WO2019228210A1

WO2019228210A1 - Pharmaceutical use of composition comprising radix astragali, radix puerariae, and herba erigerontis

Info

Publication number: WO2019228210A1
Application number: PCT/CN2019/087605
Authority: WO
Inventors: 白礼西; 段俊国; 孙克宏; 秦少容; 郑飞鸣; 卿玉玲; 黄静; 张颖; 刘世琪; 王磊; 原欢欢; 冉亚东
Original assignee: 重庆太极实业（集团）股份有限公司
Priority date: 2018-05-28
Filing date: 2019-05-20
Publication date: 2019-12-05
Also published as: CN110538214A

Abstract

Provided is a use of a composition comprising Radix Astragali, Radix Puerariae, and Herba Erigerontis in preparing a drug for treating or preventing macular edema in an individual.

Description

[Name of invention formulated by ISA according to Rule 37.2] Pharmaceutical use of a composition containing astragalus, kudzu root and breviscapine

Cross-reference to related applications

This application claims priority from Chinese Patent Application No. 201810521999.2 filed on May 28, 2018, which is incorporated herein by reference in its entirety.

Technical field

The present application relates to a composition containing Astragalus, Puerariae and Erigeron breviscapus and its use. Specifically, the present application relates to the use of a composition containing Astragalus, Puerariae and Erigeron breviscapus in treating macular disease.

Background technique

The macula is a shallow funnel-shaped depression with a diameter of about 2 mm located at the posterior pole of the retina. A small depression in the center is a macular fovea. The macular area is the main part of the visual signal produced by the retina. Any lesion in the macular area will affect vision and even lead to the serious consequences of blindness. With the development of medicine, the harm of traditional blinding eye diseases such as "cataract" has been greatly reduced, and the serious impact of macular diseases on vision has become more prominent.

Macular edema is a pathological change process caused by different intraocular diseases, which can be secondary to many diseases such as diabetes, uveitis, retinal vein occlusion, and cataract surgery. Clinically diagnosed macular edema refers to the accumulation of fluid between cells in the central part of the macula, which can seriously threaten the central vision of patients, and is the main cause of vision loss caused by various eye diseases. The long-term existence of macular edema will eventually lead to irreversible retinal atrophy and fibrosis, which will permanently lose central vision.

Current treatments for diabetic macular edema include systemic treatments to control patients' blood sugar, blood pressure, and lipids, as well as eye treatments. Eye treatment methods include surgery, laser photocoagulation, and medication. Drug treatment mainly involves injecting glucocorticoids or anti-VEGF preparations into the eye, of which the commonly used anti-VEGF preparations are aflibercept, compacept, ranibizumab, and the like. At present, the recommended treatment methods in domestic and foreign guidelines are laser photocoagulation and intraocular injection of anti-VEGF preparations. However, laser photocoagulation is prone to trauma and the effect is not sustainable. Intraocular injection of anti-VEGF preparations has high cost and short duration of efficacy. It only lasts for 1-3 months, and requires repeated intraocular injections. There are risks of intraocular infection and elevated intraocular pressure, and patients suffer greater pain. .

Traditional Chinese medicine is gradually used for the treatment of various ophthalmic diseases due to its high safety. However, due to the complex nature of natural medicines, the compatibility of drugs may produce different effects. At present, there is no effective combination of traditional Chinese medicine to treat macular edema, especially Related reports of diabetic macular edema.

Summary of the Invention

In a first aspect, the present application provides the use of a composition comprising astragalus, kudzu root and breviscapine in the manufacture of a medicament for treating or preventing macular edema in an individual.

In a second aspect, the present application provides a method for treating or preventing macular edema, which comprises administering to a subject a therapeutically or prophylactically effective amount of a composition comprising astragalus root, pueraria root, and breviscapine.

In a third aspect, the present application provides a composition comprising astragalus root, pueraria root and breviscapine for treating or preventing macular edema.

In a fourth aspect, the present application provides a composition comprising astragalus root, puerarin root, and breviscapine.

In certain embodiments, the aforementioned macular edema is macular edema. In a preferred embodiment, the macular edema is diabetic macular edema.

In certain embodiments, the above composition and a pharmaceutically acceptable carrier are formulated into a pharmaceutically acceptable dosage form, preferably a capsule, oral solution, powder, tablet, granule, pill, syrup or eye drop, More preferably, it is a capsule.

In certain embodiments, the above composition is administered orally, eye drops, enemas, subcutaneously, intramuscularly or intraperitoneally, and preferably the composition is administered orally.

In certain embodiments, the composition is administered at a dose of 30 to 100 mg / kg body weight, preferably 50 to 70 mg / kg body weight per day.

In certain embodiments, the composition is for oral administration 1 to 3 times per day, such as 2 or 3 times per day.

In certain embodiments, the composition is administered for a duration of 1 to 52 weeks, preferably 12-24 weeks, such as 24 weeks.

In some embodiments, the above composition comprises the following raw materials in a weight ratio: 10-40 parts of astragalus, 10-30 parts of pueraria root, and 10-30 parts of breviscapine.

In some embodiments, the above composition comprises the following active ingredients in a weight ratio: 1-10 parts of astragalus extract, 50-125 parts of pueraria root extract, and 20-60 parts of breviscapine extract.

In certain embodiments, the medicament of the present application is prepared from the raw materials of Astragalus, Puerariae and Erigeron breviscapus or the water or organic solvent extract of Astragalus, Puerariae and Erigeron breviscapus as active ingredients, and a pharmaceutically acceptable carrier Made. In some embodiments, the raw materials of Astragalus, Puerariae and Erigeron breviscapus are weighed in a certain weight ratio, and the extracts of Astragalus, Puerariae and Erigeron breviscapus are respectively prepared, and other active ingredients or pharmacy are added according to the preparation method of the traditional dosage form of traditional Chinese medicine. The acceptable carriers are made into different dosage forms, such as capsules, tablets, granules, pills, eye drops and other dosage forms.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the change in visual acuity of patients with macular edema detected by optical coherence tomography (OCT), which shows the change in the best corrected visual acuity (BCVA) after each group of patients received different doses of the composition of the present application Among them, the diamond is the high-dose group (n = 7), the square is the middle-dose group (n = 11), the positive triangle is the low-dose group (n = 7), and the cross is the placebo group (n = 13).

Figure 2 shows the change in visual acuity of patients with a CRT greater than 270 μm when enrolled by OCT. It shows that after high dose (n = 24), medium dose (n = 15), and low dose (n = 8) ) And the placebo (n = 12) treatment, the visual acuity of the affected eye improved by 5 characters, with respect to the placebo group, the P value in the middle dose group was 0.058, and the P value in the high dose group was 0.130.

Figure 3 is the change in macular foveal thickness in the eyes of patients with macular edema detected by OCT, which shows that the eyes of each group were treated with high dose, medium dose, low dose composition and placebo for 12 weeks and 24 weeks, respectively. Macular foveal thickness change in μm. In the histogram showing 12 and 24 weeks, from left to right, the high-dose group (n = 7), the middle-dose group (n = 11), the low-dose group (n = 6), and the placebo group (n = 10).

Detailed ways

The inventors of the present application have unexpectedly discovered that a composition comprising astragalus, kudzu root and breviscapine is capable of treating or preventing macular edema, such as diabetic macular edema.

Unless otherwise indicated, all terms in this application have the meanings commonly understood by those skilled in the art.

The application provides the use of a composition comprising astragalus root, pueraria root and breviscapine in the manufacture of a medicament for treating macular edema.

In certain embodiments, the macular edema is macular edema. In certain embodiments, the macular edema is diabetic macular edema.

Macular cystoid edema is a common fundus disease, but it is not an independent disease, but a manifestation of many fundus diseases in the macula. Common diseases that cause macular cystoid edema include: retinal vein occlusion, diabetic retinopathy, retinal vasculitis, premacular retinal membrane of the macula, retinal capillary telangiectasia or Coats disease, uveitis, cataract or other internal eye surgery, etc. .

Diabetic macular edema (DME) refers to retinal thickening or hard exudative deposits caused by the accumulation of extracellular fluid in the diameter of the optic disc within a range of optic disc diameter caused by diabetes. Diabetic macular edema is a common cause of visual impairment in diabetic patients.

As used herein, "treatment" includes inhibiting, curing, reducing, relieving or delaying macular edema and related symptoms.

In some embodiments, the composition of the present application is formulated with a pharmaceutically acceptable carrier into a pharmaceutically acceptable dosage form, preferably an eye drop, an oral solution, a capsule, a tablet or a granule, more preferably a capsule .

"Pharmaceutically acceptable carrier" as used herein refers to carriers that do not interfere with the effectiveness of the biological activity of the active ingredient, including those routinely used in the pharmaceutical field. The pharmaceutically acceptable carrier of the present application may be a solid or a liquid, and includes pharmaceutically acceptable excipients, buffers, emulsifiers, stabilizers, preservatives, diluents, encapsulants, fillers, and the like. For example, pharmaceutically acceptable buffers include phosphates, acetates, citrates, borates, carbonates, and the like.

The compositions of the present application may be presented in unit dosage form and may be prepared by any method known in the pharmaceutical art. All methods include the step of combining the active ingredient of the present application with one or more pharmaceutically acceptable carriers. Generally, the composition is prepared by combining the active ingredient with a liquid carrier, a solid carrier, or both, and then the prepared product is shaped as required. The specific method of formulation will depend on the route of administration chosen. In some embodiments, the composition can be manufactured by conventional mixing, dissolving, granulating, tabletting, milling, emulsifying, encapsulating, capturing, or lyophilizing methods.

In some embodiments, the composition is administered orally, eye drops, enemas, subcutaneously, parenterally, intravenously, intraarterially, intracranially, intrathecally, intraperitoneally, topically, intranasally, or intramuscularly. In a specific embodiment, the combination is administered orally.

In some embodiments, for oral administration, a composition such as the present application can be formulated with capsules, tablets, pills, lozenges, liquids, gels, syrups, slurries, Suspension, etc. For oral solid formulations, such as powders, capsules, and tablets, suitable excipients include bulking agents such as sugars such as lactose, sucrose, mannitol, and sorbitol; cellulose formulations such as corn starch, wheat starch, rice Starch, potato starch, gelatin, tragacanth, methyl cellulose, carboxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or povidone; granulating agents and binders and the like. If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. If desired, solid dosage forms can be sugar coated or enteric coated using standard techniques. For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycerol, oil, alcohol. In addition, flavoring agents, preservatives, colorants, and the like can be added.

In certain embodiments, the composition of the present application is administered at a dose of 30 to 100 mg / kg body weight per day, preferably 40-80 mg / kg body weight, more preferably 50-70 mg / kg body weight, such as 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg / kg body weight or a dose between any two of the above values.

In some embodiments, the composition is administered 1, 2, 3, 4 or more times per day, and the composition can also be administered less than 1 time per day, for example, every 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or every 1 or 2 weeks, or a range defined by any of the foregoing values. In some embodiments, the number of daily administrations is constant (e.g., 2 or 3 times daily). In other embodiments, the number of administrations is variable. The number of dosing may be based on the effectiveness of the composition, the observed side effects, the particular route of administration, the particular characteristics of the individual, the history and risk factors (such as age, weight and general health, etc.), another medication-related change, or the dosage form And change.

In some embodiments, the composition is administered for a duration of 1-52 weeks, such as 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 36, 48, or 52 weeks, or the number of weeks between any two of the above, or about the time period described. In some embodiments, the composition is administered continuously for 12 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, or more weeks. In some embodiments, the composition is administered continuously until the individual no longer requires treatment.

In another aspect, the present application provides a method of treating or preventing macular edema, comprising administering to a subject a therapeutically effective or preventatively effective amount of a composition comprising astragalus root, puerarin root, and breviscapine.

In yet another aspect, there is provided the use of a therapeutically effective or prophylactically effective composition comprising astragalus root, pueraria root and breviscapine in treating or preventing macular edema in an individual.

As used herein, the "therapeutically effective amount" or "prophylactically effective amount" can be determined according to specific circumstances, and those skilled in the art can easily grasp the actual required dosage, for example, according to the patient's weight, age and condition. determine. When a pharmaceutically acceptable carrier is included in the composition, they can be mixed according to a conventional method in the pharmaceutical field to prepare a desired drug.

In some embodiments, a composition comprising astragalus root, puerarin root, and breviscapine can improve the vision of a patient with macular edema. In a specific embodiment, the macular edema is diabetic macular edema. In a specific embodiment, the efficacy of the above-mentioned composition for improving the vision of patients with macular edema presents a certain dose-response relationship.

In some embodiments, a composition comprising astragalus root, pueraria radiata and breviscapine can be used to reduce the thickness of the macular fovea in an individual with macular edema and / or reduce the volume of the macular fovea in an individual with macular edema, Thereby improving the degree of macular edema. In a specific embodiment, the individual has diabetic macular edema. In specific embodiments, the individual is at risk for diabetic macular edema. In a specific embodiment, the composition of the present application has a dose-effect relationship in reducing the thickness of the macular fovea and / or reducing the volume of the macular fovea. In a specific embodiment, the effect of the composition of the present application in reducing the thickness of the macular fovea becomes more pronounced as the course of treatment is prolonged.

In some embodiments, a composition comprising astragalus root, pueraria root and breviscapine is capable of reducing intraocular pressure in a subject suffering from macular edema. In a specific embodiment, the individual has diabetic macular edema. In specific embodiments, the individual is at risk for diabetic macular edema. In a specific embodiment, the difference of the effect of the composition of the present application on reducing intraocular pressure in patients with macular edema compared with the placebo-treated group becomes more significant with time.

In some embodiments, the composition comprising astragalus root, pueraria root and breviscapine in the present application has no significant difference in the incidence of adverse events and adverse reactions compared with the placebo group in the treatment of macular edema in an individual, indicating that The medicine of the present application has no obvious toxic and side effects in the treatment of macular edema and has high safety.

"Individual" as used herein refers to mammals, including primates and non-primates, such as humans, apes, monkeys, cows, horses, pigs, sheep, goats, dogs, cats, and rats such as rats And mouse rodents and more. In yet another aspect, the present application provides a composition comprising astragalus root, pueraria root and breviscapine. In a specific embodiment, the above composition is used to treat or prevent macular edema in an individual.

In some embodiments, the composition of the present application is prepared from raw materials containing the following weight ratios: 10-40 parts of astragalus, 10-30 parts of pueraria root, and 10-30 parts of breviscapine.

In some embodiments, the composition of the present application is prepared from raw materials containing the following weight ratios: 20-30 parts of astragalus root, 20-40 parts of pueraria root, and 20-30 parts of breviscapine.

In some embodiments, the composition of the present application is prepared from raw materials containing the following weight ratios: 20 parts of astragalus, 30 parts of pueraria root, and 20 parts of breviscapine.

In certain embodiments, the composition of the present application is prepared from the raw materials of Astragalus membranaceus, Pueraria flavescens, Erigeron breviscapus or water or organic solvent extract as the active ingredient, plus a pharmaceutically acceptable excipient or auxiliary ingredient.

In certain embodiments, the composition comprises the following weight ratio components: 1-10 parts of astragalus extract, 50-125 parts of kudzu root extract, and 20-60 parts of breviscapine extract.

In certain embodiments, the composition comprises astragalus root extract, puerarin root extract, erigeron root extract, wherein puerarin root extract contains no less than 60% of total isoflavones based on puerarin, and no less than puerarin 20%; Astragalus extract contains no less than 50% of total saponin based on astragaloside IV and no less than 5% of astragaloside IV; flavescens extract contains no less than 35% of total flavonoids based on rutin. Baicalin is not less than 3%.

In certain embodiments, the weight ratio of the composition is: 1-10 parts of astragalus extract, 50-125 parts of kudzu root extract, and 20-60 parts of erigeron extract.

In some embodiments, the weight ratio of the composition is: 1 part of astragalus extract, 70 parts of kudzu root extract, and 25 parts of erigeron extract.

In a specific embodiment, the present application includes a method for preparing a composition of astragalus, pueraria, and breviscapine, including the following steps:

a. Weigh the raw materials with the following weight ratios:

10-40 servings of astragalus, 10-30 servings of pueraria root, 10-30 servings of breviscapine;

b. Pueraria pulverized into coarse powder, extracted with 60-95% ethanol, filtered, combined filtrates, recovered ethanol, concentrated, passed through a macroporous adsorption resin column, eluted with water, discarded the water eluent, and then used 10-95 % Ethanol elution, collecting the ethanol eluate, recovering the ethanol, concentrating into a thick paste, drying under reduced pressure, pulverizing into a fine powder to obtain a kudzu root extract;

c. Astragalus is pulverized into coarse powder, and extracted by heating under reflux with 60-95% ethanol, filtered, combined filtrates, recovered ethanol, concentrated, added sodium hydroxide to an alkali content of 2-5%, dynamic extraction with n-butanol 2 -5 times, combine n-butanol solution, wash with 2-5% sodium hydroxide solution, then wash with water, discard the washing solution, combine n-butanol solution, concentrate under reduced pressure to near dry, add acetone and wash until light color, The precipitate was dried under reduced pressure and pulverized into a fine powder to obtain astragalus extract;

d. Erigeron breviscapus decoction, combined with decoction, filtered, concentrated and passed through a macroporous adsorption resin column, eluted with water, discard the water eluent, continue to elute with 10-95% ethanol, collect ethanol to elute Liquid, recovered ethanol, concentrated into a thick paste, dried under reduced pressure, and pulverized into a fine powder to obtain Erigeron breviscapus extract;

e. Astragalus extract, Pueraria lobata extract and Erigeron breviscapus extract prepared in steps b, c and d are mixed, and a pharmaceutically acceptable carrier is added to prepare a commonly used pharmaceutical preparation.

In some embodiments, in step a, the weight ratio of the raw materials may be 20-30 parts of astragalus root, 20-40 parts of pueraria root, and 20-30 parts of breviscapine. Among them, Astragalus can be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 servings, and Pueraria can be 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 Or 40 servings, Erigeron breviscapus can be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 servings. In a specific embodiment, the weight ratio of the raw materials may be 20 parts of astragalus, 30 parts of kudzu root, and 20 parts of breviscapine.

Within the reasonable range of the selection of the drug raw materials of the present application, according to the drug extraction processing method of the present application, it can be prepared into a commonly used pharmaceutical preparation. For example, according to the aforementioned method, the obtained dry powder with three flavors as the main component is added into the auxiliary dosage form according to the traditional preparation method of traditional Chinese medicine to make different dosage forms, such as tablets, granules, pills, capsules and eye drops.

In some embodiments, 30 kg of astragalus root, 40 kg of pueraria root, and 30 kg of breviscapine are directly weighed to obtain powder.

In some embodiments, 1 kg of the above-mentioned astragalus extract, 50 kg of pueraria root extract, and 30 kg of breviscapus extract are mixed, starch is added, granulated, whole granulated, magnesium stearate is added, and tablets are obtained to obtain tablets.

In some embodiments, 10 kg of the above-mentioned Astragalus extract, 125 kg of Pueraria root extract, and 60 kg of Erigeron breviscapus extract are mixed, and starch is added, granulated and whole granulated, and capsules are directly filled to obtain capsules.

In some embodiments, 2 kg of the above-mentioned Astragalus extract, 80 kg of Pueraria root extract, and 40 kg of Erigeron breviscapus are mixed, starch is added, granulated and whole granulated, and capsules are directly filled to obtain pharmaceutical granules.

In some embodiments, 30 kg of astragalus root, 40 kg of pueraria root and 30 kg of breviscapine are extracted according to the method described above, 20 kg of rehmannia glutinosa, 20 kg of wolfberry, 15 kg of cassia seeds, and 20 kg of weiweizi are boiled in water, concentrated, and then the above substances Mix, add starch, granulate, and granulate, add magnesium stearate, and tablet to obtain tablets.

The method for preparing the composition of the present application can also refer to the method in Chinese Patent CN100594913C, the entire contents of which are incorporated herein by reference in its entirety.

In the specification and claims of this application, the words "including," "including," and "containing" mean "including, but not limited to," and are not intended to exclude other parts, additives, components, or steps.

It should be understood that a feature, characteristic, component or step described in a particular aspect, embodiment or example of this application may be applied to any other aspect, embodiment or example described herein unless it is in contradiction.

Unless otherwise indicated, all numbers for features, terms, quantities, parameters, properties, terms, etc. used in this specification and claims are to be understood as being modified in all cases by the term "about". As used herein, the term "about" means that a defined property, term, quantity, parameter, property, or term encompasses a positive or negative percentage above or below the value of the property, item, quantity, parameter, property, or term. The range of ten. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the description and claims are approximations that can vary. At least without attempting to limit the application of the equivalence principle of the scope of the claims, each number indication should be interpreted at least based on the number of significant digits reported and by applying ordinary rounding techniques.

The above disclosure generally describes the present application, and the following examples further illustrate the present application. These examples are described for the purpose of illustration and not to limit the scope of the application. Although special terms and values are used herein, these terms and values are also understood as exemplary and do not limit the scope of the application. Unless otherwise specified, the experimental methods and techniques in this specification are methods and techniques well known to those skilled in the art.

Examples

The following examples are provided merely to illustrate some embodiments of the present application, without any limiting purpose.

Unless otherwise specified, the methods used in the following examples are conventional methods. The materials, reagents, etc. used in the following examples can be obtained from commercial sources unless otherwise specified.

Example 1: Preparation of a composition comprising astragalus root, pueraria root and breviscapine

Weigh 30kg of Pueraria radiata, 20kg of Erigeron breviscapus, and 20kg of Astragalus root, pulverize Pueraria root into a coarse powder, and heat and extract with 60% ethanol for two times under reflux for 1 hour each time. Filter, combine the filtrates, recover ethanol, concentrate appropriately and add to the processed On a good macroporous adsorption resin column, elute with water, discard the water eluent, continue to elute with 70% ethanol, collect the ethanol eluate, concentrate under reduced pressure to a thick paste, dry under reduced pressure, and crush into fine powder. Get Kudzu root extract;

Astragalus was pulverized into a coarse powder, and heated and refluxed for three times with 90% ethanol for 1 hour each time, filtered, and the filtrates were combined, the ethanol was recovered, appropriately concentrated, sodium hydroxide was added to an alkali content of 5%, and n-butanol was added for dynamic extraction 2 times, combine the n-butanol solution, wash once with 5% sodium hydroxide solution, wash twice with water, discard the washing solution, combine the n-butanol solution, concentrate under reduced pressure to near dry, grind and wash with acetone until the color is light, take The precipitate was dried under reduced pressure and pulverized into a fine powder to obtain astragalus extract;

Erigeron breviscapus was decoated three times with water for 1 hour each time, combined with the decoction, filtered, and appropriately concentrated, added to the treated large-pore adsorption resin column, eluted with water, discarded the water eluent, and continued to use 70 Ethanol eluting, collecting the ethanol eluate, recovering the ethanol, concentrating into a thick paste, drying under reduced pressure, crushing into fine powder to obtain Erigeron breviscapus extract;

The above three fine powders are mixed with sodium carboxymethyl starch, hydroxypropyl cellulose, micronized silica gel, and magnesium stearate, and filled into capsules to obtain a composition containing astragalus root, pueraria root, and erigeron root.

Example 2: Therapeutic effect of the composition of the present application on diabetic macular edema

2.1 Test plan design

Test population

Select patients who meet the diagnostic criteria for diabetic retinopathy (qi-yin deficiency, stasis and blood-blood obstruction syndrome); the subjects are informed, and voluntary informed consent is signed. The subjects were divided into four groups A, B, C and D.

Dosing regimen

The dosage of each group is as follows, the course of treatment is 24 weeks:

Group A is a high-dose group. Each time, 4 capsules prepared according to the method described in Example 1 are administered 3 times a day. The daily dose is 66 mg / kg body weight / day.

Group B is a medium-dose group. Each time, 2 capsules prepared according to the method described in Example 1 are administered 3 times a day, and the daily dose is 33 mg / kg body weight / day.

Group C is a low-dose group, each capsule is prepared in accordance with the method described in Example 1 three times a day, the daily dose is 16.5mg / kg body weight / day; and

Group D is a placebo group. Each time a preparation made of rice as a raw material without any active pharmaceutical ingredient is administered 3 times a day, the daily dose is 66 mg / kg body weight / day.

Basic medication and combined medication regulations

During the test, the subject's blood glucose was kept stable (glycated hemoglobin HbAlc≤bA). The basic hypoglycemic drugs are biguanides, sulfonylureas, insulin and insulin sensitizers;

During the trial, all Chinese and western medicines with the same efficacy as the test drugs, including antiplatelet drugs such as clopidogrel sulfate, anticoagulants such as aspirin, and fibrinolytic drugs such as urokinase, western medicine for treating diabetic fundus lesions, and similar traditional Chinese medicines were banned.

evaluation standard

Formulated with reference to the "Guidelines for the Clinical Research of New Chinese Medicines for the Treatment of Diabetic Retinopathy" in the first edition of "Guidelines for the Clinical Research of New Chinese Medicines" in the first edition of the May 2002 issue of China Medical Science and Technology Press. Fundus photography and fundus fluorescein angiography images were read blindly by a person in the reading center.

Optical coherence tomography (OCT)

Optical coherence tomography was performed on the affected eyes of patients with macular edema, and the indexes of optical coherence tomography included foveal thickness and neuroepithelial volume (refer to 6mm area thickness and neuroepithelial volume).

Criteria for correcting vision efficacy

The actual number of letters recognized in the EDTRS visual chart were analyzed.

2.2 Results of enrollment and baseline comparability analysis

A total of 201 patients were enrolled in this trial, see Table 1.

Table 1

There was no significant difference in the rejection rate between the four groups (P = 0.4510).

There were poor compliance in 3 cases in group A, 1 in group B, 1 in group C, and 3 in group D. There was no significant difference in the incidence of poor compliance in the four groups (P = 0.5612).

The distribution of demographic characteristics, vital signs, and concomitant diseases in the four groups of patients was similar, and there were no statistically significant differences among other indicators except lipid-lowering therapy.

All patients who entered the FAS analysis set, except for the presence or absence of pulses, weakness, and stringiness, the baseline ophthalmological examination, reading results, optical coherence tomography, and quantitative scoring of symptoms and signs in the four groups of patients The differences were not statistically significant, suggesting that each group has good comparability.

2.3 Therapeutic effect of the composition of the present application on macular edema

2.3.1 The composition of the present application improves the vision of eyes with macular edema,

In this example, the visual acuity of four groups of target eyes with clinically diagnosed macular edema was examined, including 7 patients in the high-dose group, 11 patients in the middle-dose group, and 7 patients in the low-dose group. 13 patients in the drug group. The results are shown in Figure 1. After 12 weeks and 24 weeks of taking the drug, the patients in the high-dose and middle-dose groups showed significant improvement in vision. And 4.91, while the number of characters with improved visual acuity in the placebo group was only 1.69.

The data in FIG. 1 show that the composition of the present application can improve the vision of patients with macular edema, and present a certain dose and time-dependent effect.

2.3.2 The effect of improving the composition of the present application to the affected eye vision foveal thickness greater than 270μm into the group of

In this embodiment, the eyes of four groups of macular edema patients are examined by optical coherence tomography to obtain the foveal thickness (CRT). The eyes of each group with a CRT greater than 270 μm at the time of enrollment were treated with the corresponding doses. After 24 weeks of treatment, the proportion of eyes with 5 characters in each group was increased. The results are shown in Figure 2.

As can be seen from FIG. 2, the composition of the present application can significantly improve the vision of eyes with macular edema with a CRT greater than 270 μm, and the proportion of 5 characters in the high-dose group and the middle-dose group is significantly higher than that in the placebo group. For example, the high-dose group (24 cases) increased the proportion of 5 characters by as much as 42%, and the medium-dose group (15 cases) increased the proportion of 5 characters by as much as 53%, which was much higher than the placebo group's 17%. Compared with the placebo group, the p-value of the medium-dose group was 0.058 and the p-value of the high-dose group was 0.130 by applying the stata chi-square test.

2.3.3 Effect of the composition of the present application on the macular foveal thickness

In this embodiment, before and after 12 and 24 weeks of treatment, the eyes of four groups of target eyes with clinically diagnosed macular edema were examined by optical coherence tomography, and the changes in the thickness of the macular fovea were obtained. Among them, there were 7 patients in the high-dose group, 11 patients in the middle-dose group, 6 patients in the low-dose group, and 10 patients in the placebo group. The results are shown in Figure 3. Data processing was performed using SAS software. The comparison between groups before and after treatment was performed using the symbol rank test, and the comparison between the four groups after treatment (high, medium, low dose and placebo groups) was performed using the Kruskal-Wallis test.

It can be seen from Fig. 3 that the change in foveal thickness reflects a quantitative effect relationship. The high-dose group can significantly reduce the thickness of foveal eyes in patients with macular edema, and the middle and low-dose groups also have a certain effect. The difference between the treatment group and the placebo group tends to increase (P value decreases) with the duration of the treatment. For example, the P value at 12 weeks is 0.4431 and the P value at 24 weeks is 0.1530.

In addition, the inventors also expanded the number of samples and studied the effect of the composition of the present application on the thickness of the fovea of the eyes of patients with diabetic retinopathy, including the above-mentioned patients. The results of this study are related to the above-mentioned macular edema only. The results of the patients were similar: there was a certain dose-effect trend, the differences between the groups were more obvious, and the difference increased with time (P value decreased), especially the high-dose and placebo differences were consistent.

The inventors have further studied the effect of the composition of the present application on the intraocular pressure of eyes with macular edema. The results show that the composition of the present application can obviously reduce the intraocular pressure of patients with macular edema, and presents a certain dose-effect relationship as a whole. Among the patients in the high-dose group, the intraocular pressure of the affected eyes is obvious after taking the drug for 12 weeks and 24 weeks. decline.

It can be seen from the results of the above experiments that the composition of the present application has a good effect in treating diabetic macular edema. The above results also demonstrate the effect of the composition of the present application in improving intraocular microcirculation. Because intraocular pressure, foveal thickness, and volume are all key indicators of the edema state of the eyeball, the decrease in intraocular pressure combined with changes in foveal thickness or volume indicates that the edema of the eyeball has been improved, and this improvement effect varies with There is an increasing trend over time.

2.4 Safety Evaluation

After treatment, some patients showed abnormal changes in temperature, blood pressure, pulse, respiration, and laboratory indicators.

The incidence of adverse events was 22.64% in group A, 26.00% in group B, 14.00% in group C, and 19.15% in group D. Analysis by CMH test showed no significant difference between the four groups (P = 0.4910).

The incidence of serious adverse events was 1.89% in group A, 0.00% in group B, 2.00% in group C, and 0.00% in group D. There was no significant difference between the four groups (P = 0.5942).

The incidence of adverse reactions was 3.77% in group A, 2.00% in group B, 0.00% in group C, and 4.26% in group D. There was no significant difference between the four groups (P = 0.5185).

There were no statistically significant differences between the four groups of the incidence of various types of adverse events and adverse reactions, which indicates that the drug of the present application has no significant toxic and side effects in the treatment of macular edema and has high safety.

Various changes and equivalent substitutions may be made to the embodiments disclosed in the present application without departing from the essence and scope of the disclosure of the present application. Unless the context indicates otherwise, any feature, step, or embodiment of an embodiment of the present disclosure may be used in combination with any other feature or embodiment.

Claims

Use of a composition comprising astragalus root, pueraria root and breviscapine in the manufacture of a medicament for treating or preventing macular edema in an individual.
The use according to claim 1, wherein the macular edema is macular edema.
The use according to claim 1 or 2, wherein the macular edema is diabetic macular edema.
The use according to any one of claims 1 to 3, wherein the composition comprises the following raw materials of Astragalus, Puerariae and Erigeron breviscapus in the following weight ratios: 10-40 parts of Astragalus, 10-30 parts of Pueraria brevis 10-30 parts; preferably, the astragalus is 20 parts, the kudzu root is 30 parts, and the breviscapine is 20 parts.
The use according to any one of claims 1 to 3, wherein the composition is prepared from an active ingredient comprising astragalus extract, kudzu root extract, and erigeron root extract; preferably, the weight of the active ingredient The ratio is: 1-10 parts of astragalus extract, 50-125 parts of kudzu root extract, and 20-60 parts of scutellar extract.
The use according to any one of claims 1-5, wherein the composition and a pharmaceutically acceptable carrier are formulated into a pharmaceutically acceptable dosage form, preferably a capsule, an oral solution, a powder, a tablet, a granule , Pills, syrup or eye drops, more preferably capsules.
The use according to any one of claims 1-6, wherein the composition is administered orally, eye drops, enemas, subcutaneously, intramuscularly or intraperitoneally; preferably, the composition is administered orally.
The use according to any one of claims 1 to 7, wherein the composition is administered at a dose of 30 to 100 mg / kg body weight per day, preferably 50 to 70 mg / kg body weight.
The use according to any one of claims 1-8, wherein the composition is administered orally 2 or 3 times a day.
The use according to any one of claims 1-9, wherein the composition is administered for a duration of 1 to 52 weeks, preferably 12 to 24 weeks.