleen and stomach. The whole prescription treats both the symptoms and the root causes, attacks and supplements, nourishes the liver and kidneys, and also invigorates the spleen and eliminates dampness, promotes blood circulation and removes blood stasis, and clears heat and improves eyesight. The Chinese medicine composition of the present invention adopts a scientific ratio, and the components can coordinate and promote each other to play a synergistic effect.

[0068] The present invention also provides a method for preparing the above-mentioned traditional Chinese medicine composition, comprising: fully mixing the components.

[0069] The present invention also provides a Chinese medicine extract for treating age-related macular degeneration, wherein the Chinese medicine extract is prepared from the above-mentioned Chinese medicine combination. The Chinese medicine extract can be in various suitable preparation forms in the art. In a specific embodiment of the present invention, the Chinese medicine extract is obtained by water extraction, that is, it can be a water extract.

[0070] The present invention also provides a method for preparing a Chinese medicinal extract for treating age-related macular degeneration, the preparation method comprising:

[0071] 1) extracting the Chinese medicine composition consisting of components other than Panax notoginseng to obtain an extract;

[0072] 2) preparing Panax notoginseng powder;

[0073] 3) The extract is mixed with the notoginseng powder to obtain the Chinese medicine extract.

[0074] In certain embodiments of the present invention, the extraction method is decoction.

[0075] In certain embodiments of the present invention, the leaching solvent is water.

[0076] In certain embodiments of the present invention, it further includes pretreatment of the traditional Chinese medicine composition composed of components other than Panax notoginseng before extraction. The pretreatment is to soak the traditional Chinese medicine composition in the solvent for extraction, or increase the extraction time of some components. Through the above pretreatment operation, the effective components are promoted to dissolve sufficiently.

[0077] In certain embodiments of the present invention, the soaking time is 30 to 60 minutes.

[0078] In certain embodiments of the present invention, during extraction, the weight ratio of the traditional Chinese medicine composition composed of components other than Panax notoginseng to the solvent is 1:(8 - 15).

[0079] In a preferred embodiment of the present invention, the weight ratio of the traditional Chinese medicine composition composed of components other than Panax notoginseng to the solvent is selected from any of the following ranges: 1:(8 - 9), 1:(9 - 10), 1:(10 - 11), 1:(11 - 12), 1:(12 - 13), 1:(13 - 14), 1:(14 - 15).

[0080] In certain embodiments of the present invention, the extraction temperature is 90 - 100 °C. The extraction temperature is selected from any of the following ranges: 90 - 92 °C, 92 - 94, 94 - 96 °C, 96 - 98 °C, 98 - 100 °C.

[0081] In certain embodiments of the present invention, the extraction time is 40 - 60 min. The extraction time is selected from any of the following ranges: 50 - 60 min, 60 - 70 min, 70 - 80 min.

[0082] In certain embodiments of the present invention, the number of extractions is more than two. In the present invention, soaking is required for the first extraction, and no soaking is required for subsequent extractions.

[0083] In certain embodiments of the present invention, it further includes combining the filtrates after extraction.

[0084] Furthermore, the combined filtrate is taken twice a day, in the morning and evening.

[0085] In certain embodiments of the present invention, the preparation method further includes concentrating the collected extraction solution.

[0086] Furthermore, the concentration temperature is 90 - 100 °C.

[0087] Furthermore, the relative density of the concentrated product is 1.5 - 2.

[0088] The present invention also provides a traditional Chinese medicine preparation for treating age-related macular degeneration, and the traditional Chinese medicine preparation includes the above traditional Chinese medicine composition and / or the above traditional Chinese medicine extract.

[0089] In certain embodiments of the present invention, the dosage form of the traditional Chinese medicine preparation is a capsule, pill, tablet, oral liquid, powder, granule or other suitable preparation forms in the art. The preparation methods of these dosage forms should be known to those skilled in the art.

[0090] In a specific embodiment of the present invention, the traditional Chinese medicine dosage form is a granule.

[0091] In certain embodiments of the present invention, the traditional Chinese medicine preparation further comprises pharmaceutically acceptable excipients. The excipients include one or more combinations of fillers, disintegrants, lubricants, suspending agents, excipients, binders, sweeteners, flavoring agents, preservatives.

[0092] The present invention also provides the use of the above-mentioned traditional Chinese medicine composition, the above-mentioned traditional Chinese medicine extract or the above-mentioned traditional Chinese medicine preparation in the preparation of a medicament for treating age-related macular degeneration.

[0093] In certain embodiments of the present invention, the age-related macular degeneration is wet age-related macular degeneration.

[0094] In certain embodiments of the present invention, the above-mentioned traditional Chinese medicine composition, the above-mentioned traditional Chinese medicine extract or the above-mentioned traditional Chinese medicine preparation can improve retinal leakage, making the leakage area smaller.

[0095] In certain embodiments of the present invention, the above-mentioned traditional Chinese medicine composition, the above-mentioned traditional Chinese medicine extract or the above-mentioned traditional Chinese medicine preparation can effectively inhibit choroidal neovascularization (CNV) formation and reduce retinal damage.

[0096] In certain embodiments of the present invention, the above-mentioned traditional Chinese medicine composition, the above-mentioned traditional Chinese medicine extract or the above-mentioned traditional Chinese medicine preparation can improve visual acuity.

[0097] In certain embodiments of the present invention, the above-mentioned traditional Chinese medicine composition, the above-mentioned traditional Chinese medicine extract or the above-mentioned traditional Chinese medicine preparation can effectively reduce the thickness of the central sub-region of the macula.

[0098] In certain embodiments of the present invention, the above-mentioned traditional Chinese medicine composition, the above-mentioned traditional Chinese medicine extract or the above-mentioned traditional Chinese medicine preparation can reduce the retinal superficial vascular density.

[0099] In certain embodiments of the present invention, the above-mentioned traditional Chinese medicine composition, the above-mentioned traditional Chinese medicine extract or the above-mentioned traditional Chinese medicine preparation can effectively reduce the retinal superficial perfusion density.

[0100] In certain embodiments of the present invention, the above-mentioned traditional Chinese medicine composition, the above-mentioned traditional Chinese medicine extract or the above-mentioned traditional Chinese medicine preparation can effectively improve the average visual sensitivity.

[0101] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0102] Before further describing the specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the examples of the present invention are for describing the specific embodiments rather than for limiting the scope of protection of the present invention; in the present specification and claims, unless otherwise expressly stated herein, the singular forms "a", "an" and "the" include plural forms.

[0103] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art. In addition to the specific methods, equipment, and materials used in the embodiments, according to the grasp of the prior art by those skilled in the art and the record of the present invention, any methods, equipment, and materials of the prior art similar or equivalent to the methods, equipment, and materials described in the embodiments of the present invention can also be used to realize the present invention.

[0104] Unless otherwise stated, the experimental methods, detection methods, and preparation methods disclosed in the present invention all adopt conventional techniques in molecular biology, biochemistry, and related fields in the technical field.

[0105] Example 1

[0106] A traditional Chinese medicine composition for treating age-related macular degeneration comprises the following components by weight: 10 parts of cooked rehmannia, 15 parts of tuckahoe, 6 parts of codonopsis pilosula, 15 parts of atractylodes macrocephala, 6 parts of cornus officinalis, 20 parts of yam, 6 parts of oriental water chestnut, 15 parts of moutan bark, 10 parts of tangerine peel, 20 parts of wolfberry, 6 parts of chrysanthemum, 15 parts of angelica, 6 parts of white peony root, 15 parts of tribulus terrestris, 6 parts of cassia bark, 20 parts of selfheal, 3 parts of liquorice, and 5 parts of notoginseng powder.

[0107] The steps for preparing the traditional Chinese medicine extract are as follows: Decoct the prepared rehmannia root, poria, codonopsis pilosula, atractylodes macrocephala, cornelian cherry fruit, Chinese yam, alisma orientale, moutan bark, tangerine peel, wolfberry fruit, chrysanthemum flower, Chinese angelica, white peony root, tribulus terrestris, concha haliotidis, prunella vulgaris, and liquorice by water. The number of decoction times is 2 times, the decoction temperature is 100 °C, and the decoction time is 50 minutes. For the first time, decoct with 12 times the amount of water, and for the second time, decoct with 10 times the amount of water. After the decoction is completed, combine the filtrates, and mix the prepared notoginseng powder with the filtrates to obtain the traditional Chinese medicine extract.

[0108] Example 2

[0109] A traditional Chinese medicine composition for treating age-related macular degeneration, calculated by weight, includes the following components: 16 parts of rehmannia root, 8 parts of poria, 9 parts of codonopsis pilosula, 8 parts of atractylodes macrocephala, 14 parts of cornelian cherry fruit, 15 parts of Chinese yam, 10 parts of alisma orientale, 8 parts of moutan bark, 13 parts of tangerine peel, 15 parts of wolfberry fruit, 7 parts of chrysanthemum flower, 12 parts of Chinese angelica, 13 parts of white peony root, 10 parts of tribulus terrestris, 9 parts of concha haliotidis, 11 parts of prunella vulgaris, 4 parts of liquorice, and 4 parts of notoginseng powder.

[0110] The steps for preparing the traditional Chinese medicine extract are as follows: Soak the prepared rehmannia root, poria, codonopsis pilosula, atractylodes macrocephala, cornelian cherry fruit, Chinese yam, alisma orientale, moutan bark, tangerine peel, wolfberry fruit, chrysanthemum flower, Chinese angelica, white peony root, tribulus terrestris, concha haliotidis, prunella vulgaris, and liquorice for 30 minutes in advance. After the soaking is completed, decoct by water. The number of decoction times is 2 times, the extraction temperature is 95 °C, and the extraction time is 60 minutes. For the first time, decoct with 15 times the amount of water, and for the second time, decoct with 8 times the amount of water. After the decoction is completed, combine the filtrates, and mix the prepared notoginseng powder with the filtrates to obtain the traditional Chinese medicine extract.

[0111] Example 3

[0112] A traditional Chinese medicine composition for treating age-related macular degeneration, calculated by weight, includes the following components: 15 parts of rehmannia root, 9 parts of poria, 9 parts of codonopsis pilosula, 9 parts of atractylodes macrocephala, 12 parts of cornelian cherry fruit, 12 parts of Chinese yam, 9 parts of alisma orientale, 9 parts of moutan bark, 15 parts of tangerine peel, 12 parts of wolfberry fruit, 9 parts of chrysanthemum flower, 12 parts of Chinese angelica, 12 parts of white peony root, 9 parts of tribulus terrestris, 9 parts of concha haliotidis, 15 parts of prunella vulgaris, 6 parts of liquorice, and 2 parts of notoginseng powder.

[0113] The steps for preparing the traditional Chinese medicine extract are as follows: Decoct the prepared rehmannia root, poria, codonopsis pilosula, atractylodes macrocephala, cornelian cherry fruit, Chinese yam, alisma orientale, moutan bark, tangerine peel, wolfberry fruit, chrysanthemum flower, Chinese angelica, white peony root, tribulus terrestris, concha haliotidis, prunella vulgaris, and liquorice by water. The number of decoction times is 3 times, the decoction temperature is 100 °C, and the extraction time is 40 minutes. For the first time, decoct with 10 times the amount of water, for the second time, decoct with 9 times the amount of water, and for the third time, decoct with 8 times the amount of water. After the decoction is completed, combine the filtrates, remove the solvent, and add notoginseng powder to prepare a mixed medicine granule.

[0114] Example 4

[0115] The traditional Chinese medicine granule prepared in Example 3 was used for efficacy research.

[0116] 4.1 Experimental animals

[0117] A total of 53 BN rats, 6 - 7 weeks old and weighing about 140 - 160 g, were selected for this experiment. They were purchased from the Hubei Branch of Beijing Vital River Laboratory Animal Technology Co., Ltd., and the animal quality certificate number was 422023600004064. (Among them, 15 were used as spare animals, which would be used to select animals with normal eyes for grouping and drug administration for modeling, and would be euthanized together with the grouped animals after the experiment.)

[0118] All experimental rats were housed in the SPF - level animal laboratory of Pharmaron (Shanghai) Co., Ltd. The breeding environment: the temperature was maintained between 20 - 26 °C, the relative humidity was 40 - 70%. The lighting condition was 12 - hour fluorescent lamp irradiation / no lighting alternation per day. They had free access to water and food, and the water and feed were used after being sterilized by high - temperature and high - pressure. The dry and sterilized bedding was changed every 3 days, and the experiment started after 1 week of adaptive breeding.

[0119] This experiment was approved by the ethics committee of Pharmaron (Shanghai) Co., Ltd.

[0120] 4.2 Dosage of drug administration

[0121] The low - concentration traditional Chinese medicine group took the medicine at a concentration of 1.85 g / ml, and the high - concentration traditional Chinese medicine group took the medicine at a concentration of 3.7 g / ml.

[0122] 4.3 Test method

[0123] 4.3.1 Animal screening before the experiment and pre - experiment on drug tolerance

[0124] Before the start of the experiment, all rats were observed in detail using a slit lamp for their eyes, and rats with abnormal eyes were excluded. Three normal BN rats were continuously gavaged with high - concentration traditional Chinese medicine for 3 days, and their vital signs were clinically observed beside the cage.

[0125] 4.3.2 Animal grouping

[0126] According to the random numbers generated by SPSS 27.0 software, 40 BN rats were randomly divided into a blank group (Control) (5 rats) and a modeling group (35 rats). After successful modeling, 30 BN model rats were randomly divided into a model group (6 rats), a high - dose traditional Chinese medicine group (6 rats), a low - dose traditional Chinese medicine group (6 rats), an aflibercept group (6 rats), and a combined treatment group (aflibercept combined with high - concentration traditional Chinese medicine, 6 rats).

[0127] 4.3.3 Establishment of Choroidal Neovascularization (CNV) Rat Model

[0128] The rats were fasted for 12 hours before modeling, but water was not restricted. The modeling was carried out by laser photocoagulation. The operation steps are as follows:

[0129] 1) The rats were anesthetized by subcutaneous injection of 30 mg / kg Zoletil and 5 mg / kg xylazine hydrochloride injection;

[0130] 2) After the rats were anesthetized, a YAG laser photocoagulator (model: VITRA, purchased from Quantel Medical) was used to burn 4 laser spots on the RPE / Bruch's membrane of both eyes with 532 nm laser at the same energy parameters (power 300 mW, diameter 50 μm, exposure 0.05 s);

[0131] 3) Immediately after laser stimulation, OCT was used to detect the lesions to confirm whether the Bruch's membrane was penetrated. The contour caused by laser stimulation should be clear. The laser lesions were 2-3 optic discs away from the optic disc, with similar spot sizes and uniform distribution. During the laser stimulation process, it was necessary to avoid the retinal blood vessels to prevent intraocular hemorrhage;

[0132] 4) Laser success criterion: The generation of bubbles after photocoagulation indicated that the Bruch's membrane was penetrated. Immediately after laser, OCT was used to detect the position of the laser spots to confirm that the Bruch's membrane was penetrated, and at the same time, the spots that did not penetrate the Bruch's membrane or caused massive retinal hemorrhage were excluded. It was necessary to ensure that 30 animals were used for subsequent treatment experiments. The eyeballs of rats with severe bleeding after modeling were not included in the group.

[0133] 4.3.4 Drug Administration Scheme

[0134] The blank group and the model group were not given any drugs.

[0135] Low-dose traditional Chinese medicine group: Gastric gavage was started on the 2nd day after the end of modeling, once a day, and continuously administered until the 22nd day after the end of modeling. The administration concentration was 1.85 g / ml, and the gavage volume was 10 mL / kg / time;

[0136] High-dose traditional Chinese medicine group: Gastric gavage was started on the 2nd day after the end of modeling, once a day, and continuously administered until the 22nd day after the end of modeling. The administration concentration was 3.7 g / ml, and the gavage volume was 10 mL / kg / time; If the drug could not be dissolved, it was administered twice a day (bid);

[0137] Conbercept group: On the second day after modeling, conbercept was injected into the vitreous cavity of both eyes once. Before vitreous injection, the animals were anesthetized with Zoletil (25 - 50 mg / kg, i.p.) and xylazine hydrochloride injection (5 mg / kg, i.p.). The pupils were dilated with compound tropicamide eye drops. A Hamilton microsyringe with a 33G injection needle was inserted at an angle of 45° about 2 mm outside the limbus corneae on the temporal side of the eyeball, and 3 μL of conbercept was slowly injected into each eye. After injection, the needle was slowly withdrawn. After the operation, levofloxacin eye ointment was applied to the eyes;

[0138] Combined treatment group (conbercept combined with high-dose traditional Chinese medicine): The administration plan of traditional Chinese medicine was the same as that of the high-dose traditional Chinese medicine group; at the same time, conbercept was injected into the vitreous cavity of both eyes once, and the injection method was the same as that of the conbercept group;

[0139] Nursing after administration: After the vitreous cavity injection of both eyes in the conbercept group and the combined treatment group, the eyes were nursed with levofloxacin eye drops and ofloxacin eye ointment, once in the morning and once in the afternoon for three consecutive days.

[0140] 4.3.5 General condition observation

[0141] Observation was carried out beside the cage once a day to comprehensively evaluate the health status of the animals, including aspects such as behavioral activities, body weight changes, food and water intake, appearance signs, reactions, vital signs, and social behaviors. Any abnormal appearance or behavior would be detailedly recorded in the experimental observation form. The body weights of the animals were recorded before modeling, on the 1st day after modeling, on the 2nd day after modeling, on the 9th day after modeling, and on the 23rd day after modeling.

[0142] 4.3.6 Ophthalmic examination

[0143] Before modeling, on the 1st day after modeling, on the 2nd day after modeling, on the 9th day after modeling, and on the 23rd day after modeling, the anterior segments of the animals' both eyes (conjunctiva, cornea, anterior chamber, iris, pupil, lens, etc.) were observed with a slit lamp. If there were any abnormalities, they needed to be photographed and recorded.

[0144] 4.3.7 Optical coherence tomography (OCT)

[0145] All the modeled animals were immediately scanned by SD-OCT (Heidelberg Engineering) after YAG laser photocoagulation modeling to confirm the lesions.

[0146] Specific operation steps: Adjust the position of the rat's head and drop a moisturizer on the corneal surface to prevent drying. Subsequently, operate the OCT device, obtain clear retinal images through fine adjustment, use the infrared reflection and fundus photography modes to locate the laser photocoagulation area, perform B-scan on each lesion area, and drop the moisturizer on the rat's cornea again after the examination.

[0147] 4.3.8 Fundus fluorescein angiography (FFA)

[0148] On the first day after modeling, one rat was selected from each modeling group, a total of 5 rats were tested for FFA. On the 9th and 23rd days after modeling, four rats were selected from each modeling group, a total of 20 rats were tested for FFA.

[0149] Specific operation steps: Before the test, rats were anesthetized with Shutai (30 mg / kg, ip) and xylazine hydrochloride injection (5 mg / kg, ip). After the tail vein injection of 10% sodium fluorescein (10 mg / kg, IV), the Heidelberg Spectralis system was used for observation, and binocular angiography images were continuously taken. The leakage score (leakage grade 1-4) was recorded in the early (within 1 minute 30 seconds) and late (after 3 minutes) after the injection of sodium fluorescein, respectively, as shown in Table 1, and the spot area was measured using the software provided by the Heidelberg Spectralis instrument.

[0150] Table 1 Fundus fluorescein angiography scoring table

[0151]

[0152] 4.3.9 Tissue sampling and preservation

[0153] Blood collection and serum separation: After anesthesia with intraperitoneal injection of 3% sodium pentobarbital, blood was collected from the heart and allowed to stand at room temperature for 2 hours. The blood was then centrifuged at 4°C, 1500 rpm for 15 minutes, and serum was collected. The serum was packaged and stored at -80°C for enzyme-linked immunosorbent assay (ELISA) and SOD activity detection kit.

[0154] Eye fixation: The right eyes of 4 mice in each group were fixed in FAS eye fixative for subsequent histological observation.

[0155] Retina and choroid tissues: The remaining eyeballs of all mice in each group were taken, and the cornea, lens, vitreous body, and neuroepithelium were removed. The RPE-choroid-sclera complex was retained and filled into 1.5 ml centrifuge tubes and stored at -80°C for Western Blot (WB) and semi-quantitative polymerase chain reaction (sq-PCR).

[0156] 4.3.10 Fixation, embedding and H&E staining of rat eyeball tissue

[0157] 1) Fixative washing: Fix with FAS eye fixative for 7 * 24 h. After taking out, rinse with distilled water until the residual fixative on its surface is removed. Put the tissue into an embedding cassette and mark the number;

[0158] 2) Dehydration: Immerse the embedding cassette in 75% ethanol for 2 min, dehydrate step by step, and gradually replace it with 85% ethanol for 5 min, 95% ethanol I for 10 min, 95% ethanol II for 10 min, and then immerse it in absolute ethanol I and absolute ethanol II for 10 min respectively;

[0159] 3) Clearing: Replace the residual ethanol with xylene I for 5 minutes and xylene II for 15 minutes;

[0160] 4) Wax infiltration and embedding: Preheat the embedding machine in advance. Place the optic nerve on top and invert the eyeball into the mold. Rapidly pour in molten wax. Wait for it to cool and solidify naturally. Trim the periphery and store at room temperature for subsequent research;

[0161] 5) Sectioning: Make continuous sections centered on the optic nerve, cut into thin slices with a thickness of 4 μm, spread the slices on warm water, and bake for 3 h;

[0162] 6) Dewaxing and hydration: Bake the sections for 1 h before dewaxing; Immerse them in xylene I and xylene II for 10 min respectively, and then immerse them in absolute ethanol I, absolute ethanol II, 95% ethanol I, 95% ethanol II, 85% ethanol, and 75% ethanol for 10 min in sequence. Then place them in ultrapure water and soak for 10 min;

[0163] 7) Immerse the sections in hematoxylin dye for 7 min, place them in 1% hydrochloric acid alcohol solution for differentiation for 30 s in sequence, immerse them in 1% eosin dye for 1 min, dehydrate with alcohol gradient, and clear with xylene;

[0164] 8) After the stained sections are naturally dried, drop neutral resin to seal the sections and dry them in a ventilated place. Observe the morphological changes of the tissue pathological sections under an optical microscope.

[0165] 4.4 Experimental results

[0166] 4.4.1 General observation

[0167] All experimental rats survived, in good general condition, with bright and smooth hair, stable breathing, sensitive movements, normal food intake, stable weight gain, and no obvious abnormalities in the anterior segment of the eyes (conjunctiva, cornea, anterior chamber, iris, pupil, lens, etc.) of all rats examined by slit lamp.

[0168] 4.4.2 Weight changes of rats in each group

[0169] From Figure 1It can be seen that compared with the blank group, the body weight of the model group did not decrease or increase abnormally before modeling, and on the 2nd, 9th, 16th, and 23rd days after modeling, and there was no significant difference in body weight (P>0.05). Compared with the model group, there was no significant abnormal difference in body weight between the low-dose Chinese medicine group, high-dose Chinese medicine group, combined treatment group, and Conbercept group before modeling, and on the 2nd, 9th, 16th, and 23rd days after modeling (P>0.05).

[0170] 4.4.3 Establishment of CNV rat model

[0171] Depend on Figure 2 It can be seen that the CNV rats with successful modeling were scanned with the Heidelberg laser ophthalmological diagnostic instrument, which showed that with the optic disc as the center, there were 4 laser spots of similar size, uniform distribution, and clear outlines 2-3 optic discs away from the optic disc. OCT showed that the RPE / Bruchs membrane at the laser spot was punctured, and FFA showed obvious fluorescence leakage at the 4 laser spots, forming a bright fluorescent area with blurred boundaries.

[0172] 4.4.4 Effects of laser spot on the retina of CNV rats

[0173] 4.4.4.1 Effects of laser spot area on the retina of CNV rats

[0174] From Table 2, Figure 3 and Figure 4 It can be seen that on the 9th day after modeling, the laser spot area in the combined treatment group was significantly smaller than that in the model group, and the difference was statistically significant (P<0.05). There was no significant difference in the laser spot area between the other groups and the model group (P>0.05), and there was no significant difference between the groups (P>0.05), indicating that the Chinese medicine extract combined with Conbercept treatment can reduce the laser spot area.

[0175] On the 23rd day, the laser spot area of ​​all groups showed a significant downward trend compared with the area of ​​the group on the 9th day, and the difference was statistically significant (P < 0.01), indicating that the retinal CNV lesions of CNV rats have a tendency to self-heal. The laser spot area of ​​the combined treatment group was still significantly smaller than that of the model group, and the difference was statistically significant (P < 0.05). There was no significant difference in the laser spot area of ​​other groups compared with the model group (P > 0.05), indicating that the Chinese medicine extract combined with Conbercept treatment can effectively reduce the laser spot area and promote lesion recovery.

[0176] Table 2 Retinal laser spot area of ​​rats in each group at D9 and D23 (mm 2 )

[0177]

[0178] Note: Compared with the model group, *P<0.05; compared with D9,# P < 0.05; compared with D9, ## P < 0.01.

[0179] 4.4.4.2 Effect on the retinal laser spot score of CNV rats

[0180] As shown in Table 3, Figure 5 and Figure 6 it can be seen that on the 9th day after modeling, there was no significant difference in the spot scores among groups (P > 0.05), and there was no significant difference between all treatment groups and the model group (P > 0.05).

[0181] On the 23rd day, there was no significant difference in the laser spot score of the model group compared with that on the 9th day. There were significant differences in the spot scores of other treatment groups compared with that on the 9th day (P < 0.001). At the same time, compared with the spot score of the model group, the spot scores of all treatment groups were significantly lower than that of the model group (P < 0.01), and the difference between the combined treatment group and the model group was the most significant (P < 0.001), indicating that the Chinese herbal medicine extract and ranibizumab can both promote the repair of laser spots, and the combined treatment of the Chinese herbal medicine extract and ranibizumab has the best therapeutic effect.

[0182] Table 3 Retinal laser spot scores of rats in each group on D9 and D23

[0183]

[0184] Note: Compared with the model group, *P < 0.05, **P < 0.01, ***P < 0.001; compared with D9, # P < 0.05, ## P < 0.01, ### P < 0.001.

[0185] 4.4.4.3 Fundus fluorescein angiography images of rats in the model group and the combined treatment group

[0186] The model group and the combined treatment group respectively show the fundus angiography images of the same CNV rat on the 2nd day, the 9th day and the 23rd day for comparison. See Figure 7 . The fundus angiography images on D2 show that there are 4 bright fluorescence areas, that is, CNV lesions, in the retinas of both groups. The lesions in the combined treatment group seem to be brighter, suggesting that the leakage degree may be more serious; the angiography images on D9 and D23 show that the leakage brightness of both groups has weakened compared with before, indicating that the lesions of CNV rats have a certain degree of self-healing, but the leakage area of the combined treatment group is smaller and the fluorescence intensity is lower, especially in the late stage of treatment (D23), the effect is the most obvious. The yellow △ area in the figure indicates that there is basically no fluorescence leakage in the original laser injury lesion, indicating that the combined treatment group can effectively improve retinal leakage, which is consistent with the results of the previously analyzed spot area and spot score data.

[0187] 4.4.5 Effects on the Histopathology of the Retina in CNV Rats

[0188] As Figure 8 shown by the H&E staining results, the retinal hierarchical structure of the rats in the normal group was intact, the cell morphology was regular, the RPE and Bruch's membrane were not damaged, the choroid structure was normal, and there was no neovascularization; the basement membrane and Bruch's membrane were intact; in the model group, choroidal neovascularization was seen to break through Bruch's membrane and grow towards the retina, the RPE layer was disrupted, the structure was disordered, the choroid layer was thickened, there was obvious neovascularization and fibrovascular tissue hyperplasia, inflammatory cell infiltration and tissue edema were visible around the retinal lesions, and at the same time, the outer layer structure of the membrane was damaged, and degeneration changes occurred in the photoreceptors and outer nuclear layer; in the ranibizumab group, combined treatment group, low-dose traditional Chinese medicine group, and high-dose traditional Chinese medicine group, the neovascularization was significantly improved, the degree of damage to Bruch's membrane was reduced, the RPE layer was partially restored, the degree of thickening of the choroid layer was reduced, the inflammatory reaction was weakened, the structures of all layers of the retina were relatively intact, and the degree of damage to the photoreceptors and outer nuclear layer was reduced. Among them, the degree of retinal tissue damage in the combined treatment group and ranibizumab group was the lightest. It shows that each treatment group can effectively inhibit CNV formation and reduce retinal damage in CNV rats, and the combined treatment group has the best effect.

[0189] Example 5

[0190] Patients with wet age-related macular degeneration of the "liver-kidney yin deficiency" type who met the inclusion criteria in the outpatient department of Shanghai Eye Disease Prevention and Treatment Center from September 1, 2022 to June 30, 2023 were recruited. This study obtained the approval of the Ethics Committee of Shanghai Eye Disease Prevention and Treatment Center (approval number: Shanghai Eye Disease Prevention and Treatment Center 2022 Shen 011). The study has been registered and filed at the Chinese Clinical Trial Registry (registration number: ChiCTR2200062144), and all participants have completed the process of signing the informed consent form.

[0191] 5.1 Test Methods and Test Contents

[0192] 5.1.1 Diagnostic Criteria

[0193] 1) Western Medicine Diagnostic Criteria

[0194] The diagnostic basis of wAMD mainly refers to the clinical manifestation descriptions in the 7th edition of "Ophthalmology" and "Clinical Diagnosis and Treatment Pathway of Age-related Macular Degeneration in China (2013 Edition)", and is confirmed by color fundus photography, OCT, OCTA or FFA / ICGA examinations.

[0195] Clinical manifestations: Age reaches or exceeds 50 years; sudden vision loss, visual distortion or scotoma; abnormal phenomena such as drusen, pigment loss, hemorrhage, and exudation can be seen in fundus examination in the macular area.

[0196] OCT examination: It shows that the retinal RPE layer presents a highly reflective elevation, possibly accompanied by subretinal fluid or intraretinal fluid.

[0197] OCTA or FFA / ICGA examination: OCTA shows choroidal or retinal neovascularization in the macular area, with significant blood flow signals;

[0198] FFA / ICGA reveals choroidal or retinal neovascularization in the macular area, presenting a strongly fluorescent area with clear edges, surrounded by a weakly fluorescent area in the early stage. By the mid-late stage, the fluorescence continuously leaks, causing the lesion boundary to become blurred.

[0199] 2) TCM diagnostic criteria

[0200] Refer to "Traditional Chinese Medicine Clinical Diagnosis and Treatment Terms - Disease Part" (GB / T 16751.1 - 1997, National Standard of the People's Republic of China): Visual dizziness and obscurity: An internal ophthalmopathy mainly manifested by a decrease in self-perceived visual acuity and blurred vision without external eye abnormalities (including straight vision as curved, visual chromotopsia, and sudden blindness).

[0201] Refer to "Guiding Principles for Clinical Research of New Chinese Medicines (Trial)": Main symptoms: Blurred vision, distorted vision, and dark shadows in front of the eyes. Secondary symptoms: Dryness and discomfort in the eyes, dry mouth; dizziness, tinnitus, soreness and weakness of the waist and knees; insomnia and dreaminess; red tongue with little coating; thready and rapid pulse. Having at least one of the main symptoms and at least one of the five groups of secondary symptoms is the "liver-kidney yin deficiency" type.

[0202] 5.1.2 Inclusion criteria

[0203] 1) Unilateral or bilateral eyes meet the Western medicine diagnostic criteria for wAMD;

[0204] 2) Meet the "liver-kidney yin deficiency" type;

[0205] 3) Age ≥ 50 years old;

[0206] 4) Require anti-VEGF drug treatment;

[0207] 5) The refractive media are basically clear, and the results of fundus examination and fundus angiography are clearly visible;

[0208] 6) The subjects can cooperate well with the research observation and efficacy evaluation and have completed the signing of the informed consent form.

[0209] 5.1.3 Exclusion criteria

[0210] 1) Complicated with other ophthalmic diseases such as severe cataract, glaucoma, vitreous hemorrhage, uveitis, diabetic retinopathy, retinal vein occlusion, optic neuritis, and retinal detachment, which affect the effect observation or vision;

[0211] 2) Patients who have undergone any intraocular surgery, retinal laser photocoagulation, steroid hormones, or anti-VEGF drug injection treatment within 3 months;

[0212] 3) Patients with severe diseases in other organs (such as heart, brain, liver), or psychiatric patients.

[0213] 5.1.4 Exclusion and Withdrawal Criteria

[0214] 1) Patients who are mistakenly included in the study or meet the exclusion criteria will be excluded.

[0215] 2) Patients with poor compliance, who do not receive treatment and follow-up according to the clinical protocol, or who change to other treatment methods on their own during the trial, will be excluded.

[0216] 3) Patients who experience serious adverse events, complications, or protocol violations and are not suitable to continue receiving treatment in this trial will be withdrawn.

[0217] 4) Patients whose condition deteriorates and require emergency treatment measures.

[0218] 5) Patients who complete the treatment for ≥3 months according to the treatment course, have complete data, and withdraw on their own will be withdrawn.

[0219] 5.1.5 Handling of Withdrawn Cases

[0220] 1) When a subject withdraws, the researcher should immediately contact the subject or their family members, inquire in detail and record information such as the reason for withdrawal, current symptoms, completed treatment courses, and the last treatment time, and complete the assessment at the current stage.

[0221] 2) If a patient withdraws due to adverse reactions or ineffective treatment, the researcher needs to take corresponding medical measures according to the specific situation to ensure the safety and rights of the patient.

[0222] 3) For withdrawn subjects, relevant records in the trial should be completed as much as possible, including existing examination results, treatment processes, and follow-up situations, in order to provide complete data for subsequent analysis.

[0223] 4) For withdrawn subjects who have completed more than half of the treatment course (such as reaching a certain proportion of treatment times), they should be included in the final efficacy statistical analysis to ensure the integrity and scientificity of the research results.

[0224] 5.1.6 Criteria for Terminating the Trial

[0225] 1) If major adverse reactions occur in patients during the study, the trial should not continue.

[0226] 2) Serious deviations occur in the design or implementation of the clinical research protocol, making it difficult to evaluate the efficacy of Huangban Fuyuan Yin.

[0227] Note: Researchers should record information such as the discontinuation time and reasons for discontinuation in a timely, accurate, and complete manner.

[0228] 5.1.7 Sample Size Estimation

[0229] This study was designed as a randomized, controlled clinical trial with a ratio of 2:1 (experimental group: control group). The primary evaluation index was the change in best corrected visual acuity (expressed as LogMAR). According to the "Clinical Diagnosis and Treatment Pathway for Age-related Macular Degeneration in China", intravitreal injection of anti-VEGF drugs is the first-line treatment method in the current guidelines for wet macular degeneration, and traditional Chinese medicine treatment has not been included yet. This trial aims to explore the effectiveness comparison between traditional Chinese medicine combined with anti-VEGF treatment and anti-VEGF treatment alone. Therefore, it was designed as a non-inferiority test for the means of two independent samples, and the calculation formula is as follows:

[0230]

[0231] In a meta-analysis of a clinical study on the integrated traditional Chinese and Western medicine treatment of age-related macular degeneration, 10 studies reporting outcome indicators in the form of a 1-point recording method were synthesized (Du Jinyu, Mo You, Chen Mei, Wu Quanlong. Meta-analysis of the Efficacy of Anti-Vascular Endothelial Growth Factor Drugs Combined with Traditional Chinese Medicine in the Treatment of Wet Age-related Macular Degeneration [J]. Clinical Research in Traditional Chinese Medicine, 2021, 13(8): 138-142). The results showed that the average change in LogMAR in the experimental group was 0.444, and the average change in LogMAR in all control groups after 3 months of drug use was 0.348. The mean difference (MD) between the two groups was 0.10.

[0232] Calculate the sample size with reference to this literature:

[0233] 1) The average change in LogMAR in the experimental group after 3 months of drug use was 0.444, and the average change in LogMAR in the control group after 3 months of drug use was 0.348. Assume that the standard deviations of the two groups are the same, which is 0.2;

[0234] 2) Using a difference test, when the significance level of the statistical test is taken as 0.025 unilaterally and the power is taken as 90%, random grouping is carried out in a ratio of 1:2;

[0235] 3) Considering a 10% dropout rate, using PASS15 to calculate, the sample size of the experimental group for wAMD is 28 cases, and the sample size of the control group is 14 cases. Therefore, at least 42 patients with wet AMD need to be included.

[0236] 5.1.8 Randomization and Blinding

[0237] This study was divided into two groups by simple randomization. Random numbers were generated sequentially using the random number function formula in an Excel table, with a total of 100 random numbers. The order of generation of the random numbers was the enrollment sequence number of the subjects. All the random numbers were sorted from largest to smallest. The first 2 were assigned to the experimental group, and the last 1 was assigned to the control group. If both eyes of a subject met the inclusion criteria, they were randomly enrolled according to 1 subject number to ensure that both eyes were in the same group. The specific operation steps are as follows:

[0238] 1) The prospective research subjects were sequentially numbered 1, 2, 3... according to the enrollment order;

[0239] 2) The random numbers were a list of random numbers generated using the random number function formula in an Excel table, corresponding one by one to the recruited research subjects;

[0240] 3) The random numbers were sorted in order of size and grouped sequentially.

[0241] This study was designed as a double-blind trial. The researchers were divided into blinded researchers and non-blinded researchers. The non-blinded researchers were responsible for the randomization grouping of the subjects and the distribution of traditional Chinese medicine or placebo; while the blinded researchers were responsible for the screening, inclusion, follow-up, data collection and collation of the subjects. After all the subjects' follow-up and data entry were completed, the blinding was lifted, and the data was extracted and the statistical analysis of the data was completed.

[0242] 5.1.9 Drug source

[0243] 5.1.9.1 Experimental drug and control drug

[0244] 1) The experimental drug used in this example contained the following components and corresponding dosages (calculated based on the crude drug amount): 15 g of Rehmannia glutinosa, 9 g of Poria cocos, 9 g of Codonopsis pilosula, 9 g of Atractylodes macrocephala, 12 g of Cornus officinalis, 12 g of Dioscorea opposita, 9 g of Alisma orientale, 9 g of Cortex Moutan, 15 g of Citrus reticulata Blanco, 12 g of Lycium barbarum, 9 g of Chrysanthemum morifolium, 12 g of Angelica sinensis, 12 g of Paeonia lactiflora, 9 g of Tribulus terrestris, 9 g of Haliotis diversicolor Reeve, 15 g of Prunella vulgaris, 6 g of Glycyrrhiza uralensis Fisch. and 2 g of Panax notoginseng powder.

[0245] 2) The components of the control drug (placebo) were the same as those of the experimental drug, but the weight of each component was 5% of that of the experimental drug, and the balance was made up with maltodextrin.

[0246] 3) Preparation method: The granule of the above mixed drug was provided by Sichuan New Green Pharmaceutical Technology Development Co., Ltd., and the production process was carried out in an environment meeting GMP requirements.

[0247] Dosage and administration: The granule prepared according to the above weight ratio of crude drugs was one dose.

[0248] 4) Dosage: Take with water, one dose per day, divided into two doses in the morning and evening; dissolve in 200 ml of warm water each time; take orally 30 minutes after a meal, starting from the 3rd week (the first anti-VEGF dose is the starting day, and the 15th day is the third week), and continue for 12 weeks (up to 14 weeks).

[0249] 5.1.9.2 Drugs used in combination with test drugs or control drugs

[0250] 1) Drug name: Trade name: Langmu; Generic name: Conbercept ophthalmic injection;

[0251] 2) Manufacturing company: Chengdu Kanghong Biotechnology Co., Ltd.;

[0252] 3) Drug specifications: 10mg / ml, 0.2ml / vial, national medicine standard S20130012.

[0253] 5.1.10 Grouping and intervention plan

[0254] Experimental group: basic treatment (anti-VEGF treatment) + experimental drugs;

[0255] Control group: basic treatment (anti-VEGF treatment) + placebo.

[0256] 5.1.11 Indications for basic and supplementary treatments

[0257] Basic treatment: intravitreal injection of Conbercept (3+PRN).

[0258] Injection method: Patients used colabitol eye drops (levofloxacin eye drops, Japan Santen) 3 days before surgery to prevent infection. During surgery, after the patient signed the informed consent form, he was in a supine position, and the same operator used Alkain eye drops (proparacaine hydrochloride eye drops, ALCON-COUVREUR) for surface anesthesia, 5% povidone-iodine to rinse the conjunctival sac for disinfection, and after flushing with a large amount of normal saline, the needle was inserted into the ciliary body flat part 3.5-4.0mm away from the corneoscleral edge below the temporal part of the operated eye, and 0.05ml of Conbercept was slowly injected. After surgery, the eye was sealed with Dianbishu eye ointment (tobramycin dexamethasone eye ointment, ALCON), covered with sterile gauze to protect the operated eye, and colabitol eye drops were used 4 times a day within 3 days after surgery to prevent infection.

[0259] Injection frequency: once every 4 weeks, for 3 consecutive injections.

[0260] 5.1.12 Treatment course and follow-up time

[0261] Study duration: 14 weeks, of which the treatment course is 12 weeks (week 3 to week 14)

[0262] Follow-up time: Follow-up will be conducted before treatment and at week 14, with partial or complete examinations of naked eye visual acuity, corrected visual acuity, intraocular pressure, fundus photography, OCT, OCTA or FFA / ICGA, micro-perimetry, TCM syndrome score, and macular quality of life score. If the patient's symptoms worsen or serious adverse events occur, they should be recorded in time and treated accordingly.

[0263] 5.1.13 Observation indicators

[0264] 1) Basic information

[0265] The patient's name, gender, age, eye, onset time, spherical equivalent, and anti-VEGF treatment history were recorded.

[0266] 2) Main outcome measures

[0267] The changes in best corrected visual acuity (LogMAR) were recorded before and after treatment (week 14).

[0268] The best corrected visual acuity (BCVA) was measured by a fixed optometrist using a comprehensive ophthalmometer. The patient sat in front of the computer ophthalmometer and the comprehensive ophthalmometer, adjusted the sitting posture and the height of the instrument, and was completed by the same professional optometrist. The operation could be repeated if necessary. The results were recorded according to the decimal recording method and finally converted into the logarithm of the minimum angle of resolution (LogMAR) visual acuity for statistics. LogMAR = lg (1 / decimal visual acuity value). The special visual acuity was recorded as follows: index (CF): LogMAR = 2.00, manual (HM): LogMAR = 2.28, light perception (LP): LogMAR = 2.70, no light perception (NLP): LogMAR = 3.00.

[0269] 3) Secondary outcome indicators

[0270] 3a) Central sub-macular thickness (CST)

[0271] CST is the average thickness from the inner limiting membrane to the RPE layer within a circular area with a diameter of 1 mm in the center of the macula, excluding sub-RPE fluid. The data before and after treatment (week 14) were compared.

[0272] The average thickness within 1 mm of the fovea was measured using a Zeiss Cirrus OCT vascular imaging machine (Cirrus HD-OCT 5000, Zeiss, USA). The procedure was performed independently by the same examiner and repeated if necessary. Before measurement, compound tropicamide eye drops (1 ml / vial; approval number: National Medicine Standard H20066782; manufacturer: Yongguang Pharmaceutical Co., Ltd.) were used to fully dilate the pupil.

[0273] 3b) Examination of macular blood flow-related morphology

[0274] Including superficial retinal vessel density (VD), superficial retinal perfusion density (VPD), choroidal neovascularization (CNV) area, and foveal avascular zone (FAZ) in the macular area.

[0275] Compare the data before treatment and after treatment (at the 14th week).

[0276] The above data were all obtained by scanning a 6mm×6mm area of the macula with a Zeiss CIRRUS OCT angiography machine and automatically recognized, completed independently by the same examiner, and repeated if necessary. Tropicamide eye drops were used for mydriasis before measurement.

[0277] Superficial retinal vessel density (VD) and superficial retinal perfusion density (PD) in the macular area: Automatically measured and analyzed by the built-in software of the Zeiss OCTA machine, and the average value within the 6mm×6mm area was recorded.

[0278] Foveal avascular zone (FAZ): Automatically measured and analyzed by the built-in software of the Zeiss OCTA machine. If the machine fails to recognize the central FAZ or has an obvious recognition error, two professionals manually delimit the range and record the average value.

[0279] 3c) Visual quality

[0280] Including the average visual sensitivity within a 10° visual field and fixation stability (percentage of fixation points P2 within a 4° circle).

[0281] Compare the data before treatment and after treatment (at the 14th week).

[0282] The above data were measured with a microperimeter MP-3 (NIDEX, Japan). The measurement was carried out in a dark room. Tropicamide eye drops were used for mydriasis before the examination to ensure that the pupil was larger than 5mm. A customized pattern of 40 spots in the central 10° visual field was used, with a fixed target of a red circle with a diameter of 1°. The background brightness was set to 31.4 asb. The average visual sensitivity within the 10° visual field and fixation stability (percentage of fixation points P2 within a 4° circle) were recorded.

[0283] 3d) Traditional Chinese medicine syndrome score

[0284] Compare the data before treatment and after treatment (at the 14th week).

[0285] The symptoms were divided into four grades: none, mild, moderate, and severe according to the frequency of occurrence, severity, and clinical characteristics, and corresponding scores were assigned for quantification and then compared cumulatively. During the evaluation, the interview duration and terminology norms should be strictly controlled to ensure that the scores are objective and comparable.

[0286] 3e) Macular quality of life scale (MacDQoL)

[0287] Record the data before treatment and after traditional Chinese medicine treatment (at the 14th week), for a total of 2 times.

[0288] This scale is divided into two parts: the part affecting quality of life and the importance of the impact on quality of life. Each part is scored with corresponding scores, and then multiplied to obtain a weighted integral. During the evaluation process, pay attention to controlling the interview time and unifying the language to ensure the objectivity and comparability of the scores.

[0289] 3f) Other ophthalmic examinations: Uncorrected Visual Acuity (UCVA), Intraocular Pressure (IOP)

[0290] Record the data before treatment, at the 2nd week, 6th week, 10th week, and 14th week (after the end of traditional Chinese medicine treatment) to evaluate the safety of the treatment plan and the progression of the patient's condition.

[0291] Intraocular Pressure (IOP) measurement: Use a TOPCON CT-800A non-contact tonometer for detection. During the examination, the subject should sit, place the chin on the chin rest, press the forehead tightly against the forehead rest, and fix the gaze on the fixation light in the instrument. Conduct 3 valid measurements continuously for each eye, and the instrument automatically calculates the average value. Record the average value, with the unit of mmHg. Before measurement, ensure that the subject is in a stable mood, avoid holding the breath and exerting force, and give a short rest if necessary. If the measured intraocular pressure of the patient exceeds 21 mmHg, it should be recorded and followed up as a Special Event (SE), including the specific intraocular pressure value, occurrence time, treatment measures, and outcome.

[0292] Uncorrected Visual Acuity (UCVA) examination: Use a standard decimal visual acuity chart for detection under standard lighting conditions. The subject is located 5 meters away from the visual acuity chart. During the examination, cover the non-examined eye. First, instruct the subject to read the visual target at the top (0.1) of the visual acuity chart. If the subject can correctly identify it, continue to test smaller visual targets downward. When the subject can accurately identify more than 80% (e.g., at least 4 out of 5) of the visual targets in the same row, record the corresponding decimal visual acuity value of that row; if the subject cannot identify the 0.1 visual target at a distance of 5 meters, successively shorten the examination distance to 4 meters, 3 meters, 2 meters, and 1 meter, and the result needs to be converted and marked with the actual examination distance.

[0293] 3g) Safety indicators

[0294] Observe the gastrointestinal reactions of the patients during treatment and detect the liver and kidney functions before and after treatment.

[0295] Gastrointestinal reaction assessment Observe and record any gastrointestinal discomfort symptoms that occur during the period when the subjects take traditional Chinese medicine, including nausea, vomiting, abdominal pain, abdominal distension, diarrhea, constipation, etc. If moderate or above adverse reactions occur, they should be recorded as adverse events (AE). All adverse events that occur during the trial should be recorded in the original medical record and transcribed to the CRF form. The detailed record content includes: description of the adverse event, occurrence time, termination time, degree and frequency of onset, whether treatment is given, and if treatment is given, record the treatment process and outcome.

[0296] Liver and kidney function tests Collect 5 ml of peripheral venous blood from the patients before and after treatment (in a fasting state, collected at 8:00 - 10:00 in the morning). After collection using a vacuum blood collection tube, the test should be completed within 2 hours. It includes alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), γ-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), serum creatinine (Cr), blood urea nitrogen (BUN), etc. All are uniformly completed by the laboratory department of Shanghai Eye Disease Prevention and Treatment Center. If it is found that the test index exceeds 1.5 times the upper limit of the normal reference value or more, it should be recorded as a special event (SE), and the clinical symptoms of the patient should be closely followed up. If necessary, terminate the research treatment.

[0297] 5.1.14 Blinding break and unblinding plan

[0298] When grouping, each subject is provided with an emergency letter, which is sealed with a piece of paper stating the group to which the subject belongs for use in emergency unblinding. Each patient obtains a case number according to the randomization number at the time of enrollment, writes it on the cover of the emergency letter, and receives the corresponding drug.

[0299] The blinding break letter can only be unblinded when the subject has an emergency and it is necessary to know what kind of drug the subject is taking for treatment. Before unblinding, contact the person in charge of the clinical research, and it is up to the person in charge to decide whether to open the emergency letter. The emergency letter should be unsealed by a specifically designated person in advance, and a witness should be present during unblinding. The date, time, and reason for unblinding must be recorded in detail. Once the emergency letter is opened, the subject with this number will withdraw from the trial. The blinding code is stored in the Ophthalmology Department of Shanghai Eye Disease Prevention and Treatment Center.

[0300] Unblinding is carried out in two steps. First-level unblinding: When the data entry is completed, unblind to divide into Group A and Group B; Second-level unblinding: When the statistical analysis is completed, unblind to clarify the control group and the experimental group.

[0301] 5.1.15 Adverse events

[0302] Adverse events (AE) refer to any adverse medical events that occur to subjects during their participation in a clinical study, regardless of whether they are causally related to the study intervention. For AEs in clinical trials, an assessment of the causal relationship between the study drug and the adverse event should be provided and recorded. Follow-up of adverse events should be continued until the event symptoms recover or reach stability compared to the baseline. If the investigator reasonably determines (e.g., the symptoms have improved) that further follow-up is not required, the subsequent follow-up can also be terminated. For adverse events that cannot return to the baseline state, the investigator should record a reasonable explanation for the inability to recover in the original medical record.

[0303] 5.1.16 Data Management and Statistical Analysis

[0304] Case report forms are carefully filled out by researchers during patient enrollment and follow-up, and are double-entered by two people. After verification, error correction, and confirmation of accuracy, the data is locked for statistical analysis.

[0305] The SPSS 27.0 software is used to establish a database and perform data analysis. Measurement variables that conform to the normal distribution are expressed as the mean and standard deviation;

[0306] Among them:

[0307] (1) Primary outcome analysis: Repeated measures analysis of variance is used to evaluate the changes before and after treatment. The BCVA of the two groups of patients is compared between groups using an independent samples t-test (normal distribution) or a Mann-Whitney U test (non-normal distribution).

[0308] (2) Secondary outcome analysis: For measurement data such as the thickness of the central sub-region of the macula, visual quality, superficial retinal vascular density in the macular area, superficial retinal vascular perfusion density, and FAZ, data that conform to the normal distribution are described as the mean ± standard deviation (Mean ± SD), and the independent samples t-test is used for between-group comparison; continuous variables that do not conform to the normal distribution are expressed as the median (interquartile range), and the Mann-Whitney U test is used for between-group comparison; for ordinal data such as the macular quality of life score and traditional Chinese medicine syndrome score, the Wilcoxon rank sum test is used.

[0309] A P < 0.05 is considered to indicate a statistically significant difference.

[0310] 5.2 Experimental Results

[0311] 5.2.1 Baseline Data

[0312] In this study, 57 patients (61 eyes) with wet macular degeneration of the "liver-kidney yin deficiency" type who met the inclusion criteria in the outpatient department of Shanghai Eye Disease Prevention and Treatment Center from September 1, 2022 to June 30, 2023 were collected. They were randomly divided into a control group and an experimental group. Among them, 5 patients (6 eyes) dropped out, and finally 52 patients (55 eyes) completed the follow-up.

[0313] The results showed that there were 19 patients (19 eyes) in the control group and 33 patients (36 eyes) in the experimental group.

[0314] The average age of the control group was (71.05 ± 8.76) years old, including 10 males and 9 females.

[0315] The average age of the experimental group was (71.97 ± 5.44) years old, including 27 males and 9 females.

[0316] The independent samples t-test and the independent samples rank sum test (also known as the Mann-Whitney U Test) were used to statistically analyze the differences in age, disease duration, and equivalent spherical diameter between the two groups of patients.

[0317] The results showed that there was no statistically significant difference in age between the two groups of patients (P > 0.05), and there was no statistically significant difference in disease duration and equivalent spherical diameter between the two groups of patients (P > 0.05).

[0318] The chi-square test was used to statistically analyze the gender, eye type, and previous anti-VEGF history of the two groups of patients. The results showed that there was no statistically significant difference in gender, eye type, and previous anti-VEGF history between the two groups of patients (P > 0.05), as shown in Table 4 for details.

[0319] Table 4 Analysis of general demographic differences between the two groups of patients

[0320]

[0321] 5.2.2 Main outcome indicators

[0322] In this study, the best corrected visual acuity (BCVA) (LogMAR visual acuity) was used as the main outcome indicator. The results were recorded according to the decimal recording method and converted to the logarithm of the minimum angle of resolution (LogMAR) visual acuity for statistics according to the formula logMAR = lg(1 / decimal visual acuity value).

[0323] The independent samples rank sum test was used to compare the two groups at the same time point. The results showed that there was no statistically significant difference in BCVA between the two groups before treatment. After treatment, the BCVA of the experimental group was better than that of the control group, and there was a statistically significant difference (P < 0.05), as shown in Table 5 and Figure 9 .

[0324] Table 5 Comparison of BCVA between two groups of patients before and after treatment [LogMAR, M(Q1, Q3)]

[0325] BCVA (LogMAR) Before treatment After treatment <![CDATA[χ 2 value]]> P value Control group 0.70(0.3,1.52) 0.52(0.22,1.30)** 33.500 <0.001 Experimental group 0.81(0.52,1.30) <![CDATA[0.30(0.10,0.52) △ **]]> 65.966 <0.001 Z value -0.714 -1.996 / / P value 0.475 0.046 / /

[0326] Note: Compared with the control group, △ P < 0.05; compared with before treatment, *P < 0.05, **P < 0.01.

[0327] 5.2.3 Secondary outcome measures

[0328] 5.2.3.1 Central subfield thickness (CST) of the macula

[0329] The independent samples rank sum test or one-way ANOVA was used to compare the CST between the two groups of patients before and after treatment. The results showed that there was no significant difference in CST between the two groups before treatment (P > 0.05), and the CST of the experimental group after treatment was significantly lower than that of the control group (P < 0.05). See Table 6 for details. Figure 10 。

[0330] Table 6 Comparison of CST between two groups of patients before and after treatment [μm, M(Q1, Q3)]

[0331]

[0332]

[0333] Note: Compared with the control group, △P < 0.05; compared with before treatment, **P < 0.01.

[0334] 5.2.3.2 Superficial retinal vessel density (VD)

[0335] The independent samples rank sum test was used to perform a statistical analysis of VD between the two groups of patients before and after treatment. The results showed that there was no statistical difference in VD between the two groups before treatment (P > 0.05), and the VD of the control group after treatment was greater than that of the experimental group. See Table 7 for details. Figure 11 。

[0336] Table 7 Superficial retinal vessel density of two groups of patients before and after treatment [mm - , M(Q1, Q3)]

[0337] Superficial retinal vessel density Before treatment After treatment <![CDATA[χ 2 value]]> P value Control group 16.30(11.20,17.50) 15.10(12.40,17.90) 0.027 0.986 Experimental group 14.15(10.73,17.20) <![CDATA[11.80(10.45,13.30) △△ **]]> 11.371 0.003 Z value -0.584 -2.682 / / P value 0.559 0.007 / /

[0338] Note: Compared with the control group, △△P < 0.01; compared with before treatment, **P < 0.01.

[0339] 5.2.3.3 Superficial retinal perfusion density (VPD)

[0340] The independent-sample rank sum test was used to perform between-group statistical analyses on the VPD of the two groups of patients before and after treatment. The results showed that there was no statistical difference in VPD between the two groups of patients before treatment (P > 0.05), while the VPD of the experimental group after treatment was less than that of the control group (P < 0.05). See Table 8 for details. Figure 12 。

[0341] Table 8 Superficial retinal perfusion density of the two groups of patients at each time point [M(Q1, Q3)]

[0342]

[0343] Note: Compared with the control group, △P < 0.05; compared with before treatment, **P < 0.01.

[0344] 5.2.3.4 Mean visual sensitivity (MS)

[0345] The independent-sample rank sum test was used to perform statistical analysis on the differences in MS within the 10° visual field range of the two groups of patients before and after treatment. The results showed that there was no statistical difference in MS between the two groups of patients before treatment (P > 0.05), the MS of the experimental group after treatment was higher than that of the control group, and the difference was statistically significant (P < 0.05); the paired-sample rank sum test was used to perform statistical analysis on the differences in MS of the two groups of patients before and after treatment respectively. The results showed that there was no statistical significance in MS before and after treatment in the control group (P > 0.05), while the MS of the experimental group after treatment was higher than that before treatment, and the difference was statistically significant (P < 0.001). See Table 9 for details. Figure 13 。

[0346] Table 9 Analysis of mean visual sensitivity of the two groups of patients before and after treatment [dB, M(Q1, Q3)]

[0347] Average visual sensitivity (dB) Before treatment After treatment Z value P value Control group 8.60(3.95,20.00) 9.38(5.98,20.25) -1.509 0.131 Experimental group 11.45(4.06,20.73) <![CDATA[17.86(12.24,22.76) △ *]]> -4.595 <0.001 Z value -0.735 -2.053 P value 0.463 0.040

[0348] Note: Compared with the control group, △P < 0.05; compared with before treatment, *P < 0.05.

[0349] 5.2.3.5 Fixation stability (P2)

[0350] The paired-sample Wilcoxon signed-rank test was used to analyze the differences in fixation stability (the percentage of fixation within the 4° visual field, P2) before and after treatment in the two groups of patients. The results showed that the fixation stability (P2) in both groups was higher after treatment than before, and the difference was statistically significant (P < 0.001). The independent-sample Wilcoxon rank-sum test was used to analyze the differences in fixation stability (P2) before and after treatment in the two groups of patients. The results showed that there was no significant difference in fixation stability (P2) between the two groups before treatment (P > 0.05), but there was a significant difference in fixation stability (P2) between the two groups after treatment (P < 0.05), and the fixation stability (P2) in the experimental group was higher than that in the control group after treatment; see Table 10 for details. Figure 14 。

[0351] Table 10 Analysis of fixation stability (P2) in the two groups of patients before and after treatment [%, M(Q1, Q3)]

[0352] Fixation stability (P2) (%) Before treatment After treatment Z value P value Control group 65.80(38.10,76.60) 74.10(50.30,91.60)** -3.582 <0.001 Experimental group 68.90(32.88,86.70) 89.20(67.43,98.20)△** -5.232 <0.001 Z value -0.690 -2.443 P value 0.490 0.015

[0353] Note: Compared with the control group, △ P < 0.05; compared with before treatment, * P < 0.05, ** P < 0.01.

[0354] 5.2.3.6 Macular quality of life score

[0355] The paired-sample Wilcoxon signed-rank test was used to analyze the differences in the scores of the macular quality of life scale before and after treatment in the two groups of patients. The results showed that the scores of the macular quality of life scale in both groups were higher after treatment than before, and the difference was statistically significant (P < 0.001). The independent-sample Wilcoxon rank-sum test was used to analyze the differences in the macular quality of life scores before and after treatment in the two groups of patients. The results showed that there was no significant difference in the macular quality of life scores between the two groups before treatment (P > 0.05), the macular quality of life score in the experimental group was higher than that in the control group after treatment, and the difference was statistically significant (P < 0.05); see Table 11 for details. Figure 15 。

[0356] Table 11 Analysis of the scores of the macular quality of life scale in the two groups of patients before and after treatment [M(Q1, Q3)]

[0357]

[0358]

[0359] Note: Compared with the control group, △P < 0.05; compared with before treatment, *P < 0.05, **P < 0.01.

[0360] 5.2.3.7 Traditional Chinese medicine syndrome score

[0361] The paired-sample Wilcoxon signed-rank test was used to statistically analyze the differences in TCM syndrome scores before and after treatment in the control group and the experimental group. The results showed that there was no statistically significant difference in TCM syndrome scores before and after treatment in the control group (P > 0.05). The TCM syndrome score in the experimental group after treatment was lower than that in the control group, and the difference was statistically significant (P < 0.001). The independent-sample Wilcoxon rank-sum test was used to statistically analyze the differences in TCM syndrome scores before and after treatment between the two groups of patients. The results showed that there was no statistically significant difference in TCM syndrome scores before treatment between the two groups of patients (P > 0.05). After treatment, the TCM syndrome score in the experimental group was lower than that in the control group, and the difference was statistically significant (P < 0.01). See Table 12 for details. Figure 16 。

[0362] Table 12 Analysis of TCM syndrome scores of two groups of patients before and after treatment [M(Q1, Q3)]

[0363] Traditional Chinese medicine syndrome scoring scale Before treatment After treatment Z value P value Control group 26.00(23.00,28.00) 27.00(23.00,30.00) -1.389 0.165 Experimental group 28.00(25.25,29.75) 21.00(20.00,25.00)△△*** -5.256 <0.001 Z value -1.417 -3.057 P value 0.156 <0.01

[0364] Note: Compared with the control group, △△P < 0.01; compared with before treatment, ***P < 0.001.

[0365] The above embodiments are intended to illustrate the implementation schemes disclosed in the present invention and should not be construed as limitations on the present invention. In addition, various modifications listed herein and changes in the methods of the invention are obvious to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been specifically described in conjunction with various specific preferred embodiments of the present invention, it should be understood that the present invention should not be limited to these specific embodiments. In fact, all the above-mentioned obvious modifications to those skilled in the art to obtain the invention should be included in the scope of the present invention.

Claims

1. A traditional Chinese medicine composition, characterized in that, Comprising the following components by weight parts:

2. The traditional Chinese medicine composition according to claim 1, characterized in that Comprising the following components by weight parts:

3. A traditional Chinese medicine extract, characterized in that, Obtained by preparing with the traditional Chinese medicine combination described in any one of claims 1 to 2.

4. The preparation method of the traditional Chinese medicine extract according to claim 3, characterized in that The preparation method comprises: 1) Extracting the traditional Chinese medicine composition composed of components other than notoginseng to obtain an extract; 2) Making notoginseng into notoginseng powder; 3) Mixing the extract with the notoginseng powder to obtain the traditional Chinese medicine extract.

5. According to the preparation method described in claim 5, characterized in that, The extraction method is the decoction method; and / or, the extraction temperature is 90 - 100 °C; and / or, the extraction time is 40 - 60 min; and / or, the weight ratio of the traditional Chinese medicine composition composed of components other than notoginseng to the solvent during extraction is 1:(8 - 15); and / or, the number of extractions is more than two times; and / or, it further includes performing pretreatment on the traditional Chinese medicine composition composed of components other than notoginseng before extraction; preferably, the pretreatment is soaking the traditional Chinese medicine composition in the solvent for extraction; more preferably, the soaking time is 30 - 60 minutes.

6. According to the preparation method described in claim 5, characterized in that, It further includes concentrating the collected extract; preferably, the concentration temperature is 90 - 100 °C; preferably, the relative density of the concentrated product is 1.5 - 2.

7. A traditional Chinese medicine preparation, the traditional Chinese medicine preparation comprising the traditional Chinese medicine composition described in any one of claims 1 to 2 and / or the traditional Chinese medicine extract described in claim 3.

8. Use of the traditional Chinese medicine composition described in any one of claims 1 to 2, the traditional Chinese medicine extract described in claim 3, or the traditional Chinese medicine preparation described in claim 7 in the preparation of a drug for treating age-related macular degeneration.

9. The use according to claim 8, characterized in that, The age-related macular degeneration is wet age-related macular degeneration.

10. The use according to claim 8, characterized in that, The traditional Chinese medicine composition, traditional Chinese medicine extract, or traditional Chinese medicine preparation has any one or more of the following effects: 1) Improving eyesight; 2) Reducing the thickness of the central macular subregion; 3) Inhibiting choroidal neovascularization and reducing retinal damage; 4) Reducing the superficial retinal vessel density; 5) Reducing the superficial retinal perfusion density; 6) Enhancing the average visual sensitivity; 7) Improving retinal leakage.

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