WO2007022710A1 - Compositions a base de medecine chinoise pour le traitement de cephalees, formulations et procedes de preparation - Google Patents

Compositions a base de medecine chinoise pour le traitement de cephalees, formulations et procedes de preparation Download PDF

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Publication number
WO2007022710A1
WO2007022710A1 PCT/CN2006/002135 CN2006002135W WO2007022710A1 WO 2007022710 A1 WO2007022710 A1 WO 2007022710A1 CN 2006002135 W CN2006002135 W CN 2006002135W WO 2007022710 A1 WO2007022710 A1 WO 2007022710A1
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Prior art keywords
coating
ethanol
extract
composition according
water
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PCT/CN2006/002135
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English (en)
French (fr)
Inventor
Naifeng Wu
Xijun Yan
Shunnan Zhang
Jianhui Yang
Hongpo Zhang
Lina Dong
Tong Liu
Yan Sun
Lihong Zhou
Hui Wang
Jie Ma
Zhengliang Ye
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Tianjin Tasly Pharmaceutical Co. Ltd.
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Priority claimed from CN2005100148283A external-priority patent/CN1919272B/zh
Priority claimed from CN2005100148298A external-priority patent/CN1919273B/zh
Application filed by Tianjin Tasly Pharmaceutical Co. Ltd. filed Critical Tianjin Tasly Pharmaceutical Co. Ltd.
Priority to EP06775453A priority Critical patent/EP1930020B1/en
Priority to JP2008527290A priority patent/JP5162457B2/ja
Priority to KR1020087006829A priority patent/KR101088539B1/ko
Priority to SA6270470A priority patent/SA06270470B1/ar
Publication of WO2007022710A1 publication Critical patent/WO2007022710A1/zh
Priority to HK08106995.4A priority patent/HK1116426A1/xx

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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)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/618—Molluscs, e.g. fresh-water molluscs, oysters, clams, squids, octopus, cuttlefish, snails or slugs
    • 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)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
    • 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)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/234—Cnidium (snowparsley)
    • 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)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/236—Ligusticum (licorice-root)
    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • 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)
    • A61K36/50—Fumariaceae (Fumitory family), e.g. bleeding heart
    • A61K36/505—Corydalis
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the present invention relates to the field of traditional Chinese medicine, and in particular to a composition for treating headache made from a traditional Chinese medicine, a preparation thereof and a preparation method.
  • Background Art Chinese Patent Patent No.: ZL93100050.5 discloses a pharmaceutical composition consisting of Angelica sinensis, Rhizoma Chuanxiong, and the like. It is under the guidance of the medical theory of the motherland and has been summarized by many years of clinical practice. It has the effect of treating headache caused by internal injuries. It is clinically applicable to symptoms such as angina, migraine, and dizziness and headache caused by high blood pressure. According to the ratio of this prescription, it can be made into any dosage form of pharmacy.
  • the granules are produced by Tianjin Tianshili Pharmaceutical Co., Ltd., and the name is "nutrient serum brain particles". Approved “functions and indications” for nourishing blood and calming the liver, promoting blood circulation and collaterals. It is used for various headaches caused by blood deficiency and liver sputum, traumatic cranial nerve syndrome, dizziness, irritability, insomnia and so on. Clinically, it is mainly used to treat headache caused by blood deficiency, blood stasis, yin deficiency and impotence. Because of its exact curative effect, it has won the trust of the majority of patients since its launch. Although the drug has been widely recognized in clinical practice, the use of Asarum is debatable.
  • Asarum is one of the commonly used traditional Chinese medicines, first published in Shennong Bencao. Its taste is spicy, warm, and has a small poison, and it is returned to the lungs, kidneys, and heart. It has the functions of solving the symptoms, relieving the pain and relieving pain, and warming the lungs. It is suitable for the treatment of cold, cold, headache, toothache, rheumatism and other diseases. Modern pharmacological studies have shown that the toxicity of Asarum mainly comes from the volatile oil components contained in it.
  • Granules are a new formulation developed on the basis of granules, and have been developed in the past 10 years. Quickly, it maintains the characteristics of convenient use, storage and transportation of the granules, and overcomes the disadvantages of large sugar content of the granules, so that the elderly and diabetic patients can also take it.
  • the volume is smaller and the relative drug content is higher than that of the granules.
  • the granules are less likely to cause moisture absorption, agglomeration and discoloration, and the bitterness of the drug is extremely high.
  • Some drugs are highly irritating to the stomach or easily damaged in the stomach.
  • the problem that needs to be solved for granules After a long period of practice, the inventors have found that the appropriate extraction of the drug is carried out after adding the appropriate excipient to form a pill, and the coated pill is prepared by a film coating technique. It can effectively avoid the problem of large dosage, easy moisture absorption, bitter taste, and poor acidity and mouthfeel.
  • the present invention is directed to optimizing prior art formulations and providing a composition for treating headache without asarum.
  • the traditional Chinese medicine composition for treating headache is made of the following weight-matching medicinal materials: Angelica 5-15%, Chuanxiong 5-15%, Angelica 2 ⁇ 10%> Rehmannia 2 ⁇ 10%, Goto 7 ⁇ 17 %, 7 ⁇ 17% of spatholobus, 7 ⁇ 17% of Prunella vulgaris, 7 ⁇ 17% of cassia seed, 7 ⁇ 17% of mother-of-pearl, and 3 ⁇ 10% of Yuanhu.
  • the preferred raw material ratio is:
  • the pharmaceutical composition of the present invention can be directly administered as a decoction, or can be obtained by extracting and processing the extract into a pharmaceutically acceptable preparation together with an appropriate excipient. Accordingly, it is another object of the present invention to provide a conventional pharmaceutical preparation containing the composition, which is prepared by a conventional pharmaceutical method in the pharmaceutical field, in accordance with the above-mentioned raw material ratio, by adding a conventional pharmaceutical carrier.
  • compositions of the present invention are preparations suitable for oral administration, such as oral solid preparations, liquid preparations, and sustained release or controlled release preparations, and the like, and the oral preparations include tablets, capsules, granules, pills, powders.
  • oral preparations include tablets, capsules, granules, pills, powders.
  • a concentrated pellet is preferred, a film-coated pellet is more preferred, and a stomach-soluble film-coated pellet is particularly preferred.
  • the stomach-soluble film-coated pill of the pharmaceutical composition of the present invention can well overcome the problems caused by the existing granule preparations, such as preparations and storage problems such as large amount of extract, moisture absorbing, caking and discoloration, and The drug has a great bitter taste, a strong irritation to the stomach, and a problem in which the active ingredient is easily destroyed in the stomach.
  • the test results show that the concentrated pellet of the present invention, particularly a stomach-soluble film-coated pellet (hereinafter referred to as "nutrient serum brain pellet”) and granules known in the prior art (hereinafter referred to as "nutrient serum brain particles”)
  • nutrient serum brain particles granules known in the prior art
  • the pellet of the present invention may contain conventional pharmaceutical excipients and binders selected from the following materials: dextrin, starch, low-substituted hydroxypropylcellulose and microcrystalline cellulose, preferably microcrystalline cellulose;
  • the auxiliary material is used in an amount of 28 to 35% of the dry powder amount of the medicinal material; and the selected material is selected from the group consisting of water, 20 to 30% (v/v) aqueous ethanol solution and honey water,
  • the binder is water.
  • the amount of the binder is preferably such that the bonding effect can be achieved.
  • sugar pill refers to a pill in the general sense of the pharmaceutical art, and specifically refers to an uncoated pill.
  • pill or “concentrated pellet” as used herein refers to a pellet prepared by extracting and concentrating a medicinal material with an adjuvant.
  • relative density refers to a density value when lg/cm 3 of water (4 ° C) is used as a reference density.
  • Another object of the invention is also to provide a process for the preparation of the composition. According to the traditional Chinese medicine method, the pharmaceutical composition of the present invention can be directly administered as a decoction, or can be obtained by extracting and processing the extract into a pharmaceutically acceptable preparation together with an appropriate excipient.
  • the medicinal materials such as Angelica sinensis, Radix Paeoniae Alba, Rhizoma Chuanxiong or Yuanhu may be separately or separately extracted and processed into extracts, and the extraction method is selected from the following but not limited to: water extraction and alcohol precipitation method, ultrasonic extraction method or super Critical extraction method, etc.
  • the extraction methods of Radix Paeoniae Alba, Rhizoma Chuanxiong, Yuanhu, and Angelica sinensis are now described as follows, but are not limited thereto.
  • Ultrasonic extraction of white peony Take the medicinal herbs of white peony, pulverize, ultrasonically extract with water, and concentrate to obtain white peony extract.
  • Alcohol extraction method of white peony root, Chuanxiong, Yuanhu or Chinese angelica The medicinal material is pulverized, refluxed with ethanol, concentrated and recovered, and concentrated to obtain an extract.
  • Angelica supercritical extraction method Take Angelica medicinal herbs, use supercritical carbon dioxide extraction under appropriate conditions, and filter Angelica extract.
  • Angelica water extraction plus resin method Take the boiled alcoholic precipitate of Angelica sinensis and dissolve it in distilled water. Adjust the pH value with calcium hydroxide saturated solution, place it overnight, filter it, adjust the pH of the filtrate with sulfuric acid to 5-6, store overnight, filter, filtrate.
  • the anion-cation mixed resin was exchanged, and the exchange liquid was concentrated to a certain volume, precipitated with ethanol, and stored overnight by ice filtration, and the alcohol precipitate was evaporated to ethanol and concentrated to obtain an extract of Angelica sinensis.
  • Angelica Distillation Extraction Method Weigh the angelica powder in a flask, reflux leaching with distilled water, then distilling the raw material and the immersion liquid under reduced pressure to obtain a mixture of Angelica sinensis, and then adding an appropriate amount of NaCl to stand still. The volatile oil of Angelica sinensis was separated by a separating funnel, and the residue was concentrated to obtain an extract of Angelica sinensis.
  • Chuanxiong ethanol plus resin method Take Chuanxiong decoction pieces, crush, extract with ethanol in Soxhlet reflux extraction device, suction filtration, extract the filtrate to dryness under reduced pressure, add appropriate amount of water, heat to dissolve, filter, filtrate added
  • the well-treated macroporous resin column was first eluted with water, discarded, and then eluted with ethanol. The eluate was combined, and the ethanol was recovered, and then concentrated to obtain the Chuanxiong extract.
  • Ethanol extraction method of Chuanxiong Take Chuanxiong medicinal materials, smash it properly, add ethanol for several times, combine the extracts, filter, recover ethanol, and concentrate to obtain Chuanxiong extract.
  • the Chuanxiong, Angelica sinensis and Radix Paeoniae Alba can also be mixed and extracted, mainly: pulverized white peony root, Chuanxiong and angelica medicinal materials, boiled in boiling water, filtered, and the filtrate is appropriately concentrated; Ethanol is added to the concentrate to carry out alcohol precipitation, and the mixture is allowed to stand. The supernatant is recovered to be ethanol, and concentrated into an extract to obtain a medicinal material extract.
  • the present invention also provides a method for preparing the above composition, which comprises the following steps:
  • step (b) the mixture of Angelica sinensis, Rhizoma Chuanxiong, Radix Paeoniae Alba and Yuanhu is heated and refluxed with ethanol, and extracted, and the reflux liquid is stored for standby; the obtained medicine and the remaining five flavors except the hook vine are boiled three times with water.
  • hook vine was added, and the decoction was combined and concentrated to a relative density of 1.09 to 1.13 at 55 ° C. The ethanol was precipitated, and the supernatant was combined with the reflux liquid to recover the ethanol extract.
  • the ethanol concentration in the step (b) of the above method is 60% to 80% (v/v), preferably about 70% (v/v); each reflux time is 0.5 to 1.5 hours, preferably about 1 hour.
  • the time of each boiling is 0.5 to 1.5 hours, preferably about 1 hour, and the relative density of the extract after concentration is preferably about 1.10 (55 ° C);
  • the weight of the water added during boiling is preferably 5 times the weight of the medicinal material;
  • the step (d) adding ethanol for precipitation should be such that the final alcohol content is 60% to 70% (v/v), preferably It is about 65% (v/v); the relative density of the concentrated extract is about 1.15 (55 ° C).
  • the extract in the form of a dip obtained by the above method can be dried by a conventional drying method of the prior art to obtain a dried extract or extract powder, wherein the drying step can be carried out by a spray drying method, an inlet air temperature. 165 ⁇ 205 ° C, preferably the inlet air temperature is about 185 °.
  • the above preparation method of the present invention further comprises preparing the obtained extract, dry extract or extract powder together with a pharmaceutically acceptable carrier, preferably a pill. More preferably, the coated pill is particularly preferably a gastric-soluble film-coated pill. Therefore, the method of the present invention further comprises the step of coating the pill.
  • the coating step may select a film known in the prior art. Two techniques of coating and common coating, preferably coated with a stomach-soluble film.
  • the film coating can be coated with a stomach-soluble coating material, such as Shanghai Kaile Oubadai (stomach-soluble) of COLORCON Coating Technology Co., Ltd. is the coating material for this product.
  • the coating conditions are as follows: water is used as the dissolving agent; the concentration of the coating liquid is 14-20% (w/w), preferably the concentration is 18%; the coating weight gain is 2%-6%, preferably 4%; the inlet air temperature is 40 -90 ° C, preferably 65 ° C; bed temperature 40-70 ° C, preferably 43 ° C; atomization pressure 1.5-2.5 bar, preferably 2.0 bar; coating pan speed 15-20rmp, preferably 17rmp; The feed rate is 2-4 g/min, preferably 3 g/min.
  • the common coating can use the technology of adding a proper amount of talc powder to the coloring agent and then waxing.
  • the specific conditions are as follows: Take appropriate amount of talcum powder 1%, dilute with water, moisturizing pill. After the talc powder is evenly applied, add 1% of the coloring agent. After the color is evenly applied, add 10% wax to light. Coating pan speed: 5-30 rpm.
  • the amount of alcohol or water used in the alcohol extraction, decoction and alcohol precipitation steps of the process of the invention is carried out according to the conventional amounts and methods described in the Pharmacopoeia.
  • the creaming rate that is, the dry weight of the Chinese herbal medicine, is usually about 16% by weight of the dry extract.
  • the concentrated pellets prepared by the above method are calculated according to the amount of the crude drug, and the amount per adult is 12-20 g, preferably 15-17 g.
  • the number of medications depends on the condition, usually 2 ⁇ 3 times/day.
  • the composition for treating headache of the present invention provides a more rational and safer drug, and the invention has been removed from the prior art (Chinese Patent, Patent No.: ZL93100050.5, hereinafter referred to as YXQN-01). It is easy to produce toxic asarum, making the prescription more reasonable and safer to use, while maintaining the efficacy of the original composition for the treatment of headache.
  • the pharmaceutical preparation of Chinese patent ZL93100050.5 uses granules, which is a new dosage form developed on the basis of granules.
  • the preferred technical solution of the present invention is a novel preparation prepared by spray drying the extract, concentrating the dosage form and combining the film coating, etc., and the practice shows that the preparation can well overcome the problems caused by the existing granule preparation.
  • the dissolution measurement shows that the concentrated pellet of the present invention (hereinafter referred to as "nutrient serum brain pills") has a similar dissolution profile to the nourishing serum brain particles of the above patent, indicating that the serum is raised.
  • the brain pill has an in vitro dissolution effect consistent with the serum brain particles.
  • the excellent effects of the pharmaceutical composition of the present invention are further illustrated by examining the effect of the two compositions on the acetic acid-induced writhing reaction in mice to demonstrate their creativity. Effect of Chinese Herbal Medicine Composition on Analgesia and Hypoxia Tolerance in Mice
  • YXQN-01 the Chinese patent ZL93100050.5, provided by Tianjin Tianshili Group Research Institute (see the comparison method for preparation method), batch number: 20041101.
  • distilled water was used to prepare a solution of 1.4 g crude drug / ml, 0.7 g crude drug / ml, 0.35 g crude drug / ml concentration for mouse ig (administration).
  • YXQN-02 provided by Tianjin Tianshili Group Research Institute (see Example 5 for preparation method), batch number: 20041201.
  • the above drugs were prepared with distilled water to prepare 1.4 g of crude drug/ml, 0.7 g of crude drug/ml, and 0.35 g of crude drug/ml solution for use in mice.
  • Xindean (10mg/tablet), produced by Tianjin Lisheng Pharmaceutical Co., Ltd., batch number 0411015. Before the experiment, distilled water was used to prepare a solution of 5 mg/ml concentration for use in mice.
  • Glacial acetic acid Tianjin Chemical First Plant, batch number: 890508.
  • Vaseline Tianjin Petrochemical Experimental Factory, batch number: 860404.
  • AE-200 electronic analytical balance product of METTLER TOLEDO Shanghai Co., Ltd.
  • TF2-type thermal radiation pain tester light source 12V/50W, developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences.
  • Stopwatch 250ml wide mouth grinding bottle, large scissors.
  • ICR mice half male and half female, weigh 20 ⁇ 2g.
  • SCXK Beijing
  • 112 healthy mice male and female, were randomly divided into 8 groups according to body weight and sex, with 14 rats in each group.
  • YXQN-01 high, medium and low doses were 28, 14 and 7 g crude drug/kg group
  • YXQN-02 high, medium and low doses were 28, 14 and 7 g crude drug/kg group
  • the positive control group was treated with aspirin.
  • the above drugs were administered at 0.2 ml/10 g body weight ig once a day for 5 consecutive days, aspirin enteric-coated tablets were administered once, and the control group was given an equal volume of distilled water.
  • YXQN-01 was administered continuously for 5 days, and the inhibition rates of 28g crude drug/kg, 14g crude drug/kg and 7g crude drug/kg group were 49.88% (P ⁇ 0.001), 45.99% (P ⁇ 0.01) and 33.58%, respectively (P ⁇ 0.05) ; YXQN-02 continuous ig administration for 5 days, the inhibition rates of 28g crude drug/kg, 14g crude drug/kg and 7g crude drug/kg group were 44.53% (P ⁇ 0.01), 62.29% (P ⁇ 0.001) and 3.07%, respectively. (P ⁇ 0.05). YXQN-01 and YXQN-02 have significant inhibitory effects on acetic acid-induced writhing in mice.
  • the TF2-type thermal radiation pain tester uses a 12V/50W small spotlight gun, which produces a beam of intensity according to a small spotlight, and focuses the lens on the tail of the mouse to cause pain.
  • mice with healthy and similar body weight were used as the pain threshold of the mouse by receiving the thermal radiation from the tail skin of the mouse to the latent period (TFL) of the appendix reaction.
  • Mice with a pain threshold greater than 2 s and less than 5 s were selected for the experiment as the basic pain threshold for the mouse.
  • mice 112 qualified mice were randomly divided into 8 groups according to gender and pain threshold. Each group of U and control groups, YXQN-01 high, medium and low doses were 28, 14 and 7 g crude drug/kg group, YXQN-02 was high. The medium and low doses were 28, 14 and 7 g of crude drug/kg group, and the positive control drug aspirin enteric-coated tablets 200 mg/kg.
  • the above drugs were administered at 0.2 ml/10 g body weight ig once a day for 5 days, aspirin enteric tablets were administered once, and the control group was given an equal volume of distilled water.
  • mice were placed in a fixed barrel of TF2-type thermal radiation pain tester, and the tail was exposed to the outside (the rat tail was cleaned with 75% ethanol before the test), and the tail of the mouse was 1.5 cm away from the tip.
  • the inner skin area is aligned with the lens focus, after the animal is quiet A pain test was performed.
  • the traditional Chinese medicine composition YXQN-01 was continuously administered ig for 5 days, and the percentages of pain threshold increase in the 28 g/kg and 14 g/kg groups were 100.98% (PO.01) and 130.30% (P ⁇ 0.01), respectively; YXQN-02 was administered intravenously for 5 days, and the pain threshold was increased by 160.70% (P ⁇ 0.05) in the 28g/kg group. YXQN-01 and YXQN-02 were significantly different from the control group. The percentage increase of pain threshold in aspirin enteric-coated tablets in the 0.2g/kg group was 176.89% (P ⁇ 0.01), and there was also a significant difference compared with the control group. The results are shown in Table 2.
  • Both YXQN-01 and YXQN-02 can significantly inhibit the number of writhing in mice induced by acetic acid, prolong the tail-flicking time of mice caused by light, and exhibit almost the same degree of analgesic effect.
  • the measurement method adopts a basket method, and the dissolution medium is 900 ml of degassed water, and the water temperature is 37 ⁇ 0.5. C, the speed is 100r/min.
  • the invention raises serum brain pills 29.16 46.84
  • FIG. 1 is a graph showing the cumulative release-time curve of the cerebral granules and the serum-retaining brain particles of the present invention.
  • Example 1 Preparation of granules of traditional Chinese medicine composition of the present invention
  • Angelica 68.5g Chuanxiong 68.5g, Angelica 55g, Rehmannia glutinosa 55g, Uncaria 136.9g, Spatholobus chinensis 136.9g, Prunella vulgaris 136.9g, Cassia 136.9g, Mother of Pearl 136.9g, Yuanhu 68.5g.
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 70% ethanol, heated and refluxed for 1 hour, and the reflux liquid is stored for use; the dregs and the other rehmannia roots other than the hook vine are boiled three times with water, each time.
  • Angelica sinensis 68.5g Chuanxiong 68.5g, Radix Paeoniae Alba 55g, Radix Rehmanniae 55g, Uncaria serrata 136.9g, Spatholobus serrata 136.9g, Prunella vulgaris 136.9g, Cassia 136.9 g , Mother of Pearl 136.9g, Yuanhu 68.5g.
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 70% ethanol, heated and refluxed for 1 hour, and the reflux liquid is stored for use; the dregs and the other rehmannia roots other than the hook vine are boiled three times with water, each time.
  • Example 3 Preparation of a capsule of the traditional Chinese medicine composition of the present invention
  • Angelica 68.5g Chuanxiong 68.5g, Angelica 55g, Rehmannia glutinosa 55g, Uncaria 136.9g, Spatholobus chinensis 136.9g, Prunella vulgaris 136.9g, Cassia 136.9g, Mother of Pearl 136.9g, Yuanhu 68.5g.
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 70% ethanol, heated and refluxed for 1 hour, and the reflux liquid is stored for use; the dregs and the other rehmannia roots other than the hook vine are boiled three times with water, each time.
  • the obtained extract powder was mixed with microcrystalline cellulose, wherein the amount of the microcrystalline cellulose was 35% of the extract powder, and water was added as a binder to form a pellet.
  • the above-mentioned capsules were coated with the coating material of the product of Opelda (stomach-soluble type) of COLORCON Coating Technology Co., Ltd., and the stomach-soluble coating concentrated pill of the present invention was obtained.
  • the coating conditions are as follows: water is used as the dissolving agent; the concentration of the coating liquid is 18% (w/w); the weight of the coating is 4%; the inlet air temperature is 65 ⁇ ; the bed temperature is 43 ° C; the atomization pressure is 2.0 bar; The pan speed was 17 raip; the feed rate was 3 g/miri.
  • Example 5 Preparation of a coated pill of the traditional Chinese medicine composition of the present invention
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 60% ethanol, heated and refluxed for 0.5 hours, and the reflux liquid is stored for use.
  • the dregs and the other rehmannia roots other than Uncaria are boiled three times with water, each time.
  • the obtained extract powder was mixed with dextrin, wherein the dextrin was used in an amount of 25% of the extract powder, and water was added as a binder to prepare a pill.
  • the above-mentioned capsules were coated with the coating material of the product of Opelda (stomach-soluble type) of COLORCON Coating Technology Co., Ltd., and the stomach-soluble coating concentrated pill of the present invention was obtained.
  • the coating conditions are as follows: water is used as the dissolving agent; the concentration of the coating liquid is 14% (w/w); the weight of the coating is 2%; the inlet air temperature is 85 ° C ; the bed temperature is 40 ⁇ ; the atomization pressure is 2.0 bar; The speed of the pan was 17 rmp; the feed rate was 3 g/r in.
  • Example 6 Preparation of a coated pill of the traditional Chinese medicine composition of the present invention
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 80% ethanol, heated and refluxed for 1.5 hours, and the reflux liquid is stored for use.
  • the dregs and the other rehmannia roots other than the genus Rhizome are boiled three times with water, each time.
  • the obtained extract powder was mixed with microcrystalline cellulose, wherein the amount of the microcrystalline cellulose was 25% of the extract powder, and water was added as a binder to form a pellet.
  • the above-mentioned capsules were coated with the coating material of the product of Opelda (stomach-soluble type) of COLORCON Coating Technology Co., Ltd., and the stomach-soluble coating concentrated pill of the present invention was obtained.
  • the coating conditions are as follows: Water is used as the dissolving agent; the concentration of the coating liquid is 20% (w/w); the weight of the coating is 6%; the inlet air temperature is 90 °C; the bed temperature is 45 °C; the atomization pressure is 2.50 bar. ; coating pan speed 20rmp; feed flow rate 4g / miii.
  • Example 7 Preparation of a coated pill of the traditional Chinese medicine composition of the present invention
  • Angelica sinensis 240.1g Chuanxiong 240.1g, Angelica sinensis 120.0g, Rehmannia glutinosa 120.0g, Uncaria sinensis 600.0g, Chicken blood vine 600.0g, Prunella vulgaris 600.0g, cassia seed 600.0g, mother-of-pearl 600.0g, Yuanhu 240.0g.
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 70% ethanol, heated and refluxed for 1 hour, and the reflux liquid is stored for use; the dregs and the other rehmannia roots other than the hook vine are boiled three times with water, each time.
  • the above-mentioned capsules were coated with the coating material of the product of Opelda (stomach-soluble type) of COLORCON Coating Technology Co., Ltd., and the stomach-soluble coating concentrated pill of the present invention was obtained.
  • the coating conditions are as follows: Water is used as the dissolving agent; the concentration of the coating liquid is 18% (w/w); the weight of the coating is 4%; the inlet air temperature is 87 ° C; the bed temperature is 43 ° C; the atomization pressure is 2.0 bar ; coating pan speed 17raip; feed flow rate 3g / miii.
  • Example 8 Preparation of a coated pill of the traditional Chinese medicine composition of the present invention
  • Angelica sinensis 540.2g Chuanxiong 540.0g, Angelica 480.0g, Rehmannia glutinosa 480.0g, Uncaria 900.0g, Chicken blood vine 900.0g, Prunella 900.0g, Cassia 900.0g, Mother of Pearl 900.0g, Yuanhu 540.0g.
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 70% ethanol, heated and refluxed for 1 hour, and the reflux liquid is stored for use.
  • the dregs and the other rehmannia roots other than the hook vine are boiled three times with water, each time.
  • the obtained impregnated powder was mixed with microcrystalline cellulose, wherein the amount of the microcrystalline cellulose was 35% of the extract powder, and water was added as a binder to form a pellet.
  • the above-mentioned capsules were coated with the coating material of the product of Opelda (stomach-soluble type) of COLORCON Coating Technology Co., Ltd., and the stomach-soluble coating concentrated pill of the present invention was obtained.
  • the coating conditions are as follows: water is used as the dissolving agent; the concentration of the coating liquid is 18% (w/w); the weight of the coating is 4%; the inlet air temperature is 87 ⁇ ; the bed temperature is 43 ⁇ ; the atomization pressure is 2.0 bar; The rotational speed was 17 rpm; the feed flow rate was 3 g/miii.
  • Example 9 Preparation of a coated pill of the traditional Chinese medicine composition of the present invention
  • Angelica sinensis 240.1g Chuanxiong 240.1g, Angelica sinensis 120.0g, Rehmannia glutinosa 120.0g, Uncaria serrata 600.0g, Spatholobus serrata 600.0g, Prunella vulgaris 600,0g, cassia seed 600.0g, mother-of-pearl 600.0g, Yuanhu 240.0g.
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 60% ethanol, heated and refluxed for 0.5 hours, and the reflux liquid is stored for use.
  • the dregs and the other rehmannia roots other than Uncaria are boiled three times with water, each time.
  • the obtained extract powder was mixed with microcrystalline cellulose, wherein the amount of the microcrystalline cellulose was 35% of the extract powder, and water was added as a binder to form a pellet.
  • the above-mentioned capsules were coated with the coating material of the product of Opelda (stomach-soluble type) of COLORCON Coating Technology Co., Ltd., and the stomach-soluble coating concentrated pill of the present invention was obtained.
  • the coating conditions are as follows: water is used as the dissolving agent; the concentration of the coating liquid is 16% (w/w); the weight of the coating is 2%; the inlet air temperature is 85 ° C; the bed temperature is 40 ⁇ ; the atomization pressure is 1.5 bar; The speed of the pan was 15 rpm; the feed rate was 2 g/min.
  • Example 10 Preparation of a coated pill of the traditional Chinese medicine composition of the present invention
  • Angelica sinensis 540.2g Chuanxiong 540.0g, Angelica 480.0g, Rehmannia glutinosa 480.0g, Uncaria 900.0g, Chicken blood vine 900.0g, Prunella 900.0g, Cassia 900.0g, Mother of Pearl 900.0g, Yuanhu 540.0g.
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 70% ethanol, heated and refluxed for 1.5 hours, and the reflux liquid is stored for use.
  • the dregs and the other rehmannia roots other than the genus Rhizome are boiled three times with water, each time.
  • the obtained extract powder was mixed with microcrystalline cellulose, wherein the amount of the microcrystalline cellulose was 35% of the extract powder, and honey water was added as a binder to form a pellet.
  • the above-mentioned pill is selected from Ou Baide (stomach of Shanghai COLORCON Coating Technology Co., Ltd. Soluble type)
  • the coating material of the product is coated to obtain the stomach-soluble coating concentrate pill of the present invention.
  • the coating conditions are as follows: water is used as the dissolving agent; the concentration of the coating liquid is 20% (w/w); the weight of the coating is 6%; the inlet air temperature is 90 ° C; the bed temperature is 45 ⁇ ; the atomization pressure is 2.5 bar; The speed of the pan was 20 rpm; the feed rate was 4 g/min.
  • Example 11 Preparation of a coated pill of the traditional Chinese medicine composition of the present invention
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 80% ethanol, heated and refluxed for 1.5 hours, and the reflux liquid is stored for use.
  • the dregs and the other rehmannia roots other than the genus Rhizome are boiled three times with water, each time.
  • the obtained extract powder was mixed with starch, wherein the amount of the starch was 25% of the extract powder, and honey water was added as a binder to form a pill.
  • the above-mentioned capsules were coated with the coating material of the product of Opelda (stomach-soluble type) of COLORCON Coating Technology Co., Ltd., and the stomach-soluble coating concentrated pill of the present invention was obtained.
  • the coating conditions are as follows: Water is used as the dissolving agent; the concentration of the coating liquid is 20% (w/w); the weight of the coating is 6%; the inlet air temperature is 90 ° C; the bed temperature is 45 ° C; the atomization pressure is 2.50 bar ; coating pan speed 20rmp; feed flow rate 4g / min.
  • Example 12 Preparation of a coated pill of the traditional Chinese medicine composition of the present invention
  • the obtained extract powder is mixed with low-substituted hydroxypropylcellulose, wherein the amount of the low-substituted hydroxypropylcellulose is 25% of the extract powder, and 30% (v/v) of ethanol is used as the binder. Chengsu Pills.
  • the above-mentioned capsules were coated with the coating material of the product of the Opel (stomach-soluble type) of COLORCON Coating Technology Co., Ltd., and the stomach-soluble coating concentrated pill of the present invention was obtained.
  • the coating conditions are as follows: water is used as the dissolving agent; the concentration of the coating liquid is 20% (w/w); the weight of the coating is 6%; the inlet air temperature is 9 CTC; the bed temperature is 45 ° C; the atomization pressure is 2.50 bar; Cooker speed 20 rpm; feed flow rate 4 g / min 0
  • Example 13 Preparation of the coated pill of the traditional Chinese medicine composition of the present invention
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 80% ethanol, heated and refluxed for 1.5 hours, and the reflux liquid is stored for use.
  • the dregs and the other rehmannia roots other than the genus Rhizome are boiled three times with water, each time.
  • the obtained extract powder is mixed with low-substituted hydroxypropylcellulose, wherein the low-substituted hydroxypropylcellulose is used in an amount of 25% of the extract powder, and 20% (v/v) of ethanol is added as a binder. Chengsu Pills.
  • the above-mentioned capsules were coated with the coating material of the product of Opelda (stomach-soluble type) of COLORCON Coating Technology Co., Ltd., and the stomach-soluble coating concentrated pill of the present invention was obtained.
  • the coating conditions are as follows: Water is used as the dissolving agent; the concentration of the coating liquid is 20% (w/w); the weight of the coating is 6%; the inlet air temperature is 40 ° C; the bed temperature is 70 ° C; the atomization pressure is 2.50 bar ; coating pan speed 20rmp ; feed flow rate 4g/min.
  • Water is used as the dissolving agent; the concentration of the coating liquid is 20% (w/w); the weight of the coating is 6%; the inlet air temperature is 40 ° C; the bed temperature is 70 ° C; the atomization pressure is 2.50 bar ; coating pan speed 20rmp ; feed flow rate 4g/min.
  • Angelica, Chuanxiong, Baiji and Yuanhu are added with 70% ethanol, heated and refluxed for 1 hour, and the reflux liquid is stored for use.
  • the dregs and the other rehmannia roots other than the hook vine are boiled three times with water, each time.
  • the obtained extract powder was mixed with microcrystalline cellulose, wherein the amount of the microcrystalline cellulose was 35% of the extract powder, and 25% ( ⁇ / ⁇ ) of ethanol was added as a binder to form a pellet.

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Description

一种治疗头痛的中药组合物、 其制剂和制备方法 技术领域 本发明涉及中药领域， 特别涉及由中药制成的治疗头痛的组合物、其制 剂和制备方法。 背景技术 中国专利 （专利号： ZL93100050.5 ) 公开了一种由当归、 川芎等组成的 药物组合物。 它是在祖国医学理论的指导下， 并经多年临床实践总结而成， 具有治疗内伤引起的头痛的作用。 临床上适用于血管神经性头痛、偏头痛以 及高血压引起的头晕、 头痛等症状。 按本处方比例， 可以制成药剂学上任何 一种剂型。其中的颗粒剂型由天津天士力制药股份有限公司生产，名称为 "养 血清脑颗粒"。 获准的"功能与主治"为养血平肝， 活血通络。 用于血虚肝亢 所致各种头痛、 创伤性脑神经综合症、 眩晕眼花、 心烦易怒、 失眠多梦等。 临床上主要用于治疗血虚、血瘀、阴虚阳亢所致的头痛。由于其确切的疗效， 自上市以来， 赢得了广大患者的信赖。 虽然临床上该药物取得了广泛的认可，但其中细辛的使用还有值得商榷 之处。 很久以来， 对于细辛的使用剂量就有广泛的争论。 古有"细辛用量不过 钱"的说法， 足以说明其用量是非常讲究的。 细辛是临床常用的中药之一， 首载于 《神农本草经》。 其性味辛、 温， 有小毒， 归肺、 肾、 心经。 具有解表、 祛风止痛通窍， 温肺化饮的作用， 适 用于风寒感冒、 头痛、 牙痛、 风湿痹痛等疾病的治疗。 现代药理学研究表明， 细辛的毒性主要来自于其所含的挥发油成分， 大 剂量的挥发油可以导致动物兴奋， 继而麻痹随意运动以及呼吸运动逐渐减 弱， 反射消失， 终因呼吸麻痹而死亡（丁涛， 《中药不良反应及其防治》， 北 京， 中国中医药出版社， 1992， p85 ) o 颗粒剂是在冲剂的基础上发展起来的一种新剂型， 近 10年来国内发展 迅速， 它即保持了冲剂服用、贮藏及运输方便的特色， 又克服了冲剂含糖量 较大的缺点， 使老年人及糖尿病患者也能服用。 由于大大减少了辅料用量， 因此其体积更小， 相对含药量也较冲剂高。 但颗粒剂由于浸膏含量大， 添加 剂少， 易产生吸潮、 结块及变色等现象， 同时药物苦味极大， 某些药对胃有 较强刺激性或在胃中易被破坏， 这些均为颗粒剂需要解决的问题。 经过长期的实践，本发明人发现将药物适当提取后加入适当辅料制成丸 剂， 并采用薄膜包衣技术制成包衣的浓縮丸剂。可以有效地避免每次服用量 大、 易吸湿、 冲服时味苦、 酸涩口感欠佳的问题。 发明内容 本发明目的在于优化现有技术的处方，提供一种不含细辛的治疗头痛的 组合物。 本发明用于治疗头痛的中药组合物由下列重量配比的药材制成： 当归 5〜15%、川芎 5-15%, 白芍 2~10%>熟地 2〜10%、勾藤 7~17%、 鸡血藤 7〜17%、 夏枯草 7~17%、 决明子 7~17%、 珍珠母 7~17%、 元胡 3〜10%。 优选原料配比为：
当归 5~8%、 川芎 5~8%、 白芍 3〜7%、 熟地 3〜7%、 勾藤 10〜15%、 鸡血藤 10~15%、 夏枯草 10~15%、 决明子 10〜15%、 珍珠母 10~15%、 元 胡 3〜10%。 最佳的原料配比为：
当归 6.85%、 川芎 6.85%、 白芍 5.5%、 熟地 5.5%、 勾藤 13.69%、 鸡 血藤 13.69%、 夏枯草 13.69%、 决明子 13.69%、 珍珠母 13.69%、 元胡 6.85%。 按照传统中医药的方法， 可以将本发明药物组合物制成汤剂直接服用， 也可以经过提取加工制成提取物与适当的辅料一起制成药剂学上任意制剂。 因此， 本发明的另一目的在于提供含有该组合物的常规药物制剂， 所述 的药物制剂是用制药领域常规的制药方法， 按照上述原料配比， 加入常规的 药用载体制成的。 本发明组合物的药物制剂中优选的是适于口服的制剂， 如口服固体制 剂， 液体制剂以及缓释或控释制剂等， 所述的口服制剂包括片剂、 胶囊、 颗 粒剂、 丸剂、 粉剂以及可缓释或控释的各种制剂等， 优选浓縮丸剂， 更优选 薄膜包衣的丸剂， 特别优选胃溶型薄膜包衣的丸剂。 本发明药物组合物的胃溶型薄膜包衣丸剂很好地克服现有颗粒制剂带 来的问题， 例如浸膏含量大、 易产生吸潮、 结块及变色等制剂和储存方面的 问题， 以及药物苦味极大、对胃有较强刺激性和有效成分在胃中易被破坏等 服用方面的问题。 试验结果表明， 本发明的浓缩丸剂， 特别是胃溶型薄膜包 衣的丸剂（以下或称"养血清脑丸"）与现有技术已知的颗粒剂（以下或称"养 血清脑颗粒"） 具有相似的溶出曲线,说明该丸剂和颗粒剂具有一致的体外溶 出效果。 本发明丸剂可含有常规的药用辅料和粘合剂， 所述的辅料选自下列材 料： 糊精、 淀粉、 低取代羟丙基纤维素和微晶纤维素， 优选微晶纤维素； 辅 料用量为药材干粉量的 25%以上，优选辅料的用量为药材干粉量的 28〜35%； 以及所述的选自下列材料： 水、 20〜30% (v/v) 的乙醇水溶液和蜂蜜水， 优 选粘合剂为水。 粘合剂的用量以能达到粘合效果为宜。 本文中所使用的术语"素丸"是指药学领域一般意义上的丸剂， 并特指未 包衣的丸剂。 本文中所使用的术语 "丸剂 "或"浓缩丸 "是指将药材提取浓缩后与辅料 制成的丸剂。 本文中所使用的术语 "相对密度"是指以 lg/cm3的水 （4°C ) 作为参考密 度时的密度值。 本发明的另一目的还在于提供了该组合物的制备方法。 按照传统中医药的方法， 可以将本发明药物组合物制成汤剂直接服用， 也可以经过提取加工制成提取物与适当的辅料一起制成药剂学上任意制剂。 其中可以选择将当归、 白芍、 川芎或元胡等药材单独或任意组合提取加 工制成提取物， 所述的提取方法选自但并不限于此： 水提醇沉法、 超声提取 法或超临界萃取法等。 为了便于理解， 现将白芍、 川芎、 元胡以及当归四味药材的提取方法举 例描述如下， 但并不限于此。 白芍超声提取法： 取白芍药材， 粉碎， 加水超声提取， 浓缩得白芍提取 物。 白芍、 川芎、 元胡或当归的醇提取法： 取药材粉碎， 加乙醇回流提取， 浓缩回收乙醇， 继续浓缩得提取物。 当归超临界萃取法：取当归药材，适当条件下采用二氧化碳超临界萃取， 过滤得当归提取物。 当归水提取加树脂法： 取当归的水煮醇沉淀物加热蒸馏水溶解， 用氢氧 化钙饱和液调 pH值， 放置过夜抽滤， 滤液用硫酸调 pH5-6， 冰存过夜， 抽 滤，滤液通过阴阳离子混合树脂交换，交换液浓缩至一定体积，加乙醇沉淀， 冰存过夜抽滤， 将醇沉物挥去乙醇并浓缩得当归提取物。 当归蒸馏提取法： 称取当归粉于烧瓶中， 用蒸馏水进行回流浸提， 然后 将原料及浸液在一定条件下， 减压蒸馏， 得当归馏出液， 然后加入适量的 NaCl静置分层，用分液漏斗将当归挥发油分离出，剩余物浓缩得当归提取物。 川芎乙醇加树脂法： 取川芎饮片， 粉碎， 用乙醇于索氏回流提取装置中 回流提取， 抽滤， 抽滤液减压浓缩至干， 再加适量水， 加热使溶解， 滤过， 滤液加到已处理好的大孔树脂柱上， 先用水洗脱， 弃去， 再用乙醇洗脱， 合 并洗脱液， 回收乙醇后， 继续浓缩得川芎提取物。 川芎乙醇提取法： 取川芎药材， 适当粉碎， 加乙醇提取若干次， 合并提 取液， 滤过， 回收乙醇， 浓缩得川芎提取物。 除上述药材单独提取外， 所述川芎、 当归和白芍还可以混合提取， 主要 为： 取经粉碎的白芍、 川芎和当归药材， 沸水煮提， 滤过， 合并滤液， 并将 滤液适当浓缩； 在浓缩液中加入乙醇进行醇沉， 静置， 上清液回收乙醇， 浓 缩成浸膏， 得药材提取物。 具体地， 本发明还提供了一种上述组合物的制备方法， 该方法包括下列 步骤：
a) 按上述任一重量配比取药材： b).当归、 川芎、 白芍和元胡可分别用乙醇提取制备提取液， 然后合并 待用； 或在四种药材的混合物中加入乙醇， 加热回流进行提取， 提取液储存 备用；
C).将上一步骤的药渣与除钩藤外的其余五味药材加水煎煮多次， 在最 后一次煎煮时加入钩藤， 合并所得到的煎液， 浓缩；
d) .将上一步骤得到的浓缩煎液加乙醇沉淀， 上清液与回流液合并， 浓 缩并回收乙醇得到浸膏形式的组合物； 和
e) .将所获得的提取物加入适当辅料制成所需的药物制剂。 优选的， 步骤 （b) 中将当归、 川芎、 白芍和元胡的混合物加乙醇加热 回流， 进行提取， 回流液储存备用备用； 得到的药渔与除钩藤外的其余五味 加水煎煮三次， 在第三煎时加入钩藤， 合并煎液， 浓缩至相对密度为 55°C 下 1.09~1.13， 加乙醇沉淀， 上清液与回流液合并， 回收乙醇得药材提取物。 其中， 上述方法的步骤 （b) 中的乙醇浓度为 60%〜80% (v/v) , 优选为 大约 70% (v/v); 每一次回流时间为 0.5〜1.5小时， 优选大约 1小时； 得到 的药渣与其它药物煎煮时， 每一次煎煮的时间为 0.5~1.5小时， 优选大约 1 小时， 浓缩后浸膏的相对密度优选为大约 1.10 (55°C ); 所述步骤 （c) 中， 进行煎煮时加入水的重量优选为药材重量的 5倍； 所述步骤 （d) 加入乙醇 进行沉淀应使最后的含醇量达 60%~70% (v/v)， 优选为大约 65% (v/v); 浓 缩后浸膏的相对密度为大约 1.15 ( 55°C )。 用上述方法所得到的浸膏形式的提取物可以采用现有技术的常规干燥 方法进行干燥， 得到干燥的浸膏或浸膏粉，、其中所述干燥步骤可采用喷雾千 燥法， 进风温度 165〜205°C， 优选进风温度大约 185° ( 。 本发明的上述制备方法还包括将得到的浸膏、干浸膏或浸膏粉与药用载 体一起制成所需的制剂， 优选丸剂， 更优选包衣的丸剂， 特别优选胃溶型薄 膜包衣的丸剂。 因此， 本发明的方法还包括对丸剂进行包衣的步骤。所述的包衣步骤可 以选择现有技术已知的薄膜包衣和普通包衣两种技术，优选采用胃溶型薄膜 包衣。 具体的， 其中的薄膜包衣可以采用胃溶型的包衣材料， 如选择上海卡乐 康 （COLORCON) 包衣技术有限公司的欧巴代 （胃溶型） 为本品的包衣材 料。 包衣条件如下： 选用水为溶解剂； 包衣液浓度为 14-20% (w/w), 优选 浓度为 18%; 包衣增重 2%-6%， 优选 4%; 进风温度 40-90 °C， 优选为 65°C ; 片床温度 40-70°C， 优选为 43°C ; 雾化压力 1.5-2.5bar, 优选 2.0bar; 包衣 锅转速 15-20rmp， 优选 17rmp; 进料流速 2-4g/min， 优选 3g/min。 其中普通包衣则可釆用了适量滑石粉加入着色剂后进行打腊上光的技 术。 具体条件为： 取适量滑石粉 1%， 用水稀释， 润湿素丸， 待滑石粉涂抹 均匀后， 加入 1%的作色剂， 待颜色涂抹均匀后， 加入 10%蜡打光即可。 包 衣锅转速： 5-30转 /每分钟。 本发明方法的醇提、水煎和醇沉步骤中的醇或水的用量按照药典中描述 的常规用量和方法进行。 出膏率， 即以中药材的干重计， 获得的干浸膏的重 量百分数， 通常为 16%左右。 上述方法制备的浓缩丸按照生药量计算， 成人每次服用的量为 12-20g， 优选 15-17g。 服药次数视病情而定， 通常为 2~3次 /日。 本发明治疗头痛的组合物提供了一种处方更加合理，使用更加安全的药 物， 与现有技术 （中国专利， 专利号： ZL93100050.5, 以下简称 YXQN-01 ) 相比， 本发明去掉了处方中容易产生毒性的细辛， 使得该处方更加合理， 使 用更加安全， 同时又保持了原有组合物治疗头痛的疗效。 中国专利 ZL93100050.5的药物制剂采用了颗粒剂， 该制剂是在冲剂的 基础上发展起来的一种新剂型， 近 10年来国内发展迅速， 它即保持了冲剂 服用、 贮藏及运输方便的特色， 又克服了冲剂含糖量较大的缺点， 使老年人 及糖尿病患者也能服用。 由于大大减少了辅料用量， 因此其体积更小， 相对 含药量也较冲剂高。 但颗粒剂由于浸膏含量大， 添加剂少， 易产生吸潮、 结 块及变色等现象， 同时药物苦味极大， 某些药对胃有较强刺激性或在胃中易 被破坏， 这些也成为颗粒剂需要解决的问题。 本发明优选的技术方案是釆用将浸膏喷雾干燥、浓缩丸剂剂型并结合薄 膜包衣等技术制备的一种新型的制剂，实践显示该制剂能很好地克服现有颗 粒制剂带来的问题。 同时， 溶出度测定显示， 本发明的浓缩丸剂 （以下简称 "养血清脑丸"）与上述专利的养血清脑颗粒具有相似的溶出曲线，说明养血清 脑丸具有和养血清脑颗粒一致的体外溶出效果。 下面通过对于考察两种组合物对于醋酸所致小鼠扭体反应均有明显的 抑制作用， 来进一步说明本发明药物组合物的优良效果， 以证明其创造性。 本发明中药组合物对小鼠镇痛和耐缺氧的影响
1. 实验目的
观察本发明中药组合物 （YXQN-02) 和现有技术已知药物 YXQN-01对 小鼠镇痛和耐缺氧的影响。
2. 实验材料
2.1 药品及配制
2.1.1 受试药物：
YXQN-01 , 中国专利 ZL93100050.5的药物， 由天津天士力集团研究院 提供 （制备方法见对比例）， 批号： 20041101。 实验前分别用蒸馏水配制成 1.4g生药 /ml、 0.7g生药 /ml、 0.35g生药 /ml浓度的溶液供小鼠 ig (灌胃给药） 用。
YXQN-02, 由天津天士力集团研究院提供 （制备方法见实施例 5 )， 批 号： 20041201。
上述药物在实验前分别用蒸馏水配制成 1.4g 生药 /ml、 0.7g 生药 /ml、 0.35g生药 /ml浓度的溶液供小鼠 ig用。
2.1.2 阳性对照药
阿司匹林肠溶片 （25mg/片）， 石家庄康力药业有限公司， 批号 041219。 实验前用 0.5%CMC-Na配制成 10 mg /ml浓度的混悬液供小鼠 ig用。
心得安 （10mg/片）， 天津力生制药股份有限公司生产， 批号 0411015。 实验前用蒸馏水配制成 5mg/ml浓度的溶液供小鼠 ig用。
2.2 试剂
冰醋酸， 天津市化学一厂， 批号： 890508。
凡士林， 天津市石油化学实验厂， 批号： 860404。
钠石灰， 上海市纳辉干燥试剂厂， 批号： 20040724。
2.3 器材
AE-200型电子分析天平 (梅特勒-托利多仪器上海有限公司产品)。 TF2-型热辐射测痛仪 （光源 12V/50W, 中国医学科学院药物研究所研 制）。
秒表， 250ml广口磨口瓶， 大剪刀。
2.4 动物
ICR小鼠， 雌雄各半， 体重 20±2g。 由北京维通利华实验动物技术有限 公司提供， 合格证号： SCXK (京） 2002-0003。
3. 统计学方法
用 SPSS10.0软件包进行统计学处理， 数据用 （；± 表示， 采用组间 比较用 t检验。
4. 实验方法与结果
4.1 YXQN-01和 YXQN-02对小鼠醋酸致痛的影响
4.1.1 实验方法
取健康小鼠 112只， 雌雄各半， 按体重、 性别随机分为 8组， 每组 14 只。对照组， YXQN-01高、 中、低剂量为 28、 14、 7g生药 /kg组， YXQN-02 高、 中、 低剂量为 28、 14、 7g生药 /kg组， 阳性对照组用药阿司匹林肠溶片 200mg/kg。 以上药物均按 0.2ml/10g体重 ig给药， 每日 1次， 连续 5天， 阿 司匹林肠溶片 1 次给药， 对照组给予等容积的蒸馏水。 于末次给药后 lh, 各鼠腹腔注射 0.6%醋酸溶液（ 0.1ml/10g)。 记录注射醋酸后 15min内出现扭 体反应的次数，并按下式计算药物对扭体反应的抑制率，评价药物镇痛效果。 镇痛抑制率 =对照组扭 扭体驗 χ 100%
对照组扭体均数
4.1.2 实验结果
YXQN-01连续 ig给药 5天， 28g生药 /kg、 14g生药 /kg和 7g生药 /kg 组抑制率分别为 49.88% (P<0.001 )、 45.99% (P<0.01 )和 33.58% (P<0.05 ); YXQN-02连续 ig给药 5天， 28g生药 /kg、 14g生药 /kg和 7g生药/ kg组抑 制率分别为 44.53% (P<0.01 )、 62.29% (P<0.001 ) 和 3.07% (P<0.05 )。 YXQN-01和 YXQN-02对醋酸所致对小鼠扭体反应有明显抑制作用。阿司匹 林肠溶片 0.2g/kg组与对照组比较抑制率为 69.83% (P<0.001 ), 亦有明显抑 制作用。 结果见表 1。 YXQN-01 和 YXQN-02对小鼠醋酸致痛的影响 （^±^ ) 组别 剂量 动物数 15min扭体数 抑制率
(g/kg) (只） (次） (%) 对照组 - 14 29.36±7.78 -
YXQN-01 28 14 16.50±7.56"* 49.88
YXQN-01 14 14 18.93±6.79** 45.99
YXQN-01 7 14 22.36±9.48* 33.58
YXQN-02 28 14 17.71±9.56" 44.53
YXQN-02 14 14 13.93±7.14"* 62.29
YXQN-02 7 14 21.71±10.03* 43.07 阿司匹林肠溶片 0.2 14 8.57±4.85*** 69.83 注： 与对照组比较， *P<0.05 , P<0.01 , ***P<0.001。
4.2 YXQN-01和 YXQN-02对小鼠光辐射热甩尾的影响
4.2.1 实验方法
4.2.1.1检测原理
TF2-型热辐射测痛仪采用 12V/50W小型聚光灯炮， 根据小型聚光灯产 生一定强度的光束， 通过透镜聚焦照射小鼠的尾巴致痛。
4.2.1.2 筛选合格小鼠
取健康、体重相近小鼠， 以小鼠尾端皮肤接受热辐射剌激到甩尾反应的 潜伏期 （TFL) 作为该鼠的痛阈。 选择痛阈大于 2s、 小于 5s的小鼠用于实 验， 作为该鼠的基础痛阈。
4.2.1.3 分组及给药
将 112只合格小鼠按性别、痛阈值随机分为 8组，每组 U只， 对照组， YXQN-01高、 中、 低剂量为 28、 14、 7g生药 /kg组， YXQN-02高、 中、 低 剂量为 28、 14、 7g生药 /kg组， 阳性对照药阿司匹林肠溶片 200mg/kg。 以 上药物均按 0.2ml/10g体重 ig给药， 每日 1次， 连续给药 5天， 阿司匹林肠 溶片 1 次给药， 对照组给予等容积的蒸馏水。 末次给药后 lh, 将小鼠装入 TF2-型热辐射测痛仪固定桶内， 尾部暴露于外（试验前先用 75%乙醇擦净鼠 尾）， 将小鼠尾距尖端 1.5cm处内侧皮肤部位对准透镜焦点， 待动物安静后 进行致痛试验。 为防止皮肤烫伤光照截止时间为 16s为限， 按下列公式计算 镇痛提高百分率， 评定药物镇痛强度。 痛阈提高率 =给药后 _ ^ -基础 TFL x lQQ%
基础 TFL
4.2.2 实验结果
本发明中药组合物 YXQN-01连续 ig给药 5d， 28g/kg和 14g/kg组痛阈 提高百分率分别为 100.98% (PO.01 )和 130.30% (P<0.01 ); 现有技术已知 药物 YXQN-02 连续 ig 给药 5d， 28g/kg 组痛阈提高百分率为 160.70% (P<0.05 ), YXQN-01和 YXQN-02与对照组比较， 均有显著性差异。 阿司 匹林肠溶片 0.2g/kg组痛阈提高百分率为 176.89% (P<0.01 )，与对照组比较， 亦有显著性差异。 结果见表 2。
表 2 YXQN-01和 YXQN-02对小鼠热辐射甩尾致痛的影响（x ± ) 组别 剂量 动物数 基础痛阈 给药后痛阈 痛阈提率
(g/kg) (只） (S) (S) (%) 对照组 - 14 2.89±0.78 3.42±0.82 -
YXQN-01 28 14 2.93±0.66 5.89±2.42 100.98
YXQN-01 14 14 2.90±0.67 6.68±3.74 130.30
YXQN-01 7 14 2.98±0.75 4.89±3.32 64.03
YXQN-02 28 14 2.87±0.72 7.49±4.31 160.70
YXQN-02 14 14 2.88±0.72 4.67±3.03 62.28
YXQN-02 7 14 2.99±0.76 4.76±2.84 59.57 阿司匹林 0.2 14 2.94±0.77 8.13±4.35 176.89 肠溶片 注： 与对照组比较， *P<0.05， P<0.01。
5. 结论
YXQN-01和 YXQN-02 均能明显抑制醋酸所致小鼠扭体次数，延长光 射所致小鼠甩尾时间， 呈现出大致相同的程度的镇痛作用。 本发明组合物的丸剂与现有技术已知的颗粒剂的溶出度比较 按照溶出度测定法 （中国药典 2000版二部附录 X C) 测定。
该测定方法采用转篮法， 溶出介质为经脱气处理的水 900ml， 水温 37±0.5。C， 转速为 100r/min。
1.溶出量测定
分别称取养血清脑颗粒 （按照对比实施例制备） 4g、 养血清脑丸 2.5g (按照实施例 5方法制备）， 置转篮中， 开动电机 6小时后取样， 立即滤过， 取续滤液， 精密吸取 10μ1， 分别注入液相色谱仪， 测定。
2. 溶出度测定
称取养血清脑颗粒 4份， 每份 4g， 置转篮中， 分别标记为样 1、 样 2、 样 3和样 4， 立即开动电机， 定时于 5、 10、 25、 40、 60、 80、 100分钟时 取样。 每次取出 5ml,并立即补充 37°C水 5ml。 取样后立即滤过， 取续滤液， 精密吸取 ΙΟμΙ, 注入液相色谱仪， 测定。 称取养血清脑丸 4份， 每份 2.5g， 置转篮中， 标记为 "样 1、 样 2、 样 3和样 4"， 立即开动电机， 定时于 10、 25、 40、 60、 80、 100、 120 分钟时取样， 取样后操作方法同颗粒。 根据测 定结果分别计算养血清脑颗粒和养血清脑丸的累积释放百分率，结果见表 3、 表 4。
养血清脑颗粒的累积释放百分率 （％)
T(min) 5 10 25 40 60 80 100 样 1 14.78 25.49 44,60 54.56 66.46 79.24 84.71 样 2 15.76 25.68 45.06 56.19 69.44 80.64 88.27 样 3 14.34 25.27 43.39 53.08 65.27 78.62 86.98 样 4 15.54 25.68 45.32 53.79 67.68 79.58 97.39 平均值 15.10 25.53 44.59 54.40 67.21 79.52 89.34 表 4 养血清脑丸的累积释放百分率 （％)
T (min) 10 25 40 60 80 100 120 样 1 27.03 44.07 58.08 73.59 78.88 85.54 95.85 样 2 26.05 45.73 58.57 72.20 74.05 76.71 82.75 样 3 27.71 41.90 59.13 73.34 80.98 82.56 90.93 样 4 25.06 44.25 64.56 70.32 76.19 77.46 85.38
曰. 平均值 26.46 43.99 60.08 72.36 77.53 80.57 88.73
3. 数据处理
3.1 T50, Td计算
以 lnt、 ln[-ln(l-F)]为变量计算出颗粒、 丸剂的回归方程， 计算出溶出参 数 T5Q、 Td,结果表明养血清脑丸的体外溶出效果同养血清脑颗粒基本一致。
表 5 养血清脑丸和养血清脑颗粒的溶出参数比较 剂型 Td (min)
本发明养血清脑丸 29.16 46.84
养血清脑颗粒 29.66 49.81
3.2 相似因子 (f2) 计算
以养血清脑丸和养血清脑颗粒的 10、 25、 40、 60、 80、 100 分钟处的 累积释放百分率代入相似因子计算公式， 结果： f2=5(M。g{[l+(l/n) (Rt-St)2]-°-5xl00}=68.77 >50 根据美国 FDA 《口服讳 (l剂的生物等效性研究指导原则》， 相似因子>50 表明两者具有相似的溶出曲线，说明本发明的养血清脑丸具有和养血清脑颗 粒一致的体外溶出效果。 附图说明 图 1表示本发明的养血清脑丸和养血清脑颗粒累积释放百分率 -时间曲线。 具体实施方式
以下通过对比例和实施例对本发明作进一步的说明， 但不能以此限制本发明 的保护范围。
对比实施例 制备已知药物 YXQN-01颗粒剂 本实施例的方法参照中国专利 ZL93100050.5所描述的方法进行。
1. 药材的提取
取当归 405.6g， 川芎 405.6g， 白芍 324.3g， 熟地黄 324.3g， 钩藤 810.8g， 鸡 血藤 810.8g， 夏枯草 810.8g， 决明子 810.8g， 珍珠母 810.8g， 元胡 405.6g, 细辛 80.8g。
以上十一味中， 当归、 川芎、 白芍和元胡加 70%乙醇， 加热回流 1小时， 回流 液储存备用； 药渣与除钩藤外的其余熟地黄等六味加水煎煮三次， 每次 1小时， 在 第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55°C); 加乙醇使含醇 量达到 65%， 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙醇并浓 缩至相对密度为 1.15 (55 °C), 干燥至干浸膏， 喷雾干燥成浸膏粉， 进风温度 185°C 左右。
2. 颗粒剂的制备
在上述步骤制得的提取物中加入糊精， 采用喷雾干燥法制成颗粒。 实施例 1 制备本发明中药组合物的颗粒剂
1. 药材的提取
取当归 68.5g，川芎 68.5g， 白芍 55g，熟地黄 55g，钩藤 136.9g，鸡血藤 136.9g， 夏枯草 136.9g， 决明子 136.9g， 珍珠母 136.9g， 元胡 68.5g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 70%乙醇， 加热回流 1小时， 回 流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1小时， 在第三煎时加入钩籐， 合并煎液， 减压浓缩至相对密度为 1.10 (55 °C); 加乙醇使含 醇量达 65%， 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙醇并浓 缩至相对密度为 1.15 (55°C);干燥至干浸膏，喷雾干燥成浸膏粉，进风温度 185°C。
2. 颗粒剂的制备 提取制得的提取物加入糊精， 釆用喷雾干燥法制成颗粒。 实施例 2 制备本发明中药组合物的片剂
1. 药材的提取
取当归 68.5g，川芎 68.5g， 白芍 55g，熟地黄 55g，钩藤 136.9g，鸡血藤 136.9g， 夏枯草 136.9g， 决明子 136.9g， 珍珠母 136.9g， 元胡 68.5g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 70%乙醇， 加热回流 1小时， 回 流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1小时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55°C); 加乙醇使含 醇量达 65%, 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙醇并浓 缩至相对密度为 1.15 (55°C); 千燥至干浸膏， 喷雾干燥成浸膏粉， 进风温度 185°C。
2. 片剂的制备
提取制得的提取物加入淀粉， 压片制成片剂。 实施例 3 制备本发明中药组合物的胶囊剂
1. 药材的提取
取当归 68.5g，川芎 68.5g， 白芍 55g，熟地黄 55g，钩藤 136.9g，鸡血藤 136.9g， 夏枯草 136.9g， 决明子 136.9g， 珍珠母 136.9g， 元胡 68.5g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 70%乙醇， 加热回流 1小时， 回 流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1小时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55Ό); 加乙醇使含 醇量达 65%， 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙醇并浓 缩至相对密度为 U5 (55°C); 干燥至干浸膏， 喷雾干燥成浸膏粉， 进风温度 185°C。
2. 胶囊的制备
提取制得的提取物加入淀粉， 灌入 1号胶囊。 实施例 4 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 405.6g， 川芎 405.6g， 白芍 324.3g， 熟地黄 324.3g， 钩藤 810.8g， 鸡 血藤 810.8g， 夏枯草 810.8g， 决明子 810.8g， 珍珠母 810.8g， 元胡 405.6g。
以上十味药材中， 当归、川芎、 白芍和元胡加 70%乙醇，加热回流 1小时， 回 流液储存备用； 药渣与除钩籐外的其余熟地黄等五味加水煎煮三次， 每次 1小时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55Ό); 加乙醇使含 醇量达 65%， 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙醇并 浓缩至相对密度为 1.15(55°C);干燥至干浸膏，喷雾干燥成浸膏粉，进风温度 185°C。
2. 浓缩丸剂的制备
将上述所得浸膏粉与微晶纤维素进行混合， 其中微晶纤维素的用量为浸膏粉 的 35%， 加入水作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康 （COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓缩丸剂。
包衣条件如下： 选用水为溶解剂； 包衣液浓度为 18% (w/w); 包衣增重 4%; 进风温度 65Ό ; 片床温度 43 °C ; 雾化压力 2.0bar; 包衣锅转速 17raip; 进料流速 3g/miri。 实施例 5 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 405.6g， 川芎 405.6g， 白芍 324.3g, 熟地黄 324.3g， 钩藤 810.8g， 鸡 血藤 810.8g， 夏枯草 810.8g， 决明子 810.8g， 珍珠母 810.8g, 元胡 405.6g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 60%乙醇， 加热回流 0.5小时， 回流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 0.5小 时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55°C); 加乙醇 使含醇量达 60%, 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙 醇并浓缩至相对密度为 1.15 (55°C); 干燥至千浸膏， 喷雾干燥成浸膏粉， 进风温度 165。C。
2. 浓缩丸剂的制备
将上述所得浸膏粉与糊精进行混合， 其中糊精的用量为浸膏粉的 25%， 加入 水作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康 （COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓缩丸剂。
包衣条件如下： 选用水为溶解剂； 包衣液浓度为 14% (w/w); 包衣增重 2%; 进风温度 85°C ; 片床温度 40Ό ; 雾化压力 2.0bar; 包衣锅转速 17rmp; 进料流速 3g/r in。 实施例 6 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 405.6g， 川芎 405.6g， 白芍 324.3g， 熟地黄 324.3g， 钩藤 810.8g， 鸡 血藤 810.8g， 夏枯草 810.8g, 决明子 810.8g， 珍珠母 810.8g， 元胡 405.6g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 80%乙醇， 加热回流 1.5小时， 回流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1.5小 时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55°C); 加乙醇 使含醇量达 70%, 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙 醇并浓缩至相对密度为 1.15(55°C); 干燥至干浸膏， 喷雾千燥成浸膏粉， 进风温度 205 °C。
2. 浓缩丸剂的制备
将上述所得浸膏粉与微晶纤维素进行混合， 其中微晶纤维素的用量为浸膏粉 的 25%， 加入水作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康 （COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓缩丸剂。
包衣条件如下： 选用水为溶解剂； 包衣液浓度为 20% (w/w); 包衣增重 6%; 进风温度 90 °C ; 片床温度 45°C ; 雾化压力 2.50bar; 包衣锅转速 20rmp; 进料流速 4g/miii。 实施例 7 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 240.1g， 川芎 240.1g， 白芍 120.0g， 熟地黄 120.0g， 钩藤 600.0g， 鸡 血藤 600.0g， 夏枯草 600.0g， 决明子 600.0g， 珍珠母 600.0g， 元胡 240.0g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 70%乙醇， 加热回流 1小时， 回流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1 小 时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55°C); 加乙醇 使含醇量达 65%， 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙 醇并浓缩至相对密度为 1.15 (55°C); 干燥至干浸膏， 喷雾干燥成浸膏粉，进风温度 185。C。
2. 浓缩丸剂的制备 将上述所得浸膏粉与微晶纤维素进行混合， 其中微晶纤维素的用量为浸膏粉 的 35%， 加入水作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康 （COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓缩丸剂。
包衣条件如下： 选用水为溶解剂； 包衣液浓度为 18% (w/w); 包衣增重 4%; 进风温度 87°C ; 片床温度 43 °C ; 雾化压力 2.0bar; 包衣锅转速 17raip; 进料流速 3g/miii。 实施例 8 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 540.2g， 川芎 540.0g， 白芍 480.0g， 熟地黄 480.0g， 钩藤 900.0g， 鸡 血藤 900.0g， 夏枯草 900.0g， 决明子 900.0g， 珍珠母 900.0g， 元胡 540.0g。
以上十味药材中， 当归、川芎、 白芍和元胡加 70%乙醇，加热回流 1小时， 回 流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1小时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55°C); 加乙醇使含 醇量达 65%, 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙醇并 浓缩至相对密度为 1.15 (55°C);干燥至干浸膏，喷雾千燥成浸膏粉，进风温度 185°C。
2. 浓缩丸剂的制备
将上述所得浸 粉与微晶纤维素进行混合， 其中微晶纤维素的用量为浸膏粉 的 35%, 加入水作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康 （COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓缩丸剂。
包衣条件如下： 选用水为溶解剂； 包衣液浓度为 18% (w/w); 包衣增重 4%; 进风温度 87Ό ; 片床温度 43Ό ; 雾化压力 2.0bar; 包衣锅转速 17rmp; 进料流速 3g/miii。 实施例 9 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 240.1g, 川芎 240.1g， 白芍 120.0g， 熟地黄 120.0g, 钩藤 600.0g, 鸡 血藤 600.0g， 夏枯草 600,0g， 决明子 600.0g， 珍珠母 600.0g, 元胡 240.0g。 以上十味药材中， 当归、 川芎、 白芍和元胡加 60%乙醇， 加热回流 0.5小时， 回流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 0.5小 时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.09 (55°C); 加乙醇 使含醇量达 60%, 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙 醇并浓缩至相对密度为 1.15 (55°C); 干燥至干浸膏， 喷雾干燥成浸膏粉， 进风温度 165°C。
2. 浓缩丸剂的制备
将上述所得浸膏粉与微晶纤维素进行混合， 其中微晶纤维素的用量为浸膏粉 的 35%， 加入水作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康 （COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓缩丸剂。
包衣条件如下： 选用水为溶解剂； 包衣液浓度为 16% (w/w); 包衣增重 2%; 进风温度 85°C ; 片床温度 40Ό ; 雾化压力 1.5bar; 包衣锅转速 15rmp; 进料流速 2g/min。 实施例 10 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 540.2g， 川芎 540.0g， 白芍 480.0g， 熟地黄 480.0g， 钩藤 900.0g， 鸡 血藤 900.0g, 夏枯草 900.0g, 决明子 900.0g， 珍珠母 900.0g， 元胡 540.0g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 70%乙醇， 加热回流 1.5小时， 回流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1.5小 时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55°C); 加乙醇 使含醇量达 70%, 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙 醇并浓缩至相对密度为 1.15 (55Ό); 干燥至千浸膏， 喷雾干燥成浸膏粉， 进风温度 205。C。
2. 浓缩丸剂的制备
将上述所得浸膏粉与微晶纤维素进行混合， 其中微晶纤维素的用量为浸膏粉 的 35%， 加蜂蜜水作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康 （COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓縮丸剂。 包衣条件如下： 选用水为溶解剂； 包衣液浓度为 20% (w/w); 包衣增重 6%; 进风温度 90°C ; 片床温度 45Ό ; 雾化压力 2.5bar; 包衣锅转速 20rmp; 进料流速 4g/min。 实施例 11 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 405.6g， 川芎 405.6g， 白芍 324.3g， 熟地黄 324.3g， 钩藤 810.8g， 鸡 血藤 810.8g， 夏枯草 810.8g， 决明子 810.8g， 珍珠母 810.8g， 元胡 405.6g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 80%乙醇， 加热回流 1.5小时， 回流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1.5小 时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10(55°C); 加乙醇 使含醇量达 70%, 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙 醇并浓缩至相对密度为 1.15 (55°C); 干燥至干浸膏， 喷雾干燥成浸膏粉， 进风温度 205。C。
2. 浓缩丸剂的制备
将上述所得浸膏粉与淀粉进行混合， 其中淀粉的用量为浸膏粉的 25%, 加入 蜂蜜水作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康 （COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓缩丸剂。
包衣条件如下： 选用水为溶解剂； 包衣液浓度为 20% (w/w); 包衣增重 6%; 进风温度 90°C ; 片床温度 45°C ; 雾化压力 2.50bar; 包衣锅转速 20rmp; 进料流速 4g/min。 实施例 12 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 405.6g， 川芎 405.6g， 白芍 324.3g， 熟地黄 324.3g， 钩藤 810.8g， 鸡 血藤 810.8g， 夏枯草 810.8g， 决明子 810.8g， 珍珠母 810.8g， 元胡 405.6g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 80%乙醇， 加热回流 1.5小时， 回流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1.5小 时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55 °C); 加乙 醇使含醇量达 70%， 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收 乙醇并浓缩至相对密度为 1.15 (55°C); 干燥至干浸膏， 喷雾干燥成浸膏粉， 进风温 度 205°C。
2. 浓缩丸剂的制备
将上述所得浸膏粉与低取代羟丙基纤维素进行混合， 其中低取代羟丙基纤维 素的用量为浸膏粉的 25%， 加 30% (v/v) 的乙醇作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康（COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓缩丸剂。
包衣条件如下： 选用水为溶解剂； 包衣液浓度为 20% (w/w); 包衣增重 6%; 进风温度 9CTC ; 片床温度 45°C ; 雾化压力 2.50bar; 包衣锅转速 20rmp; 进料流速 4g/min0 实施例 13 制备本发明中药组合物的包衣丸剂
1. 药材的提取
取当归 405.6g， 川芎 405.6g， 白芍 324.3g， 熟地黄 324.3g， 钩藤 810.8g， 鸡 血藤 810.8g， 夏枯草 810.8g， 决明子 810.8g， 珍珠母 810.8g， 元胡 405.6g。
以上十味药材中， 当归、 川芎、 白芍和元胡加 80%乙醇， 加热回流 1.5小时， 回流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1.5小 时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55°C), 加乙 醇使含醇量达 70%， 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收 乙醇并浓缩至相对密度为 1.15 (55°C); 干燥至干浸膏， 喷雾干燥成浸膏粉， 进风温 度 205。C。
2. 浓缩丸剂的制备
将上述所得浸膏粉与低取代羟丙基纤维素进行混合， 其中低取代羟丙基纤维 素的用量为浸膏粉的 25%, 加入 20% (v/v) 的乙醇作为粘合剂制成素丸。
3. 丸剂包衣
将上述素丸选用上海卡乐康 （COLORCON) 包衣技术有限公司的欧巴代 （胃 溶型） 为本品的包衣材料进行包衣， 得本发明胃溶型包衣浓缩丸剂。
包衣条件如下： 选用水为溶解剂； 包衣液浓度为 20% (w/w); 包衣增重 6%; 进风温度 40°C ; 片床温度 70 °C ; 雾化压力 2.50bar; 包衣锅转速 20rmp; 进料流速 4g/min。 实施例 14 制备本发明中药组合物的丸剂
1. 药材的提取
取当归 405.6g， 川芎 405.6g， 白芍 324.3g， 熟地黄 324.3g， 钩藤 810.8g， 鸡 血藤 810.8g， 夏枯草 810.8g, 决明子 810.8g， 珍珠母 810.8g, 元胡 405.6g。
以上十味药材中， 当归、川芎、白芍和元胡加 70%乙醇，加热回流 1小时， 回 流液储存备用； 药渣与除钩藤外的其余熟地黄等五味加水煎煮三次， 每次 1小时， 在第三煎时加入钩藤， 合并煎液， 减压浓缩至相对密度为 1.10 (55°C); 加乙醇使 含醇量达 65%， 静置 24小时， 过滤沉淀， 滤液与上述回流液合并， 减压回收乙醇 并浓缩至相对密度为 1.15 (55°C); 干燥至干浸膏， 喷雾干燥成浸膏粉， 进风温度 185Ό。
2. 浓缩丸剂的制备
将上述所得浸膏粉与微晶纤维素进行混合， 其中微晶纤维素的用量为浸膏粉 的 35%， 加入 25% (ν/ν) 的乙醇作为粘合剂制成素丸。

Claims

权利要求书:
1、 一种治疗头痛的中药组合物， 该组合物由下列重量配比的药材制成： 当归 5〜15%、川芎 5~15%、 白芍 2~10%、熟地 2~10%、勾藤 7〜17%、 鸡血藤 7〜17%、 夏枯草 7~17%、 决明子 7~17%、 珍珠母 7~17%和元胡 3~10%。
2、 权利要求 1所述的组合物， 该组合物由下列重量配比的药材制成- 当归 5〜8%、 川芎 5〜8%、 白芍 3~7%、 熟地 3~7%、 勾藤 10〜15%、 鸡血藤 10~15%、 夏枯草 10~15%、 决明子 10~15%、 珍珠母 10〜15%和元 胡 3~10%。
3、 权利要求 2所述的组合物， 该组合物由下列重量配比的药材制成- 当归 6.85%、 川芎 6.85%、 白芍 5.5%、 熟地 5.5%、 勾藤 13.69%、 鸡 血藤 13.69%、 夏枯草 13.69%、 决明子 13.69%、 珍珠母 13.69%和元胡 6.85%。
4、 如权利要求 1-3 任意一项的组合物， 其中所述的组合物被制成适于 口服的制剂。
5、 如权利要求 4所述的组合物， 其中所述适于口服的制剂是适于口服 的固体制剂。
6、如权利要求 5所述的组合物， 其中所述适于口服的固体制剂是丸剂。
7、 如权利要求 6所述的组合物， 其中所述的丸剂是薄膜包衣的丸剂。
• 8、 如权利要求 7所述的组合物， 其中所述的薄膜包衣丸剂是胃溶型包 衣丸剂。
9、 如权利要求 6-8任意一项所述的组合物， 其中所述丸剂含有辅料和 粘合剂， 所述的辅料选自下列材料： 糊精、 淀粉、 低取代羟丙基纤维素和微 晶纤维素,， 辅料用量为药材干粉量的 25%以上； 和所述的粘合剂选自下列材 料： 水、 20〜30% (v/v)的乙醇水溶液和蜂蜜水。
10、如权利要求 9所述的组合物，其中所述丸剂中的辅料为微晶纤维素， 用量为药材干粉量的 28〜35%， 粘合剂为水。
11、 一种权利要求 1-10任意一项的组合物的制备方法， 该方法包括下 列步骤：
a) 按权利要求 1-3任意一项组合物所述的药材重量配比取药材； b)将当归、 川芎、 白芍和元胡分别用乙醇提取制备提取液， 然后合并 待用； 或在上述四种药材的混合物中加入乙醇， 加热回流进行提取， 提取液 储存备用；
c) 将上一步骤的药渣与除钩藤外的其余五味药材加水煎煮多次， 在最 后一次煎煮时加入钩藤， 合并所得到的煎液， 浓缩；
d) 所得到的浓缩煎液加乙醇沉淀， 上清液与回流液合并， 浓缩并回收 乙醇得到浸膏形式的组合物； 和
e) 将所获得的提取物加入适当辅料制成所需的药物制剂。
12、 如权利要求 11所述组合物的制备方法， 其中步骤 b是在当归、 川 芎、 白芍和元胡的混合物中加入乙醇， 加热回流进行提取； 以及步骤 c是将 步骤 b的药渣与除钩藤外的其余五味加水煎煮三次， 在第三煎时加入钩藤， 每一次煎煮的时间为 0.5〜1.5小时； 浓縮合并的煎液， 得到的浸膏在 55Ό下 的相对密度为 1.09〜1.13。
13、 如权利要求 12所述组合物的制备方法， 其中步骤 b中使用的乙醇 浓度为 60%~80% (v/v)， 每次回流时间为 0.5~1.5小时； 步骤 d中所加入乙 醇的浓度是使最后的含醇量达到 60%~70% (v/v); 最后浓缩得到的浸膏在 55°C下的相对密度为大约 1.15。
14、 如权利要求 13所述组合物的制备方法， 其中步骤 b中使用的乙醇 浓度为大约 70% (v/v); 步骤 d中所加入乙醇的浓度是使最后的含醇量达到 大约 65% (v/v)0
15、 如权利要求 11所述组合物的制备方法， 其中所得到的浸膏可采用 喷雾干燥法进行干燥， 得到浸膏粉。
16、 如权利要求 11-15任意一项所述组合物的制备方法， 其中所述的药 物制剂是丸剂。
17、 如权利要求 16所述组合物的制备方法， 其中所述的丸剂是薄膜包 衣的丸剂。
18、 如权利要求 17所述组合物的制备方法， 其中所述的薄膜包衣丸剂 的薄膜包衣选用胃溶型包衣材料， 包衣条件如下： 选用水为溶解剂； 包衣液 浓度为 14-20% (w/w), 包衣增重 2%-6%， 进风温度 40-90 °C， 片床温度 40-70°C， 雾化压力 1.5-2.5bar， 包衣锅转速 15-20rmp, 进料流速 2-4g/min。
19、 如权利要求 18所述组合物的制备方法， 其中所述的包衣条件如下: 选用水为溶解剂； 包衣液浓度 18% (w/w); 包衣增重 4%; 进风温度为 65Ό ; 片床温度为 43 °C； 雾化压力 2.0ba 包衣锅转速 17rmp; 进料流速 3g/min。
20、 按照权利要求 1-10任意一项的组合物用于制备治疗头痛的药物。
PCT/CN2006/002135 2005-08-24 2006-08-22 Compositions a base de medecine chinoise pour le traitement de cephalees, formulations et procedes de preparation WO2007022710A1 (fr)

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JP2008527290A JP5162457B2 (ja) 2005-08-24 2006-08-22 頭痛を治療するための漢方薬組成物、製剤及びそれを製造する方法。
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