WO2022057157A1 - 一种治疗儿童性早熟的中药组合物及其制备方法与应用 - Google Patents

一种治疗儿童性早熟的中药组合物及其制备方法与应用 Download PDF

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WO2022057157A1
WO2022057157A1 PCT/CN2020/141451 CN2020141451W WO2022057157A1 WO 2022057157 A1 WO2022057157 A1 WO 2022057157A1 CN 2020141451 W CN2020141451 W CN 2020141451W WO 2022057157 A1 WO2022057157 A1 WO 2022057157A1
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chinese medicine
traditional chinese
weight
precocious puberty
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PCT/CN2020/141451
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English (en)
French (fr)
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倪鑫
王晓玲
柳静
于飞
宋更申
赵立波
郭春彦
白国良
郑红兵
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首都医科大学附属北京儿童医院
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Publication of WO2022057157A1 publication Critical patent/WO2022057157A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8964—Anemarrhena
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/58—Reptiles
    • A61K35/586—Turtles; Tortoises, e.g. terrapins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/51—Gentianaceae (Gentian family)
    • A61K36/515—Gentiana
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/536—Prunella or Brunella (selfheal)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/756—Phellodendron, e.g. corktree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A61K36/804—Rehmannia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A61K36/808—Scrophularia (figwort)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A61K36/815—Lycium (desert-thorn)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/884—Alismataceae (Water-plantain family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A61K36/8998—Hordeum (barley)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the invention relates to a traditional Chinese medicine composition for treating precocious puberty in children, and also relates to a preparation method and application of the traditional Chinese medicine composition.
  • precocious puberty refers to the premature appearance of secondary sexual characteristics before puberty, that is, girls begin to develop breasts before the age of 8 and menstruation occurs before the age of 10; boys have sexual characteristics such as testicles and penis enlargement before the age of 9. It has become one of the most common pediatric endocrine diseases that endanger children's health. Because children's intelligence and psychology are not yet mature, premature sexual maturity is extremely harmful to their physical and mental health. At the same time, precocious puberty leads to rapid bone growth and early closure of the epiphysis in children, and their height is often shorter than normal in adulthood.
  • Precocious puberty is mainly divided into:
  • Central precocious puberty that is, true precocious puberty, which is caused by the early initiation of the hypothalamic-pituitary-gonadal axis. The mechanism of occurrence is the same as that of the normal situation. With the rapid increase in height and weight, the epiphysis is closed in advance, and the growth is advanced. Stop, eventually resulting in short stature, including: 1 idiopathic central precocious puberty (ICPP), hypothalamic neurosecretion disorders, excessive production of GnRH (gonadotropin-releasing hormone), and premature development of sexual characteristics; 2 Central nervous system lesions.
  • ICPP idiopathic central precocious puberty
  • GnRH gonadotropin-releasing hormone
  • PPP Peripheral precocious puberty
  • pseudo precocious puberty also known as pseudo precocious puberty
  • the hypothalamic-pituitary-gonadal axis is not mature, and the symptoms of homosexual or heterosexual precocious puberty occur due to the sex hormones produced by peripheral tissues, that is, boys can Enlarged penis, pubic hair, armpit hair, and Adam's apple, but not enlarged testicles, and boys may also have female secondary sexual characteristics such as gynecomastia; similarly girls may have breast development, pubic and armpit hair, and males Secondary sexual characteristics such as beard, clitoral enlargement.
  • precocious puberty It is a special type of precocious puberty, which refers to the premature appearance of secondary sexual characteristics in patients. The most common type is simple premature breast development, which usually occurs in girls under the age of two.
  • Peripheral precocious puberty and incomplete precocious puberty are simple early breast development or simple early pubic hair development, without the development and growth of other sexual characteristics, and most do not require special drug treatment, or appropriate medication.
  • GnRHa gonadotropin-releasing hormone analog
  • TCM syndrome differentiation The symptoms of TCM syndrome differentiation include fear of heat, thirst, flushed face, irritability, heat in the five hearts, night sweats, constipation, red tongue or red tip of the tongue.
  • TCM treatment of precocious puberty in children often adopts TCM syndrome differentiation.
  • Clinically children with early or mid-stage disease are not advised to use western medicine for treatment, but are suitable for traditional Chinese medicine treatment.
  • a number of traditional Chinese medicine preparations have been used in clinical practice.
  • the existing traditional Chinese medicine preparations for the treatment of precocious puberty in children also have inaccurate curative effects, poor curative effect for children with severe illness, long medication cycle, and poor compliance with medication in children due to drug dosage form and taste.
  • some children During taking the medicine, some children have vomiting, abdominal discomfort, abdominal pain, acid regurgitation, and some discomfort such as anorexia after taking the medicine for a long time.
  • the embodiment of the present invention provides a traditional Chinese medicine composition for treating precocious puberty in children, which has better curative effect and less medicinal material dosage compared with the prior art.
  • a traditional Chinese medicine composition for treating precocious puberty in children comprising the following raw materials in parts by weight: 6-15 parts of Anemarrhena, 6-15 parts of Rehmannia glutinosa, 3-10 parts of Scrophulari 5 parts, 3-15 parts of Digupi, 6-15 parts of Cortex Moutan, 3-10 parts of Alisma, 6-15 parts of Prunella vulgaris, 3-10 parts of gentian, and 6-15 parts of malt.
  • the traditional Chinese medicine composition for treating precocious puberty in children includes the following raw materials in parts by weight: 8-12 parts of Anemarrhena, 8-12 parts of Rehmannia glutinosa, 4-8 parts of Scrophulariaceae, and 8-12 parts of Turtle A. 2 to 4 parts of Treats, 4 to 10 parts of Digupi, 8 to 12 parts of Cortex Moutan, 4 to 8 parts of Alisma, 8 to 12 parts of Prunella vulgaris, 4 to 8 parts of gentian, and 8 to 12 parts of malt;
  • the Chinese medicine composition for treating precocious puberty in children includes the following raw materials in parts by weight: 10 parts of Anemarrhena, 10 parts of Rehmannia glutinosa, 6 parts of Scrophulariaceae, 10 parts of Turtle A, 3 parts of Treats, 6 parts of Digupi 10 parts of Cortex Moutan, 6 parts of Alisma, 10 parts of Prunella vulgaris, 6 parts of gentian, and 10 parts of malt;
  • the Anemarrhena is salt Anemarrhena.
  • the turtle shell is the turtle shell.
  • the malt is sautéed malt.
  • the traditional Chinese medicine composition for treating precocious puberty in children is composed of Anemarrhena, Rehmannia glutinosa, Scrophulariaceae, Turtle A, Treats, Digupi, Cortex Moutan, Alisma, Prunella vulgaris, Gentiana and The malt is composed or prepared according to the above weight ratio.
  • the present invention also provides a method for preparing the above-mentioned traditional Chinese medicine composition for treating precocious puberty in children, for example, each medicinal material can be mixed according to a conventional method in the art. In some embodiments, each medicinal material is pulverized and mixed.
  • the present invention also provides a traditional Chinese medicine preparation for treating precocious puberty in children, which is prepared by using the above-mentioned traditional Chinese medicine composition for treating precocious puberty in children as the main active ingredient, or further includes pharmaceutically usable auxiliary materials.
  • the traditional Chinese medicine preparation for treating precocious puberty in children is prepared by using the above-mentioned traditional Chinese medicine composition for treating precocious puberty in children as the only active ingredient, or further includes pharmaceutically acceptable excipients.
  • the traditional Chinese medicine preparation for treating precocious puberty in children is prepared separately from the above-mentioned traditional Chinese medicine composition for treating precocious puberty in children as the main active ingredient or the only active ingredient (that is, without pharmaceutically acceptable excipients). , or made from the traditional Chinese medicine composition as the main active ingredient or the only active ingredient and pharmaceutically acceptable auxiliary materials.
  • the traditional Chinese medicine preparation for treating precocious puberty in children of the present invention can be made into various commonly used pharmaceutical forms.
  • the traditional Chinese medicine preparation for treating precocious puberty in children may specifically be granules, tablets (including dispersible tablets, effervescent tablets), pills (including drop pills), capsules, oral liquids, syrups or External preparations, etc.
  • the pharmaceutically acceptable adjuvants refer to conventional pharmaceutical carriers in the pharmaceutical field, selected from fillers, binders, disintegrants, lubricants, suspending agents, wetting agents, pigments, flavors, solvents , one or more of surfactants or flavoring agents.
  • the filler is selected from starch, sucrose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose or glucose and the like.
  • the binder is selected from cellulose derivatives, alginates, starch, water, dextrin, gelatin or polyvinylpyrrolidone and the like.
  • the disintegrant is selected from microcrystalline cellulose, sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose or croscarmellose sodium.
  • the lubricant is selected from stearic acid, polyethylene glycol, calcium carbonate, sodium bicarbonate, micropowder silica gel, talc or magnesium stearate;
  • the suspending agent is selected from micropowder silica gel, beeswax, cellulose, solid polyethylene glycol.
  • the humectant is selected from glycerin, Tween-80, ethoxylated hydrogenated castor oil or lecithin.
  • the solvent is selected from ethanol, liquid polyethylene glycol, isopropanol, Tween-80, glycerol, propylene glycol or vegetable oil
  • the vegetable oil is selected from soybean oil, castor oil, peanut oil, blended oil and the like.
  • the surfactant is selected from sodium dodecylbenzenesulfonate, stearic acid, polyoxyethylene-polyoxypropylene copolymer, fatty acid sorbitan or polysorbate (Tween) and the like.
  • the flavoring agent is selected from aspartame, sucralose, essence, steviol, acesulfame potassium, citric acid or sodium saccharin.
  • the traditional Chinese medicine preparation is an oral liquid, wherein the used excipients are selected from xylitol and oligosaccharides, and the used pH adjuster is citric acid or its sodium salt.
  • the preparation method of the traditional Chinese medicine preparation for treating precocious puberty in children includes: taking each medicinal material according to the above-mentioned proportion of the traditional Chinese medicine composition; first adding water to decoct (vinegar) turtle shell; Add Anemarrhena, raw Rehmannia glutinosa, Scrophularia Radix, Cortex Phellodendri, Digupi, Cortex Moutan, Alisma, Prunella vulgaris, Gentian grass, malt again in the boiling liquid (A), add water and decocting; get the second decocting liquid (B ).
  • the obtained second decocting liquid (B) can be made into an oral liquid or syrup by adding pharmaceutically acceptable auxiliary materials such as a flavoring agent.
  • the obtained second decoction liquid (B) can be further concentrated to prepare an extract.
  • the extract is concentrated to a relative density of 1.10-1.30 (60°C).
  • the obtained extract can be further prepared into granules, tablets (including dispersible tablets and effervescent tablets), pills (including drop pills), capsules, oral liquids, syrups or external preparations and the like.
  • the preparation method of the traditional Chinese medicine preparation for the treatment of childhood precocious puberty comprising:
  • step 2) in step 1) gained decocting liquid, add (salt) Anemarrhena, Rehmannia glutinosa, Scrophularia, Cork, Digupi, Cortex Moutan, Alisma, Prunella, gentian, malt by proportioning, then add medicinal materials 8 to 15 times the weight of water, decoct 2 to 4 times, decocted for 0.5 to 1.5 hours each time, filter, and concentrate the filtrate into extract; or further include:
  • step 2) Take the extract described in step 2) as a spray material liquid, take an appropriate amount of sucrose and dextrin as a base material, place it in a spray granulator, spray evenly, make granules, and add an appropriate amount of aspartame and sweet orange essence , mixed, whole, made into granules.
  • step 1) the amount of water added depends on the container, and the material can be submerged; in some embodiments, it is boiled for 30min.
  • step 2) water with 8 to 15 times the weight of the medicinal material is added, and decocted for 2 to 4 times, each decocted for 0.5 to 1.5 hours.
  • step 2) add water for 3 times, add 12, 8, and 6 times the weight of water, respectively, for 1 h each time.
  • step 2) the filtrate is concentrated to an extract with a relative density of 1.10-1.30 (60° C.).
  • step 2) the filtrate is concentrated to an extract with a relative density of 1.15-1.25 (60° C.).
  • the auxiliary materials used include aspartame, sweet orange essence, sucrose and dextrin.
  • the weight ratio of the added sucrose and dextrin is (5:5) to (8:2), for example, 7:3, 8:2, 6:4, or 5:5.
  • step 3 the amount of added sucrose and dextrin is 0.1-0.5 times the weight of the original medicinal material.
  • sucrose and dextrin are added in a weight ratio of 7:3, and the weight of the added sucrose and dextrin is 0.3 times the weight of the original medicinal material.
  • step 3 add an appropriate amount of aspartame, which is 0.1% to 3.0% of the weight of the granules; sweet orange essence is 0.05% to 2.0% of the weight of the granules; specifically, aspartame is 0.5% of the weight of the granules %; sweet orange flavor is 0.2% by weight of the particles.
  • the present invention also includes the application of the above-mentioned traditional Chinese medicine composition or preparation in preparing a medicine for treating precocious puberty in children.
  • Rehmannia glutinosa clears heat and cools blood, nourishes yin and promotes body fluid. It is used for heat entering the blood, warm toxins, spotting, hematemesis, epistaxis, yin injury due to fever, dark tongue and polydipsia, constipation caused by body fluid, fever due to yin deficiency, fever due to steaming of the bones, and internal heat to reduce thirst.
  • Scrophulariaceae clears heat and cools blood, nourishes yin and reduces fire, detoxifies and disperses knots. It is used for heat entering the blood, warm toxins, spots, fever, dark tongue and polydipsia, constipation caused by body fluid, constipation caused by steaming of the bones, red eyes, sore throat, diphtheria, scrofula, carbuncle, swollen and sore.
  • Cortex Phellodendri clears heat and dries dampness, purifies fire and removes steam, detoxifies and treats sores. Used for damp-heat diarrhea, jaundice, red urine, vaginal itching, hot stranguria with astringent pain, athlete's foot, athlete's foot, Gu steaming fever, night sweats, nocturnal emission, sore swollen toxin, eczema and eczema.
  • Digupi Cooling blood and removing steam, clearing lungs and reducing fire. It is used for hot flashes due to yin deficiency, night sweats due to Gu steaming, cough due to lung heat, hemoptysis, epistaxis, internal heat and quenching thirst.
  • Cortex Moutan clearing heat and cooling blood, promoting blood circulation and removing blood stasis. It is used for heat entering into the camp blood, warm poison, spotting, hematemesis and epistaxis, hot night and early cool, no sweating and bone steaming, amenorrhea, dysmenorrhea, pain from falls, carbuncle swelling and sore.
  • Alisma diuresis to infiltrate dampness, release heat, resolve turbidity and lower lipids. It is used for dysuria, edema, oliguria, dizziness due to phlegm, hot stranguria, and hyperlipidemia.
  • Prunella vulgaris clearing liver and purging fire, improving eyesight, dispersing knots and reducing swelling. It is used for redness and swelling and pain in the eyes, night pain in the eyeballs, headache and dizziness, scrofula, gall tumors, breast carbuncle, breast addiction, breast tenderness.
  • Gentian Cao clearing away heat and dampness, purging liver and gallbladder fire. For damp-heat jaundice, vaginal swelling, vaginal itching, vaginal discharge, eczema itching, red eyes, deafness, hypochondral pain, bitter mouth, convulsions and convulsions.
  • One of the characteristics of the present invention is that the prescriptions are formulated according to the theory of traditional Chinese medicine, which are carefully screened, processed separately, and combined with modern advanced technology.
  • Another feature of the present invention is that the traditional Chinese medicine preparation has exact curative effect and is safe and reliable for treating early and middle-stage precocious puberty.
  • Another characteristic of the present invention is that the formula is reasonable, the medicine is easy to obtain, and the price is low.
  • Traditional Chinese medicine composition for treating precocious puberty in children formula: 800g of Amaranthus japonica, 1000g of Rehmannia glutinosa, 800g of Scrophulariaceae, 1300g of vinegared turtle shell, 400g of Treats, 1000g of Digupi, 1200g of Cortex Moutan, 800g of Alisma vulgaris, 1200g of Prunella vulgaris, Longan Bile grass 800g, fried malt 1200g.
  • the traditional Chinese medicine preparation for the treatment of childhood precocious puberty is made from the Chinese medicinal composition of the present embodiment, and the concrete preparation method is as follows:
  • step 2) According to the formula, in the decoction obtained in step 1), add Anemarrhena chinensis, Rehmannia glutinosa, Scrophulariaceae, Cork, Digupi, Cortex Moutan, Alisma, Prunella, gentian, stir-fried malt, add water Decoction 3 times (the amount of water added is 12, 8, and 6 times the weight of the medicinal material respectively), 1 hour each time, filtered, and the filtrate is concentrated to an extract with a relative density of 1.15 to 1.25 (60°C);
  • step 3 get the extract described in step 2) as a spray feed liquid, get 2600g of sucrose and dextrin as a base material (the weight ratio of sucrose and dextrin is 7:3), place it in a spray granulator, spray evenly, and prepare Form into granules, add 26 g of aspartame and 10.4 g of sweet orange essence, mix and granulate to prepare granules.
  • Traditional Chinese medicine composition for treating precocious puberty in children formula: 1000g salt Zhimu, 800g Rehmannia glutinosa, 500g Scrophulariaceae, 1000g vinegar turtle shell, 200g Phellodendron chinensis, 400g Digupi, 1000g Cortex Moutan, 600g Alisma vulgaris, 800g Prunella vulgaris, dragon 400g of bile grass, 800g of fried malt.
  • the traditional Chinese medicine preparation for the treatment of childhood precocious puberty is made from the Chinese medicinal composition of the present embodiment, and the concrete preparation method is as follows:
  • step 2) According to the formula, in the decoction obtained in step 1), add Anemarrhena chinensis, Rehmannia glutinosa, Scrophulariaceae, Cork, Digupi, Cortex Moutan, Alisma, Prunella, gentian, stir-fried malt, add water Decoction 3 times (the amount of water added is 12, 8, and 6 times the weight of the medicinal material respectively) for 1 h each time, filtered, and the filtrate is concentrated to an extract with a relative density of 1.15-1.25 (60°C);
  • step 3 get the extract described in step 2) as a spray feed liquid, get 2700 g of sucrose and dextrin as a base material (the weight ratio of sucrose and dextrin is 8:2), place it in a spray granulator, spray evenly, and prepare Form into granules, add 27 g of aspartame and 10.8 g of sweet orange essence, mix and granulate to prepare granules.
  • Traditional Chinese medicine composition for treating precocious puberty in children formula: 1000g salt Zhimu, 1000g Rehmannia glutinosa, 1000g Scrophulariaceae, 1500g vinegar turtle shell, 300g Phellodendron chinensis, 1200g Digupi, 800g Cortex Moutan, 400g Alisma vulgaris, 600g Prunella 400g of bile grass, 600g of fried malt.
  • the traditional Chinese medicine preparation for the treatment of childhood precocious puberty is made from the Chinese medicinal composition of the present embodiment, and the concrete preparation method is as follows:
  • step 2) According to the formula, in the decoction obtained in step 1), add Anemarrhena chinensis, Rehmannia glutinosa, Scrophulariaceae, Cork, Digupi, Cortex Moutan, Alisma, Prunella, gentian, stir-fried malt, add water Decoction 3 times (the amount of water added is 12, 8, and 6 times the weight of the medicinal material respectively) for 1 h each time, filtered, and the filtrate is concentrated to an extract with a relative density of 1.15-1.25 (60°C);
  • step 3 get the extract described in step 2) as a spray feed liquid, get 2860g of sucrose and dextrin as a base material (the weight ratio of sucrose and dextrin is 6:4), place it in a spray granulator, spray evenly, and prepare Form into granules, add 28.6 g of aspartame and 11.4 g of sweet orange essence, mix and granulate to prepare granules.
  • Traditional Chinese medicine composition for treating precocious puberty in children formula: 1200g salt Zhimu, 1200g Rehmannia glutinosa, 400g Scrophulariaceae, 800g vinegar turtle shell, 300g Phellodendron rhizoma, 800g Digupi, 1200g Cortex Moutan, 400g Alisma vulgaris, 1000g Prunella vulgaris, dragon Bile grass 800g, fried malt 800g.
  • the traditional Chinese medicine preparation for the treatment of childhood precocious puberty is made from the Chinese medicinal composition of the present embodiment, and the concrete preparation method is as follows:
  • step 2) According to the formula, in the decoction obtained in step 1), add Anemarrhena chinensis, Rehmannia glutinosa, Scrophulariaceae, Cork, Digupi, Cortex Moutan, Alisma, Prunella, gentian, stir-fried malt, add water Decoction 3 times (the amount of water added is 12, 8, and 6 times the weight of the medicinal material respectively), 1 hour each time, filtered, and the filtrate is concentrated to an extract with a relative density of 1.15 to 1.25 (60°C);
  • step 3 take the extract described in step 2) as a spray feed liquid, take 2730 g of sucrose and dextrin as a base material (the weight ratio of sucrose and dextrin is 5:5), place it in a spray granulator, spray evenly, and prepare Form into granules, add 27.3 g of aspartame and 11.0 g of sweet orange essence, mix and granulate to prepare granules.
  • Traditional Chinese medicine composition for treating precocious puberty in children formula: 1000g of Amaranthus salt, 1000g of Rehmannia glutinosa, 600g of Scrophulariaceae, 1000g of Vinegar Turtle, 300g of Treats, 600g of Digupi, 1000g of Cortex Moutan, 600g of Alisma vulgaris, 1000g of Prunella vulgaris, Longan Bile grass 600g, fried malt 1000g.
  • the traditional Chinese medicine preparation for the treatment of childhood precocious puberty is made from the Chinese medicinal composition of the present embodiment, and the concrete preparation method is as follows:
  • step 2) According to the formula, in the decoction obtained in step 1), add Anemarrhena chinensis, Rehmannia glutinosa, Scrophulariaceae, Cork, Digupi, Cortex Moutan, Alisma, Prunella, gentian, stir-fried malt, add water Decoction 3 times (the amount of water added is 12, 8, and 6 times the weight of the medicinal material respectively), 1 hour each time, filtered, and the filtrate is concentrated to an extract with a relative density of 1.15 to 1.25 (60°C);
  • step 3 take the extract described in step 2) as a spray feed liquid, take 2610g of sucrose and dextrin as a base material (the weight ratio of sucrose and dextrin is 7:3), place it in a spray granulator, spray evenly, and prepare Form into granules, add 26 g of aspartame and 10.4 g of sweet orange essence, mix and granulate to prepare granules.
  • Traditional Chinese medicine composition for treating precocious puberty in children formula: 1000g of Amaranthus salt, 1000g of Rehmannia glutinosa, 600g of Scrophulariaceae, 1000g of Vinegar Turtle, 300g of Treats, 600g of Digupi, 1000g of Cortex Moutan, 600g of Alisma vulgaris, 1000g of Prunella vulgaris, Longan Bile grass 600g, fried malt 1000g.
  • the traditional Chinese medicine preparation for the treatment of childhood precocious puberty is made from the Chinese medicinal composition of the present embodiment, and the concrete preparation method is as follows:
  • step 2) According to the formula, in the decoction obtained in step 1), add Anemarrhena chinensis, Rehmannia glutinosa, Scrophulariaceae, Cork, Digupi, Cortex Moutan, Alisma, Prunella, gentian, stir-fried malt, add water Decoction 3 times (the amount of water added is 12, 8, and 6 times the weight of the medicinal material respectively), 1 hour each time, filtered, and the filtrate is concentrated to an extract with a relative density of 1.15 to 1.25 (60°C);
  • step 3 get the extract described in step 2) as a spray feed liquid, get 2830g of sucrose and dextrin as a base material (the weight ratio of sucrose and dextrin is 7:3), place it in a spray granulator, spray evenly, and prepare Form into granules, add 28.3 g of aspartame and 11.3 g of sweet orange essence, mix and granulate to prepare granules.
  • Traditional Chinese medicine composition for treating precocious puberty in children formula: 1000g of Amaranthus salt, 1000g of Rehmannia glutinosa, 600g of Scrophulariaceae, 1000g of Vinegar Turtle, 300g of Treats, 600g of Digupi, 1000g of Cortex Moutan, 600g of Alisma vulgaris, 1000g of Prunella vulgaris, Longan Bile grass 600g, fried malt 1000g.
  • the traditional Chinese medicine preparation for the treatment of childhood precocious puberty is made from the Chinese medicinal composition of the present embodiment, and the concrete preparation method is as follows:
  • step 2) According to the formula, in the decoction obtained in step 1), add Anemarrhena chinensis, Rehmannia glutinosa, Scrophulariaceae, Cork, Digupi, Cortex Moutan, Alisma, Prunella, gentian, stir-fried malt, add water Decoction 3 times (the amount of water added is 12, 8, and 6 times the weight of the medicinal material respectively), 1 hour each time, filtered, and the filtrate is concentrated to about 8000ml;
  • Traditional Chinese medicine composition for treating precocious puberty in children formula: 1000g of Amaranthus salt, 1000g of Rehmannia glutinosa, 600g of Scrophulariaceae, 1000g of Vinegar Turtle, 300g of Treats, 600g of Digupi, 1000g of Cortex Moutan, 600g of Alisma vulgaris, 1000g of Prunella vulgaris, Longan Bile grass 600g, fried malt 1000g.
  • the traditional Chinese medicine preparation for the treatment of childhood precocious puberty is made from the Chinese medicinal composition of the present embodiment, and the concrete preparation method is as follows:
  • step 2) According to the formula, in the decoction obtained in step 1), add Anemarrhena chinensis, Rehmannia glutinosa, Scrophulariaceae, Cork, Digupi, Cortex Moutan, Alisma, Prunella, gentian, stir-fried malt, add water Decoction 3 times (the amount of water added is 12, 8, and 6 times the weight of the medicinal material, respectively), 1 hour each time, filtered, and the filtrate is concentrated to an extract with a relative density of 1.15 to 1.25 (60°C), dried at 60°C under reduced pressure , crushed, passed through a 60-mesh sieve to obtain dry paste powder.
  • step 2) According to the formula, in the decoction obtained in step 1), add Rehmannia glutinosa, Scrophulariaceae, Anemarrhena, Cork, Cortex Moutan, Alisma, Prunella vulgaris, Gentian grass, stir-fried malt, Root bark, Eclipta Grass, Agrimony, add water to decoct 3 times (the amount of water added is 12, 8, and 6 times the weight of the medicinal material, respectively), 1 hour each time, filter, and concentrate the filtrate to an extract with a relative density of 1.15-1.25 (60°C); After drying under reduced pressure at 60°C, it was pulverized and passed through a 60-mesh sieve to obtain dry paste powder.
  • Anemarrhena 1200g Phellodendron 1200g, Rehmannia glutinosa 1200g, Dogwood meat 1800g, Red peony root 1200g, Alisma 1800g, Poria 1800g, Rehmannia glutinosa 1200g, Scutellaria baicalensis 1200g, Ligustrum lucidum 1200g, Cyanophora 1800g, Gardenia 1200g, Guangyujin 1800g, Angelica 1200g.
  • the specific preparation method is as follows:
  • mice Eighteen litters of female mice were randomly divided into normal group, model group, leuprolide group, Example 8 group, Comparative Example 1 group, and Comparative Example 2 group, a total of 6 groups. Breastfeed until 23 days of age. On the 5th day of age, except the normal group, the other 5 groups were subcutaneously injected with 25ul danazol solution at one time to establish the model of precocious puberty.
  • the solution preparation method was to dissolve 300ug danazol in 25ul ethylene glycol-ethanol solution. (1:1, v/v).
  • the positive drug group was subcutaneously injected with leuprolide at a dose of 100ug/kg;
  • Example 8 group was administered by gavage with the dry paste powder prepared in Example 8, and the daily dose was 6.53g/kg ;
  • Comparative example 1 group adopts the dry ointment powder made of comparative example 1 to carry out gavage administration, and the daily dosage is 10.66g/kg;
  • Comparative example 2 groups adopts the dry ointment powder made of comparative example 2 to carry out gavage
  • the daily dose was 7.43 g/kg; the normal group and the model group were given the same amount of normal saline by gavage respectively. Weigh every 3 days and recalculate the dose.
  • the opening of the vulva in each group was observed regularly every morning, and the animals with vaginal opening were examined by vaginal exfoliated cell smear.
  • the other groups were killed at a ratio of 1:1.
  • uterine and ovarian samples were fixed with paraformaldehyde, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (HE staining). Uterine wall thickness and ovarian luteinization rate were measured.
  • the experimental results showed that compared with the normal group, the vulva opening time of the young rats in the model group was significantly earlier, and the levels of serum hormones E2, LH and FSH were significantly increased.
  • the traditional Chinese medicine composition of the present invention has no significant difference in the vulva opening time and uterine wall thickness of young mice, and no significant difference in the levels of serum hormones E2, LH and FSH. It is shown that the present invention has the same curative effect compared with the prescription of Comparative Example 1, but the dosage is less, and the prescription is more reasonable.
  • the traditional Chinese medicine composition of the present invention significantly prolongs the opening time of the vulva of young mice, significantly reduces the uterine wall thickness, and significantly reduces the levels of serum hormones E2, LH and FSH. It shows that the present invention has better curative effect than the prescription of Comparative Example 2, and the prescription is more reasonable. The results show that the traditional Chinese medicine composition of the present invention has a good therapeutic effect on the precocious puberty model induced by danazol.
  • the invention provides a traditional Chinese medicine composition for treating precocious puberty in children, a preparation method and application thereof.
  • a traditional Chinese medicine composition for treating precocious puberty in children comprising the following raw materials in parts by weight: 6-15 parts of Anemarrhena, 6-15 parts of Rehmannia glutinosa, 3-10 parts of Scrophulariaceae, 6-15 parts of turtle shell, and 1-5 parts of Cortex Phellodendri , 3 to 15 parts of Digupi, 6 to 15 parts of Cortex Moutan, 3 to 10 parts of Alisma, 6 to 15 parts of Prunella vulgaris, 3 to 10 parts of gentian, and 6 to 15 parts of malt.
  • the present invention is formulated according to the theory of traditional Chinese medicine, through strict screening, processing separately, and combining with modern advanced technology. It has the functions of nourishing yin and expelling fire, cooling blood and promoting blood circulation, infiltrating dampness and removing turbidity, clearing liver and dispelling stagnation. It is mainly used for the treatment of precocious puberty in children.
  • the preparation is safe and reliable, the medicine is easy to obtain, the price is low, the administration method is simple, the portability is convenient, the prescription is reasonable, the curative effect is definite, and has good economic value and application prospect.

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Abstract

一种治疗儿童性早熟的中药组合物及其制备方法与应用，该中药组合物包括以下重量份计的原料：知母6-15份、生地黄6-15份、玄参3-10份、鳖甲6-15份、黄柏1-5份、地骨皮3-15份、牡丹皮6-15份、泽泻3-10份、夏枯草6-15份、龙胆草3-10份、麦芽6-15份。该组合物具有滋阴降火、凉血活性、渗湿化浊、清肝散结的功效。

Description

一种治疗儿童性早熟的中药组合物及其制备方法与应用
交叉引用
本申请要求2020年9月21日提交的专利名称为“一种治疗儿童性早熟的中药组合物及其制备方法与应用”的第202010998025.0号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
技术领域
本发明涉及一种治疗儿童性早熟的中药组合物，本发明还涉及该中药组合物的制备方法及其应用。
背景技术
儿童性早熟是指在青春期以前过早地出现第二性征，即女孩8周岁以前开始乳房发育，10周岁以前出现月经；男孩9周岁以前出现睾丸、阴茎增大等性征。已成为最常见的危害儿童健康的小儿内分泌疾病之一，由于患儿智力与心理尚未成熟，过早的性成熟对其身心健康危害极大。同时，性早熟导致患儿骨骼快速生长，骨骺提前闭合，成年后身高往往比正常人矮小。
性早熟主要分为：
(1)中枢性性早熟(CPP)：即真性性早熟，是由于下丘脑-垂体-性腺轴提前启动所致，其发生机理与正常情况相同，伴随身高体重快速增长，骨骺提前闭合，生长提前停止，最终造成身材矮小，其中包括：①特发性中枢性性早熟(ICPP)，下丘脑神经分泌失调，产生过多的GnRH(促性腺激素释放激素)，进而使性特征过早发育；②中枢神经系统病变。
(2)周围性性早熟(PPP)：又称假性性早熟，其下丘脑－垂体－性腺轴并未成熟，由于外周组织产生的性激素而致同性或异性性早熟症状的出现，即男孩可以出现阴茎大、阴毛、腋毛和喉结，但是睾丸并不增大，而且男孩也可出现女性的第二性征表现如女性型乳房；同样女孩可以有乳房发育、阴毛和腋毛出现，也可以出现男性第二性征表现如有胡须、阴蒂 增大。
(3)不完全性早熟：是一个特殊的性早熟的类型，指患者有第二性征的过早出现，它的发病的机制在于某一些因子的发动，但是它的性征发育是呈现自限性的，常见的类型就是单纯乳房早发育，一般发生在两岁以内的女孩子。
周围性性早熟和不完全性早熟是单纯性乳房早发育或单纯阴毛早发育，不伴有其他性特征发育及生长加速，多不需要特殊药物治疗，或适当对症下药。
本病的早期发现和及时治疗非常关键。
西医首选药是促性腺激素释放激素类似剂(GnRHa)治疗，抑制促性腺激素的分泌和释放，阻滞下丘脑垂体性腺轴的正常功能，使性激素分泌减少，控制性发育，依此达到延缓骨骼加速成熟的目的。但是其作用过强，治疗周期一般需要2年左右，一般患儿在应用3-6个月之后会出现生长抑制的现象，其注射剂不良反应多，用药期间可能还需要和重组人生长激素合用，花费巨大，且安全性尚待考证。
中医认为性早熟儿童的病机多为肾阴不足，肾阴阳不平衡导致相火旺。中医《素问·上古天真论篇》记载，“女子七岁肾气盛，齿更发长，二七天癸至，任脉通，太冲脉盛，月事以时下，故有子。……七七任脉虚，太冲脉衰，天癸竭，地道不通，故形坏而无子也。”古人认识到女子在十四岁月经初来，冲任源于肾。
中医辨证出现的症状有怕热，口渴，面红升火，烦躁易怒，五心烦热，盗汗，便秘，舌质红绛或舌边尖红。中医治疗儿童性早熟常采用中医辨证治疗，临床上病情处于早、中期的患儿不主张采用西药治疗，适宜于采用中药治疗。现已有多个中药制剂在临床中得到了使用。然而，现有的多种用于治疗儿童性早熟的中药制剂也存在着疗效不确切、对于病情较重的患儿疗效差、用药周期长、因药物剂型和口感所引起的患儿服药顺应性差，服药期间有患儿出现呕吐、腹部不适、腹痛、反酸，也有服用时间长后出 现纳差等不适。
发明内容
本发明实施例提供一种治疗儿童性早熟中药组合物，相对于现有技术的疗效更好，药材用量更少。
一种治疗儿童性早熟的中药组合物，包括以下重量份计的原料：知母6～15份，生地黄6～15份，玄参3～10份，鳖甲6～15份，黄柏1～5份，地骨皮3～15份，牡丹皮6～15份，泽泻3～10份，夏枯草6～15份，龙胆草3～10份，麦芽6～15份。
优选地，所述治疗儿童性早熟的中药组合物，包括以下重量份计的原料：知母8～12份，生地黄8～12份，玄参4～8份，鳖甲8～12份，黄柏2～4份，地骨皮4～10份，牡丹皮8～12份，泽泻4～8份，夏枯草8～12份，龙胆草4～8份，麦芽8～12份；
具体地，所述治疗儿童性早熟的中药组合物，包括以下重量份计的原料：知母10份，生地黄10份，玄参6份，鳖甲10份，黄柏3份，地骨皮6份，牡丹皮10份，泽泻6份，夏枯草10份，龙胆草6份，麦芽10份；
在一些实施例中，所述知母为盐知母。
在一些实施例中，鳖甲为醋鳖甲。
在一些实施例中，麦芽为炒麦芽。
在一些实施例中，所述治疗儿童性早熟的中药组合物即是由知母、生地黄、玄参、鳖甲、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草和麦芽按上述重量配比组成或制成。本发明还提供上述治疗儿童性早熟的中药组合物的制备方法，例如可按本领域常规方法将各药材混合。在一些实施例中，是将各药材粉碎后混合。
本发明还提供一种治疗儿童性早熟的中药制剂，其以上述治疗儿童性早熟的中药组合物为主要活性成分制成，或者进一步地还包括药学上可用的辅料。
在本发明一些实施例中，所述治疗儿童性早熟的中药制剂是以上述治疗儿童性早熟的中药组合物为唯一活性成分制成，或者进一步地还包括药学上可用的辅料。
在本发明一些实施例中，所述治疗儿童性早熟的中药制剂是以上述治疗儿童性早熟的中药组合物为主要活性成分或唯一活性成分单独制成(即不含药学上可接受的辅料)，或由所述中药组合物为主要活性成分或唯一活性成分和药学上可接受的辅料制成。
本发明所述治疗儿童性早熟的中药制剂可制成为药学上各种常用剂型。
在本发明一些实施例中，所述治疗儿童性早熟的中药制剂具体可为颗粒剂、片剂(含分散片、泡腾片)、丸剂(含滴丸剂)、胶囊、口服液、糖浆剂或外用制剂等。
本发明中，所述药学上可接受的辅料是指药学领域常规的药物载体，选自填充剂、粘合剂、崩解剂、润滑剂、助悬剂、润湿剂、色素、香精、溶剂、表面活性剂或矫味剂中的一种或几种。
所述填充剂选自淀粉、蔗糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素或葡萄糖等。
所述粘合剂选自纤维素衍生物、藻酸盐、淀粉、水、糊精、明胶或聚乙烯吡咯烷酮等。
所述崩解剂选自微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙基纤维素或交联羧甲基纤维素钠。
所述润滑剂选自硬脂酸、聚乙二醇、碳酸钙、碳酸氢钠、微粉硅胶、滑石粉或硬脂酸镁；
所述助悬剂选自微粉硅胶、蜂蜡、纤维素、固态聚乙二醇。
所述润湿剂选自甘油、吐温-80、乙氧基氢化蓖麻油或卵磷脂。
所述溶剂选自乙醇、液态聚乙二醇、异丙醇、吐温-80、甘油、丙二醇或植物油，所述植物油选自大豆油、蓖麻油、花生油、调和油等。
所述表面活性剂选自十二烷基苯磺酸钠、硬脂酸、聚氧乙烯-聚氧丙烯共聚物、脂肪酸山梨坦或聚山梨酯(吐温)等。
所述矫味剂选自阿斯巴甜、蔗糖素、香精、甜菊素、安赛蜜、柠檬酸或糖精钠。
在本发明一些实施例中，所述中药制剂是口服液，其中所用辅料选择木糖醇和低聚糖，所用pH调节剂为柠檬酸或其钠盐。
在本发明一些实施例中，所述治疗儿童性早熟的中药制剂的制备方法包括：按上述中药组合物的配比取各药材；先将(醋)鳖甲加水煎煮；在所得第一煎煮液(A)中再加入知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、麦芽，加水煎煮；得第二煎煮液(B)。
在本发明一些实施例中，将所得第二煎煮液(B)加入矫味剂等药学上可用的辅料可制成口服液或糖浆剂。
在本发明一些实施例中，将所得第二煎煮液(B)进一步浓缩，可制成浸膏。例如浓缩至相对密度为1.10～1.30(60℃)的浸膏。
在一些实施例中，将所得浸膏可进一步制成颗粒剂、片剂(含分散片、泡腾片)、丸剂(含滴丸剂)、胶囊、口服液、糖浆剂或外用制剂等。
在一些实施例中，所述治疗儿童性早熟中药制剂的制备方法，包括：
1)按配比取鳖甲，加10～50倍重量的水(浸没)，煎20～60min；得煎煮液；
2)按配比在步骤1)所得煎煮液中加入(盐)知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、麦芽，再加入药材8～15倍重量的水，煎煮2～4次，每次煎煮0.5～1.5h，滤过，将滤液浓缩成浸膏；或者进一步还包括：
3)取步骤2)所述浸膏作为喷雾料液，取适量蔗糖和糊精作为底料，置于喷雾制粒机内，均匀喷雾，制成颗粒，加入适量阿司帕坦和甜橙香精，混合，整粒，制成颗粒剂。
具体地，步骤1)中，加水量视容器而定，可浸没物料；在一些实施 例中煎煮30min。
具体地，步骤2)中，加入药材8～15倍重量的水，煎煮2～4次，每次煎煮0.5～1.5h。
具体地，步骤2)中，加水煎煮3次，分别加入12、8、6倍重量水，每次1h。
具体地，步骤2)中，将滤液浓缩至相对密度为1.10～1.30(60℃)的浸膏。
具体地，步骤2)中，将滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏。
具体地，当所述中药制剂为颗粒剂时，优选所用辅料包括阿司帕坦、甜橙香精、蔗糖和糊精。
具体地，步骤3)中，加入的蔗糖和糊精的重量比为(5:5)～(8:2)，例如7:3，8:2，6:4，或5:5。
具体地，步骤3)中，加入的蔗糖和糊精的用量为原药材重量的0.1-0.5倍。
具体地，步骤3)中，加入蔗糖和糊精，重量比为7:3，所加入的蔗糖和糊精的重量之和是原药材重量之和的0.3倍。
具体地，步骤3)中，加入适量阿司帕坦，为颗粒重量的0.1％～3.0％；甜橙香精为颗粒重量的0.05％～2.0％；具体的，阿司帕坦为颗粒重量的0.5％；甜橙香精为颗粒重量的0.2％。
本发明还包括上述中药组合物或中药制剂在制备治疗儿童性早熟的药物中的应用。
本发明治疗儿童性早熟的中药组合物的药理作用及中医理论：(盐)知母和生地黄为君药，玄参、(醋)鳖甲、黄柏和地骨皮为臣药，牡丹皮、泽泻、夏枯草、龙胆草和(炒)麦芽为佐使药。
本发明中各原料的分析：
(盐)知母：清热泻火，滋阴润燥。用于外感热病，高热烦渴，肺热 燥咳，骨蒸潮热，内热消渴，肠燥便秘；
生地黄：清热凉血，养阴生津。用于热入营血，温毒发斑，吐血衄血，热病伤阴，舌绛烦渴，津伤便秘，阴虚发热，骨蒸劳热，内热消渴。
玄参：清热凉血，滋阴降火，解毒散结。用于热入营血，温毒发斑，热病伤阴，舌绛烦渴，津伤便秘，骨蒸劳嗽，目赤，咽痛，白喉，瘰疬，痈肿疮毒。
(醋)鳖甲：滋阴潜阳，退热除蒸，软坚散结。用于阴虚发热，骨蒸劳热，阴虚阳亢，头晕目眩，虚风内动，手足瘈疚，经闭，癥瘕，久疟疟母。
黄柏：清热燥湿，泻火除蒸，解毒疗疮。用于湿热泻痢，黄疸尿赤，带下阴痒，热淋涩痛，脚气痿躄，骨蒸劳热，盗汗，遗精，疮疡肿毒，湿疹湿疮。
地骨皮：凉血除蒸，清肺降火。用于阴虚潮热，骨蒸盗汗，肺热咳嗽，咯血，衄血，内热消渴。
牡丹皮：清热凉血，活血化瘀。用于热入营血，温毒发斑，吐血衄血，夜热早凉，无汗骨蒸，经闭痛经，跌扑伤痛，痈肿疮毒。
泽泻：利水渗湿，泄热，化浊降脂。用于小便不利，水肿胀满，泄泻尿少，痰饮眩晕，热淋涩痛，高脂血症。
夏枯草：清肝泻火，明目，散结消肿。用于目赤肿痛，目珠夜痛，头痛眩晕，瘰疬，瘿瘤，乳痈，乳癖，乳房胀痛。
龙胆草：清热燥湿，泻肝胆火。用于湿热黄疸，阴肿阴痒，带下，湿疹瘙痒，目赤，耳聋，胁痛，口苦，惊风抽搐。
(炒)麦芽：行气消食回乳。用于食积不消，妇女断乳。
本发明的特点之一是按中医理论组方，经严格筛选，分别炮制，结合现代先进工艺制法组合而成。
本发明的另一特点是本中药制剂对于治疗早、中期儿童性早熟，疗效确切，安全可靠。
本发明的还有一特点是组方合理，药物易得，价格低廉。
具体实施方式
以下实施例用于说明本发明，应该理解的是，本发明的实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明保护的范围。
实施例1
治疗儿童性早熟的中药组合物，配方：盐知母800g，生地黄1000g，玄参800g，醋鳖甲1300g，黄柏400g，地骨皮1000g，牡丹皮1200g，泽泻800g，夏枯草1200g，龙胆草800g，炒麦芽1200g。
治疗儿童性早熟的中药制剂，是以本实施例中药组合物制成的，具体的制备方法如下：
1)按配方取所需重量的醋鳖甲，加20倍重量的水浸没，先煎60min；
2)按配方在步骤1)所得到的煎液中，再加入盐知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、炒麦芽，加水煎煮3次(加水量分别为药材重量的12、8、6倍)，每次1h，滤过，滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏；
3)取步骤2)所述浸膏作为喷雾料液，取蔗糖和糊精2600g作为底料(蔗糖和糊精的重量比为7:3)，置于喷雾制粒机内，均匀喷雾，制成颗粒，加入26g阿司帕坦和10.4g甜橙香精，混合，整粒，制成颗粒剂。
实施例2
治疗儿童性早熟的中药组合物，配方：盐知母1000g，生地黄800g，玄参500g，醋鳖甲1000g，黄柏200g，地骨皮400g，牡丹皮1000g，泽泻600g，夏枯草800g，龙胆草400g，炒麦芽800g。
治疗儿童性早熟的中药制剂，是以本实施例中药组合物制成的，具体的制备方法如下：
1)按配方取所需重量的醋鳖甲，加30倍重量的水浸没，先煎45min；
2)按配方在步骤1)所得到的煎液中，再加入盐知母、生地黄、玄 参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、炒麦芽，加水煎煮3次(加水量分别为药材重量的12、8、6倍)每次1h，滤过，滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏；
3)取步骤2)所述浸膏作为喷雾料液，取蔗糖和糊精2700g作为底料(蔗糖和糊精的重量比为8:2)，置于喷雾制粒机内，均匀喷雾，制成颗粒，加入27g阿司帕坦和10.8g甜橙香精，混合，整粒，制成颗粒剂。
实施例3
治疗儿童性早熟的中药组合物，配方：盐知母1000g，生地黄1000g，玄参1000g，醋鳖甲1500g，黄柏300g，地骨皮1200g，牡丹皮800g，泽泻400g，夏枯草600g，龙胆草400g，炒麦芽600g。
治疗儿童性早熟的中药制剂，是以本实施例中药组合物制成的，具体的制备方法如下：
1)按配方取所需重量的醋鳖甲，加40倍重量的水浸没，先煎15min；
2)按配方在步骤1)所得到的煎液中，再加入盐知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、炒麦芽，加水煎煮3次(加水量分别为药材重量的12、8、6倍)每次1h，滤过，滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏；
3)取步骤2)所述浸膏作为喷雾料液，取蔗糖和糊精2860g作为底料(蔗糖和糊精的重量比为6:4)，置于喷雾制粒机内，均匀喷雾，制成颗粒，加入28.6g阿司帕坦和11.4g甜橙香精，混合，整粒，制成颗粒剂。
实施例4
治疗儿童性早熟的中药组合物，配方：盐知母1200g，生地黄1200g，玄参400g，醋鳖甲800g，黄柏300g，地骨皮800g，牡丹皮1200g，泽泻400g，夏枯草1000g，龙胆草800g，炒麦芽800g。
治疗儿童性早熟的中药制剂，是以本实施例中药组合物制成的，具体的制备方法如下：
1)按配方取所需重量的醋鳖甲，加50倍重量的水浸没，先煎30min；
2)按配方在步骤1)所得到的煎液中，再加入盐知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、炒麦芽，加水煎煮3次(加水量分别为药材重量的12、8、6倍)，每次1h，滤过，滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏；
3)取步骤2)所述浸膏作为喷雾料液，取蔗糖和糊精2730g作为底料(蔗糖和糊精的重量比为5:5)，置于喷雾制粒机内，均匀喷雾，制成颗粒，加入27.3g阿司帕坦和11.0g甜橙香精，混合，整粒，制成颗粒剂。
实施例5
治疗儿童性早熟的中药组合物，配方：盐知母1000g，生地黄1000g，玄参600g，醋鳖甲1000g，黄柏300g，地骨皮600g，牡丹皮1000g，泽泻600g，夏枯草1000g，龙胆草600g，炒麦芽1000g。
治疗儿童性早熟的中药制剂，是以本实施例中药组合物制成的，具体的制备方法如下：
1)按配方取所需重量的醋鳖甲，加50倍重量的水浸没，先煎30min；
2)按配方在步骤1)所得到的煎液中，再加入盐知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、炒麦芽，加水煎煮3次(加水量分别为药材重量的12、8、6倍)，每次1h，滤过，滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏；
3)取步骤2)所述浸膏作为喷雾料液，取蔗糖和糊精2610g作为底料(蔗糖和糊精的重量比为7:3)，置于喷雾制粒机内，均匀喷雾，制成颗粒，加入26g阿司帕坦和10.4g甜橙香精，混合，整粒，制成颗粒剂。
实施例6
治疗儿童性早熟的中药组合物，配方：盐知母1000g，生地黄1000g，玄参600g，醋鳖甲1000g，黄柏300g，地骨皮600g，牡丹皮1000g，泽泻600g，夏枯草1000g，龙胆草600g，炒麦芽1000g。
治疗儿童性早熟的中药制剂，是以本实施例中药组合物制成的，具体的制备方法如下：
1)按配方取所需重量的醋鳖甲，加50倍重量的水浸没，先煎30min；
2)按配方在步骤1)所得到的煎液中，再加入盐知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、炒麦芽，加水煎煮3次(加水量分别为药材重量的12、8、6倍)，每次1h，滤过，滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏；
3)取步骤2)所述浸膏作为喷雾料液，取蔗糖和糊精2830g作为底料(蔗糖和糊精的重量比为7:3)，置于喷雾制粒机内，均匀喷雾，制成颗粒，加入28.3g阿司帕坦和11.3g甜橙香精，混合，整粒，制成颗粒剂。
实施例7
治疗儿童性早熟的中药组合物，配方：盐知母1000g，生地黄1000g，玄参600g，醋鳖甲1000g，黄柏300g，地骨皮600g，牡丹皮1000g，泽泻600g，夏枯草1000g，龙胆草600g，炒麦芽1000g。
治疗儿童性早熟的中药制剂，是以本实施例中药组合物制成的，具体的制备方法如下：
1)按配方取所需重量的醋鳖甲，加50倍重量的水浸没，先煎30min；
2)按配方在步骤1)所得到的煎液中，再加入盐知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、炒麦芽，加水煎煮3次(加水量分别为药材重量的12、8、6倍)，每次1h，滤过，滤液浓缩至8000ml左右；
3)将上述浓缩液，滤过，加入2000g蔗糖和适量香精，调节pH值至6.5，定容至8700ml，再次滤过，分装成口服液。
实施例8
治疗儿童性早熟的中药组合物，配方：盐知母1000g，生地黄1000g，玄参600g，醋鳖甲1000g，黄柏300g，地骨皮600g，牡丹皮1000g，泽泻600g，夏枯草1000g，龙胆草600g，炒麦芽1000g。
治疗儿童性早熟的中药制剂，是以本实施例中药组合物制成的，具体的制备方法如下：
1)按配方取所需重量的醋鳖甲，加50倍重量的水浸没，先煎30min；
2)按配方在步骤1)所得到的煎液中，再加入盐知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、炒麦芽，加水煎煮3次(加水量分别为药材重量的12、8、6倍)，每次1h，滤过，滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏，60℃减压干燥后，粉碎，过60目筛，得干膏粉。
对比例1
中药制剂，配方：生地黄900g，玄参900g，知母900g，黄柏900g，牡丹皮900g，泽泻900g，夏枯草900g，醋鳖甲1000g，龙胆草600g，炒麦芽3000g，椿根皮1200g，旱莲草900g，仙鹤草1200g。具体的制备方法如下：
1)按配方取所需重量的醋鳖甲，加50倍重量的水浸没，先煎30min；
2)按配方在步骤1)所得到的煎液中，再加入生地黄，玄参，知母，黄柏，牡丹皮，泽泻，夏枯草，龙胆草，炒麦芽，椿根皮，旱莲草，仙鹤草，加水煎煮3次(加水量分别为药材重量的12、8、6倍)，每次1h，滤过，滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏；60℃减压干燥后，粉碎，过60目筛，得干膏粉。
对比例2
中药制剂，配方：知母1200g、黄柏1200g、生地黄1200g、山萸肉1800g、赤芍1200g、泽泻1800g、茯苓1800g、熟地黄1200g、黄芩1200g、女贞子1200g、香附1800g、栀子1200g、广郁金1800g、当归1200g。具体的制备方法如下：
按配方取生药材，加水煎煮3次(加水量分别为药材重量的12、8、6倍)，每次1h，滤过，滤液浓缩至相对密度为1.15～1.25(60℃)的浸膏；60℃减压干燥后，粉碎，过60目筛，得干膏粉。
实验例1
1动物
清洁级5日龄SD雌鼠，18窝。每笼出生鼠由亲母自养，每笼6只，若每笼出生雌鼠数量不足6只，则用该亲母生的雄仔鼠凑足6只，确保每笼内饲养密度一致。
2方法
2.1动物分组及给药
18窝雌鼠随机分为正常组、模型组、亮丙瑞林组、实施例8组、对比例1组、对比例2组，共6组。母乳喂养至23日龄。在第5日龄时，除正常组外，其余5组均一次性皮下注射25ul达那唑溶液，以建立性早熟模型，溶液配制方法为每300ug达那唑溶于25ul乙二醇-乙醇溶液(1：1，v/v)。造模10天后，阳性药组皮下注射亮丙瑞林，剂量为100ug/kg；实施例8组，采用实施例8制备的干膏粉进行灌胃给药，每天给药剂量为6.53g/kg；对比例1组，采用对比例1制成的干膏粉进行灌胃给药，每天给药剂量为10.66g/kg；对比例2组，采用对比例2制成的干膏粉进行灌胃给药，每天给药剂量为7.43g/kg；正常组、模型组分别灌胃给予等量生理盐水。每隔3天称一次重量，重新计算一次给药剂量。20日龄时每天上午定时观察各组阴门开启情况，对已阴道开口的动物进行阴道脱落细胞涂片检查，在出现一个完整的动情周期后，于动情间期处死。同时其他各组按1:1处死。
2.2指标和检测方法
2.2.1子宫系数、卵巢系数、子宫壁厚、卵巢黄体生成率测定
大鼠处死后，解剖取出子宫和卵巢并称重，以评估器官系数(mg/100g)。随后，将子宫、卵巢样品用多聚甲醛固定，用石蜡包埋，切片，并用苏木精和伊红染色(HE染色)。检测子宫壁厚和卵巢黄体生成率。
2.2.2血清激素水平检测
麻醉后，腹主动脉取血，4℃离心取血清，在-20℃保存直至分析，测定血清雌二醇(E2)、促卵泡成熟素(FSH)、促黄体生成素(LH)水平。
3结果
表1各组大鼠阴道开口、子宫系数、卵巢系数比较
Figure PCTCN2020141451-appb-000001
Figure PCTCN2020141451-appb-000002
*表示实施例8组与对比例1组相比，p>0.05； △表示实施例8组与对比例2组相比，p＜0.05
表2各组子宫壁厚的比较
Figure PCTCN2020141451-appb-000003
Figure PCTCN2020141451-appb-000004
*表示实施例8组与对比例1组相比，p>0.05； △表示实施例8组与对比例2组相比，p＜0.05
表3各组大鼠血清激素的含量的比较
Figure PCTCN2020141451-appb-000005
Figure PCTCN2020141451-appb-000006
Figure PCTCN2020141451-appb-000007
*表示实施例8组与对比例1组相比，p>0.05； △表示实施例8组与对比例2组相比，p＜0.05
实验结果显示：与正常组相比，模型组大鼠幼鼠阴门开启时间显著提前，血清激素E2、LH和FSH水平显著增加。与对比例1组相比，本发明中药组合物对幼鼠阴门开启时间和子宫壁厚无明显差异，血清激素E2、LH和FSH水平无明显差异。表明本发明相对于对比例1的组方，疗效等同，但给药量更少，组方更合理。与对比例2组相比，本发明中药组合物对幼鼠阴门开启时间显著延长，子宫壁厚显著降低，显著降低血清激素E2、LH和FSH水平。表明本发明相对于对比例2的组方疗效更佳，组方更合理。结果表明：本发明中药组合物对达那唑诱导的性早熟模型具有较好的治疗作用。
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
工业实用性
本发明提供一种治疗儿童性早熟的中药组合物及其制备方法与应用。治疗儿童性早熟的中药组合物，包括以下重量份计的原料：知母6～15份，生地黄6～15份，玄参3～10份，鳖甲6～15份，黄柏1～5份，地骨皮3～15份，牡丹皮6～15份，泽泻3～10份，夏枯草6～15份，龙胆草3～10份，麦芽6～15份。本发明按中医理论组方，经严格筛选，分别炮制，结合现代先进工艺制法组合而成。具有滋阴泄火，凉血活血，渗湿化浊，清肝散结的功效，主要用于治疗儿童性早熟。本制剂安全可靠，药物易得，价格低廉，给药方式简单，携带方便，组方合理，疗效确切，具有较好的经济价值和应用前景。

Claims (10)

  1. 一种治疗儿童性早熟的中药组合物，其特征在于，包括以下重量份计的原料：知母6～15份，生地黄6～15份，玄参3～10份，鳖甲6～15份，黄柏1～5份，地骨皮3～15份，牡丹皮6～15份，泽泻3～10份，夏枯草6～15份，龙胆草3～10份，麦芽6～15份。
  2. 根据权利要求1所述的治疗儿童性早熟的中药组合物，其特征在于，包括以下重量份计的原料：知母8～12份，生地黄8～12份，玄参4～8份，鳖甲8～12份，黄柏2～4份，地骨皮4～10份，牡丹皮8～12份，泽泻4～8份，夏枯草8～12份，龙胆草4～8份，麦芽8～12份；
    可选地，所述治疗儿童性早熟的中药组合物，包括以下重量份计的原料：知母10份，生地黄10份，玄参6份，鳖甲10份，黄柏3份，地骨皮6份，牡丹皮10份，泽泻6份，夏枯草10份，龙胆草6份，麦芽10份；
    可选的，所述知母为盐知母，鳖甲为醋鳖甲，麦芽为炒麦芽。
  3. 一种治疗儿童性早熟的中药制剂，其特征在于，其是以权利要求1或2所述中药组合物为主要活性成分或唯一活性成分制成，或者进一步地还包括药学上可用的辅料。
  4. 根据权利要求3所述的治疗儿童性早熟的中药制剂，其特征在于，其为颗粒剂、片剂(含分散片、泡腾片)、丸剂(含滴丸剂)、胶囊、口服液、糖浆剂或外用制剂；
    其中，当所述中药制剂为颗粒剂时，优选所用辅料包括阿司帕坦、甜橙香精、蔗糖和糊精；其中，
    优选蔗糖和糊精的重量比为(5:5)～(8:2)；和/或，
    优选蔗糖和糊精的重量之和是原药材重量之和的0.1～0.5倍；和/或，
    优选加入阿司帕坦为颗粒重量的0.1％～3.0％；甜橙香精为颗粒重量的0.05％～2.0％。
  5. 权利要求3或4所述治疗儿童性早熟的中药制剂的制备方法，其 特征在于，包括：按配比取各药材；先将鳖甲加水煎煮；在所得第一煎煮液中再加入知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、麦芽；得第二煎煮液。
  6. 权利要求3或4所述治疗儿童性早熟的中药制剂的制备方法，其特征在于，包括以下步骤：
    1)按配比取鳖甲，加10～50倍重量的水，煎20～60min；得煎煮液；
    2)按配比在步骤1)所得煎煮液中加入知母、生地黄、玄参、黄柏、地骨皮、牡丹皮、泽泻、夏枯草、龙胆草、麦芽，再加入药材8～15倍重量的水，煎煮2～4次，每次煎煮0.5～1.5h，滤过，将滤液浓缩成浸膏；或者进一步还包括：
    3)取步骤2)所述浸膏作为喷雾料液，取适量蔗糖和糊精作为底料，置于喷雾制粒机内，均匀喷雾，制成颗粒，加入适量阿司帕坦和甜橙香精，混合，整粒，制成颗粒剂。
  7. 根据权利要求6所述的制备方法，其特征在于，步骤1)中，煎煮30min；和/或，
    步骤2)中，加水煎煮3次，分别加入12、8、6倍重量水，每次1h；和/或，
    具体地，步骤2)中，将滤液浓缩密度至相对密度为1.10～1.30(60℃)的浸膏。
  8. 根据权利要求6或7所述的制备方法，其特征在于，步骤3)中，所加入蔗糖和糊精的重量比为(5:5)～(8:2)；和/或，所加入的蔗糖和糊精的重量之和是原药材重量之和的0.1-0.5倍；和/或，阿司帕坦为颗粒重量的0.1％～3.0％；和/或，甜橙香精为颗粒重量的0.05％～2.0％。
  9. 一种治疗儿童性早熟的中药制剂，其特征在于，由权利要求5～8任一项所述方法制备得到。
  10. 权利要求1或2所述中药组合物或权利要求3、4、9任一项所述中药制剂在制备治疗儿童性早熟的药物中的应用。
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