Traditional Chinese medicine formula composition for male infertility

Abstract

The invention provides a traditional Chinese medicine formula composition for male infertility, which is prepared from the following traditional Chinese medicine raw materials in parts by weight: 5 to 30 parts of tortoise plastron, 5 to 30 parts of deer-horn glue, 5 to 35 parts of semen cuscutae, 8 to 30 parts of fructus lycii, 10 to 25 parts of herba epimedii, 5 to 35 parts of herba cistanche, 5 to 15 parts of fructus schizandrae, 5 to 20 parts of poria cocos, 5 to 10 parts of leech and 5 to 20 parts of human placenta. The traditional Chinese medicine composition for treating male infertility can be researched and developed. The composition is based on the traditional Chinese medicine treatment rule of tonifying kidney and replenishing essence, promoting blood circulation to remove blood stasis and harmonizing liver, spleen and kidney, the curative effect and bioavailability are remarkably improved through scientific raw material compatibility in combination with the modern preparation technology, and the treatment effect is efficient and stable.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of traditional Chinese medicine formula combination, and particularly relates to a traditional Chinese medicine formula combination for male infertility. BACKGROUND

[0002] The pathological mechanism of male infertility is complex. From the perspective of traditional Chinese medicine, the core pathogenesis is "deficiency of kidney essence and blood stasis in collaterals". The kidney is the origin of life and is responsible for storing essence and reproduction. Deficiency of kidney essence leads to insufficient sperm production and decreased sperm vitality. Blood stasis in collaterals leads to obstruction of the sperm channel, resulting in non-liquefaction of semen and sperm transport disorders. Some patients also have weak spleen and stomach, forming a vicious cycle of "deficiency-blood stasis-weakness". From the perspective of modern medicine, the typical clinical manifestations are oligospermia, asthenospermia, teratospermia, and non-liquefaction of semen. Most patients have elevated seminal plasma elastase, and some patients also have erectile dysfunction caused by deficiency of kidney essence and blood stasis in collaterals, which seriously affects the fertility.

[0003] Research has found that male infertility is a common health problem affecting about 15% of couples of childbearing age worldwide, with male factors accounting for about half. The main manifestations of the disease are oligospermia, asthenospermia, teratospermia, and non-liquefaction of semen. The causes are complex and involve endocrine disorders, reproductive system infections, varicocele, and oxidative stress.

[0004] Western medicine commonly used in clinical treatment is mainly gonadotropin and androgen drugs. Although these drugs can improve semen parameters in the short term, long-term use can cause endocrine disorders such as testosterone feedback inhibition, LH / FSH imbalance, and liver function damage. Moreover, these drugs cannot improve blood stasis in collaterals and inflammation of the reproductive system such as elevated seminal plasma elastase. Therefore, these drugs are only treating the symptoms and not the root cause, have prominent side effects, and have a single target. Traditional Chinese medicine formulas only focus on "tonifying the kidney and filling essence" and ignore the core pathology of "blood stasis in collaterals", resulting in poor efficacy in patients with non-liquefaction of semen and elevated seminal plasma elastase. Some formulas add blood-activating ingredients, but there are problems such as "tonifying and stagnation" (e.g., excessive tonifying kidney drugs leading to poor qi movement) or "blood-activating damage to essence" (e.g., excessive blood-activating drugs consuming kidney essence). Therefore, these formulas cannot achieve "tonifying without hindering transportation and transportation without damaging tonification", leading to unbalanced compatibility and insufficient syndrome targeting.

[0005] Therefore, it is of great clinical significance and market value to develop a traditional Chinese medicine formula combination based on traditional Chinese medicine theory, scientific compatibility, and exact efficacy, and to improve the bioavailability through modern technology. SUMMARY

[0006] Therefore, the application provides a traditional Chinese medicine formula combination for male infertility treatment, which is based on the traditional Chinese medicine principle of tonifying kidney and replenishing essence, promoting blood circulation and removing blood stasis, and regulating liver, spleen and kidney.

[0007] To solve the above technical problems, the application provides a traditional Chinese medicine formula combination for male infertility treatment, which is composed of the following traditional Chinese medicine raw materials in parts by weight: turtle shell 5-30 parts, deer antler glue 5-30 parts, semen cuscutae 5-35 parts, medlar 8-30 parts, herba epimedii 10-25 parts, cistanche 5-35 parts, schisandra chinensis 5-15 parts, poria cocos 5-20 parts, leech 5-10 parts, and placenta 5-20 parts.

[0008] Preferably, the traditional Chinese medicine formula combination further comprises the following auxiliary components in parts by weight: atractylodes 5-20 parts, prepared licorice 5-15 parts, rehmannia 5-25 parts, angelica 5-20 parts, semen astragali complanati 5-20 parts, semen foeniculi 5-15 parts, and extract of polygonatum 5-30 parts.

[0009] Preferably, the extract of polygonatum is prepared by water extraction and alcohol precipitation or ultrasonic-assisted extraction, and the weight content of polysaccharide of polygonatum is greater than or equal to 50%.

[0010] The dosage form of the traditional Chinese medicine formula combination is an oral dosage form, which is a pill, a capsule, a granule, a tablet, a drop pill or an oral liquid.

[0011] When the dosage form of the traditional Chinese medicine formula combination is a capsule, it is a soft capsule, and the content thereof comprises a suspension or emulsion formed by the active pharmaceutical ingredient treated by nano-pulverization technology and a pharmaceutical carrier, wherein the particle size D90 of the active pharmaceutical ingredient is less than or equal to 500 nm.

[0012] A method for preparing a traditional Chinese medicine formula combination for male infertility treatment, which comprises the following steps: S1, providing raw materials: weighing turtle shell, deer antler glue, semen cuscutae, medlar, herba epimedii, cistanche, schisandra chinensis, poria cocos, leech, placenta, atractylodes, prepared licorice, rehmannia, angelica, semen astragali complanati, semen foeniculi, extract of polygonatum, and deer horn in parts by mass; S2, processing animal medicines: first, performing ultramicro-pulverization on the turtle shell, deer antler glue, leech, placenta and deer horn, and then passing them through a 200-400 mesh screen to obtain ultramicro powder; S3, extracting plant medicines: extracting semen cuscutae, medlar, herba epimedii, cistanche, schisandra chinensis, poria cocos by water extraction, alcohol extraction or water-alcohol combined extraction, and collecting and combining the extract; S4, concentrating: the extract is concentrated to a relative density of 1.10-1.30 at 50-60 DEG C; S5, mixing and preparation: the ultrafine powder prepared in S2 is mixed with the extract prepared in S4, dried, and prepared into a traditional Chinese medicine composition intermediate in a required dosage form.

[0013] After step S5, step S6 is further included: the traditional Chinese medicine composition intermediate is subjected to modern preparation technology processing, and the modern preparation technology is selected from the group consisting of nanocrystallization technology, liposome encapsulation technology, microencapsulation technology, or a combination thereof, so as to improve the bioavailability of the active ingredient.

[0014] The liposome encapsulation technology specifically comprises: mixing the traditional Chinese medicine composition intermediate with phospholipid and cholesterol at a weight ratio of (5-10):(1-3):1, and preparing liposome particles by using a film evaporation-high pressure homogenization method or an injection method.

[0015] The traditional Chinese medicine formula combination is applied to the preparation of a medicine for preventing and / or treating male infertility.

[0016] The male infertility is specifically oligospermia, asthenospermia, teratospermia, non-liquefaction of semen, or erectile dysfunction caused by kidney essence deficiency and blood stasis blocking collaterals; wherein, the medicine can significantly improve sperm density, sperm motility (a+b grade), and normal sperm morphology rate, and reduce the concentration of seminal plasma elastase.

[0017] In summary, compared with the prior art, the present application includes at least one of the following beneficial technical effects: 1. Compatibility science, treating both the main and the secondary: the core formula of the present application uses turtle shell, deer antler glue, and black Chinese donkey-hide as the monarch drug to greatly tonify kidney essence; cuscuta, medlar, herba epimedii, and cistanche as the ministerial drug to assist yang and fill essence; leech to activate blood and resolve stasis and dredge collaterals; and poria and schisandra to invigorate the spleen, calm the heart, and astringe the kidney, all of which are the auxiliary drugs. The whole formula closely focuses on the two core pathogenesis of kidney deficiency and blood stasis, and realizes the unity of tonifying the kidney and essence to treat the root and activating blood and resolving stasis to treat the secondary.

[0018] 2. Significant and explicit curative effect: the present application is confirmed by preclinical tests that the composition can significantly improve the sperm quantity, activity, and morphology of the modeling animals, and the mechanism of action may be related to regulating the hypothalamic-pituitary-gonadal axis function, improving testicular microcirculation, resisting oxidative stress, and resisting cell apoptosis.

[0019] 3. Technology integration, value improvement: the present application combines traditional Chinese medicine theory with modern preparation technologies such as nanocrystallization and liposome encapsulation. This not only solves the problems of slow effect and poor absorption of traditional Chinese medicine, greatly improves the bioavailability and targeting of active ingredients, but also endows traditional prescriptions with modern scientific and technological connotations, lays a foundation for the development of second-generation traditional Chinese medicine products, and has significant commercial value.

[0020] 4. Comprehensive protection scope: The application builds a three-dimensional and multi-level intellectual property protection system from the core formula, preferred formula, specific extract, various dosage forms, innovative preparation method to specific medical use, effectively prevents competitors from evading design, and provides solid protection for market exclusivity of the product.

[0021] 5. Strong syndrome targeting, realizing "tonifying, unblocking and nourishing" synergy, and improving inflammation indicators The application takes "tonifying kidney essence, promoting blood circulation and removing blood stasis, and invigorating spleen and essence" as the therapeutic principle, which not only solves the insufficient sperm production caused by kidney essence deficiency, but also unblocks the unsmooth essence channel caused by blood stasis, and realizes the kidney essence nourishment through invigorating spleen, and has no problems of "tonifying stagnation" and "unblocking injury" in combination. At the same time, the polysaccharide of Lycium barbarum and the polysaccharide of Polygonatum can reduce the concentration of seminal plasma elastase and improve the inflammation of the reproductive system, and solve the technical problem of ignoring the improvement of inflammation by existing traditional Chinese medicines.

[0022] 6. Advanced preparation process, high dissolution rate of active ingredients, and solid pharmacological basis The animal and mineral medicinal materials are super-micro-pulverized to 200-400 meshes, and the dissolution rate of active ingredients is greatly improved. The plant medicines are extracted by targeting, such as water extraction, alcohol extraction or water-alcohol combination, and the extraction rate of icariin and polysaccharide of Lycium barbarum is greatly improved, which solves the problem of "poor efficacy caused by insufficient active ingredients" in traditional process, ensures that sufficient pharmacological substances are taken in each time, and greatly shortens the treatment course. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The preparation flowchart of the male infertility functional traditional Chinese medicine formula combination of the application. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical scheme and advantages of the embodiments of the application clearer, the following will combine the drawings of the embodiments of the application to clearly and completely describe the technical scheme of the embodiments of the application. Obviously, the described embodiments are part of the embodiments of the application, rather than all the embodiments. Based on the described embodiments of the application, all other embodiments obtained by those skilled in the art belong to the scope of protection of the application. Figure 1 The technical scheme of the embodiments of the application is clearly and completely described. Obviously, the described embodiments are part of the embodiments of the application, rather than all the embodiments. Based on the described embodiments of the application, all other embodiments obtained by those skilled in the art belong to the scope of protection of the application.

[0025] A male infertility functional traditional Chinese medicine formula combination is composed of the following weight parts of traditional Chinese medicine raw materials: turtle shell 5-30 parts, deer antler glue 5-30 parts, dodder seed 5-35 parts, Lycium barbarum fruit 8-30 parts, Herba Epimedii 10-25 parts, Cistanche 5-35 parts, Schisandra chinensis 5-15 parts, Poria cocos 5-20 parts, leech 5-10 parts, and purple river car 5-20 parts. The sources and functions of the traditional Chinese medicine raw materials are as follows: Tortoise plastron is selected from the dorsal and ventral shells of the turtle, which is used after processing, such as sand roasting and vinegar soaking. Tortoise plastron has the effects of nourishing yin and suppressing yang, benefiting kidney and strengthening bones, and nourishing blood and tonifying heart, and is one of the monarch drugs. It can supplement kidney yin and improve the insufficient sperm motility caused by kidney essence deficiency. Deer horn glue is selected from the horns of Cervus elaphus or Cervus nippon, which is made into a solid glue by water decoction and concentration. Deer horn glue has the effects of warming and tonifying kidney yang and benefiting essence and blood, and is one of the monarch drugs. It can supplement kidney yang and promote sperm production. Cuscuta is selected from the dried mature seeds of Cuscuta chinensis of the Cuscuta family. Cuscuta has the effects of tonifying liver and kidney and astringing essence and urine, and is a ministerial drug. It can assist the monarch drug to enhance the kidney and essence tonifying power and improve the low sperm count. Medlar is selected from the dried mature fruits of Lycium barbarum of the Solanaceae family. Medlar has the effects of tonifying liver and kidney and benefiting essence and eyesight, and is a ministerial drug. It is rich in polysaccharides, which can enhance the immune function of the reproductive system and improve semen quality. Herba Epimedii is selected from the dried aboveground parts of Herba Epimedii of the Berberidaceae family. Herba Epimedii has the effects of tonifying kidney yang and strengthening tendons and bones, and is a ministerial drug. It contains icariin, which can promote testosterone secretion and improve sperm motility. Cistanche is selected from the dried succulent stems of Cistanche deserticola of the Orobanchaceae family. Cistanche has the effects of tonifying kidney yang, benefiting essence and blood, and moistening the intestines and promoting defecation, and is a ministerial drug. It can improve the infertility caused by kidney yang deficiency. Schisandra is selected from the dried mature fruits of Schisandra chinensis of the Magnoliaceae family. Schisandra has the effects of astringing, benefiting qi and promoting saliva secretion, tonifying kidney and calming the heart, and is an auxiliary drug. It can reduce the loss of kidney essence and improve the sperm abnormality rate. Poria cocos is selected from the dried sclerotia of Poria cocos of the Polyporaceae family. Poria cocos has the effects of promoting water excretion and dampness, and tonifying the spleen and calming the heart, and is an auxiliary drug. It can tonify the spleen and promote the nourishment of kidney essence. Leech is selected from the dried bodies of Limnatis humilis, Hirudo nipponia, or Limnatis convoluta of the Hirudinidae family. Leech has the effects of breaking blood and unblocking channels, and is an auxiliary drug. It can dredge the essence channel and improve the non-liquefaction of semen. Purple river car is selected from the dried placenta of a healthy human. Purple river car has the effects of warming the kidney and tonifying essence, and benefiting qi and nourishing blood, and is a ministerial drug. It contains proteins and hormones, which can promote sperm production and development.

[0026] Preferably, it further comprises the following auxiliary components: 5-20 parts of Atractylodes, 5-15 parts of fried licorice, 5-25 parts of prepared rehmannia, 5-20 parts of angelica, 5-20 parts of sauvignon, 5-15 parts of leek seeds, 5-30 parts of polygonatum extract, and 5-30 parts of deer antler. The above auxiliary components can further enhance the effects of tonifying the kidney and spleen, promoting blood circulation and nourishing blood, and are suitable for patients with more complex conditions, such as patients with deficiency of qi and blood and weakness of the spleen and stomach. Among them, the source and function of each auxiliary component are as follows: Atractylodes is selected from the dried rhizomes of Atractylodes lancea of the Asteraceae family. Atractylodes has the effects of tonifying the spleen and benefiting qi, and drying dampness and promoting water excretion, and is an auxiliary drug. It can enhance the spleen tonifying power of Poria cocos. Prepared licorice is made from the dried roots and rhizomes of licorice, a legume. It is processed with honey and has the functions of tonifying the spleen and replenishing qi, harmonizing other medicines, acting as an adjuvant, and mitigating the harshness of other medicinal materials. Prepared Rehmannia root is made from the dried tuberous root of Rehmannia glutinosa, a plant of the Scrophulariaceae family. It is prepared by stewing or steaming with wine. Prepared Rehmannia root has the functions of nourishing yin and blood, replenishing essence and marrow, and enhancing the yin-nourishing effect of tortoise shell. Angelica sinensis is selected from the dried root of Angelica sinensis, a plant of the Apiaceae family. Angelica sinensis has the functions of nourishing blood and promoting blood circulation, regulating menstruation and relieving pain, assisting leeches in promoting blood circulation and removing blood stasis, and nourishing blood without harming essence. Astragalus complanatus seeds are the dried, mature seeds of Astragalus membranaceus, a legume. Astragalus complanatus seeds have the functions of tonifying the kidneys and consolidating essence, nourishing the liver and improving eyesight, and enhancing the kidney-tonifying and essence-consolidating effects of Cuscuta chinensis. Leek seeds are the dried, mature seeds of the leek plant (Allium tuberosum), a member of the lily family. Leek seeds have the functions of warming and tonifying the liver and kidneys, strengthening yang and consolidating essence, and enhancing the kidney-warming and yang-tonifying effects of deer antler glue. The extract of Polygonatum sibiricum is made from the dried rhizome of Polygonatum sibiricum, a plant of the Liliaceae family. After extraction and purification, the extract of Polygonatum sibiricum has the functions of replenishing qi and nourishing yin, strengthening the spleen and benefiting the kidneys, and is rich in polysaccharides (content ≥50%), which can enhance immunity and kidney essence reserves. Deer antler is made from the unossified, densely haired young antlers of male sika deer or red deer. Deer antler has the functions of invigorating kidney yang, nourishing essence and blood, and strengthening tendons and bones. It is used as an adjuvant medicine to enhance the kidney-warming and essence-nourishing effects of deer antler glue and is suitable for patients with severe kidney yang deficiency.

[0027] Preferably, the Polygonatum extract is obtained by water extraction and alcohol precipitation or ultrasound-assisted extraction, and its Polygonatum polysaccharide content is greater than or equal to 50% by weight; Polygonatum extract is prepared using one of the following two methods: The steps of the water extraction and alcohol precipitation method are as follows: S1. Take dried Polygonatum rhizome and grind it to 100 mesh. The grinder used is Qingdao Jinghua XJ-100. S2. Add 8-12 times the amount of purified water, heat to 80-90℃ and reflux for extraction 2-3 times, 1.5-2 hours each time, and combine the extracts; S3. Filter the extract through a plate and frame filter. The plate and frame filter used is Hangzhou Kelu XAZ-500. Concentrate the filtrate under reduced pressure to a clear paste with a relative density of 1.15-1.20 measured at 60℃. S4. Slowly add 95% ethanol to the clear paste to make the ethanol volume fraction reach 60%-70%, let it stand for 12-16 hours, and take the precipitate by centrifugation. The centrifuge used is Shanghai Anting TGL-16G. S5, the precipitate is washed with 70% ethanol for 2-3 times, and vacuum drying is performed at a temperature of 50-60°C. After complete drying, crushing is performed, and a drying box of Shanghai Yiheng DZF-6050 is selected to obtain the rhizoma polygonati extract, and the polysaccharide content is greater than or equal to 55%. The ultrasonic-assisted extraction method is as follows: S1, the dried rhizoma polygonati is taken, crushed to 100 meshes, 6-8 times of purified water is added, and placed in an ultrasonic extractor. The extraction equipment of Zhengzhou Keda Machinery Instrument and Equipment Co., Ltd. is selected, the ultrasonic power is set to 300-400W, the temperature is set to 60-70°C, and the extraction is performed for 40-60 minutes. The extraction is performed for 2 times. S2, the extraction liquid is combined. The subsequent filtration, concentration, alcohol precipitation and drying steps are the same as those of the water extraction and alcohol precipitation method. Finally, the polysaccharide content of the rhizoma polygonati extract is greater than or equal to 50%.

[0028] The dosage form of the traditional Chinese medicine formula combination is an oral dosage form, which is a pill, a capsule, a granule, a tablet, a dripping pill or an oral liquid. Soft capsule: the preferred dosage form, the capsule shell is composed of gelatin, the brand of gelatin is Rose Lee food grade gelatin, glycerol is Yihai Jiali pharmaceutical grade glycerol, and purified water is composed according to a weight ratio of 3:1:1; the content is a suspension or emulsion formed by "nanopowdered active pharmaceutical ingredient mixed with a pharmaceutical carrier", the pharmaceutical carrier is selected from pharmaceutical grade soybean oil produced by Sanlian Group and pharmaceutical grade medium-chain triglyceride produced by Jialite Special Oil, the particle size D90 of the active pharmaceutical ingredient is less than or equal to 500 nm, each contains 0.5g of the pharmaceutical composition, and the disintegration time is less than or equal to 30 minutes.

[0029] Pill: honey pill uses Tong Ren Tang pharmaceutical grade honey as a binder, each pill weighs 9g; water pill uses purified water as a binder, each pill weighs 0.2g, and the disintegration time is less than or equal to 60 minutes.

[0030] Granule: uses Suisaike pharmaceutical grade stevioside as a flavoring agent, and Zhongliang pharmaceutical grade sucrose as a filler, each bag weighs 5g, and contains 2g of the pharmaceutical composition, which is clear and free of precipitate after dissolution.

[0031] Tablet: uses Shandong Heda pharmaceutical grade microcrystalline cellulose as a filler and Nippon Shokubai pharmaceutical grade hydroxypropyl methylcellulose as a binder to make a film-coated tablet, each tablet contains 0.3g of the pharmaceutical composition, and the disintegration time is less than or equal to 15 minutes.

[0032] When the dosage form of the traditional Chinese medicine formula combination is a capsule, it is a soft capsule, and the content contains a suspension or emulsion formed by the active pharmaceutical ingredient treated by the nanopowdering technology and the pharmaceutical carrier, wherein the particle size D90 of the active pharmaceutical ingredient is less than or equal to 500 nm.

[0033] Depending on the target dosage form, the intermediate or the product treated with S6 is formulated into an oral dosage form: A method for combining traditional Chinese medicine formulas for treating male infertility, such as Figure 1 As shown, it includes the following steps: S1. Raw materials provided: Weigh the following ingredients by weight: tortoise shell, deer antler glue, dodder seed, wolfberry fruit, epimedium, cistanche, schisandra fruit, poria cocos, leech, placenta, atractylodes macrocephala, prepared licorice root, prepared rehmannia root, angelica sinensis, psoralea corylifolia seed, allium tuberosum seed, polygonatum extract, and deer antler raw material. Specifically, weigh the ingredients by weight. Note that the basic raw materials are essential, and auxiliary components can be selected according to the patient's condition. Use a Mettler Toledo Instruments PL602E electronic balance with an accuracy of 0.01g to accurately weigh each raw material. Among them, animal or mineral medicinal materials, such as tortoise shell and deer antler glue, need to remove impurities in advance, and plant medicinal materials need to be washed and dried to ensure that their moisture content is ≤10%. Polygonatum extract is a pre-prepared finished product. S2. Processing Animal Drugs: Tortoise shell, deer antler glue, leeches, placenta, and deer antler are first ultra-finely pulverized and passed through a 200-400 mesh sieve to obtain ultra-fine powder. Specifically, the tortoise shell, deer antler glue, leeches, placenta, and deer antler are fed into an ultra-fine pulverizer. The ultra-fine pulverizer is manufactured by Jinan Dawei Machinery Co., Ltd., model XDW-6, with a pulverizing time of 18 minutes. After pulverization, the powder is passed through a 200-400 mesh sieve, for example, a 300 mesh sieve is preferable. The sieve screen is a filter screen produced by Xinxiang City Screen Factory. The ultra-fine powder is then sealed and stored in an environment with a relative humidity ≤60% to prevent moisture absorption and clumping. S3. Extraction of Herbal Medicines: The herbal medicines, including Cuscuta chinensis, Lycium barbarum, Epimedium brevicornu, Cistanche deserticola, Schisandra chinensis, and Poria cocos, are extracted using water extraction, alcohol extraction, or a combination of water and alcohol extraction. The extracts are collected and combined. Specifically, the herbal medicines, such as Cuscuta chinensis, Lycium barbarum, and Epimedium brevicornu, are placed into a multi-functional extraction tank. The extraction tank is manufactured by Wenzhou Fengyuan Machinery Co., Ltd., model TQ-1000. The extraction method is selected based on the solubility of the active ingredients. Water extraction: Suitable for polysaccharides, such as wolfberry and polygonatum. Add 9 times the amount of purified water, reflux at 95℃ twice, 2 hours each time, and combine the extracts. Alcohol extraction: Suitable for flavonoids or saponins, such as Epimedium and Cuscuta. Add 7 times the amount of 70% ethanol, reflux at 75°C twice, 1.5 hours each time, and combine the extracts. Water-ethanol combined extraction: first extract with water, following the same steps as water extraction; then extract the residue with 70% ethanol, following the same steps as ethanol extraction; finally, combine the two extracts to take into account both water-soluble and fat-soluble active ingredients. S4, concentration: the extract is concentrated to 50-60°C under the relative density of 1.10-1.30 extract, specifically, the extract is filtered by plate and frame filter, Hangzhou Kelu purification equipment Co., Ltd., model XAZ-500 to remove the residue; the filtrate is sent to the vacuum concentration tank, set temperature 57°C to concentrate to the relative density of 1.10-1.30 extract, the water content of the extract is ≤20%, the concentration tank is selected from Shanghai shengsheng technology Co., Ltd. The concentration equipment with model ZN-1000, note 50°C with hydrometer, select Shanghai precision scientific instrument Co., Ltd., model WBZ-1 hydrometer; S5, mixing and preparation: the ultrafine powder prepared in S2 is mixed with the extract prepared in S4, dried, and the dried material is crushed by a universal crusher to prepare a traditional Chinese medicine composition intermediate of the required dosage form. Specifically, the mixing equipment is a double helix mixer with model CH-200 produced by Changzhou Limajian drying engineering Co., Ltd., the drying box is a drying double equipment with model DZF-6050 produced by Shanghai Yiheng scientific instrument Co., Ltd., and the crushing machine is a crushing equipment with model XJ-100 produced by Qingdao Jinghua, and the ultrafine powder and extract material is crushed to 120 mesh.

[0034] After step S5, step S6 is further included: the traditional Chinese medicine composition intermediate is treated by modern preparation technology, and the modern preparation technology is selected from: nanocrystallization technology, liposome wrapping technology, microencapsulation technology or a combination thereof, so as to improve the bioavailability of the active ingredient. Specifically, nanocrystallization: the intermediate is put into a nanocrystallization machine, the crushing time is set to 35 minutes, the nanometer powder is prepared, the powder dispersibility index is ≤0.3, and the crushing machine is selected from a crushing equipment with model NMM-80 produced by Shanghai nanometer micropowder equipment Co., Ltd.; Liposome wrapping: the intermediate is mixed with soybean phospholipid and cholesterol for pharmaceutical use in Shanghai Taiwei pharmaceutical Co., Ltd. According to the weight ratio (5-10): (1-3): 1, pH 7.4 phosphate buffer is added, stirring and dissolving, then transferred into a rotary evaporator, the evaporator is selected from a evaporation equipment with model RE-52AA produced by Shanghai Yalong biochemical instrument factory, evaporated into a film at 60°C; add buffer to the film and oscillate to get the initial milk, the initial milk is passed through a high pressure homogenizer, the homogenizer is selected from a homogenization equipment with model FH100 produced by Shanghai Frueko fluid machinery manufacturing Co., Ltd., a total of 4 times, to prepare liposomes, the encapsulation efficiency is ≥80%; Microencapsulation: Danisco pharmaceutical grade arabic gum and Xiwang group pharmaceutical grade malt dextrin are used as wall material at a ratio of 1:1, and the intermediate is used as core material, wherein the core material: wall material = 1:2.5, the emulsion is prepared by mixing; the emulsion is dried by a spray dryer, the dryer is a drying equipment with model LPG-5 produced by Wuxi Wosun drying equipment Co., Ltd., the inlet air temperature is set to 190°C, and the outlet air temperature is set to 85°C, to prepare microcapsules, the encapsulation efficiency is ≥75%.

[0035] Dosage form molding: according to the target dosage form, the intermediate or S6 treated product is made into an oral dosage form, specifically, Soft capsule: nanometer powder is mixed with soybean oil at a ratio of 1:2 to form a suspension, and a soft capsule machine is used to press and form, using a model HJY-1000 device produced by Beijing Hanlin Aerospace Technology Development Co., Ltd., and dried at 42°C for 4 hours; Granules: the intermediate is mixed with sucrose at a ratio of 1:1 to form a soft material, granulated with a 16-mesh sieve, dried at 60°C, and granulated with a 12-mesh sieve; Tablets: liposomes are mixed with 20% microcrystalline cellulose and 1% magnesium stearate, and a tablet press is used to press the tablets, using a model ZP35A tablet press produced by Shanghai Tianfan Pharmaceutical Machinery Manufacturing Co., Ltd., and coated with a hydroxypropyl methylcellulose film.

[0036] The liposome encapsulation technique is as follows: the intermediate of the traditional Chinese medicine composition is mixed with phospholipid and cholesterol at a weight ratio of (5-10):(1-3):1, and a thin film evaporation-high pressure homogenization method or injection method is used to prepare liposome particles.

[0037] Application of the traditional Chinese medicine formula combination in the preparation of a drug for preventing and / or treating male infertility.

[0038] Male infertility is specifically oligospermia, asthenospermia, teratospermia, non-liquefaction of semen, or erectile dysfunction caused by kidney essence deficiency and blood stasis blocking the collaterals; among them, the drug can significantly improve sperm density, sperm motility (a+b grade), and normal sperm morphology rate, and reduce the concentration of seminal plasma elastase.

[0039] Example 1: preparation of soft capsules containing auxiliary components Formula composition, note: by weight Basic raw materials: turtle shell 20 parts, deer antler glue 20 parts, Chinese milkvetch 25 parts, medlar 20 parts, herba epimedii 18 parts, cistanche 25 parts, schisandra chinensis 10 parts, poria cocos 15 parts, leech 8 parts, and purple river car 12 parts; Auxiliary components: atractylodes 15 parts, fried licorice 10 parts, radix rehmanniae preparata 20 parts, angelica 15 parts, sophora alopecuroides 15 parts, leek seed 10 parts, and extract of polygonatum 20 parts (prepared by water extraction and alcohol precipitation method, with a polysaccharide content of 56%); antler 20 parts.

[0040] The preparation steps are as follows: S1, raw material weighing: weigh all the above-mentioned raw materials with a Mettler-Toledo PL602E electronic balance, and prepare the extract of polygonatum in advance by the water extraction and alcohol precipitation method; S2, animal medicine super micro-pulverization: turtle shell, deer horn glue, leech, black Chinese donkey-hide, deer horn was put into Jinan Da micro XDW-6 super micro-pulverizer, pulverized for 18 minutes, passed through 300 mesh sieve, and super micro-powder was obtained; S3, plant medicine extraction: the remaining 12 kinds of plant medicines were put into Wenzhou Fengyuan TQ-1000 extraction tank, and water-alcohol combined extraction was adopted: 9 times amount of purified water was added, 95 DEG C reflux was carried out for 2 times, each time for 2 hours, the residue was added with 7 times amount of 70% ethanol, 75 DEG C reflux was carried out for 2 times, each time for 1.5 hours, and the extraction liquid was combined; S4, concentration: the extraction liquid was filtered through Hangzhou Ke filter XAZ-500, and the filtrate was concentrated to extract of relative density 1.20 (50 DEG C measurement) by Shanghai Shensheng ZN-1000 concentration tank (55 DEG C, -0.07 MPa); S5, intermediate drying: the super micro-powder and extract were mixed by Changzhou Limama CH-200 mixer at 250 r / min for 20 minutes, and dried in Shanghai Yiheng DZF-6050 vacuum drying oven at 55 DEG C until the water content was 4%, and then pulverized to 120 mesh to obtain the intermediate; S6, nano-pulverization: the intermediate was put into Shanghai Nano NMM-80 nano-pulverizer, and pulverized at 0.9 MPa for 35 minutes, and the particle size D90=420 nm was measured; S7, soft capsule forming: the nano-powder was mixed with soybean oil at 1:2 to form a suspension, and the suspension was pressed into 0.5 g / particle soft capsules by Beijing Hanlin Hangyu HJY-1000 soft capsule machine, and dried at 42 DEG C for 4 hours, and packaged.

[0041] Quality detection is as follows: Disintegration time: 22 minutes, which meets the standard of not more than 30 minutes, and the detector is selected as Tianjin Tianguang TJ-2000; Active ingredient content: icariin 0.92 mg / particle, lycium barbarum polysaccharide 16.5 mg / particle, and polygonatum sibiricum polysaccharide 12.3 mg / particle; Microbial limit: total bacterial count 850 cfu / g, and mold and yeast 65 cfu / g, which meets the standard of Chinese Pharmacopoeia for oral preparations of traditional Chinese medicine.

[0042] Example two: preparation of granules of the basic formula Formula composition, note: by weight: Turtle shell 15 parts, deer horn glue 15 parts, cuscuta 30 parts, lycium barbarum 25 parts, epimedium 20 parts, cistanche 30 parts, schisandra 12 parts, poria cocos 18 parts, leech 7 parts, black Chinese donkey-hide 10 parts.

[0043] The preparation steps are as follows: S1, animal medicine super micro-pulverization: turtle shell, deer horn glue, leech, and black Chinese donkey-hide were put into Jinan Da Micro XDW-6 super micro-pulverizer, pulverized for 20 minutes at 3000 r / min, and passed through a 200-mesh sieve; S2, plant medicine extraction: six kinds of plant medicines, including cuscuta and medlar, were put into Wenzhou Fengyuan TQ-1000 extraction tank, 9 times of purified water was added, and 90°C reflux extraction was performed for 2 times, 2 hours each time, and the extraction liquid was combined; S3, concentration: after the extraction liquid was filtered, Shanghai Shensheng ZN-1000 concentration tank was used, the temperature was set to 50°C, and the extraction was concentrated to the extract with a relative density of 1.15, and the density was measured at 50°C; S4, intermediate and granule preparation: the super micro-powder and the extract were mixed, vacuum dried at 50°C until the water content was 5%, and pulverized to 100 mesh; the soft material was mixed with sucrose at a ratio of 1:1 and 5% hydroxypropyl methyl cellulose, granulated on a 16-mesh sieve, dried at 60°C, and the granules were packaged into 5g bags.

[0044] Example three: preparation of liposome-encapsulated tablets Formula composition, note: by weight Basic raw materials: turtle shell 20 parts, deer horn glue 20 parts, cuscuta 25 parts, medlar 20 parts, herba epimedii 18 parts, cistanche 25 parts, schisandra chinensis 10 parts, poria cocos 15 parts, leech 8 parts, and black Chinese donkey-hide 12 parts; Auxiliary components: atractylodes 15 parts, fried licorice 10 parts, rehmannia 20 parts, angelica 15 parts, milk vetch seed 15 parts, leek seed 10 parts, and extract of polygonatum 20 parts (ultrasonic-assisted extraction preparation, polysaccharide content 52%); antler 20 parts.

[0045] The preparation steps are as follows: Intermediate preparation: steps 1-5 in example 1, intermediate was obtained; Liposome preparation: the intermediate, soybean phospholipid, and cholesterol were mixed at a ratio of 8:2:1, phosphate buffer was added, and Shanghai Yalian RE-52AA rotary evaporator was used to form a film at 60°C, and the primary milk was obtained by adding buffer and oscillation; the primary milk was homogenized 4 times by Shanghai Fulu FH100 high-pressure homogenizer; Tablet forming: the liposome was mixed with 20% microcrystalline cellulose and 1% magnesium stearate, and Shanghai Tianfan ZP35A tablet press was used to press into tablets, and hydroxypropyl methyl cellulose film coating was used, and the tablets were obtained.

[0046] Bioavailability detection The blood drug concentration of icariin of the tablet and the traditional pill of the embodiment is detected by high performance liquid chromatography (HPLC) in healthy volunteers, and the detection equipment is Agilent 1260 HPLC: The medicinal mechanism and taking method of the present application: First of all, it needs to be clear that the traditional Chinese medicine formula combination involved in the present application is mainly used for treating male infertility, and the present application takes the preparation of the traditional Chinese medicine formula combination and its medicinal mechanism as an example to elaborate the treatment principle and taking method in detail, and the medicinal mechanism is as follows: The present application realizes the treatment of male infertility from the synergistic effect of traditional Chinese medicine theory and modern pharmacology: Traditional Chinese medicine theory level: accurate compatibility, syndrome treatment Supplementing kidney and filling essence, strengthening the root and nourishing the body: turtle shell (tonifying yin) and deer horn glue (tonifying yang) are the monarch drugs, tonifying yin and yang, and directly attacking the root of "kidney essence deficiency"; the servant drugs of cuscuta, medlar and icariin promote sperm production and maturation, improve oligospermia and asthenospermia through the dual effects of "warming the kidney to produce essence and tonifying yin to nourish essence"; Promoting blood circulation and removing blood stasis, dredging collaterals and essence: water leech breaks blood and removes blood stasis, and angelica tonifies blood and promotes blood circulation, which synergistically dredges the essence channel and solves the "blood stasis blocking the collaterals" of the syndrome, and improves the non-liquefaction of semen; at the same time, angelica can alleviate the potential risk of water leech "promoting blood circulation and damaging essence", and achieve "dredging without damage and tonifying"; Spleen and essence, after nourishing the body: poria and atractylodes are the auxiliary drugs, which can invigorate the spleen and tonify qi, transport water and dampness, and provide nourishing substances for "kidney essence" through "after spleen and stomach" to transport qi and blood, so as to avoid "simple kidney tonification leading to tonification without transformation", and further enhance the effect of kidney tonification and essence filling.

[0047] Modern pharmacology level: synergistic effect and resistance reduction, improving drug efficacy Superfine grinding enhances dissolution: superfine grinding of 200-400 mesh increases the specific surface area of animal or mineral medicinal materials by 15-20 times, and the cell wall damage rate is increased by 80%, the dissolution rate of active ingredients such as collagen (turtle shell) and amino acids (deer horn glue) is greatly improved, and the problem of insufficient dissolution of traditional grinding is solved; Targeted extraction and retention of activity: water extraction, alcohol extraction or water-alcohol combined extraction can retain different types of active ingredients, such as 35% increase in the extraction rate of medlar polysaccharide and 28% increase in the extraction rate of icariin, to ensure sufficient pharmacodynamic material basis; Modern preparation improves bioavailability: Nanometer grinding greatly reduces the particle size of active ingredients, greatly improves the permeability of intestinal mucosa, and avoids the obstruction of intestinal physical barrier; Liposome encapsulation forms "drug vesicles", which can protect active ingredients from being degraded by gastrointestinal enzymes, for example, polysaccharides are not destroyed by pepsin, and at the same time, it promotes the absorption of intestinal epithelial cells, and the overall bioavailability is greatly improved; Multi-component synergistic improvement of pathological indicators: Icariin promotes testosterone secretion and enhances sperm motility; Lycium barbarum polysaccharides and Polygonatum sibiricum polysaccharides inhibit inflammatory responses in the reproductive system, reduce seminal plasma elastase concentration, and lower inflammatory markers; Hirudin improves the microcirculation of reproductive organs, providing a favorable microenvironment for sperm production and reducing sperm abnormality rate.

[0048] The method of administration is as follows: The herbal formula combination of this invention requires "regular use and course of treatment monitoring," and the specific usage and dosage should be adjusted according to the dosage form. The usage and dosage of different dosage forms are as follows: Dosage form, administration method, dosage, and administration time Take 2 soft capsules with warm water each time, each capsule containing 0.5g, 3 times a day, preferably 30 minutes after meals; Take one honey pill with warm water or chew it. Each pill contains 9g. Take twice a day, once in the morning and once in the evening. It is best to take it 30 minutes after meals. For granules, dissolve in warm water. Take one sachet each time, with each sachet containing 5g, three times a day, preferably 30 minutes after meals. Take 3 tablets (each tablet weighing 0.3g) with warm water, 3 times a day, preferably 30 minutes after meals. The oral liquid is taken directly, one vial each time, each vial containing 10 ml and 2g of medicine, three times a day, preferably 30 minutes after meals; The treatment course and precautions are as follows: Treatment course setting: 4 weeks is one course of treatment. After taking 2-3 courses of treatment, the efficacy is evaluated by routine semen analysis. If the sperm density, motility grade A+B, normal morphology rate and seminal plasma elastase test are positive, the efficacy can be evaluated. If the efficacy is significant, the dosage can be reduced, for example, the soft capsules can be reduced to 1 capsule each time, and 1 course of treatment can be consolidated. Contraindications and Diet: Avoid spicy foods such as chili peppers and Sichuan peppercorns, raw and cold foods such as ice cream, and greasy foods such as fried foods during the course of treatment. Avoid smoking and alcohol. Avoid staying up late. Get more than 6 hours of sleep per day and less than 8 hours of sitting per day. Appropriately increase exercise such as jogging and Tai Chi, 3-4 times a week for 30 minutes each time, to improve the microcirculation of the reproductive system. Special populations: This product is contraindicated for those who are allergic to any of the ingredients in this formula, such as leeches or deer antler; patients with hypertension or diabetes should take it under the guidance of a physician. For example, diabetic patients can replace sucrose with steviol glycosides in the granules. Drug interaction: avoid taking with western medicine hormone drugs, such as testosterone tablets, if necessary, the interval should be more than 2 hours, to prevent endocrine disorders; When combined with antibiotics, such as levofloxacin, the interval should be 1 hour to avoid affecting absorption.

[0049] The present application can be used for treating male infertility by developing a traditional Chinese medicine composition. The composition is based on the TCM principle of "tonifying kidney and filling essence, promoting blood circulation and removing blood stasis, and regulating liver, spleen and kidney", and by scientific raw material compatibility and combination with modern preparation technology, the efficacy and bioavailability are significantly improved, and the treatment effect is efficient and stable.

[0050] In addition, it should be noted that in the description of the present application, unless otherwise specified and limited, the terms "mounting", "connecting", "connecting" should be understood broadly, for example, it can be fixedly connected, or it can be detachably connected, or integrally connected; it can be mechanically connected, or it can be electrically connected; it can be directly connected, or it can be indirectly connected through an intermediate medium; it can be the communication inside two elements. For those skilled in the art, the specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0051] The above is the preferred embodiment of the present application, it should be pointed out that for ordinary skilled in the art, without departing from the principles of the present application, a number of improvements and refinements can also be made, these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A combination of traditional Chinese medicine for male infertility, characterized in that: The traditional Chinese medicine formula combination comprises the following components by weight: turtle shell 5-30 parts, deer antler glue 5-30 parts, semen cuscutae 5-35 parts, medlar 8-30 parts, herba epimedii 10-25 parts, cistanche 5-35 parts, schisandra chinensis 5-15 parts, poria cocos 5-20 parts, leech 5-10 parts, and dried human placenta 5-20 parts. ​ 2. The traditional Chinese medicine formula combination for treating male infertility as described in claim 1, characterized in that: The traditional Chinese medicine formula combination further comprises the following components by weight: atractylodes 5-20 parts, licorice 5-15 parts, rehmannia 5-25 parts, angelica 5-20 parts, milk vetch seed 5-20 parts, Chinese chive seed 5-15 parts, polygonatum extract 5-30 parts, and deer horn 5-30 parts.

3. The combination of claim 2, wherein the combination is used for male infertility. The polygonatum extract is prepared by water extraction and alcohol precipitation or ultrasonic-assisted extraction, and the weight content of polysaccharide of polygonatum is greater than or equal to 50%.

4. The traditional Chinese medicine formula combination for treating male infertility as described in claim 3, characterized in that: The dosage form of the traditional Chinese medicine formula combination is an oral dosage form, which is a pill, a capsule, a granule, a tablet, a dripping pill, or an oral liquid.

5. The combination of claim 4, wherein the combination is used for male infertility. When the dosage form of the traditional Chinese medicine formula combination is a capsule, the capsule is a soft capsule, and the content of the capsule comprises a suspension or emulsion formed by the active pharmaceutical ingredient treated by nano-pulverization technology and a pharmaceutical carrier, wherein the particle size D90 of the active pharmaceutical ingredient is less than or equal to 500 nm.

6. A method for preparing the traditional Chinese medicine formula combination for male infertility according to any one of claims 1-5, characterized in that, The method comprises the following steps: S1, providing raw materials: weighing turtle shell, deer antler glue, semen cuscutae, medlar, herba epimedii, cistanche, schisandra chinensis, poria cocos, leech, dried human placenta, atractylodes, licorice, rehmannia, angelica, milk vetch seed, Chinese chive seed, polygonatum extract, and deer horn according to the mass fraction; S2, processing animal medicines: performing ultramicro-pulverization on the turtle shell, deer antler glue, leech, dried human placenta, and deer horn, and passing the ultramicro-powder through a 200-400 mesh screen to obtain ultramicro-powder; S3, extracting plant medicines: extracting semen cuscutae, medlar, herba epimedii, cistanche, schisandra chinensis, and poria cocos by water extraction, alcohol extraction, or water-alcohol combined extraction, and collecting and combining the extract; S4, concentrating: concentrating the extract to an extract at 50-60 ℃ and having a relative density of 1.10-1.30; S5, mixing and preparation: mixing the ultramicro-powder prepared in S2 and the extract prepared in S4, drying, and preparing a traditional Chinese medicine composition intermediate in a required dosage form.

7. The method for male infertility treatment of claim 6, wherein the method comprises: After step S5, step S6 is further included: processing the traditional Chinese medicine composition intermediate by modern preparation technology, and the modern preparation technology is selected from nano-pulverization technology, liposome encapsulation technology, microencapsulation technology, or a combination thereof, so as to improve the bioavailability of the active ingredient.

8. The combination of claim 7, wherein the combination is used for male infertility. The liposome encapsulation technology is specifically: mixing the traditional Chinese medicine composition intermediate with phospholipid and cholesterol according to a weight ratio of (5-10):(1-3):1, and preparing liposome particles by a film evaporation-high pressure homogenization method or an injection method.

9. Use of the traditional Chinese medicine formula combination according to any one of claims 1-5 in the preparation of a medicine for preventing and / or treating male infertility.

10. The combination of claim 9, wherein the combination is used for male infertility. The male infertility is specifically oligospermia, asthenospermia, teratospermia, non-liquefaction of semen, or erectile dysfunction caused by kidney essence deficiency and blood stasis blocking the collaterals; and the medicine can significantly improve the sperm density, sperm motility, and normal sperm morphology rate, and reduce the concentration of seminal plasma elastase.

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