Traditional Chinese medicine composition for treating obstructive sleep apnea hypopnea syndrome

Abstract

The invention provides a traditional Chinese medicine composition for treating obstructive sleep apnea hypopnea syndrome and a preparation method thereof. The traditional Chinese medicine composition is prepared from pseudo-ginseng, ramie root, thunberg fritillary bulb, cordyceps sinensis, liquorice, poria cocos and pericarpium citri reticulatae. According to the technical scheme, the traditional Chinese medicine composition adopts natural traditional Chinese medicine raw materials, is simple in preparation method, wide in raw material source, low in cost and free of hormone stimulation type toxic and side effects, has an obvious curative effect on the obstructive sleep apnea hypopnea syndrome, and can reduce AHI and improve the response rate.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to a traditional Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome and a preparation method thereof. Background Art

[0002] Obstructive sleep apnea (OSA), also known as obstructive sleep apnea hypopnea syndrome (OSAHS), refers to recurring episodes of breathing pauses and hypopneas during sleep. Clinically, it can manifest as loud and irregular snoring, a feeling of suffocation or awakening at night, sleep disturbances, daytime sleepiness, memory loss, and, in severe cases, cognitive decline and behavioral abnormalities. Clinically, OSA has been shown to be an independent risk factor for cardiovascular disease. OSA patients may also suffer from refractory hypertension, coronary heart disease, congestive heart failure, arrhythmias, and stroke. Multiple systemic diseases may also be associated with OSA or be exacerbated by its presence, including metabolic syndrome, diabetes, hyperlipidemia, increased blood viscosity, gastroesophageal reflux, proteinuria, and abnormal liver function. Nearly every systemic organ may be affected.

[0003] OSA falls under the categories of "snoring syndrome" and "snoring sleep" in Traditional Chinese Medicine. The Treatise on the Causes and Symptoms of Various Diseases states: "Snoring is a sound made in the throat and pharynx during sleep... When there is a disharmony of qi, it impacts the throat and pharynx, making the sound. Some obese people make sounds when they sleep, but this is because obese people have thick qi and blood, which constrict the throat, making it difficult and uncomfortable, and also making the sound." Snoring can be caused by congenital abnormalities, airway obstruction, and breathing difficulties; or by an irregular diet, excessive consumption of fatty and sweet foods, and a fondness for alcohol and cheese, which causes phlegm and dampness to block the airways, resulting in stagnation and obstruction; or by the six external pathogens, such as wind, heat, and burning fluid, which turns into phlegm, causing swelling and congestion in the throat, and obstruction of qi and blood; or by wind, cold, and dampness, which induce phlegm and dampness, triggering or aggravating the disease; and it is also common for people to suffer from a weak constitution, physical weakness after illness, internal injuries caused by fatigue, organ dysfunction, and disharmony in breathing. This shows that snoring has both deficiency and excess mechanisms. Based on the clinical characteristics of snoring, it can be roughly divided into six syndromes: internal obstruction of phlegm and dampness, phlegm and blood stasis, internal accumulation of phlegm and heat, qi deficiency and phlegm and blood stasis, lung and spleen qi deficiency, and spleen and kidney deficiency. The pathological factors of this disease are often "phlegm," "blood stasis," and "deficiency," indicating that phlegm and blood stasis are important causes of OSA, resulting in symptoms of deficiency, excess, or a mixture of deficiency and excess. Modern physicians generally believe that patients are often obese and have a predisposing constitution characterized by qi deficiency and phlegm dampness. In the early stages, phlegm and dampness are the primary manifestation, while phlegm turbidity permeates the superficial excess, gradually leading to the internalization of blood stasis. Therefore, in the middle stage, phlegm and blood stasis are the main symptoms, accompanied by the transformation of phlegm and blood stasis into heat. In the later stages, internal organ deficiency and phlegm and blood stasis coexist, with the primary deficiency being mainly lung, spleen, and kidney deficiency. Treatment should be based on the predominance of evil and deficiency, and the principles of strengthening the body and eliminating evil should be selected respectively. For those with superficial excess, the methods of resolving phlegm and removing blood stasis, invigorating the mind, clearing away heat and resolving phlegm, calming the liver and purging fire should be adopted according to the nature of the pathogenic evil, and the methods of strengthening the spleen and replenishing qi should be used as an aid; for those with underlying deficiency, the methods of strengthening the spleen and replenishing the lungs, consolidating the kidneys and nourishing the essence, and harmonizing yin and yang should be used according to the deficiency of yin and yang in the internal organs, and the methods of resolving phlegm and unblocking the orifices should be used as an aid.

[0004] The existing traditional Chinese medicine formulas for treating obstructive sleep apnea-hypopnea syndrome have limited therapeutic effects. Therefore, further exploring drugs for the treatment of obstructive sleep apnea-hypopnea syndrome from the field of traditional Chinese medicine to provide more abundant options for formulating clinical medication plans has become a technical problem that needs to be solved urgently. Summary of the Invention

[0005] The purpose of the present invention is to provide a traditional Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome and a preparation method thereof, aiming to further explore drugs in the field of traditional Chinese medicine for treating obstructive sleep apnea-hypopnea syndrome.

[0006] In order to achieve the purpose of the present invention, the present invention provides a traditional Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome, which is prepared from the following traditional Chinese medicines: Panax notoginseng, ramie root, Fritillaria thunbergii, Cordyceps sinensis, licorice, Poria cocos, and tangerine peel.

[0007] Optionally, the traditional Chinese medicine composition is prepared from the following traditional Chinese medicines in parts by weight: 10-50 parts of Panax notoginseng, 10-100 parts of ramie roots, 10-50 parts of Fritillaria thunbergii, 0.2-10 parts of Cordyceps sinensis, 10-30 parts of Licorice, 10-40 parts of Poria cocos, and 10-50 parts of dried tangerine peel.

[0008] The present invention also provides a method for preparing the above-mentioned traditional Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome, the preparation method comprising the following steps: Crush Panax notoginseng and Cordyceps sinensis, sieve and mix well; Extract Fritillaria thunbergii with 45% to 90% ethanol solution under reflux for 2 to 3 times, combine the extracts, filter, recover ethanol from the filtrate and concentrate to form a thick paste A; First, boil dried tangerine peel with water, then boil it with ramie root, poria cocos, and liquorice 2-3 times. Combine the decoctions, filter, and concentrate the filtrate into a thick paste B. The thick paste B was cooled, ethanol was added, allowed to stand, filtered, and the filtrate was used to recover ethanol and concentrate to form a thick paste C; The thick paste A and the thick paste C are dried and crushed, mixed with the crushed powder of Panax notoginseng and Cordyceps sinensis, granulated, and dried to obtain a traditional Chinese medicine composition.

[0009] Optionally, in the step of adding 45% to 90% ethanol solution to reflux extraction of Fritillaria thunbergii for 2 to 3 times, combining the extracts, filtering, recovering ethanol from the filtrate and concentrating it into a thick paste A, the weight ratio of Fritillaria thunbergii to ethanol in each reflux extraction is 1: (6 to 15).

[0010] Optionally, in the step of adding 45% to 90% ethanol solution to reflux extract 2 to 3 times, combining the extracts, filtering, recovering ethanol from the filtrate and concentrating it into a thick paste A, each reflux extraction takes 1 to 3 hours.

[0011] Optionally, in the step of decocting dried tangerine peel with water first, then decocting with ramie root, Poria cocos and liquorice for 2 to 3 times, combining the decoctions, filtering and concentrating the filtrate into thick paste B, the dried tangerine peel is first decocted with water for 20 to 60 minutes.

[0012] Optionally, in the step of decocting dried tangerine peel with water first, then decocting it with ramie root, Poria cocos and liquorice for 2 to 3 times, combining the decoctions, filtering and concentrating the filtrate into a thick paste B, the weight ratio of the medicinal materials to water is 1: (6 to 15) each time water is added for decoction.

[0013] Optionally, in the step of decocting dried tangerine peel with water first, then decocting with ramie root, Poria cocos and liquorice for 2 to 3 times, combining the decoctions, filtering and concentrating the filtrate into a thick paste B, decocting with water for 1 to 3 hours each time.

[0014] Optionally, the relative density of the thick paste A and the thick paste C is 1.05-1.30 (50° C.); the relative density of the thick paste B is 1.05-1.30 (50° C.).

[0015] Optionally, in the step of cooling the thick paste B, adding ethanol, allowing it to stand, filtering, recovering ethanol from the filtrate and concentrating it into a thick paste C, ethanol is added to the thick paste B until the alcohol content is 50% to 80%.

[0016] Optionally, the Chinese medicine composition is an oral preparation.

[0017] Optionally, the oral preparation is a fluid extract, capsule, tablet, concentrated pill, oral liquid, granule, etc.

[0018] The present invention also provides an analytical method for the above-mentioned Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome, wherein the steps for detecting the content of Fritillaria thunbergii are as follows: The Chinese medicine composition was soaked in concentrated ammonia test solution, chloroform-methanol was added and mixed, and the mixture was shaken to obtain a test solution; Mix the reference substances of Fritillaria A and Fritillaria B in methanol respectively and shake well to obtain the reference substance solution; The test solution and the reference solution are tested by high performance liquid chromatography; The mobile phase was acetonitrile-water-triethylamine solution with a volume ratio of 70:30:0.1.

[0019] Optionally, the chromatographic column for detection uses octadecylsilane bonded silica gel as a filler.

[0020] Optionally, the detection device uses an evaporative light scattering detector.

[0021] The common functions and pharmacological effects of the Chinese medicinal ingredients selected in this invention are as follows: The prescription makes heavy use of Panax notoginseng, which is the main medicine for promoting blood circulation, dispersing blood stasis and reducing swelling; Fritillaria thunbergii is bitter and cold in nature, enters the lung and heart meridians, and has excellent heat-clearing and stagnation-dispersing effect, so it is used to clear heat, resolve phlegm and resolve stagnation; Tangerine peel is salty and cold in nature, softens hard masses to disperse lumps; Ramie root is sweet and cold in nature, clears heat, detoxifies and disperses blood stasis (the "Compendium of Materia Medica" says that it "tonifies yin, resolves blood stasis, relieves fever, and moisturizes dryness", and the "Supplement to Compendium of Materia Medica" states that it "treats various poisons, promotes blood circulation, stops bleeding, has dispersing functions, quenches thirst and stabilizes the fetus; it is used to treat erysipelas in children, relieves bloating, metrorrhagia, leukorrhea, spermatorrhea, toothache, throat closure, bone choking, hernia, fire dandelion, carbuncle, wasp and snake bites, back rash, furuncle, and bruises"); the three medicines are used together to resolve phlegm and resolve blood stasis, relieve heat and toxins and benefit the throat, and are collectively the minister medicines. Cordyceps sinensis is sweet and warm in nature, entering the lung and kidney meridians to nourish the lungs and kidneys, tonifying kidney yang and yin essence. Poria cocos is sweet and neutral in nature, entering the spleen, lung, and kidney meridians to tonify the spleen and stomach, benefiting the lungs and kidneys as an adjuvant. Licorice root is sweet and neutral in nature, entering the heart, lung, spleen, and stomach meridians to invigorate qi and strengthen the middle, clear away heat and detoxify, eliminate phlegm and relieve cough, relieve acute pain, and moderate the effects of the herbal formula. The entire formula has the effects of dispersing blood stasis and resolving phlegm, detoxifying and relieving sore throats, and strengthening the vital energy and foundation. Combining one monarch, three ministers, two assistants, and one minister, it is used to treat obstructive sleep apnea-hypopnea syndrome (a syndrome of phlegm and blood stasis).

[0022] Panax notoginseng: Warm in nature, sweet with a slightly bitter taste; it enters the liver and stomach meridians. It has the effects of nourishing blood, combating inflammation, promoting blood circulation and removing blood stasis, and possesses antioxidant and anti-aging properties. It dilates blood vessels, reduces coronary resistance, increases coronary flow, strengthens and improves coronary microcirculation, increases myocardial blood flow, lowers arterial pressure, and slightly reduces heart rate, thereby significantly reducing myocardial oxygen consumption.

[0023] Ramie root: Cold in nature, sweet in flavor; enters the liver, heart, and bladder meridians. It clears heat, promotes urination, stabilizes pregnancy, stops bleeding, and detoxifies. It is used for colds, fevers caused by measles, urinary tract infections, edema caused by nephritis, abdominal pain in pregnant women, restless fetuses, threatened abortion, injuries from falls, fractures, sores, swelling, and pain, and hemorrhagic disorders.

[0024] Fritillaria thunbergii: Cold in nature, bitter in flavor; enters the Lung and Heart meridians. Its fragrance is refreshing and dispersing, and it has the effects of clearing heat and resolving phlegm, lowering Qi and relieving cough, and dispersing nodules and reducing swelling. It is used for coughs caused by wind-heat or phlegm-heat, lung abscesses with vomiting pus, and sores, carbuncles, and swelling.

[0025] Cordyceps sinensis: Warm in nature, sweet in flavor; enters the lung and kidney meridians. It nourishes the kidneys and lungs, stops bleeding and resolves phlegm. It is used for kidney deficiency, spermatorrhea, impotence, spermatorrhea, back and knee pain, chronic cough, asthma, and hemoptysis caused by overwork.

[0026] Licorice: Sweet in flavor, neutral in nature; enters the Heart, Lung, Spleen, and Stomach meridians. It tonifies the spleen and replenishes Qi, clears away heat and toxins, relieves phlegm and coughs, relieves pain, and harmonizes various medicinal properties. It is used for spleen and stomach deficiency, fatigue, palpitations and shortness of breath, cough with sputum, abdominal and limb cramps and pain, carbuncles, sores, and to alleviate drug toxicity and potent effects.

[0027] Poria: Sweet in flavor, warm in nature, neutral, and non-toxic; it enters the spleen, lung, and kidney meridians. It has the effects of tonifying deficiency, removing cold and heat pathogenic qi, tonifying the middle, strengthening qi and strength, building muscle mass, and strengthening yin. It is used to treat wind in the head and face, dizziness, purgation of qi, and relieving low back pain.

[0028] Tangerine peel: Salty in flavor, neutral in nature; enters the Liver and Kidney meridians. It has the effects of astringing Yin, suppressing Yang, stopping sweating, astringing essence, resolving phlegm, and softening hard masses. It is used to treat palpitations, insomnia, dizziness, tinnitus, scrofula, phlegm nodules, lumps, spontaneous sweating, night sweats, spermatorrhea, metrorrhagia, stomachache, and heartburn.

[0029] In the technical solution of the present invention, the Chinese medicine composition uses natural Chinese medicine raw materials, has a simple preparation method, a wide source of raw materials, low cost, no hormone stimulation and side effects, has obvious efficacy in treating obstructive sleep apnea hypopnea syndrome, can reduce AHI, and improve response rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0031] Figure 1 A schematic flow chart of an embodiment of a method for preparing a traditional Chinese medicine composition provided by the present invention; Figure 2 The liquid chromatogram of licorice in the traditional Chinese medicine composition prepared in Example 1 provided by the present invention; Figure 3 This is a liquid chromatogram of licorice in the traditional Chinese medicine composition prepared in Example 4 provided by the present invention; Figure 4 The liquid chromatogram of the negative sample (lacking Fritillaria thunbergii) provided by the present invention; Figure 5 A liquid chromatogram of the reference solution provided by the present invention; Figure 6 The liquid chromatogram of the test solution provided by the present invention.

[0032] The purpose, features and advantages of the present invention will be further described with reference to the accompanying drawings and in conjunction with the embodiments. DETAILED DESCRIPTION

[0033] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them.

[0034] It should be noted that, in the embodiments, those without specifying specific conditions, are carried out according to conventional conditions or the conditions recommended by the manufacturer. Those for reagents or instruments used that do not specify the manufacturer are conventional products that can be purchased commercially. In addition, the meaning of "and / or" appearing in the full text includes three parallel schemes. Taking "A and / or B" as an example, it includes schemes A, B, or A and B that meet the same time. In addition, the technical solutions between the various embodiments can be combined with each other, but must be based on those of ordinary skill in the art. When the combination of the technical solutions is contradictory or cannot be realized, it should be considered that the combination of such technical solutions does not exist and is not within the scope of protection required by the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work belong to the scope of protection of the present invention.

[0035] The present invention will be further described below with reference to the examples, but the embodiments of the present invention are not limited thereto. The experimental methods used in the following examples are conventional methods unless otherwise specified.

[0036] The existing traditional Chinese medicine formulas for the treatment of obstructive sleep apnea-hypopnea syndrome and its postherpetic neuralgia have limited therapeutic effects. Therefore, further exploring drugs for the treatment of obstructive sleep apnea-hypopnea syndrome from the field of traditional Chinese medicine to provide more abundant options for the formulation of clinical medication plans has become a technical problem that needs to be solved urgently.

[0037] In view of this, the present invention proposes a traditional Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome, which is prepared from the following traditional Chinese medicines: Panax notoginseng, ramie root, Fritillaria thunbergii, Cordyceps sinensis, licorice, Poria cocos, and tangerine peel.

[0038] In some embodiments, the Chinese medicine composition is prepared from the following Chinese medicines in parts by weight: 10-50 parts of Panax notoginseng, 10-100 parts of ramie root, 10-50 parts of Fritillaria thunbergii, 0.2-10 parts of Cordyceps sinensis, 10-30 parts of licorice, 10-40 parts of Poria cocos, and 10-50 parts of dried tangerine peel.

[0039] In the technical solution of the present invention, the Chinese medicine composition uses natural Chinese medicine raw materials, has a simple preparation method, a wide source of raw materials, low cost, no hormone stimulation and side effects, has obvious efficacy in treating obstructive sleep apnea hypopnea syndrome, can reduce AHI, and improve response rate.

[0040] In order to better extract and utilize the effective ingredients in the Chinese medicine composition, the present invention also proposes a preparation method of a Chinese medicine composition for treating obstructive sleep apnea hypopnea syndrome, Figure 1 A schematic flow chart of an embodiment of a method for preparing a traditional Chinese medicine composition is provided, wherein the preparation method comprises the following steps.

[0041] Step S1: Grind Panax notoginseng and Cordyceps sinensis, sieve, and mix.

[0042] In some embodiments of the present invention, Panax notoginseng and Cordyceps sinensis are crushed, and according to the differences in production process or scale, they can be selectively crushed into any one of medium powder, fine powder, finest powder, and ultrafine powder, and then sieved and mixed.

[0043] Step S2: adding 45% to 90% ethanol solution to the Fritillaria thunbergii and extracting it under reflux for 2 to 3 times, combining the extracts, filtering, recovering ethanol from the filtrate and concentrating it into a thick paste A.

[0044] In some embodiments of the present invention, Fritillaria thunbergii is refluxed and extracted with a 45% to 90% ethanol solution for 2 to 3 times, each time adding 6 to 15 times the weight of the 45% to 90% ethanol solution, and refluxed for 1 to 3 hours. The extracts are combined and filtered, and the filtrate is used to recover ethanol and concentrate to a thick paste A with a relative density of 1.05 to 1.30 (50°C).

[0045] In a specific implementation, Fritillaria thunbergii is refluxed and extracted with 80% ethanol solution for 3 times, with 12 times the weight of 80% ethanol solution added each time, and refluxed for 3 hours. The extracts are combined and filtered, and the filtrate is used to recover ethanol and concentrate to a thick paste A with a relative density of 1.05 to 1.30 (50°C).

[0046] Step S3: firstly decoct the dried tangerine peel with water, then decoct it with ramie root, Poria cocos and liquorice for 2-3 times, combine the decoctions, filter and concentrate the filtrate into a thick paste B.

[0047] In some embodiments of the present invention, dried tangerine peel is first decocted with 3 to 5 times the weight of water for 20 to 60 minutes, and then ramie root, poria cocos, and licorice are added. The decocting process is continued for 2 to 3 times, with 6 to 15 times the weight of water added each time. The decocting process is continued for 1 to 3 hours, and the decoctions are combined, filtered, and the filtrate is concentrated to a thick paste B with a relative density of 1.05 to 1.15 (50° C.). It should be noted that the weight ratio of the medicinal materials to water in each decoction is 1:(6 to 15).

[0048] In a specific implementation, dried tangerine peel is first decocted with 4 times the weight of water for 30 minutes, and then decocted with ramie root, poria cocos, and licorice for 3 times, adding 12 times the weight of water each time, and simmered for 2 hours. The decoctions are combined, filtered, and the filtrate is concentrated to a thick paste B with a relative density of 1.05-1.15 (50°C).

[0049] Step S4: cool the thick paste B, add ethanol, let it stand, filter, recover the ethanol from the filtrate and concentrate it into a thick paste C.

[0050] In a specific implementation, the thick paste B is cooled, ethanol is added to make the weight proportion of ethanol 70%, and the mixture is allowed to stand for 30 hours. The mixture is filtered, and the filtrate is used to recover the ethanol and concentrate to a thick paste C with a relative density of 1.05 to 1.30 (50°C).

[0051] Step S5: Dry and crush the thick paste A and the thick paste C, mix them with the crushed powder of Panax notoginseng and Cordyceps sinensis, granulate them, and dry them to obtain the traditional Chinese medicine composition.

[0052] In a specific implementation, thick pastes A and C are dried at 80°C, pulverized, and sieved. Drying methods include reduced pressure drying, spray drying, boiling drying, and freeze drying, with reduced pressure drying being preferred in this embodiment. Furthermore, depending on the production process or scale, the dried product can be pulverized into any of medium, fine, ultrafine, and ultrafine powders.

[0053] In some further embodiments, the prepared composition particles are filled into hollow capsules with a filling amount ranging from 0.38 g ± 10%.

[0054] The technical solutions of the present invention are further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only used to explain the present invention and are not used to limit the present invention. Example 1

[0055] 3000g of Panax notoginseng and 300g of Cordyceps sinensis were crushed, sieved and mixed; 3000g of Fritillaria thunbergii was refluxed and extracted 3 times with 80% ethanol solution, each time adding 12 times the weight of 80% ethanol solution, and refluxed for 3 hours. The extracts were combined and filtered, and the filtrate was used to recover ethanol and concentrated to a thick paste A with a relative density of 1.05-1.30 (50°C); 3000g of dried tangerine peel was first decocted with 4 times the weight of water for 30 minutes, and then decocted with 3000g of ramie root, 3000g of Poria cocos and 2000g of liquorice for 3 times with water, each time adding water to 12 times the weight of ethanol solution. 12 times the weight, decocted for 3 hours, the decoctions were combined, filtered, and the filtrate was concentrated to a thick paste B with a relative density of 1.05-1.15 (50°C); after the thick paste B was cooled, ethanol was added to make the alcohol content 70%, and the mixture was allowed to stand for alcohol precipitation for 30 hours, filtered, and the filtrate was used to recover the ethanol and concentrated to a thick paste C with a relative density of 1.05-1.30 (50°C); the thick pastes A and C were dried under reduced pressure, then crushed, mixed with the crushed powder of Panax notoginseng and Cordyceps sinensis, granulated, dried, and filled into capsules with a filling amount range of 0.38g±10%. Example 2

[0056] 3000g of Panax notoginseng and 300g of Cordyceps sinensis were crushed, sieved and mixed; 3000g of Fritillaria thunbergii was refluxed and extracted twice, 10 times the weight of 60% ethanol solution was added each time, and refluxed for 2 hours. The extracts were combined and filtered, and the filtrate was used to recover ethanol and concentrated to a thick paste A with a relative density of 1.05-1.30 (50°C); 1500g of dried tangerine peel was first decocted with 4 times the weight of water for 30 minutes, and then decocted with 3000g of ramie root, 1000g of Poria cocos and 2000g of liquorice twice with water, and water was added to 10 times the weight of ethanol each time. 0 times weight, decocted for 2 hours, the decoctions were combined, filtered, and the filtrate was concentrated to a thick paste B with a relative density of 1.05-1.15 (50°C); after the thick paste B was cooled, ethanol was added to make the alcohol content 50%, and the mixture was allowed to stand for alcohol precipitation for 24 hours, filtered, and the filtrate was used to recover the ethanol and concentrated to a thick paste C with a relative density of 1.05-1.30 (50°C); the thick pastes A and C were spray-dried, crushed into fine powder, mixed with the crushed powder of Panax notoginseng and Cordyceps sinensis, granulated, dried, and filled into capsules with a filling amount range of 0.38g±10%. Example 3

[0057] 3000g of Panax notoginseng and 300g of Cordyceps sinensis were crushed, sieved and mixed; 3000g of Fritillaria thunbergii was refluxed and extracted twice, 12 times the weight of 80% ethanol solution was added each time, and refluxed for 2 hours. The extracts were combined and filtered, and the filtrate was used to recover ethanol and concentrated to a thick paste A with a relative density of 1.05-1.30 (50°C); 3000g of dried tangerine peel was first decocted with 4 times the weight of water for 30 minutes, and then decocted with 3000g of ramie root, 3000g of Poria cocos and 2000g of liquorice twice with water, and water was added to 12 times the weight of ethanol solution each time. 10 times the weight, decocted for 2 hours, the decoctions were combined, filtered, and the filtrate was concentrated to a thick paste B with a relative density of 1.05-1.15 (50°C); after the thick paste B was cooled, ethanol was added to make the alcohol content 70%, and the mixture was allowed to stand for alcohol precipitation for 30 hours, filtered, and the filtrate was used to recover the ethanol and concentrated to a thick paste C with a relative density of 1.05-1.30 (50°C); the thick pastes A and C were boiled and dried, then crushed, mixed with the crushed powder of Panax notoginseng and Cordyceps sinensis, granulated, dried, and filled into capsules with a filling amount range of 0.38g±10%. Example 4

[0058] 3000g of Panax notoginseng and 300g of Cordyceps sinensis were crushed, sieved and mixed; 3000g of Fritillaria thunbergii was refluxed and extracted 3 times with 60% ethanol solution, 10 times the weight of 60% ethanol solution was added each time, and refluxed for 1.5 hours. The extracts were combined and filtered, and the filtrate was used to recover ethanol and concentrated to a thick paste A with a relative density of 1.05-1.30 (50°C); 1500g of dried tangerine peel was first decocted with 4 times the weight of water for 30 minutes, and then decocted with 3000g of ramie root, 1000g of Poria cocos and 2000g of liquorice for 3 times with water, and water was added to 10 times the weight of ethanol each time. 0 times weight, decocted for 2.5 hours, the decoction was combined, filtered, and the filtrate was concentrated to a thick paste B with a relative density of 1.05-1.15 (50°C); after the thick paste B was cooled, ethanol was added to make the alcohol content 50%, and the alcohol was allowed to settle for 24 hours, filtered, and the filtrate was used to recover the ethanol and concentrated to a thick paste C with a relative density of 1.05-1.30 (50°C); the above thick pastes A and C were dried under reduced pressure, crushed into fine powder, mixed with the crushed powder of Panax notoginseng and Cordyceps sinensis, granulated, dried, and filled into capsules, with a filling amount range of 0.38g±10%.

[0059] Comparative Example 1 3000g of Panax notoginseng and 300g of Cordyceps sinensis were crushed into fine powder, sieved and mixed; 3000g of Fritillaria thunbergii was refluxed and extracted twice, 10 times the weight of 60% ethanol solution was added each time, and refluxed for 2 hours. The extracts were combined and filtered, and the filtrate was used to recover ethanol and concentrated to a thick paste A with a relative density of 1.05-1.30 (50°C); 3000g of ramie root and 2000g of liquorice were decocted with water for 3 times, 10 times the weight of water was added each time, and the decocted for 2 hours. The decoction was filtered and the filtrate was concentrated to a thick paste B with a relative density of 1.05-1.15 (50°C). After the thick paste B was cooled, ethanol was added to make the alcohol content 70%, and the mixture was allowed to stand for alcohol precipitation for 30 hours. The filtrate was filtered to recover the ethanol and concentrated to a thick paste C with a relative density of 1.05-1.30 (50°C); the thick pastes A and C were dried under reduced pressure, crushed into fine powder, mixed evenly with the fine powder of Panax notoginseng and Cordyceps sinensis, granulated, dried, and filled into capsules with a filling amount range of 0.38g±10%.

[0060] 1. Therapeutic effect of the Chinese medicine composition of the present invention on obstructive sleep apnea-hypopnea syndrome 440 patients with obstructive sleep apnea-hypopnea syndrome were selected from a hospital for an experiment. The Chinese medicine composition capsules of Examples 1-3 were clinically observed from May 2022 to July 2024 on 440 patients with obstructive sleep apnea-hypopnea syndrome (330 cases in the experimental group and 110 cases in the control group). The clinical report is as follows: (1) Purpose of the experiment The apnea-hypopnea index (AHI) response rate at the 4th week of medication was used as the primary efficacy indicator, and placebo was used as the control to confirm the effectiveness and safety of the Chinese medicine composition capsules prepared in Examples 1-3 in treating obstructive sleep apnea-hypopnea syndrome.

[0061] (2) Test method Design type: A multicenter, randomized, double-blind, placebo-controlled parallel trial design was used.

[0062] Sample Size: The primary efficacy endpoint of the trial was the AHI response rate at week 4 (the proportion of patients whose AHI returned to normal or decreased by >50% from baseline after treatment). The expected response rate was 60% in the experimental group and 30% in the control group. A two-sided α = 0.05, β = 0.10, and power = 0.90 were used, with a 3:1 allocation ratio for superiority testing. The statistically estimated sample size was 111:37, for a total of 148 patients. Taking into account dropouts and safety observation sample size requirements, the final planned enrollment ratio was 330:110 in the experimental group and 440 in the control group.

[0063] Study period: The subjects will first undergo a screening examination, and eligible subjects will receive 4 weeks of trial drug or placebo treatment. Responding subjects will continue to be followed up for 4 weeks. The entire study will take about 8-9 weeks.

[0064] Control Group Setup: Reference was made to the "General Principles for Clinical Research of New Traditional Chinese Medicines," sections on "Development of Clinical Trial Plans and Control of R&D Risks for New Traditional Chinese Medicines," and "General Considerations for Clinical Trial Design of New Traditional Chinese Medicines," which state: "The use of a placebo control not only allows for understanding the absolute efficacy of the drug and facilitates a clear assessment of safety, but also serves to test the sensitivity of the trial itself." Furthermore, there are currently no proven effective drugs for the treatment of obstructive sleep apnea-hypopnea syndrome, and no recognized, comparable positive control drugs were identified. Therefore, a placebo control was chosen for this study.

[0065] Randomization sequence generation: Block randomization was used. Using SAS 9.4 statistical software, an appropriate block length was selected and, based on a given random seed number, a random sequence was generated in a 3:1 ratio to assign the subjects to treatment groups (experimental group, control group). The random sequence was used to assign drug numbers to the trial drugs. The researchers distributed the drugs in ascending order of drug number, according to the order of enrollment.

[0066] Implementation of the blind method: Development of simulants: Prepare simulants in accordance with the requirements of the General Principles for Clinical Research of New Chinese Medicines, so that the placebo is similar to the test drug in color, smell, taste, shape, texture and other characteristics, making it difficult for clinical trial participants to distinguish them.

[0067] General treatment: Refer to the "Guidelines for the Diagnosis and Treatment of Obstructive Sleep Apnea in Adults" (2018) published by the Chinese Medical Association, the Chinese Medical Association Journal, the General Practice Branch of the Chinese Medical Association, the Sleep Disorders Group of the Respiratory Disease Branch of the Chinese Medical Association, etc., the "Multidisciplinary Diagnosis and Treatment Guidelines for Obstructive Sleep Apnea in Adults" (2018) published by the Sleep Medicine Professional Committee of the Chinese Medical Association, and the "Guidelines for the Diagnosis and Treatment of Obstructive Sleep Apnea-Hypopnea Syndrome" (2011 revised edition) published by the Sleep Disorders Group of the Respiratory Disease Branch of the Chinese Medical Association.

[0068] Medication regimen Treatment period: 4 weeks; Test group I: 4 capsules of the capsules prepared in Example 1, 3 times a day, orally; Test group II: 4 capsules of the capsules prepared in Example 2, taken orally 3 times a day; Test group III: 4 capsules of the capsules prepared in Example 3, taken orally 3 times a day; Control group: 4 capsules of the capsules prepared in Comparative Example 1 were taken orally 3 times a day.

[0069] Efficacy indicators: Primary endpoints: Apnea-hypopnea index (AHI) response rate at week 4 (proportion of patients whose AHI returned to normal or decreased by >50% compared with baseline after treatment).

[0070] Disease classification (the patient's AHI is less than 5 times is normal):

[0071] (3) Test results and conclusions Distribution of enrolled cases and determination of analysis data set A total of 440 patients were enrolled in this clinical trial, with 18 patients withdrawing prematurely. Of these, 110 patients were enrolled in Trial Group I, 4 of whom dropped out, and 106 completed the trial. 110 patients were enrolled in Trial Group II, 5 of whom dropped out, and 105 completed the trial. 110 patients were enrolled in Trial Group III, 5 of whom dropped out, and 105 completed the trial. The control group enrolled 110 patients, 4 of whom dropped out, and 106 completed the trial. The first patient in this trial, drug number 057, was enrolled at Center 10 on August 2, 2022, and discharged on August 29, 2022. The last patient in this trial, drug number 512, was enrolled at Center 01 on May 1, 2024, and discharged on June 28, 2024.

[0072] Baseline data were compared between the trial and control groups during the screening period, including basic information, previous treatment history, drug allergy history, other medical conditions and medication history, Traditional Chinese Medicine (TCM) syndromes, tongue and pulse conditions, Epworth sleepiness test, urine pregnancy test, electrocardiogram (ECG), and polysomnography. The results showed that baseline characteristics of the subjects were well-balanced between the groups and comparable at baseline.

[0073] Efficacy analysis---Main efficacy indicator---Apnea-Hypopnea Index (AHI) response rate in the 4th week of medication At the fourth week of treatment, 48 subjects (45.28%), 47 (44.76%), and 46 (43.40%) of the experimental groups I to III had AHI responses, respectively, while 31 subjects (29.25%) of the control group had AHI responses. Primary endpoint: AHI response rate at week 4 Research data showed that in terms of the primary endpoint indicator "AHI response rate in the fourth week of medication", the experimental group had significantly better efficacy than the control group.

[0074] Safety evaluation In this study, the incidence of adverse events in the experimental group II and the control group were 24.70% and 21.82%, respectively. The incidence of adverse reactions in the experimental group II and the control group were 3.35% and 5.45%, respectively. In the experimental group II, 11 cases had adverse reactions, including 3 cases of urine protein detection, 3 cases of increased blood creatinine, 1 case of increased blood urea, 1 case of decreased glomerular filtration rate, 1 case of positive urine occult blood, 1 case of nausea, 1 case of upper abdominal pain, 1 case of diarrhea, and 1 case of coagulation disorder. There were 6 cases of adverse reactions in the control group, including 1 case of urine protein detection, 1 case of increased glucosidase, 1 case of increased aspartate aminotransferase, 1 case of urine protein detection, 1 case of increased alanine aminotransferase, 1 case of urticaria, and 1 case of pruritus. There were no significant differences between the two groups.

[0075] In terms of safety, the incidence of adverse reactions in the experimental group II and the control group were 3.35% and 5.45%, respectively, indicating that the Chinese medicine composition of the present invention has good safety in clinical use.

[0076] The present invention also provides an analytical method for the above-mentioned traditional Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome, which includes a step of detecting the content of Fritillaria thunbergii. The procedure in this embodiment is as follows. 1. Materials

[0077] Preparation of reference solution: Accurately weigh appropriate amounts of Fritillaria sucroferatin A and Fritillaria sucroferatin B reference substances, add methanol to make a mixed solution containing 0.2 mg of Fritillaria sucroferatin A and 0.15 mg of Fritillaria sucroferatin B per 1 mL to obtain the reference solution.

[0078] Preparation of the test solution: Take 1 g of the contents of the capsule obtained in Example 1, accurately weigh it, add 4 mL of concentrated ammonia test solution, soak for 1 hour, accurately add 60 mL of chloroform-methanol (4:1) mixed solution, weigh it, mix it, and sonicate it (power 150 W, frequency 20 kHz) for 20 minutes. Let it cool, weigh it again, make up the lost weight with the mixed solution, filter it, accurately measure 10 mL, evaporate it to dryness in an evaporating dish, dissolve the residue in an appropriate amount of methanol, quantitatively transfer it to a 2 mL volumetric flask, shake it, filter it with a microporous filter membrane (0.45 µm), and take the filtrate to obtain the test solution.

[0079] Column: Welch Ultimate LP-C18 4.6mm150mm; The mobile phase was acetonitrile-water-triethylamine solution with a volume ratio of 70:30:0.1.

[0080] Elution procedure: isocratic elution; Flow rate: 1.0 mL / min; Column temperature: 35°C; Injection volume: 2 μL of Fritillaria glutinosin A reference solution, 10 μL of Fritillaria glutinosin B reference solution, and 15 μL of the test solution.

[0081] Determination was performed using high-performance liquid chromatography (Chinese Pharmacopoeia 2020, Part IV, General Chapter 0512). Test and reference solutions were accurately measured and injected into an evaporative light scattering detector (ELSD), and the chromatograms were recorded. Various records from the analysis of the TCM composition were collated and the recorded data analyzed and evaluated. 2. Results Analysis 2.1 System Applicability

[0082] Combine Figure 4-6 ,Throughout the entire verification process, the system applicability met the requirements.,The experimental results are shown in Table 1.

[0083] Table 1 System applicability experimental results

[0084] The experimental results show that the chromatographic column efficiency is high and the system applicability meets the requirements based on the number of theoretical plates. 2.2 Exclusivity

[0085] Combine Figure 4-6 ,The specificity met the requirements throughout the entire verification process.,The experimental results are shown in Table 2.

[0086] Table 2 Specificity test results

[0087] The experimental results showed that the negative sample solution did not interfere with the determination of the main component, indicating that the method had good specificity for determining the content of fritillin A and fritillin B.

[0088] In summary, this scheme uses acetonitrile-water-triethylamine in a volume ratio of 70:30:0.1 as the mobile phase, and the experimental results of the analytical method validation are in line with the regulations, proving that the analytical method is stable and reliable and suitable for the detection of the content of Fritillaria thunbergii in the traditional Chinese medicine composition.

[0089] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0090] The above-described embodiments merely represent several implementation methods of the present application. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art could make various modifications and improvements without departing from the spirit of the present application, all of which fall within the scope of protection of the present application. Therefore, the scope of protection of the present patent application shall be determined by the appended claims.

Claims

1. A Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome, characterized in that: The traditional Chinese medicine composition is prepared from the following traditional Chinese medicines in parts by weight: 10-50 parts of Panax notoginseng, 10-100 parts of ramie roots, 10-50 parts of thunbergii bulbs, 0.2-10 parts of cordyceps sinensis, 10-30 parts of liquorice, 10-40 parts of poria cocos and 10-50 parts of tangerine peel.

2. A method for preparing the Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome according to claim 1, characterized in that: The preparation method comprises the following steps: Crush Panax notoginseng and Cordyceps sinensis, sieve and mix well; Extract Fritillaria thunbergii with 45% to 90% ethanol solution under reflux for 2 to 3 times, combine the extracts, filter, recover ethanol from the filtrate and concentrate to form a thick paste A; First, boil dried tangerine peel with water, then boil it with ramie root, poria cocos, and liquorice 2-3 times. Combine the decoctions, filter, and concentrate the filtrate into a thick paste B. The thick paste B was cooled, ethanol was added, allowed to stand, filtered, and the filtrate was used to recover ethanol and concentrate to form a thick paste C; The thick paste A and the thick paste C are dried and crushed, mixed with the crushed powder of Panax notoginseng and Cordyceps sinensis, granulated, and dried to obtain a traditional Chinese medicine composition.

3. The method for preparing the Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome according to claim 2, wherein: In the step of adding 45% to 90% ethanol solution to reflux extract 2 to 3 times, combining the extracts, filtering, recovering ethanol from the filtrate and concentrating it into a thick paste A, the weight ratio of thunbergii to ethanol is 1: (6 to 15) for each reflux extraction, and the extraction time is 1 to 3 hours.

4. The method for preparing the Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome according to claim 2, wherein: In the step of decocting dried tangerine peel with water first, then decocting with ramie root, poria cocos and liquorice for 2-3 times, combining the decoctions, filtering and concentrating the filtrate into thick paste B, the dried tangerine peel is first decocted with water for 20-60 minutes.

5. The method for preparing the Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome according to claim 2, wherein: In the step of decocting dried tangerine peel with water first, then decocting with ramie root, poria cocos, and licorice 2 to 3 times, combining the decoctions, filtering, and concentrating the filtrate into a thick paste B, the weight ratio of the medicinal materials to water is 1: (6 to 15) each time the water is added for decocting, and the decoction time is 1 to 3 hours.

6. The method for preparing the Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome according to claim 2, wherein: The relative density of the thick paste A and the thick paste C is 1.05-1.30 (50°C); the relative density of the thick paste B is 1.05-1.30 (50°C).

7. The method for preparing the Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome according to claim 2, wherein: In the step of cooling the thick paste B, adding ethanol, standing, filtering, recovering ethanol from the filtrate and concentrating it into a thick paste C, ethanol is added to the thick paste B until the alcohol content is 50% to 80%.

8. A method for analyzing the Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome according to claims 1-7, characterized in that: The steps for detecting the content of Fritillaria thunbergii in the Chinese medicine composition are as follows: The Chinese medicine composition was soaked in concentrated ammonia test solution, chloroform-methanol was added and mixed, and the mixture was shaken to obtain a test solution; Mix the reference substances of Fritillaria A and Fritillaria B in methanol respectively and shake well to obtain the reference substance solution; The test solution and the reference solution are tested by high performance liquid chromatography; The mobile phase was acetonitrile-water-triethylamine solution with a volume ratio of 70:30:0.

1.

9. The method for analyzing the Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome according to claim 8, wherein: The chromatographic column used in the detection uses octadecylsilane bonded silica gel as a filler.

10. The method for analyzing the Chinese medicine composition for treating obstructive sleep apnea-hypopnea syndrome according to claim 8, wherein: The detection device adopts an evaporative light scattering detector.

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