WO2020042988A1 - 一种中药组合物及其制备方法和应用 - Google Patents

一种中药组合物及其制备方法和应用 Download PDF

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Publication number
WO2020042988A1
WO2020042988A1 PCT/CN2019/101869 CN2019101869W WO2020042988A1 WO 2020042988 A1 WO2020042988 A1 WO 2020042988A1 CN 2019101869 W CN2019101869 W CN 2019101869W WO 2020042988 A1 WO2020042988 A1 WO 2020042988A1
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Prior art keywords
amount
poria
extraction
paeonol
preparation
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PCT/CN2019/101869
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English (en)
French (fr)
Inventor
肖伟
王正宽
程宁波
王振中
朱克近
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江苏康缘药业股份有限公司
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Application filed by 江苏康缘药业股份有限公司 filed Critical 江苏康缘药业股份有限公司
Priority to EP19853786.2A priority Critical patent/EP3824897B1/en
Priority to JP2021511597A priority patent/JP7213955B2/ja
Priority to US17/271,487 priority patent/US11576942B2/en
Priority to KR1020217007364A priority patent/KR102577380B1/ko
Publication of WO2020042988A1 publication Critical patent/WO2020042988A1/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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
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    • 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
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
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    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
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    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
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Definitions

  • the invention relates to a composition including Chinese herbal medicine Ramulus cinnamnamomi and Poria cocos, and a preparation method and application thereof.
  • Guizhi Fuling Capsule is composed of five Chinese medicines: Guizhi, Poria, Peony Bark, Bai Zhi and Tao Ren. It has the functions of promoting blood circulation, dissipating blood stasis and eliminating symptoms. Endless postpartum lochia; uterine fibroids, chronic pelvic inflammatory inflammation mass, dysmenorrhea, endometriosis, ovarian cysts see the above symptoms; can also be used in women with breast sachet hyperplasia disease See breast pain, breast lumps, thoracic ribs; or used for bladder syndrome of benign prostatic hyperplasia, symptoms of unpleasant urination, abdominal pain.
  • the preparation method of Guizhi Fuling Capsules disclosed in the prior art is mainly made by the steps of steam distillation, ethanol extraction, concentration, granulation, and drying of Guizhi, Baiji, Poria, Peach Kernel and Peony Peel according to the required weight ratio.
  • Capsules have the disadvantages of relatively low content of active ingredients, poor dissolution, low production efficiency, high noise, and high requirements for dust removal, etc .; therefore, it is necessary to improve existing processes to obtain effective ingredients. High content of drug substances or preparations.
  • the present invention proposes a method for preparing a composition made of Guizhi, Poria, Peony Peel, Bai Zhi, Tao Ren according to equal proportions, which is characterized in that it includes steps:
  • Poria powder intermediate take a sufficient amount of Poria powder to dry at 70 ° C to moisture ⁇ 5.0%, pulverize by 120 sieve, and take 30-49% of the prescribed amount of Poria powder to obtain Poria powder intermediate; preferably 45% The prescribed amount of Poria is obtained;
  • peony peel is used for steam distillation to extract paeonol, collect aromatic water, medicine residue, and set aside; the aromatic water is left to stand for 48-72 hours until the crystals are completely crystallized, filtered, dried in dry, and obtained Paeonol crystals; inclusion of ⁇ -cyclodextrin to prepare paeonol inclusion compounds;
  • the obtained powder is passed through a 60-200 mesh sieve, preferably a 120 mesh sieve.
  • the moisture content of Poria medicinal materials for drying and sterilization is preferably ⁇ 5%; the moisture difference between the samples before and after mixing is tested, and the moisture content is controlled at ⁇ 5%.
  • the steam distillation process collects about 4-6 times the amount of aromatic water, preferably 5 times the amount of aromatic water. Specifically, the peony skin pieces are put into the extraction tank, and the paeonol is extracted by steam distillation. about 5 times the amount of aromatic water; preferably, the mesh number of the filter cloth is selected from 100 mesh;
  • the obtained paeonol aromatic water is left to stand until the crystals are completely crystallized, and filtered and purified to dry in the shade to obtain paeonol crystals for future use.
  • the filter cloth is selected from 200 mesh. ;
  • ⁇ -cyclodextrin is specifically: taking ⁇ -cyclodextrin into 2.7 times the amount of purified water, stirring it, heating it to 60 ° C., and taking 1/6 to 1/12 of tannin in ⁇ -cyclodextrin. Phenol is added to 4-6 times its amount of ethanol, heated to dissolve it, poured into ⁇ -cyclodextrin solution while hot, colloid milled for 30min, discharged, left to stand for 16-24h overnight, suction filtered, dried under normal pressure, and crushed After mixing for 15min, the paeonol inclusion compound is obtained; preferably, the pulverization passes through a 100-mesh sieve, and the drying temperature is selected from 50 ° C.
  • the added amount of ethyl acetate is 3.5% (weight-volume ratio) of the amount of medicinal materials.
  • the cinnamon stick pieces are put into the extraction tank, and the volatile oil is extracted by steam distillation. Extraction, collecting ethyl acetate layer of aromatic water; preferably, the extraction time is selected from 5 hours;
  • the scented laurel aroma water refining step after the ethyl acetate layer is left to stand, the upper ethyl acetate layer is separated, and the lower layer is re-extracted with an equal amount of ethyl acetate. Double the amount of ethanol, and concentrate again to obtain the pure volatile oil, ready for use;
  • the initial concentration temperature of the ethyl acetate is selected from 60 ° C
  • the concentration temperature after adding ethanol is selected from 80 ° C; preferably, the final concentration temperature is 90 ° C, concentrated 20min.
  • ⁇ -cyclodextrin is as follows: take ⁇ -cyclodextrin into 4-6 times the amount of ethanol, preferably 5 times the amount of ethanol, stir well to make it into a suspension, take ⁇ -cyclodextrin 1/6 ⁇ 1/12 amount of volatile oil is poured into it, preferably 1/10 amount, stir well, colloid milled for 30min, unloaded, left for 16-24h, suction filtered, dried, crushed, and mixed for 15min to obtain the cinnamon stick volatile oil (cinnamon Oil) clathrate, preferably, the ethanol is selected from the group consisting of 20% ethanol, crushed through a 100 mesh sieve, and the drying temperature is selected from 50 ° C.
  • the feeding order of the white chrysanthemum, peach kernel and Poria cocos with a prescription amount of 51-70% is the bottom of the baiji, the middle part of the peach kernel, and the upper part of the Poria cocos;
  • the inlet air temperature is set to 165-170 ° C, and the temperature of the outlet air during the spray-drying process is controlled to 90-95 ° C; cool to room temperature, discharge, and mix to obtain a spray-dried powder.
  • the above preparation method includes a pre-treatment process for the medicinal materials used, such as:
  • Poria is cut into pieces with a size of about 0.5-1cm; peony skin is made into pieces after rinsing and other processes; the remaining medicinal materials can be fed as pure medicinal pieces.
  • the present invention provides a traditional Chinese medicine composition, which is characterized in that the traditional Chinese medicine composition is made of Guizhi, Poria, peony peel, Paeonia lactiflora, and peach kernel in equal proportions, wherein the traditional Chinese medicine composition further comprises paeoniflorin and bitter almond Glycosides, benzoyl paeoniflorin, cinnamic acid, paeonol, cinnamaldehyde.
  • the paeoniflorin content accounts for more than 15 mg / g of the traditional Chinese medicine composition
  • the amygdalin content accounts for more than 10 mg / g of the traditional Chinese medicine composition
  • the paeonol content accounts for the traditional Chinese medicine composition More than 10mg / g.
  • the transfer rate of Poria acid in the Chinese medicine composition is greater than 90%.
  • the invention provides a method for preparing a composition or a preparation containing guizhi and tuckahoe, which uses Chinese herbal medicines twig, tuckahoe, peony peel, paeonia lactiflora and peach kernel as raw materials.
  • the method includes the following steps:
  • step (d) further comprises a step of extracting Bai Zhi, Tao Ren and Poria cocos from 55% of the prescription amount;
  • the step (e) comprises mixing a Poria powder intermediate, a spray-dried powder intermediate, a paeonol inclusion compound and a cinnamon oil inclusion compound.
  • the medicinal materials used before the step (a) are pretreated, wherein
  • the medicinal materials are cut into pieces with a size of about 0.5-1cm;
  • the remaining medicinal materials are all pure medicinal herbs.
  • the pre-processing further comprises rinsing and drying the peony skin, and then preparing it into pieces.
  • step (a) 45% Poria cocos is dried and sterilized, pulverized and powdered, and mixed uniformly to obtain Poria cocos powder intermediate;
  • the pulverized powder is passed through a 60-200 mesh sieve, preferably a 120 mesh sieve.
  • the step (b) further comprises paeonol aroma water extraction, peony skin aroma water purification and preparation of paeonol inclusion compound;
  • the peony peel piece is put into the extraction tank, and the paeonol is extracted by steam distillation, and the filter cloth is filtered to collect about 4-6 times the amount of the aromatic water, preferably 5 times the amount of the aromatic water; Stand-by; the mesh number of the filter cloth is selected from 80-200 mesh, preferably 100 mesh;
  • the obtained paeonol aroma water is left to stand until the crystals are completely crystallized, filtered and purified to dry in the shade, to obtain paeonol crystals, for future use;
  • the filter cloth is selected from 80-200 mesh, Preferably 200 mesh;
  • ⁇ -cyclodextrin is added to 2.7 times the amount of purified water, and the mixture is heated, and ⁇ -cyclodextrin 1/6 to 1/12 of paeonol is added to 4 -6 times the amount of ethanol, heat to dissolve it, pour into ⁇ -cyclodextrin solution while hot, pass colloid mill, unload, leave overnight, suction filter, dry at normal pressure, crush, and mix to obtain paeonol Inclusion compound;
  • the paeonol is preferably added in an amount of 1/10 of ⁇ -dextrin, the ethanol is preferably added in an amount of 5 times, the pulverized is passed through a 60-200 mesh sieve, preferably 100 mesh; the atmospheric pressure
  • the drying temperature is selected from 40-90 ° C, preferably 50 ° C.
  • the step (c) further comprises extracting twig fragrant water, refining twig fragrant water and preparing a cinnamon oil inclusion compound;
  • the pieces of cassia twig are put into the extraction tank, and the volatile oil is extracted by steam distillation.
  • 3.5% of the medicinal material is added to the ethyl acetate for extraction, and the ethyl acetate layer is used to collect the aromatic water. 4-8 hours, preferably 5 hours;
  • the ethyl acetate concentration temperature is selected from 51-70 ° C, preferably 60 ° C, and the ethanol concentration temperature is selected from 70-95 ° C, preferably 80 ° C;
  • cinnamon oil inclusion compound In the step of preparing cinnamon oil inclusion compound, ⁇ -cyclodextrin is added to 4-6 times the amount of ethanol, preferably 5 times the amount of ethanol, and the mixture is stirred to form a suspension, and ⁇ -cyclodextrin is taken 1/6 ⁇ 1/12 amount of cinnamon oil is poured into it, preferably 1/10 amount, stir well, colloid milled, unloaded, left overnight, suction filtered, dried under normal pressure, crushed and mixed to obtain cinnamon oil inclusion compound;
  • the ethanol is selected from a concentration of 10-50% ethanol, preferably 20% ethanol, crushed through a 60-200 mesh sieve, preferably 100 mesh, and the atmospheric drying temperature is selected from 40-90 ° C, preferably 50 ° C.
  • the step (d) further comprises an extraction process, a concentration and a spray drying step; wherein the extraction process further comprises the extraction of peony peel medicinal residue, the extract of twig of cinnamon stick, the extraction of paeonia lactiflora, peach kernel and 55% of Poria cocos Concentration further includes the steps of alcohol extraction liquid concentration, water extraction liquid concentration, and combined concentration; spray drying further includes combining extracts for spray drying to obtain a spray-dried powder crude product, and the spray-dried powder crude product is crushed and mixed to obtain an extract spray-dried powder.
  • the extraction process further comprises the extraction of peony peel medicinal residue, the extract of twig of cinnamon stick, the extraction of paeonia lactiflora, peach kernel and 55% of Poria cocos Concentration further includes the steps of alcohol extraction liquid concentration, water extraction liquid concentration, and combined concentration
  • spray drying further includes combining extracts for spray drying to obtain a spray-dried powder crude product, and the spray-dried powder crude product is crushed and mixed to obtain an extract spray-
  • the medicinal residue obtained after the peony peel extracts the aromatic water is added to 90% ethanol in batches according to the volume-weight ratio extraction, filtered, and the filtrates are combined to obtain A1, which is reserved for use;
  • the amount of ethanol added is 3-5 times, preferably 4 times, and then 2-4 times, preferably 3 times.
  • the peony skin medicine residue is added to water extraction in batches according to the volume-weight ratio, filtered, and the filtrates are combined to obtain B1, which is reserved; the medicine residue is discarded; the amount of water added in batches is 5-8 times, preferably 6 Double the amount, then add 2-6 times the amount, preferably 4 times the amount;
  • the number of extractions of ethanol is selected from 1-4, preferably 2 times
  • the number of extractions of water is selected from 1-4, preferably 2 times
  • the extraction time of ethanol and water is selected from 2 hours.
  • the tartrazine dregs after extracting the aromatic water are added in 90% ethanol in batches according to the volume-weight ratio, filtered, and the filtrates are combined to obtain A2, which is used in standby; ethanol is added in batches.
  • the amount is 3-5 times the amount, preferably 4 times the amount, and then 2-4 times the amount, preferably 3 times the amount;
  • Guizhi dregs are added to water in batches according to the volume-weight ratio, filtered, and the filtrates are combined to obtain B2, which is reserved; the dregs are discarded; the amount of water added in batches is 5-8 times the amount first, preferably 6 Double the amount, then add 2-6 times the amount, preferably 4 times the amount;
  • the number of extractions of ethanol is selected from 1-4, preferably 2 times
  • the number of extractions of water is selected from 1-4, preferably 2 times
  • the extraction time of ethanol and water is selected from 2 hours.
  • the Paeonia lactiflora, peach kernel and 55% Poria cocoa are put into the extraction tank in the order of feeding, and 90% ethanol is added in batches according to the volume weight ratio of the medicinal materials for extraction. Filtering; combining the filtrates to obtain A3, ready for use; the amount of ethanol added in batches is 3-5 times, preferably 4 times, and then 2-4 times, preferably 3 times;
  • the medicine residue is added to the water in batches according to the volume-weight ratio, and filtered, and the filtrates are combined to obtain B3, which is reserved; the medicine residue is discarded; the amount of water added in batches is 5-8 times, preferably 6 times, , And then add 2-6 times the amount, preferably 4 times the amount.
  • the feeding order is the bottom of Baiji, the middle of peach kernel, and the upper part of Poria; the number of ethanol extraction is selected from 1-4 times, preferably 2 times, and the number of water extraction is selected from 1-4 times, preferably 2 times.
  • the extraction time of ethanol and water was selected from 2 hours.
  • the A1, A2, and A3 alcohol extraction liquids are combined and concentrated under reduced pressure to a relative density of 1.0-1.10, preferably 1.02-1.05, and weighed to obtain an alcohol extraction extract;
  • the B1, B2, and B3 water extracts are combined and concentrated under reduced pressure to a relative density of 1.02-1.20, preferably 1.05-1.10, and weighed to obtain a water-extracted extract;
  • the concentrated liquids of the alcohol extract and the water extract are combined and then concentrated to a relative density of 1.05-1.30, preferably 1.15, passed through a 60-200 mesh sieve, preferably 80-100 mesh, to obtain an extract, and refrigerated Store or spray dry directly.
  • the combined extract is spray-dried, and the inlet air temperature is set to 120-200 ° C, preferably 165-170 ° C, to control the air temperature during the spray-drying process. 80-110 ° C, preferably 90-95 ° C; cool to room temperature, discharge, get spray-dried powder;
  • the entire spray-dried powder crude product is pulverized by 60-200 meshes, preferably 100 meshes, to obtain pulverized spray-dried powder.
  • the total mixing time is ⁇ 5min, preferably ⁇ 30min, to obtain the final drug substance.
  • the invention also relates to a method for preparing Guizhi Fuling Capsules, which is characterized in that the method comprises dry granulating, granulating, uniformly mixing and obtaining granules of the raw material medicine obtained in claim 14, filling the capsule shell, The finished product is obtained; preferably, the dry granulation is passed through a 16-30 mesh sieve, preferably 24 mesh.
  • the method further comprises the step of mixing the drug substance with cyclodextrin.
  • the invention also relates to a pharmaceutical composition, which comprises the composition according to the invention and a pharmaceutically acceptable carrier.
  • composition is formulated as a formulation product
  • formulation is selected from the group consisting of pills, capsules, granules, tablets, suspensions, or syrups.
  • the invention also provides a medicine for treating or preventing primary dysmenorrhea, secondary dysmenorrhea, dysfunctional uterine bleeding, chronic pelvic inflammatory disease or small intramural uterine fibroids, which is characterized in that the medicine is any one of the foregoing
  • the composition and a pharmaceutically acceptable excipient are made into a clinically acceptable dosage form. Such as decoctions, granules, capsules, tablets, oral liquids, pills, elixirs, suspensions, syrups, suppositories, suppositories, gels, sprays, injections and so on.
  • the method for preparing the capsules comprises dry granulating, granulating, mixing uniformly, and obtaining granules of the foregoing composition or drug substance.
  • the moisture content of the granules is controlled within 5%, and the capsule shell is filled to obtain a finished product.
  • the dry granulation is passed through a 24 mesh sieve.
  • the invention also proposes the use of any of the foregoing compositions in the manufacture of a medicament for the treatment or prevention of any of the following diseases or conditions: primary dysmenorrhea, secondary dysmenorrhea, dysfunctional uterine bleeding, chronic pelvic inflammatory disease or small wall Intrauterine fibroids.
  • any of the foregoing compositions is administered orally, rectally, parenterally, intravaginally, intraperitoneally, topically, or as an oral or nasal spray.
  • composition of the invention has high content of effective ingredients, high production efficiency, high rate of Poria acid transfer, reduced hygroscopicity, and improved dissolution of various index components. Its preparation method has the following advantages:
  • each index component in the preparation is significantly higher than that in the original process preparation
  • the invention discloses a composition containing Chinese herbal medicine Guizhi and Poria, and a preparation method and application thereof. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters for implementation. In particular, it should be noted that all similar replacements and modifications will be apparent to those skilled in the art, and they are all considered to be included in the present invention.
  • the medicines, reagents and instruments used in the technical solution provided by the present invention can be purchased from conventional channels or markets.
  • the peony skin in the above five medicines is rinsed with water for 2 minutes, dried, and cut into pieces with a size of 0.5-1cm, ready for feeding;
  • the remaining medicinal materials are all decoction pieces of pure medicinal materials
  • the above five flavor medicinal materials are all pure medicinal herbs
  • Poria powder Take a sufficient amount of Poria for drying at 70 ° C to ⁇ 5.0% moisture, pulverize it with 120 sieve, and take 30-49% of the prescribed amount of Poria powder to obtain the Poria powder intermediate; preferably take 45% of the prescribed amount of Poria powder to obtain
  • Peony peel pieces are put into a multi-functional extraction tank, and the paeonol is extracted by direct steam distillation.
  • the mesh size of the filter cloth is about 100 meshes, and about 5 times the amount (720kg) of aromatic water is collected; the medicine residue is ready for use.
  • Guizhi decoction pieces were put into a multifunctional extraction tank, and the volatile oil was extracted by steam distillation. During the process, 3.5% medicinal material of ethyl acetate was added for extraction. The extraction time was 5 hours, and the ethyl acetate layer was collected as aromatic water.
  • the ethyl acetate layer of aromatic water was placed in a separating funnel and left to stand.
  • the upper ethyl acetate layer was separated, and the lower layer was re-extracted with an equal amount of ethyl acetate.
  • the ethyl acetate layers were combined and recovered under reduced pressure at 60 ° C to obtain no obvious liquid.
  • Dropwise reflux add approximately equal volume of ethanol of crude volatile oil, concentrate at 80 ° C until no significant droplet reflux, and concentrate at 90 ° C for 20min to obtain 0.50-0.90L of pure volatile oil for future use.
  • the slag after extracting the fragrant water from peony skin is added with 4 + 3 (volume-to-weight ratio, 576L + 432L) twice the amount of 90% ethanol and extracted twice, each time for 2 hours (5 minutes after each extraction and boiling cycle), filtered The filtrates were combined to obtain A1, ready for use.
  • the peony skin medicine residue was added with 6 + 4 (864L + 576L) times the amount of water for two extractions, each time for 2 hours (5 minutes after each extraction boiling cycle), the filtrates were combined to obtain B1, and the medicine residue was discarded.
  • the slag after extracting aromatic water from twig cinnamon is added with 4 + 3 (volume-to-weight ratio, 576L + 432L) 90% ethanol twice, and extracted twice, each extraction is 2 hours (5 minutes after each extraction boiling cycle), and the filtrates are combined Get A2, spare.
  • Bai Zhi, Tao Ren and 55% Poria are put into the multi-functional extraction tank.
  • the feeding order is bottom of Bai Zhi, middle of Tao Ren, upper part of Poria, adding 4 + 3 times the amount of medicinal materials (volume-to-weight ratio, 1468.8L + 1101.6L) 90% ethanol extraction Twice, extract for 2 hours each time (cycle for 5 minutes after each extraction boiling), and obtain A3 from the filtrate, and reserve.
  • the A1, A2, and A3 alcohol extracts were combined and concentrated under reduced pressure, and the alcohol extracts were recovered to a relative density of 1.02-1.05 (70 ⁇ 5 ° C) and weighed to obtain an alcohol extract.
  • the B1, B2, and B3 water extracts were combined and concentrated under reduced pressure, and the water extracts were concentrated to a relative density of 1.05-1.10 (80 ⁇ 5 ° C), and weighed to obtain a water-extracted extract.
  • the pulverized powder is mixed after being pulverized, and the mixture is ⁇ 15min.
  • the final powder is spray-dried and used.
  • the Poria powder, spray-dried powder, paeonol inclusion compound, and cinnamon oil inclusion compound are mixed together, and the total mixing is performed for a time ⁇ 30 minutes to obtain the final drug substance.
  • the raw materials are dry-granulated (24 mesh), granulated and mixed uniformly to obtain granules. 0.465 g / granule is filled into a green capsule shell of No. 0 to obtain a finished product.
  • the combined extract of the present invention is directly spray-dried to obtain a medicinal powder, and the paeonol inclusion compound, the tangerine volatile oil inclusion compound, and the Poria powder are directly combined for dry granulation.
  • the mixing of the extract is reduced.
  • the production efficiency of the preparation method of the present invention is improved by more than 30%.

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Abstract

一种中药组合物，由桂枝、茯苓、牡丹皮、白芍、桃仁按等比例制成，其中，所述中药组合物包含芍药苷、苦杏仁苷、苯甲酰芍药苷、肉桂酸、丹皮酚、桂皮醛。该组合物生产效率高、有效成份含量高、茯苓酸转移率高、吸湿性降低、提高各指标成分的溶出度。

Description

一种中药组合物及其制备方法和应用 技术领域
本发明涉及包括中草药桂枝(Ramulus cinnamomi)和茯苓(Poria cocos)的组合物、及其制备方法和应用。
背景技术
桂枝茯苓胶囊由桂枝、茯苓、牡丹皮、白芍和桃仁共五味中药组成，具有活血、化瘀、消癥之功效，主治妇人瘀血阻络所致癥块、经闭、痛经、产后恶露不尽；子宫肌瘤，慢性盆腔炎包块，痛经，子宫内膜异位症，卵巢囊肿见上述证候者；也可用于女性乳腺香囊性增生病属瘀血阻络症，症见乳房疼痛、乳房肿块、胸肋胀闷；或用于前列腺增生属瘀阻膀胱证，症见小便不爽、小腹胀痛。
现有技术公开的桂枝茯苓胶囊制备方法主要是通过由桂枝、白芍、茯苓、桃仁和牡丹皮按所需重量比经水蒸汽蒸馏、乙醇提取、浓缩、制粒、干燥等步骤制成胶囊，缺陷在于：该方法制备的药物的有效成份含量相对较低、溶出度较差，生产效率较低，噪音大、对除尘要求高等；因此，有必要改进现有工艺方法，以获得有效成份含量高的原料药或制剂。
发明内容
有鉴于此，本发明提出一种由桂枝、茯苓、牡丹皮、白芍、桃仁按照等比例制成的组合物的制备方法，其特征在于，包括步骤：
(a)茯苓粉中间体的制备：取足量的茯苓70℃干燥至水分≤5.0％，120筛粉碎，取30-49％处方量的茯苓粉，即得茯苓粉中间体；优选取45％处方量的茯苓，即得；
(b)丹皮酚包合物的制备：牡丹皮直通蒸汽蒸馏提取丹皮酚，收集芳香水，药渣，待用；芳香水静置48-72小时至晶体结晶完全，过滤，阴干，得丹皮酚晶体；取β-环糊精包合制得丹皮酚包合物；
(c)桂枝挥发油包合物的制备；桂枝直通蒸汽蒸馏提取挥发油，过程中加乙酸乙酯萃取，收集乙酸乙酯层芳香水，药渣，待用；芳香水层放置于分液漏斗中，静置，分取上层乙酸乙酯层，下层用等倍量乙酸乙酯再萃取，合并乙酸乙酯层，减压回收，加乙醇继续浓缩，得纯品挥发油；取β-环糊精包合制得桂枝挥发油包合物；
(d)提取物喷干粉中间体的制备：将牡丹皮药渣进行醇提取和水提取，桂枝药渣进行醇提取和水提取，白芍、桃仁及处方量51-70％的茯苓进行醇提取和水提取；将上述醇提液或水提液分别浓缩，合并浓缩液后继续浓缩，喷雾干燥后混合得喷干粉；
(e)总混：将茯苓粉中间体、提取物喷干粉中间体、丹皮酚包合物、桂枝挥发油包合物，混合，即得。总混时间优选≥30min。
进一步地，所述步骤(a)中，将部分茯苓粉碎后，所得粉末过60-200目筛，优选120目筛。茯苓药材干燥灭菌的水分优选<5％；混合后检测样品前后水分差异，所述水分控制在<5％。
具体地，所述步骤(b)中：
所述蒸汽蒸馏过程收集约4-6倍量芳香水，优选5倍量芳香水；具体为牡丹皮饮片投入提取罐中，通蒸汽蒸馏提取丹皮酚，滤布过滤，芳香水流速控制在5kg/min左右，收集约5倍量芳香水；优选地，滤布目数选自100目；
牡丹皮芳香水静置析晶步骤中，将所得丹皮酚芳香水静置至晶体结晶完全，过滤、净化区阴干，即得丹皮酚晶体，备用；优选地，过滤滤布选自200目；
所述β-环糊精包合具体为，取β-环糊精加入其2.7倍量纯化水中搅匀，加热至60℃，取β-环糊精1/6～1/12量的丹皮酚加入其4-6倍量乙醇中，加热使之溶解，趁热倒入β-环糊精溶液中，过胶体磨30min，放料，放置过夜16-24h，抽滤，常压干燥，粉碎，混合15min，即得丹皮酚包合物；优选地，所述粉碎过100目筛，干燥温度选自50℃。
进一步地，所述步骤(c)中：
所述蒸汽蒸馏过程乙酸乙酯的加入量为药材量的3.5％(重量体积比)；具体为桂枝饮片投入提取罐中，通蒸汽蒸馏提取挥发油，过程中加入3.5％药材量的乙酸乙酯萃取，收集乙酸乙酯层芳香水；优选地，萃取时间选自5小时；
在桂枝芳香水精制步骤中，乙酸乙酯层芳香水静置后，分取上层乙酸乙酯层，下层用等倍量乙酸乙酯再萃取，合并乙酸乙酯层，浓缩后加入粗品挥发油等倍量的乙醇，再次浓缩，得纯品挥发油，备用；优选地，所述乙酸乙酯初始浓缩温度选自60℃，加乙醇后浓缩温度选自80℃；优选最终浓缩温度为90℃，浓缩20min。
所述β-环糊精包合为，取β-环糊精加入4-6倍量乙醇中，优选5倍量乙醇，搅拌均匀，使成混悬状，取β-环糊精1/6～1/12量的挥发油倒入其中，优选1/10量，搅拌均匀，过胶体磨30min，放料，放置16-24h，抽滤，干燥，粉碎，混合15min，即得桂枝挥发油(肉桂油)包合物，优选地，所述乙醇选自浓度为20％乙醇，粉碎过100目筛，干燥温度选自50℃。
优选地，所述步骤(d)中，
所述白芍、桃仁及处方量51-70％的茯苓的投料顺序为白芍底部、桃仁中部、茯苓上部；
喷干粉制备过程中，设定进风温度165-170℃，控制喷干过程中出风温度90-95℃；冷却至室温，出料，混合，得喷干粉。
优选地，上述制备方法包括对所用药材的前处理过程，如：
茯苓切成规格为0.5-1cm左右的饮片；牡丹皮经冲洗等工序后，再制成饮片；其余药材可以为净药材饮片投料。
本发明提出一种中药组合物，其特征在于，该中药组合物由桂枝、茯苓、牡丹皮、白芍、桃仁按等比例制成，其中，所述中药组合物还包含芍药苷、苦杏仁苷、苯甲酰芍药苷、肉桂酸、丹皮酚、桂皮醛。
进一步地，所述芍药苷含量占所述中药组合物的15mg/g以上，所述苦杏仁苷含量占所述中药组合物的10mg/g以上，所述丹皮酚含量占 所述中药组合物的10mg/g以上。
优选地，所述中药组合物中茯苓酸的转移率大于90％。
本发明提供一种包含桂枝和茯苓组合物或制剂的制备方法，以中草药材桂枝、茯苓、牡丹皮、白芍和桃仁为原料，所述方法包括步骤：
(a)制备茯苓(Poria)粉中间体；
(b)制备牡丹皮(Cortex moutan)的提取物丹皮酚包合物；
(c)制备桂枝的提取物桂枝挥发油包合物；
(d)制备提取物喷干粉中间体；
(e)总混；和
(f)制粒得产品；
其特征在于，所述步骤(d)中还包括白芍、桃仁及处方量55％的茯苓提取的步骤；
所述步骤(e)包括将茯苓粉中间体、喷干粉中间体、丹皮酚包合物、肉桂油包合物进行混合。
优选地，所述步骤(a)之前所用药材进行前处理，其中
药材切成规格为0.5-1cm左右的饮片；
称取55％茯苓饮片，供提取用；
其余药材均为净药材饮片投料。
进一步地，所述前处理还包括将牡丹皮经冲洗、晾干后，再制成饮片。
优选地，所述步骤(a)中，取45％茯苓药材进行干燥灭菌后，粉碎打粉，混合均匀，即得茯苓粉中间体；
优选地，其中，
粉碎所得粉末过60-200目筛，优选120目筛。
优选地，所述步骤(b)还包括丹皮酚芳香水提取、牡丹皮芳香水精制及制备丹皮酚包合物；
在丹皮酚芳香水提取步骤中，牡丹皮饮片投入提取罐中，通蒸汽蒸馏提取丹皮酚，滤布过滤，收集约4-6倍量芳香水，优选5倍量芳香水；药渣，待用；所述滤布目数选自80-200目，优选100目；
在牡丹皮芳香水精制步骤中，将所得丹皮酚芳香水静置至晶体结晶 完全，过滤、净化区阴干，即得丹皮酚晶体，备用；所述过滤滤布选自80-200目，优选200目；
在制备丹皮酚包合物步骤中，取β制环糊精加入其2.7倍量纯化水中搅匀，加热，取β量环糊精1/6～1/12量的丹皮酚加入其4-6倍量乙醇中，加热使之溶解，趁热倒入β量环糊精溶液中，过胶体磨，放料，放置过夜，抽滤，常压干燥，粉碎，混合，即得丹皮酚包合物；所述丹皮酚加入量优选β糊环糊精的1/10，所述乙醇加入量优选5倍量，所述粉碎过60-200目筛，优选100目；所述常压干燥温度选自40-90℃，优选50℃。
优选地，所述步骤(c)还包括桂枝芳香水提取、桂枝芳香水精制及制备肉桂油包合物；
在桂枝芳香水提取步骤中，桂枝饮片投入提取罐中，通蒸汽蒸馏提取挥发油，过程中加入3.5％药材量的乙酸乙酯萃取，收集乙酸乙酯层芳香水；所述萃取时间选自4-8小时，优选5小时；
在桂枝芳香水精制步骤中，乙酸乙酯层芳香水静置后，分取上层乙酸乙酯层，下层用等倍量乙酸乙酯再萃取，合并乙酸乙酯层，浓缩后加入粗品挥发油等倍量的乙醇，再次浓缩，得纯品挥发油，备用；优选地，所述乙酸乙酯浓缩温度选自51-70℃，优选60℃，乙醇浓缩温度选自70-95℃，优选80℃；
在制备肉桂油包合物步骤中，取β制环糊精加入4-6倍量乙醇中，优选5倍量乙醇，搅拌均匀，使成混悬状，取β量环糊精1/6～1/12量的肉桂油倒入其中，优选1/10量，搅拌均匀，过胶体磨，放料，放置过夜，抽滤，常压干燥，粉碎，混合，即得肉桂油包合物；所述乙醇选自浓度为10-50％乙醇，优选20％乙醇，粉碎过60-200目筛，优选100目，所述常压干燥温度选自40-90℃，优选50℃。
优选地，所述步骤(d)还包括提取过程、浓缩、喷雾干燥步骤；其中，提取过程进一步包括牡丹皮药渣提取，桂枝药渣提取，白芍、桃仁及处方量55％的茯苓提取；浓缩进一步包括醇提液浓缩、水提液浓缩及合并浓缩的步骤；喷雾干燥进一步包括合并浸膏进行喷雾干燥得喷干粉粗品、喷干粉粗品粉碎后混合得到提取物喷干粉。
进一步地，所述牡丹皮药渣提取步骤中，将牡丹皮提取芳香水后所得的药渣按照体积重量比分批次加入90％乙醇提取，过滤，合并滤液得A1，备用；所述分批次加入乙醇的量为先加入3-5倍量，优选4倍量，再加入2-4倍量，优选3倍量；
将牡丹皮药渣再按照体积重量比分批次加入水提取，过滤，合并滤液得B1，备用；药渣弃之；所述分批次加入水的量为先加入5-8倍量，优选6倍量，再加入2-6倍量，优选4倍量；
优选地，所述乙醇提取次数选自1-4次，优选2次，所述水提取次数选自1-4次，优选2次，乙醇和水每次提取时间选自2小时。
进一步地，所述桂枝药渣提取步骤中，桂枝提取芳香水后的药渣按照体积重量比分批次加入90％乙醇提取，过滤，合并滤液得A2，备用；所述分批次加入乙醇的量为先加入3-5倍量，优选4倍量，再加入2-4倍量，优选3倍量；
将桂枝药渣再按照体积重量比分批次加入水提取，过滤，合并滤液得B2，备用；药渣弃之；所述分批次加入水的量为先加入5-8倍量，优选6倍量，再加入2-6倍量，优选4倍量；
优选地，所述乙醇提取次数选自1-4次，优选2次，所述水提取次数选自1-4次，优选2次，乙醇和水每次提取时间选自2小时。
进一步地，所述白芍、桃仁及处方量55％的茯苓提取步骤中，将白芍、桃仁、55％茯苓按照投料顺序投入提取罐中，按照药材体积重量比分批次加入90％乙醇提取，过滤；合并滤液得A3,备用；所述分批次加入乙醇的量为先加入3-5倍量，优选4倍量，再加入2-4倍量，优选3倍量；
将药渣再按照体积重量比分批次加入水提取，过滤，合并滤液得B3，备用；药渣弃之；所述分批次加入水的量为先加入5-8倍量，优选6倍量，再加入2-6倍量，优选4倍量。
优选地，所述投料顺序为白芍底部、桃仁中部、茯苓上部；所述乙醇提取次数选自1-4次，优选2次，所述水提取次数选自1-4次，优选2次，乙醇和水每次提取时间选自2小时。
进一步地，所述醇提液浓缩步骤中，合并A1、A2、A3醇提液、减 压浓缩至相对密度1.00-1.10，优选1.02-1.05，称重，得醇提浸膏；
所述水提液浓缩步骤中，合并B1、B2、B3水提液、减压浓缩至相对密度1.02-1.20，优选1.05-1.10，称重，得水提浸膏；
所述合并浓缩的步骤中，合并醇提液及水提液的浓缩液、继续浓缩至相对密度1.05-1.30，优选1.15，过60-200目筛，优选80-100目，得浸膏，冷藏保存或直接喷雾干燥。
进一步地，所述合并浸膏进行喷雾干燥得喷干粉粗品步骤中，取合并浸膏进行喷雾干燥，设定进风温度120-200℃，优选165-170℃，控制喷干过程中出风温80-110℃，优选90-95℃；冷却至室温，出料，得喷干粉；
所述喷干粉粗品粉碎步骤中，将所得全部喷干粉粗品进行60-200目粉碎，优选100目，得粉碎后喷干粉。
进一步地，所述总混时间≥5min，优选≥30min，即得最终原料药。
本发明还涉及一种桂枝茯苓胶囊的制备方法，其特征在于，所述方法包括将权利要求14所得的原料药进行干法制粒、整粒、混合均匀、得颗粒，充填入胶囊壳中，得成品；优选地，所述干法制粒过16-30目筛，优选24目。
优选地，所述方法还包括将原料药与环糊精混合的步骤。
本发明还涉及一种药物组合物，所述药物组合物包括本发明所述的组合物和药用载体。
进一步地，其中所述组合物被配制成制剂产品，所述制剂选自由丸剂、胶囊、颗粒剂、片剂、混悬剂或糖浆剂。
本发明还提出了一种治疗或预防原发性痛经、继发性痛经、功能障碍性子宫出血、慢性盆腔炎或小的壁内子宫肌瘤的药物，其特征在于，该药物为任一前述组合物和药学上可接受的赋型剂制成临床可接受的剂型。如汤剂、颗粒剂、胶囊剂、片剂、口服液、丸剂、酊剂、混悬剂、糖浆剂、栓剂、栓剂、凝胶剂、喷雾剂、注射液等。
具体地，所述胶囊的制备方法，包括前述组合物或原料药进行干法制粒、整粒、混合均匀、得颗粒，颗粒水分控制在5％以内，充填入胶囊壳中，得成品；优选地，所述干法制粒过24目筛。
本发明还提出了任一前述组合物在制备治疗或预防下列任一疾病或病症的药物中的应用：原发性痛经、继发性痛经、功能障碍性子宫出血、慢性盆腔炎或小的壁内子宫肌瘤。具体地，所述应用为前述任一组合物以口服、直肠、肠胃外、阴道内、腹膜内、局部、或作为口或鼻喷雾剂而施用。
本发明的组合物有效成份含量高、生产效率高、茯苓酸转移率高、吸湿性降低、提高各指标成分的溶出度。其制备方法具有如下优点：
(1)减少了浸膏拌茯苓粉干燥、粉碎、湿法制粒干燥等过程，生产效率提高了30％以上；
(2)减少了茯苓拌浸膏干燥粉碎过程，茯苓酸转移率高于90％；
(3)由于茯苓粉在制剂时混合其他三个中间体进行干法制粒，产品吸湿性明显优于原工艺，吸湿性降低60％以上；
(4)制剂中各指标成分含量明显高于原工艺制剂中的含量；
(5)由于浸膏直接喷雾干燥并合并其他中间体直接制剂，各指标成分的溶出度明显优于现有制备方法的溶出度；
(6)本发明改进后的工艺合理性明显优于现有技术。
(7)由于减少了茯苓拌浸膏干燥粉碎过程，生产强度低、噪音小、产尘率低等。
具体实施方式
本发明公开了一种包含中草药桂枝和茯苓的组合物、及其制备方法和应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。
除特别指出，本发明提供的技术方案中所用药品、试剂、仪器均可由常规渠道或市场购得。
实施例1本发明组合物胶囊的制备
1、胶囊标准处方
Figure PCTCN2019101869-appb-000001
2、生产组方(400处方量)
Figure PCTCN2019101869-appb-000002
3、具体制备方法
前处理
前处理1：
以上五味药中的牡丹皮，水冲洗2分钟，晾干，切成规格为0.5-1cm的饮片，备投料；
其余药材均为净药材饮片投料；
称取55％茯苓饮片，供提取用。或者，
前处理2：
以上五味药材均为净药材饮片投料；
称取55％处方量的茯苓饮片，供提取用。
(a)茯苓粉中间体制备
取足量的茯苓70℃干燥至水分≤5.0％，120筛粉碎，取30-49％处方量的茯苓粉，即得茯苓粉中间体；优选取45％处方量的茯苓，即得；
(b)丹皮酚包合物制备
(1)丹皮酚芳香水提取
牡丹皮饮片投入多功能提取罐中，直通蒸汽蒸馏提取丹皮酚，滤布目数约100目左右，收集约5倍量(720kg)芳香水；药渣，待用。
(2)牡丹皮芳香水精制
静置48-72小时至晶体结晶完全，200目过滤，净化区阴干，即得丹皮酚晶体1.8-2.4kg，备用。
(3)丹皮酚包合
取β-环糊精加入其2.7倍量纯化水中搅匀，加热至60℃；取β-环糊精1/10量的丹皮酚加入其5倍量95％乙醇中，加热使之溶解，趁热倒入β-环糊精溶液中；过胶体磨30min，放料，放置16-24h；抽滤，50℃常压干燥，100目粉碎，混合，即得丹皮酚包合物16.0-22.0kg。
(c)枝挥发油包合物制备
(1)桂枝芳香水提取
桂枝饮片投入多功能提取罐中，直通蒸汽蒸馏提取挥发油，过程中加入3.5％药材量的乙酸乙酯萃取，提取时间5小时，收集乙酸乙酯层芳香水。
(2)桂枝芳香水精制
乙酸乙酯层芳香水放置于分液漏斗中，静置，分取上层乙酸乙酯层，下层用等倍量乙酸乙酯再萃取，合并乙酸乙酯层，60℃减压回收至无明显液滴回流，加约粗品挥发油等倍量乙醇，80℃浓缩至无明显液滴回流，90℃浓缩20min，得纯品挥发油0.50-0.90L，备用。
(3)肉桂油包合
取β-环糊精加入5倍量20％乙醇中，搅拌均匀，使成混悬状；取β-环糊精1/10量的肉桂油倒入其中，搅拌均匀，过胶体磨30min，放料，放置16-24h，抽滤，50℃常压干燥，100目粉碎，混合，即得肉桂油包合物5.0-9.0kg。
(d)提取物喷干粉中间体制备
(1)提取过程
1)牡丹皮药渣提取
牡丹皮提取芳香水后的药渣加入4+3(体积重量比，576L+432L)倍量90％乙醇提取两次，每次提取2小时(每次提取沸腾后打循环5分钟)，滤过，合并滤液得A1，备用。
牡丹皮药渣再加入6+4(864L+576L)倍量水提取两次，每次提取2小时(每次提取沸腾后打循环5分钟)，合并滤液得B1，备用；药渣弃之。
2)桂枝药渣提取
桂枝提取芳香水后的药渣加入4+3(体积重量比，576L+432L)倍量90％乙醇提取两次，每次提取2小时(每次提取沸腾后打循环5分钟)，合并滤液得A2，备用。
桂枝药渣再加入6+4(864L+576L)倍量水提取两次，每次提取2小时(每次提取沸腾后打循环5分钟)，合并滤液得B2，备用；药渣弃之。
3)白芍、桃仁及处方量55％的茯苓提取
白芍、桃仁及55％茯苓投入多功能提取罐中，投料顺序为白芍底部、桃仁中部、茯苓上部，加入药材4+3倍量(体积重量比，1468.8L+1101.6L)90％乙醇提取两次，每次提取2小时(每次提取沸腾后打循环5分钟)，并滤液得A3，备用。
药渣再加6+4(2203.2L+1468.8L)倍量水提取两次，每次提取2小时(每次提取沸腾后打循环5分钟)，合并滤液得B3，备用；药渣弃之。
(2)浓缩
1)醇提液浓缩
合并A1、A2、A3醇提液减压浓缩，醇提液回收至相对密度1.02-1.05(70±5℃)，称重，得醇提浸膏。
2)水提液浓缩
合并B1、B2、B3水提液减压浓缩，水提液浓缩至相对密度1.05-1.10(80±5℃)，称重，得水提浸膏。
3)合并浓缩
合并二浓缩液继续浓缩至相对密度1.15(80±5℃)，过80～100目筛，得浸膏；冷藏保存或直接喷雾干燥。
(3)喷雾干燥过程
1)喷雾干燥
取合并浸膏进行喷雾干燥，设定进风温度165-170℃，控制喷干过程中出风温度90-95℃；冷却至室温，出料，得喷干粉。
2)喷干粉混合
将粉碎后喷干粉进行混合，混合≥15min，最终得提取物喷干粉，备用。
(e)总混
将茯苓粉、喷干粉、丹皮酚包合物、肉桂油包合物，混合在一起，进行总混，时间≥30min，即得最终原料药。
(f)制剂
将原料药进行干法制粒(24目)，整粒，混合均匀，得颗粒，以0.465g/粒，充填入0号绿色胶囊壳中，得成品。
4、本发明制备方法与现有技术CN200780027994.4公开的方法比较
表1生产效率的比较
Figure PCTCN2019101869-appb-000003
由表1可知，本发明合并浸膏直接喷雾干燥得药粉，并直接合并丹皮酚包合物、桂枝挥发油包合物、茯苓粉进行干法制粒，与现有技术比较减少了浸膏拌茯苓粉干燥、粉碎、湿法制粒干燥等过程，本发明制备方法的生产效率提高了30％以上。
表2各指标成分含量比较
Figure PCTCN2019101869-appb-000004
由表2数据可判断，本发明制剂中，有效成分明显增加，且各指标成分含量明显高于现有技术方法中的含量。
表3、茯苓酸转移率比较
Figure PCTCN2019101869-appb-000005
由表3数据可判断，本发明由于减少了茯苓拌浸膏干燥粉碎过程，湿法制粒干燥过程，茯苓酸转移率达90％以上，远高于现有技术所用方法中茯苓酸的转移率。
表4、产品吸湿率比较
Figure PCTCN2019101869-appb-000006
由表4数据可判断，本发明由于茯苓粉在制剂时混合其他三个中间体直接干法制粒(无外加溶剂)，产品吸湿率明显比现有技术所用方法降低60％以上。
表5、制剂中各指标成分的溶出度比较
Figure PCTCN2019101869-appb-000007
由表5数据可判断，本发明由于浸膏直接喷雾干燥并合并其他中间体直接制剂，各指标成分的溶出度明显优于现有技术所用方法的溶出度。
表6、制剂工艺合理性比较
Figure PCTCN2019101869-appb-000008
由表6可判断，本发明制剂工艺合理性明显优于现有技术所用方法。
可见，本发明组合物有效成分含量、溶出度、吸湿率、茯苓酸转移率、生产效率等，以及各项工艺参数均明显优于现有技术。
需要指出的是，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。

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  1. 一种由桂枝、茯苓、牡丹皮、白芍、桃仁按照等比例制成的中药组合物的制备方法，其特征在于，包括步骤：
    (a)茯苓粉中间体的制备：取30-49％处方量的茯苓粉碎，即得茯苓粉中间体；
    (b)丹皮酚包合物的制备：牡丹皮直通蒸汽蒸馏提取丹皮酚，收集芳香水，药渣，待用；芳香水静置48-72小时至晶体结晶完全，过滤，阴干，得丹皮酚晶体；取β-环糊精包合制得丹皮酚包合物；
    (c)桂枝挥发油包合物的制备；桂枝直通蒸汽蒸馏提取挥发油，过程中加乙酸乙酯萃取，收集乙酸乙酯层芳香水，药渣，待用；芳香水层放置于分液漏斗中，静置，分取上层乙酸乙酯层，下层用等倍量乙酸乙酯再萃取，合并乙酸乙酯层，减压回收，最后加乙醇继续浓缩，得纯品挥发油；取β-环糊精包合制得桂枝挥发油包合物；
    (d)提取物喷干粉中间体的制备：将牡丹皮药渣进行醇提取和水提取，桂枝药渣进行醇提取和水提取，白芍、桃仁及处方量51-70％的茯苓进行醇提取和水提取；将上述醇提液或水提液分别浓缩，合并浓缩液后继续浓缩得浸膏，喷雾干燥后混合得喷干粉；
    (e)总混：将茯苓粉中间体、提取物喷干粉中间体、丹皮酚包合物、桂枝挥发油包合物，混合后即得。
  2. 根据权利要求1所述的制备方法，其特征在于，所述步骤(a)中，将茯苓70℃干燥至水分≤5.0％，120目筛粉碎，取45％处方量的茯苓粉，即得。
  3. 一种如权利要求1所述的制备方法，其特征在于，所述步骤(b)中，
    所述蒸汽蒸馏过程收集约4-6倍药材量的芳香水；
    所述β-环糊精包合为，取β-环糊精加入其2.7倍量纯化水中搅匀，加热至60℃，得β-环糊精溶液，取β-环糊精1/6～1/12量的丹皮酚加入 其4-6倍量乙醇中，加热使之溶解，趁热倒入β-环糊精溶液中，过胶体磨30min，放料，放置16-24h，抽滤，50℃干燥，100目筛粉碎，混合，即得所述丹皮酚包合物。
  4. 一种如权利要求1所述的制备方法，其特征在于，所述步骤(c)中，
    所述蒸汽蒸馏过程乙酸乙酯的加入量为药材量的3.5％；
    所述β-环糊精包合为，取β-环糊精加入4-6倍量乙醇中，搅拌均匀，使成混悬状，取β-环糊精1/6～1/12量的挥发油倒入其中，优选1/10量，搅拌均匀，过胶体磨30min，放料，放置16-24h，抽滤，50℃干燥，100目筛粉碎，混合，即得桂枝挥发油包合物。
  5. 一种如权利要求1所述的制备方法，其特征在于，所述步骤(d)中，
    所述白芍、桃仁及处方量51-70％的茯苓的投料顺序为白芍底部、桃仁中部、茯苓上部。
  6. 一种中药组合物，其特征在于，该中药组合物由桂枝、茯苓、牡丹皮、白芍、桃仁按等比例制成，其中，所述中药组合物包含芍药苷、苦杏仁苷、苯甲酰芍药苷、肉桂酸、丹皮酚、桂皮醛。
  7. 根据权利要求6所述的中药组合物，其特征在于，所述芍药苷含量占所述中药组合物的15mg/g以上，所述苦杏仁苷含量占所述中药组合物的10mg/g以上，所述丹皮酚含量占所述中药组合物的10mg/g以上。
  8. 根据权利要求7所述的中药组合物，其特征在于，所述中药组合物中茯苓酸的转移率大于90％。
  9. 一种药物，其特征在于，该药物为权利要求6-8任一所述组合 物和药学上可接受的赋型剂制成临床可接受的剂型。
  10. 权利要求6-8任一所述中药组合物在制备治疗或预防下列任一疾病或病症的药物中的应用：原发性痛经、继发性痛经、功能障碍性子宫出血、慢性盆腔炎或小的壁内子宫肌瘤。
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