WO2023109574A1 - 一种治疗甲状腺癌的中药组合物及其制备方法 - Google Patents

一种治疗甲状腺癌的中药组合物及其制备方法 Download PDF

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WO2023109574A1
WO2023109574A1 PCT/CN2022/136850 CN2022136850W WO2023109574A1 WO 2023109574 A1 WO2023109574 A1 WO 2023109574A1 CN 2022136850 W CN2022136850 W CN 2022136850W WO 2023109574 A1 WO2023109574 A1 WO 2023109574A1
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parts
atractylodes
chinese medicine
preparation
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French (fr)
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葛明华
谭卓
李清林
黄萍
潘宗富
徐加杰
刘宇佳
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浙江省人民医院
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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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • 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
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • 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)
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/284—Atractylodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/536—Prunella or Brunella (selfheal)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/888—Araceae (Arum family), e.g. caladium, calla lily or skunk cabbage
    • A61K36/8884—Arisaema, e.g. Jack in the pulpit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/888—Araceae (Arum family), e.g. caladium, calla lily or skunk cabbage
    • A61K36/8888—Pinellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8966—Fritillaria, e.g. checker lily or mission bells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization

Definitions

  • the invention relates to a traditional Chinese medicine composition and a preparation method thereof, in particular to a traditional Chinese medicine composition for treating thyroid cancer and a preparation method thereof, belonging to the field of traditional Chinese medicines.
  • Thyroid cancer is the most common malignant tumor of the thyroid gland. In recent years, the incidence of thyroid cancer has increased significantly, especially in coastal cities. Young adults are a high-risk group for thyroid cancer, and there are more women than men, with a male to female ratio of 1:3. The reason why there are more women than men in thyroid cancer is related to the physiological functions of the thyroid gland.
  • thyroid cancer In the early stage of thyroid cancer, there are usually no obvious symptoms, only a mass appears in the thyroid tissue, which often gradually increases, the surface is uneven, the texture is hard, and the up and down movement of the mass decreases when swallowing; in the late stage, compression symptoms and distant metastasis may appear, such as compression of the recurrent laryngeal nerve and trachea, hoarseness and dyspnea can occur, and compression of the cervical sympathetic ganglion can produce Horner syndrome.
  • the vast majority of thyroid cancers originate from follicular epithelial cells, including papillary carcinoma, follicular adenocarcinoma, undifferentiated carcinoma, and medullary carcinoma from parafollicular cells.
  • Papillary carcinoma has a relatively good prognosis and multiple For young people, the survival rate is above 90%.
  • Follicular adenocarcinoma tumors grow rapidly, are moderately malignant, and easily metastasize via blood supply; undifferentiated carcinoma has a poor prognosis, with an average survival time of 3-6 months.
  • thyroid cancer is generally based on surgical treatment, combined with adjuvant chemotherapy, radiotherapy for differentiated cancer, and targeted therapy has also been normalized.
  • Western medicine alone has a better overall prognosis for various types of thyroid cancer, it is still There is a high recurrence rate, and symptoms such as recurrent laryngeal nerve injury, postoperative chylous fistula, hemorrhage, and tracheal collapse are prone to occur after surgery.
  • Chemotherapy drugs are highly toxic. While killing tumor cells, they also non-selectively kill white blood cells, lymphocytes and other human immune cells. As a result, patients often suffer from infection due to low autoimmunity. High, there are greater limitations in clinical use.
  • Thyroid cancer belongs to the category of "gall" in traditional Chinese medicine. Emotional internal injury and improper diet are the two main causes of thyroid cancer. Qi stagnation, phlegm coagulation, and blood stasis in front of the neck are the basic etiology and pathogenesis of gall. In the early stage of the disease, it is mostly stagnation of qi, condensed phlegm gathers, phlegm qi beats in front of the neck, and blood stasis can be caused for a long time.
  • Traditional Chinese medicine can regulate the patient's physique as a whole while treating the primary disease. It has the advantages of comprehensive curative effect, few adverse reactions, and few contraindications. Traditional Chinese medicine plays an important role in reducing the adverse reactions of thyroid cancer radiotherapy and surgery, improving the quality of life of patients and comprehensive treatment.
  • the object of the present invention is to provide a traditional Chinese medicine composition for the treatment of thyroid cancer
  • said traditional Chinese medicine composition is composed of 9 raw medicinal materials of Radix Astragali, Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizome, Poria cocos, Radix Paeoniae Alba, Zhinanxing, Fritillaria fritillaria, Pinellia, Orchid Butterfly, and Prunella vulgaris It is prepared and has the effects of invigorating the spleen and replenishing qi, drying dampness and resolving phlegm, softening hard masses and resolving stagnation, and can be used for the treatment of thyroid cancer with remarkable effect.
  • a traditional Chinese medicine composition for treating thyroid cancer which is made of the following traditional Chinese medicine components in parts by weight:
  • the Chinese medicine composition is made of the following Chinese medicine components in parts by weight:
  • Astragalus membranaceus is sweet and slightly warm, and has the effects of invigorating qi and promoting yang, benefiting the body, promoting diuresis and reducing swelling;
  • the effect of invigorating the spleen and replenishing qi, diuresis and expelling dampness is enhanced, and the two are combined into a monarch drug.
  • Pinellia pungent and warm, can dry dampness and resolve phlegm, eliminate swelling and dissipate stagnation;
  • Zhinanxing is bitter and cool in nature, can clear away heat and phlegm, dispel wind and relieve convulsions; Fritillaria fritillaria is bitter and cold, and returns to the lungs and heart meridians.
  • Poria cocos is sweet in taste and flat in nature, and returns to the heart, lung, spleen, and kidney meridians, which can diuresis and dampness, invigorates the spleen and stomach, calms the heart and calms the nerves; Concentrating blood and relieving pain; combined with Poria cocos, it can nourish blood and soften the liver, dry dampness and invigorate the spleen, and is an adjuvant drug.
  • Prunella vulgaris tastes bitter, pungent and cold, and has the effect of dispelling stagnation and detoxification; Butterfly is bitter, sweet, and cool, and returns to the lung, liver, and stomach meridian, which can clear away heat and relieve phlegm; the combination of the above two herbs can clear the lung and relieve pharynx , soothe the liver and stomach, is to make medicine.
  • Another object of the present invention is to provide a Chinese medicine oral pharmaceutical preparation containing the above-mentioned Chinese medicine composition and a preparation method thereof, wherein the traditional Chinese medicine oral pharmaceutical preparation is oral liquid, mixture, granule, microcapsule, capsule, pill and tablet One of.
  • the preparation method of described traditional Chinese medicine oral pharmaceutical preparation comprises the following steps:
  • step B Weigh the decoction pieces of the raw materials of step A according to the prescription, mix them evenly, add 6-10 times the amount of water to decoct 2-3 times, decoct for 1-3 hours each time, filter the decoction, concentrate under reduced pressure, Get the extract I, set aside;
  • step C Add ethanol to the extract I obtained in step B, let stand for cooling, filter, recover the ethanol from the filtrate and concentrate to obtain extract II, and set aside;
  • step D Take the extract II of step C, and add pharmaceutically acceptable excipients according to the conventional process to make an oral pharmaceutical preparation.
  • step B add water to decoct twice in step B, first add 8-10 times the amount of water to decoct for 2-3 h, and secondly add 6-8 times the amount of water to decoct for 1-2 h.
  • the decoction in step B is concentrated under reduced pressure to extract I with a relative density of 1.12-1.18 at 50-60°C.
  • step C is concentrated under reduced pressure to extract II with a relative density of 1.20-1.30 at 50-60°C.
  • step C add ethanol to make the alcohol content reach 50%-70%, and let it stand and cool down for 24-48 h.
  • step C includes, but is not limited to, steps such as water precipitation, filtration, concentration, drying, crushing, and sieving.
  • the acceptable excipients include one or more of fillers, lubricants, preservatives, flavoring agents, disintegrants, binders, colorants, and dispersants.
  • the pharmaceutically acceptable excipients include but are not limited to lactose, starch, dextrin, powdered sugar, magnesium stearate, maltose, lemonade, tartaric acid, sodium hydroxide, aspartame, stevioside, sweetener Sucralose, protein sugar, acesulfame potassium, aspartame, sucralose, sodium benzoate, etc.
  • the traditional Chinese medicine composition is used in the preparation of medicines for treating thyroid cancer.
  • the invention provides the use of a traditional Chinese medicine composition in the preparation of drugs for treating thyroid cancer.
  • the results of pharmacodynamic experiments show that the traditional Chinese medicine composition of the invention can significantly inhibit the growth of human thyroid cancer tumors in tumor-bearing nude mice, and can significantly inhibit the growth of human thyroid cancer tumors in vitro.
  • the proliferation of thyroid cancer cells has a definite therapeutic effect on thyroid cancer, providing patients with a new choice of clinical medication, and providing a new direction for the development and utilization of Chinese medicine resources in my country.
  • step B Weigh the herbal medicine pieces of raw materials in step A according to the prescription amount, mix well, and decoct twice, add 8 times the amount of water to decoct for 3 hours for the first time, add 6 times the amount of water for decoction for 2 hours for the second time, and decoct
  • the boiled liquids were combined, filtered, and concentrated under reduced pressure to the extract I with a relative density of 1.12 at 50-60 ° C, and set aside;
  • step C Add ethanol to the extract I obtained in step B to make the alcohol content reach 70%, let it stand for 24 h, filter, recover the ethanol from the filtrate and concentrate it to extract II with a relative density of 1.20 at 50-60 ° C, and set aside;
  • step D Take the extract II of step C, add sucrose for flavoring, add purified water to make the total amount, filter until the clarity is qualified, fill, sterilize, and pack to obtain the oral liquid.
  • step B Weigh the herbal medicine pieces of raw materials in step A according to the prescription, mix well, and decoct twice. For the first time, add 10 times the amount of water to decoct for 2 hours. For the second time, add 8 times the amount of water to decoct for 1 hour. Combine the boiled liquids, filter, concentrate under reduced pressure to the extract I with a relative density of 1.15 at 50-60 °C, and set aside;
  • step C Add ethanol to the extract I obtained in step B to make the alcohol content reach 60%, let it stand for 24 h, filter, recover the ethanol from the filtrate and concentrate it to the extract II with a relative density of 1.28 at 50-60 ° C, and set aside;
  • step D Take the extract II of step C, add sodium benzoate, add purified water to prepare the total amount, filter until the clarity is qualified, fill, sterilize, and pack to obtain the mixture.
  • step B Weigh the herbal pieces of raw materials in step A according to the prescription amount, mix well, and decoct twice. For the first time, add 10 times the amount of water to decoct for 3 hours. For the second time, add 8 times the amount of water to decoct for 1 hour. The boiled liquids were combined, filtered, and concentrated under reduced pressure until the relative density was 1.18 at 50-60 ° C. Extract I, set aside;
  • step C Add ethanol to the extract I obtained in step B to make the alcohol content reach 60%, let it sit for 48 h and filter, recover the ethanol from the filtrate and concentrate it to extract II with a relative density of 1.30 at 50-60 ° C, and set aside;
  • step C extract II, in vacuum degree -0.09MPa ⁇ -0.10Mpa, vacuum-dried at 60°C, crushed into fine powder, sieved, added the formula amount of sucrose powder, dextrin, mannitol (weight ratio 3:1:1), mixed well, and used 95% ethanol made soft material, granulated, dried, granulated to obtain granules.
  • Astragalus 1.0 kg Atractylodes 1.5 kg Poria cocos 0.5 kg
  • step B Weigh the herbal pieces of raw materials in step A according to the prescription amount, mix well, and decoct twice. For the first time, add 8 times the amount of water to decoct for 2 hours. For the second time, add 6 times the amount of water to decoct for 2 hours. Combine the boiled liquids, filter, concentrate under reduced pressure until the relative density is 1.15 at 50-60 ° C, extract I, set aside;
  • step B Add ethanol to the extract I obtained in step B to make the alcohol content reach 50%, let it stand for 48 h and filter, recover the ethanol from the filtrate and concentrate it to extract II with a relative density of 1.28 at 50-60 ° C, and set aside;
  • step C extract II, dry under normal pressure at 60°C, pulverize into fine powder, sieve, add dextrin and 0.2% aspartame in the formula amount, mix well, granulate, dry, and granulate , to obtain granules.
  • step B Weigh the decoction pieces of the raw materials of step A according to the prescription, mix them evenly, and decoct 3 times. For the first time, add 10 times the amount of water to decoct for 2 hours. For the second time, add 8 times the amount of water to decoct for 2 hours. Add 6 times the amount of water three times to decoct for 1 hour, combine the decoction liquid, filter, and concentrate under reduced pressure until the relative density is 1.12 at 50-60 ° C. Extract I, set aside;
  • step B Add ethanol to the extract I obtained in step B to make the alcohol content reach 60%, let it stand for 48 h to filter, recover the ethanol from the filtrate and concentrate it to the extract II with a relative density of 1.25 at 50-60 ° C, and set aside;
  • step D the emulsion is spray-dried under the conditions of an inlet air temperature of 162 °C, a spray pressure of 0.45 MPa, and a feed rate of 22.5 mL/min, and the microcapsules are collected, cooled, and obtained.
  • step B Weigh the herbal medicine pieces of raw materials in step A according to the prescription amount, mix well, and decoct twice, add 8 times the amount of water to decoct for 3 hours for the first time, add 6 times the amount of water for decoction for 2 hours for the second time, and decoct
  • the boiled liquids were combined, filtered, and concentrated under reduced pressure until the relative density was 1.18 at 50-60 ° C. Extract I, set aside;
  • step B Add ethanol to the extract I obtained in step B to make the alcohol content reach 70%, let it sit for 24 h and filter, recover the ethanol from the filtrate and concentrate it to extract II with a relative density of 1.30 at 50-60 ° C, and set aside;
  • step C extract II, vacuum-dry at -0.09MPa ⁇ -0.10Mpa, 60°C, grind into fine powder, sieve, add appropriate amount of starch, mix evenly, add 90% ethanol solution to prepare Form into soft material, granulate, dry, granulate, add appropriate amount of magnesium stearate, mix and compress into tablets to obtain tablets.
  • step B Weigh the raw medicinal material decoction pieces of step A according to the prescription amount, mix well, and decoct 3 times. For the first time, add 9 times the amount of water to decoct for 2 hours. For the second time, add 8 times the amount of water to decoct for 1 hour. Add 7 times the amount of water to decoct for 1 hour at a time, combine the decoction liquid, filter, concentrate under reduced pressure until the relative density is 1.15 at 50-60 ° C, extract I, and set aside;
  • step B Add ethanol to the extract I obtained in step B to make the alcohol content reach 60%, let it sit for 24 h and filter, recover the ethanol from the filtrate and concentrate it to extract II with a relative density of 1.25 at 50-60 ° C, and set aside;
  • step D Take the extract II of step C, vacuum-dry it under the condition of vacuum degree -0.09MPa ⁇ -0.10Mpa, 60°C, pulverize into fine powder, sieve, add the formula amount of starch, micropowder silica gel, low-substituted hydroxypropyl Cellulose (weight ratio 2:1:1), mixed, granulated, dried, granulated, filled, polished in a grinder, and broken capsules were removed to obtain the product.
  • step B Weigh the herbal pieces of raw materials in step A according to the prescription, mix well, and decoct twice. For the first time, add 9 times the amount of water and decoct for 3 hours. For the second time, add 7 times the amount of water and decoct for 2 hours. The liquids were combined, filtered, and concentrated under reduced pressure until the relative density was 1.18 at 50-60 ° C. The extract I was set aside;
  • step B Add ethanol to the extract I obtained in step B to make the alcohol content reach 50%, let it sit for 48 h and filter, recover the ethanol from the filtrate and concentrate it to extract II with a relative density of 1.30 at 50-60 ° C, and set aside;
  • step D Take the extract II of step C, carry out belt vacuum drying at a vacuum degree of -0.09MPa ⁇ -0.10Mpa, and 60°C, pulverize into fine powder, sieve, add starch and microcrystalline cellulose (weight Ratio 5:1), mixed, granulated, dried, granulated, filled, polished in a grinder, and broken capsules were removed to obtain the product.
  • step B Weigh the herbal pieces of raw materials in step A according to the prescription amount, mix well, and decoct twice. For the first time, add 10 times the amount of water to decoct for 3 hours. For the second time, add 8 times the amount of water to decoct for 1 hour. The boiled liquids were combined, filtered, and concentrated under reduced pressure until the relative density was 1.18 at 50-60 ° C. Extract I, set aside;
  • step C Add ethanol to the extract I obtained in step B to make the alcohol content reach 60%, let it sit for 48 h and filter, recover the ethanol from the filtrate and concentrate it to extract II with a relative density of 1.30 at 50-60 ° C, and set aside;
  • step C Take step C extract II, vacuum-dry at -0.09MPa ⁇ -0.10Mpa, 60°C, pulverize into fine powder, sieve, add sucrose powder, dextrin, mannitol (weight Ratio 3:1:1), mix well, use 95% ethanol to make soft material, granulate, dry, and granulate to obtain granules.
  • step B Weigh the decoction pieces of the raw materials of step A according to the prescription, mix well, and decoct 3 times. For the first time, add 8 times the amount of water to decoct for 3 hours, and for the second time, add 6 times the amount of water to decoct for 2 hours. Add 6 times the amount of water three times to decoct for 1 hour, combine the decoction liquid, filter, and concentrate under reduced pressure until the relative density is 1.18 at 50-60 ° C. Extract I, set aside;
  • step B Add ethanol to the extract I obtained in step B to make the alcohol content reach 70%, let it stand for 48 h to filter, recover the ethanol from the filtrate and concentrate it to extract II with a relative density of 1.26 at 50-60 ° C, and set aside;
  • step C Take step C extract II, vacuum-dry at -0.09MPa ⁇ -0.10Mpa, 60°C, grind into fine powder, sieve, add dextrin, mix well, make pellets, dry, coat , polished, that is, pills.
  • Test case 1 Anti-thyroid cancer effect study in vivo
  • the inventors have carried out extensive pharmacodynamic studies. It should be noted that the medicines selected in the pharmacodynamic test of the present invention are the medicines obtained from the representative formula and the preparation method of the present invention, and the tests and results of the medicines obtained from other formulas and preparation methods included in the present invention , due to space limitations, are not exhaustive here.
  • mice BALB/c nude mice, male, 6-8 weeks old, weighing 18-20 g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., license number: SYXK (Beijing) 2019-0025.
  • Human thyroid cancer cells TT cells were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences.
  • test drug is a granule sample prepared according to the formula and preparation method under Example 3; Adriamycin (specification: 10mg/bottle, batch number: 16002713), Produced by Hisun-Pfizer Pharmaceutical Co., Ltd.; F12 medium (containing 10% fetal bovine serum), produced by Gibco, USA.
  • TT cells were cultured with F12 containing 10% fetal bovine serum in an incubator at 37°C, saturated humidity, and 5% CO 2 . After 4 days of culture, the cells were subcultured, and the logarithmic phase cells in good condition after recovery were collected and centrifuged, and a cell suspension of 1 ⁇ 10 7 cells/mL was prepared with normal saline.
  • mice Fifty BALB/c nude mice were randomly divided into model group, control group and test group (low dose, medium dose and high dose), 10 in each group, and the mice in each group were subcutaneously injected with thyroid cancer TT cell suspension 0.1 mL (approximately 1 ⁇ 10 6 ), observe the growth of subcutaneously transplanted tumors in nude mice every day, and perform related experiments when the tumor volume grows to 80 mm 3 .
  • the human clinical dose of the test drug is 1.45g crude drug/kg, and rats in the test high, medium and low dose groups were given 4.50g/kg, 8.99 g crude drug/kg, and 17.98 g/kg by intragastric administration, respectively, which are equivalent to those commonly used in adult clinical practice. 2, 1, and 1/2 times the crude drug amount of the equivalent traditional Chinese medicine composition; the control group was given doxorubicin 20 mg/kg tail vein injection, and the model group was given tail vein injection of 0.9% normal saline 100 ⁇ L, drug intervention once every 2 days , were continuously intervened for 20 days.
  • SI spleen index
  • the tumor volume ratios of the mice in the test group and the control group were decreased on the 7th, 14th, and 21st day of intervention ( P ⁇ 0.05); There was no statistical difference in the tumor volume ratio ( P > 0.05), see Table 1.
  • the SI (spleen index) of the mice in the control group decreased ( P ⁇ 0.05), and the SI of the mice in the test group increased in a dose-dependent manner ( P ⁇ 0.05);
  • the proliferative activity of T cells and B cells in the mice in the control group decreased ( P ⁇ 0.05), and the proliferative activities of T cells and B cells in the mice in the experimental group increased in a dose-dependent manner ( P ⁇ 0.05), as shown in Table 2.
  • TT cells were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences.
  • Ultra-clean workbench Suzhou Purification Equipment Co., Ltd. (model SW-CJ-IFD); CO2 incubator, SANYO (model XD-101); Mode-550 automatic microplate reader, American Bio-Rad company; DMSO (Dijiao sulfoxide, specification: 100 ml), Sigma Company of the United States; the test drug is a granule sample prepared according to the formula and preparation method under Example 3; doxorubicin (specification: 10mg/bottle, batch number: 16002713) , produced by Hisun Pfizer Pharmaceutical Co., Ltd.; F12 medium (containing 10% fetal bovine serum), produced by Gibco, USA.
  • TT cells were made into a cell suspension with a concentration of 5 ⁇ 10 cells/mL, and 100 ⁇ L of the TT cells were added to a 96-well plate The cell suspension was then placed in a 37°C, 5% CO 2 incubator for 24 h; the drug was diluted with incomplete medium to the required gradient concentration, and 100 ⁇ L of the corresponding culture solution containing the test drug was added to each well (The tested drug was derived from the granules prepared in Example 3, and the contents of the crude drug in the low, medium, and high dose groups were 0.14 g/mL, 0.28 g/mL, and 0.56 g/mL, respectively), and a blank control group (100 ⁇ L without Drug-containing incomplete medium) and vehicle group (100 ⁇ L 10% DMSO), and then the 96-well plate was placed in a 37°C, 5% CO 2 incubator
  • each test group had a stronger inhibitory effect on TT cells, and each dose group showed a better dose-effect relationship.

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Abstract

一种治疗甲状腺癌的中药组合物及其制备方法。所述中药组合物由黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材制备而成，具有健脾益气，燥湿化痰，软坚散结之功效。该中药组合物能明显抑制荷瘤裸鼠体内人甲状腺癌肿瘤的生长，并明显抑制体外甲状腺癌细胞的增殖，对甲状腺癌具有治疗作用。

Description

一种治疗甲状腺癌的中药组合物及其制备方法 技术领域
本发明涉及一种中药组合物及其制备方法，尤其涉及一种治疗甲状腺癌的中药组合物及其制备方法，属于中药领域。
 背景技术
甲状腺癌是甲状腺最常见的恶性肿瘤，近年来，甲状腺癌的发病率明显上升，尤其是在沿海城市。青壮年是甲状腺癌的高发人群，且女性多于男性，男女比例为1∶3。甲状腺癌之所以出现女多男少的特点，与甲状腺承担的生理功能有关。
甲状腺癌初期多无明显症状，仅在甲状腺组织内出现肿块，常逐渐增大，表面不平，质地硬，吞咽时肿块上下移动度降低；晚期可出现压迫症状和远处转移，如压迫喉返神经和气管，可出现声音嘶哑和呼吸困难，压迫颈交感神经节可产生Horner综合征。绝大部分甲状腺癌起源于滤泡上皮细胞，包括乳头状癌、滤泡状腺癌，未分化癌，还有来自于滤泡旁细胞的髓样癌，乳头状癌的预后相对较好，多发于年轻人，生存率在90%以上；滤泡状腺癌肿瘤生长较快，属中度恶性，易经血运转移；未分化癌预后很差，平均存活时间3-6个月。
 技术问题
目前，临床上治疗甲状腺癌一般以手术治疗为主，配合辅助化疗，分化癌可行放射治疗，靶向治疗也已常态化，单纯西医治疗甲状腺各种类型癌症虽有较好的总体预后，但仍有较高复发率，且手术后易并发喉返神经损伤、术后乳糜瘘、出血、气管塌陷等症状。化疗药物毒性大，在杀死肿瘤细胞的同时也无选择性的杀死白细胞、淋巴细胞等人体自身免疫细胞，导致病人常常由于因自身免疫能力低下并发感染，不良反应大，且疗程长、费用高，在临床使用中有较大的局限性。
近年来，中医药治疗甲状腺癌的临床经验不断丰富，并已取得一定的临床效果。甲状腺癌属中医学“瘿瘤”范畴，情志内伤、饮食失宜是导致甲状腺癌的两大主要病因，气滞、痰凝、血瘀壅结颈前是瘿病的基本病因病机。本病初期多为气机郁滞，津凝痰聚，痰气搏结颈前，日久则可引起血脉瘀阻。中医药在治疗原发病的同时又可整体调节患者的体质，具有疗效全面、不良反应少、禁忌症少的优点。中医药在减轻甲状腺癌放疗及手术治疗的不良反应、改善患者的生存质量及综合施治方面均具有重要的作用。
 技术解决方案
本发明的目的是提供一种治疗甲状腺癌的中药组合物，所述中药组合物由黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材制备而成，具有健脾益气，燥湿化痰，软坚散结之功效，可用于甲状腺癌的治疗，效果显著。
 本发明的实施方式
一种治疗甲状腺癌的中药组合物，由下列重量份的中药组分制成：
黄芪10-20重量份           白术5-15重量份             茯苓5-15重量份
白芍5-15重量份             制南星5-15重量份         浙贝母5-15重量份
半夏5-15重量份             木蝴蝶3-9重量份           夏枯草5-15重量份。
优选地，所述中药组合物由下列重量份的中药组分制成：
黄芪15重量份                白术9重量份                  茯苓9重量份
白芍9重量份                  制南星9重量份              浙贝母9重量份
半夏9重量份                  木蝴蝶9重量份              夏枯草9重量份。
方中，黄芪味甘、微温，具有补气升阳、益卫固表、利水退肿之功效；白术味苦，甘，性温，可补气健脾、燥湿利水；黄芪、白术协同增效，健脾益气、利水渗湿功效增强，两者合为君药。半夏，辛、温，可以燥湿化痰、消痞散结；制南星性味苦、凉，能够清化热痰、祛风止痉；浙贝母味苦，寒，归肺、心经，能够清热化痰，散结消痈；以上3味药相须为用，共奏燥湿化痰、软坚散结之功，共为臣药。茯苓味甘、性平，归心、肺、脾、肾经，可利水渗湿，健脾和胃，宁心安神；白芍味甘、辛，性温，归肝、脾、肾经，具有养血敛阴，缓急止痛之功效；与茯苓合用可发挥养血柔肝，燥湿健脾的作用，为佐药。夏枯草味苦，辛、寒，具有散结解毒的功效；木蝴蝶味苦、甘，凉，归肺、肝、胃经，可以清热利咽化痰；以上2味药合用可清肺利咽，疏肝和胃，是为使药。
上述黄芪、白术等9味中药，依据中医“君臣佐使”配伍理论组方配伍，诸药相合，协同增效，共奏健脾益气，燥湿化痰，软坚散结，养阴清热之功，用于治疗甲状腺癌，多获良效。
本发明的另一个目的是提供一种含有上述中药组合物的中药口服药物制剂及其制备方法，所述中药口服药物制剂为口服液、合剂、颗粒剂、微囊、胶囊剂、丸剂和片剂中的一种。
所述中药口服药物制剂的制备方法包括以下步骤：
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，加6-10倍量的水煎煮2-3次，每次煎煮1-3 h，煎煮液滤过，减压浓缩，得浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇，静置冷沉，滤过，滤液回收乙醇并浓缩，得浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，按照常规工艺，加入药学上可接受的辅料制成口服药物制剂。
优选地，步骤B中加水煎煮2次，第一次加8-10倍量的水煎煮2-3 h，第二次加6-8倍量的水煎煮1-2 h。
优选地，步骤B煎煮液减压浓缩至50-60 ℃时相对密度为1.12-1.18的浸膏Ⅰ。
优选地，步骤C减压浓缩至50-60 ℃时相对密度为1.20-1.30的浸膏Ⅱ。
优选地，步骤C加乙醇使醇含量达50%-70%，静置冷沉24 -48 h。
步骤C所述常规工艺包括但不限于水沉、过滤、浓缩、干燥、粉碎、过筛等步骤。
优选地，所述的可接受的赋形剂包括填充剂、润滑剂、防腐剂、矫味剂、崩解剂、粘合剂、着色剂、分散剂中的一种或几种。
优选地，所述药学上可接受的辅料包括但不限于乳糖、淀粉、糊精、糖粉、硬脂酸镁、麦芽糖、柠檬水、酒石酸、氢氧化钠、阿斯巴甜、甜菊苷、甜蜜素、蛋白糖、乙酰磺氨酸钾、阿司帕坦、三氯蔗糖、苯甲酸钠等。
所述的中药组合物在制备治疗甲状腺癌疾病的药物用途。
本发明提供了一种中药组合物在制备治疗甲状腺癌药物中的用途，药效学实验结果显示，本发明中药组合物能明显抑制荷瘤裸鼠体内人甲状腺癌肿瘤的生长，并明显抑制体外甲状腺癌细胞的增值，对甲状腺癌有确切的治疗作用，为患者提供了新的临床用药选择，为我国中药资源的开发利用提供了新的方向。
具体实施方式
为了使本领域技术人员充分了解本发明，以下通过具体的实施例进一步说明本发明，但本领域技术人员应该知晓，本发明实施例并不以任何方式限制本发明。
实施例 1  口服液的制备
黄芪1.5 kg         白术0.9 kg                茯苓0.9 kg
白芍0.9 kg         制南星0.9 kg            浙贝母0.9 kg
半夏0.9 kg         木蝴蝶0.9 kg            夏枯草0.9 kg
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮2次，第一次加入8倍量的水煎煮3 h，第二次加入6倍量的水煎煮2 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.12的浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达70%，静置冷沉24 h，滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.20的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，加入蔗糖进行矫味，加纯化水至配制总量，过滤至澄清度合格后，灌装，灭菌，包装，即得口服液。
实施例 2  合剂的制备
黄芪2.0 kg                白术0.5 kg                茯苓1.5 kg
白芍0.5 kg                制南星1.5 kg            浙贝母0.5 kg
半夏1.5 kg                木蝴蝶0.6 kg            夏枯草1.5 kg
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮2次，第一次加入10倍量的水煎煮2 h，第二次加入8倍量的水煎煮1 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.15的浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达60%，静置冷沉24 h，滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.28的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，加入苯甲酸钠，加纯化水至配制总量，过滤至澄清度合格后，灌装，灭菌，包装，即得合剂。
实施例 3  颗粒剂的制备
黄芪1.5 kg             白术0.9 kg                茯苓0.9 kg
白芍0.9 kg             制南星0.9 kg            浙贝母0.9 kg
半夏0.9 kg             木蝴蝶0.9kg             夏枯草0.9 kg
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮2次，第一次加入10倍量的水煎煮3 h，第二次加入8倍量的水煎煮1 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.18浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达60%，静置冷沉48 h滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.30的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，在真空度 -0.09MPa~-0.10Mpa，60 ℃条件下进行真空干燥，粉碎成细粉，过筛，加入配方量的蔗糖粉、糊精、甘露醇（重量比3∶1∶1），混匀，用95%乙醇制软材，制粒，干燥，整粒，即得颗粒剂。
实施例 4  颗粒剂的制备
黄芪1.0 kg                白术1.5 kg                茯苓0.5 kg
白芍1.5 kg                制南星0.5 kg            浙贝母1.5 kg
半夏0.5 kg                木蝴蝶0.5 kg            夏枯草0.5 kg
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮2次，第一次加入8倍量的水煎煮2 h，第二次加入6倍量的水煎煮2 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.15浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达50%，静置冷沉48 h滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.28的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，60 ℃条件下进行常压干燥，粉碎成细粉，过筛，加入配方量的糊精和0.2%阿司帕坦，混匀，制粒，干燥，整粒，即得颗粒剂。
实施例 5  微囊的制备
黄芪1.4 kg                白术1.0 kg                茯苓0.8 kg
白芍1.0 kg                制南星0.8 kg            浙贝母1.0 kg
半夏0.8 kg                木蝴蝶0.7 kg            夏枯草0.8 kg
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮3次，第一次加入10倍量的水煎煮2 h，第二次加入8倍量的水煎煮2 h，第三次加入6倍量的水煎煮1 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.12浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达60%，静置冷沉48 h滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.25的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，在真空度 -0.09MPa~-0.10Mpa，60 ℃条件下进行真空干燥，粉碎成细粉，以质量比络蛋白酸钠：麦芽糊精=3∶2混合物为囊材，以质量比十八醇：二氧化钛=3∶1为抗粘剂，以质量比聚乙二醇：柠檬酸=3∶1为增塑剂，将上述囊材、抗粘剂和增塑剂加入纯化水，55 ℃条件下加热搅拌使溶解，配制成质量分数为34%的囊材溶液，冷却至室温，搅拌状态下加入提取物细粉，加入制剂配方总量的1.1%蔗糖脂肪酸酯：大豆磷脂=8∶5的复合乳化剂，均质乳化，得乳化液，备用；
E、步骤D乳化液在进风温度162 ℃、喷雾压力0.45 MPa、进料速度22.5 mL/min条件下进行喷雾干燥，收集微囊，冷却，即得。
实施例 6  片剂的制备
黄芪1.8 kg                白术0.8 kg                茯苓1.2 kg
白芍0.8 kg                制南星1.3 kg            浙贝母0.8 kg
半夏1.2 kg                木蝴蝶0.8kg             夏枯草1.2 kg
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮2次，第一次加入8倍量的水煎煮3 h，第二次加入6倍量的水煎煮2 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.18浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达70%，静置冷沉24 h滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.30的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，在真空度-0.09MPa~-0.10Mpa，60 ℃条件下进行真空干燥，粉碎成细粉，过筛，加入适量淀粉，混合均匀，加入90%的乙醇溶液制成软材，制粒，干燥，整粒，加入适量硬脂酸镁，混合后压片，即得片剂。
实施例 7  胶囊剂的制备
黄芪1.6 kg                白术0.8 kg                茯苓1.2 kg
白芍0.7 kg                制南星1.0 kg            浙贝母0.7 kg
半夏1.0 kg                木蝴蝶0.7 kg            夏枯草1.0 kg
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮3次，第一次加入9倍量的水煎煮2 h，第二次加入8量的水煎煮1 h，第三次加入7倍量的水煎煮1 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.15浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达60%，静置冷沉24 h滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.25的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，在真空度-0.09MPa~-0.10Mpa，60 ℃条件下进行真空干燥，粉碎成细粉，过筛，加入配方量的淀粉、微粉硅胶、低取代羟丙基纤维素（重量比2∶1∶1），混匀，制粒，干燥，整粒，灌装，磨光机中抛光，剔除破损胶囊，即得。
实施例 8  胶囊剂的制备
黄芪1.5 kg         白术0.9 kg                茯苓0.9 kg
白芍0.9 kg         制南星0.9 kg            浙贝母0.9 kg
半夏0.9 kg         木蝴蝶0.4kg             夏枯草0.9 kg
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮2次，第一次加入9倍量的水煎煮3 h，第二次加入7倍量水煎煮2 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.18浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达50%，静置冷沉48 h滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.30的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，在真空度-0.09MPa~-0.10Mpa，60 ℃条件下进行带式真空干燥，粉碎成细粉，过筛，加入配方量的淀粉、微晶纤维素（重量比5∶1），混匀，制粒，干燥，整粒，灌装，磨光机中抛光，剔除破损胶囊，即得。
实施例 9  颗粒剂的制备
黄芪1.5 kg             白术0.9 kg                茯苓0.9 kg
白芍0.9 kg             制南星0.9 kg            浙贝母0.9 kg
半夏0.9 kg             木蝴蝶0.3kg             夏枯草0.9 kg
A、取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮2次，第一次加入10倍量的水煎煮3 h，第二次加入8倍量的水煎煮1 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.18浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达60%，静置冷沉48 h滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.30的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，在真空度-0.09MPa~-0.10Mpa，60 ℃条件下进行真空干燥，粉碎成细粉，过筛，加入配方量的蔗糖粉、糊精、甘露醇（重量比3∶1∶1），混匀，用95%乙醇制软材，制粒，干燥，整粒，即得颗粒剂。
实施例 10  丸剂的制备
黄芪1.20 kg                     白术0.8 kg                茯苓1.2 kg
白芍0.8 kg                制南星1.2 kg            浙贝母0.8 kg
半夏1.2 kg                木蝴蝶0.8kg             夏枯草0.8 kg
A、取黄芪、白术、茯苓、白芍、、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
B、按处方量称取步骤A原料药材饮片，混匀，煎煮3次，第一次加入8倍量的水煎煮3 h，第二次加入6倍量的水煎煮2 h，第三次加入6倍量的水煎煮1 h，煎煮液合并，滤过，减压浓缩至50-60 ℃时相对密度为1.18浸膏Ⅰ，备用；
C、步骤B所得浸膏Ⅰ加入乙醇使含醇量达70%，静置冷沉48 h滤过，滤液回收乙醇并浓缩至50-60 ℃时相对密度为1.26的浸膏Ⅱ，备用；
D、取步骤C浸膏Ⅱ，在真空度-0.09MPa~-0.10Mpa，60 ℃条件下进行真空干燥，粉碎成细粉，过筛，加入糊精，混匀，制丸，干燥，包衣，抛光，即得丸剂。
试验例 1  体内抗甲状腺癌效果研究
为验证本发明中药组合物治疗甲状腺癌的功效，发明人开展了丰富的药效学研究。需要说明的是，本发明药效学试验所选取的药品为本发明具有代表性的配方及其制备方法所得的药品，本发明所包含的其它配方及制备方法所得药品所涉及的试验及其结果，限于篇幅，在此不一一穷举。
1 实验材料
1.1 实验动物和细胞  BALB/c裸鼠，雄性，6-8周龄，体重18-20 g，购自北京维通利华实验动物技术有限公司，许可证号：SYXK（京）2019-0025。人甲状腺癌细胞（TT细胞），购自中国科学院上海细胞生物学研究所。
1.2 仪器、试剂及药品  AG285型电子分析天平，瑞士Mettler-Toledo公司；Mode-550自动酶标仪，美国Bio-Rad公司；超净工作台，苏州净化设备有限公司（型号SW-CJ-IFD）；CO2培养箱，SANYO（型号XD-101）；受试药物为根据实施例3项下配方及制法所制得的颗粒剂样品；阿霉素（规格：10mg/支，批号：16002713），海正辉瑞制药有限公司生产；F12培养基（含10%胎牛血清），美国Gibco公司生产。
2 实验方法
2.1 细胞培养
TT细胞用含10%胎牛血清的F12培养基于37 ℃、饱和湿度、5% CO 2培养箱中培养。培养4 d后传代，将复苏培养后状态良好的对数期细胞收集后离心，用生理盐水制备成1×10 7个/mL的细胞悬液。
2.2 甲状腺癌荷瘤小鼠建模
取50只BALB/c裸鼠，随机分为模型组、对照组和试验组（低剂量、中剂量和高剂量），每组10只，各组小鼠均于皮下注射甲状腺癌TT细胞悬液0.1 mL（约1×10 6个），每日观察裸鼠皮下移植瘤生长情况，肿瘤体积长至80 mm 3时进行相关实验。
2.3 分组给药
受试药物人用临床剂量为1.45g生药/kg，试验高、中、低剂量组大鼠分别给予4.50g/kg、8.99 g生药/kg、17.98 g/kg灌胃，分别相当于成人临床常用等效中药组合物生药量的2、1和1/2倍；对照组给予阿霉素20 mg/kg尾静脉注射，模型组尾静脉注射0.9%生理盐水100 μL，每2天药物干预1次，均连续干预20天。
2.4 肿瘤生长情况
药物干预期间每日用游标卡尺测量瘤体的短径（A）和长径（B），肿瘤体积=B×A 2/2，计算肿瘤体积比=干预后肿瘤体积/干预前肿瘤体积。
2.5脾淋巴细胞增殖检测
干预结束后，无菌取出小鼠脾，精确称重后，计算脾指数（SI）=脾重（mg）/体重（g），脾称重后制成淋巴细胞单细胞悬液（严格无菌），计数后按照每孔1×10 4个细胞接种于96孔板中，以受试药物作为刺激源，48 h后进行MTT实验，并用酶标仪检测小鼠脾T、B淋巴细胞增殖水平。
3 实验结果
3.1 对甲状腺癌荷瘤小鼠肿瘤生长的影响
与模型组比较，干预第7、14、21天试验组和对照组小鼠肿瘤体积比均降低（ P＜0.05）；与对照组相比，试验中、高剂量组第7、14、21天的肿瘤体积比没有统计学差异性（ P＞0.05），见表1。
表1  各组甲状腺癌荷瘤小鼠肿瘤生长情况（ n=10）
 
Figure 685345dest_path_image001
注：与模型组相比： P＜0.05用“*”表示；与对照组相比： P＜0.05用“ ▲”表示。
3.2 对甲状腺癌荷瘤小鼠脾淋巴细胞增殖的影响
与甲状腺癌荷瘤小鼠模型组相比，对照组小鼠SI（脾指数）降低（ P＜0.05），试验组小鼠SI升高且呈剂量依赖性（ P＜0.05）；与模型组相比，对照组小鼠T细胞和B细胞增殖活性降低（ P＜0.05），试验组小鼠T细胞和B细胞增殖活性增强且呈剂量依赖性（ P＜0.05），见表2。
表2  甲状腺癌荷瘤小鼠脾淋巴细胞增殖的水平（ n=10）
组别 SI T细胞 B细胞
模型组 4.45±0.76 0.52±0.09 0.45±0.05
低剂量组 5.86±0.71* ▲ 0.61±0.04* ▲ 0.55±0.06* ▲
中剂量组 6.26±0.53* ▲ 0.68±0.05* ▲ 0.62±0.07* ▲
高剂量组 6.59±0.72* ▲ 0.72±0.07* ▲ 0.69±0.09* ▲
对照组 3.52±0.42* 0.40±0.03* 0.37±0.05*
注：与模型组相比： P＜0.05用“*”表示；与对照组相比： P＜0.05用“ ▲”表示。
试验例 2  体外抗甲状腺癌效果研究
1 实验材料
1.1 实验细胞
TT细胞，购自中国科学院上海细胞生物学研究所。
1.2 仪器、试剂及药品
超净工作台，苏州净化设备有限公司（型号SW-CJ-IFD）；CO 2培养箱，SANYO（型号XD-101）；Mode-550自动酶标仪，美国Bio-Rad公司；DMSO（二甲基亚砜，规格：100 ml），美国sigma公司；受试药物为根据实施例3项下配方及制法所制得的颗粒剂样品；阿霉素（规格：10mg/支，批号：16002713），海正辉瑞制药有限公司生产；F12培养基（含10%胎牛血清），美国Gibco公司生产。
2 实验方法
使用改良MTT法对本发明实施例3制备得到的颗粒剂进行体外抗人甲状腺癌细胞实验：将TT细胞制成浓度为5×10 4个/mL的细胞悬液，于96孔板中加入100 μL细胞悬液，然后置于37℃，5％CO 2培养箱中培养24 h；用非完全培养基稀释药物至所需的不同梯度浓度，每孔加入100 μL相应的含受试药品的培养液（受试药品来源于实施例3制备的颗粒剂，低、中、高剂量组生药含量分别为0.14 g/mL、0.28 g/mL、0.56 g/mL），同时设立空白对照组（100 μL不含药非完全培养基）和溶媒组（100 μL 10% DMSO），再将96孔板置于37℃，5％CO 2培养箱中培养72 h。然后每孔加入20 μL MTT（5 mg/mL），继续培养4 h，终止培养，弃去培养基，每孔加入150 μL的DMSO溶解，摇床10分钟轻轻混匀。用酶标仪检测每孔的吸光度即OD值，以各复孔的平均值作为该组细胞的OD值，计算各药物的抑制率。
3 实验结果
与空白对照组以及溶媒组相比，试验各组对TT细胞具有较强的抑制作用，各剂量组呈现了较好的量效关系。
表3  体外抗人甲状腺癌细胞实验结果
组别 OD 抑制率（%）
空白对照组 0.449 --
溶媒组 0.446 0.67
低剂量试验组 0.129 71.27
中剂量试验组 0.112 75.06
高剂量试验组 0.098 78.17
以上实验结果显示，本发明提供的中药组合物能够明显抑制荷瘤裸鼠体内人甲状腺癌肿瘤的生长，并明显抑制体外甲状腺癌细胞的增值，表明本发明中药组合物体内和体外均具有很强的抗甲状腺癌作用，可以用于治疗甲状腺癌。

Claims (9)

  1. 一种治疗甲状腺癌的中药组合物，其特征在于，由如下重量份的中药组分制成：
    黄芪10-20重量份     白术5-15重量份      茯苓5-15重量份
    白芍5-15重量份      制南星5-15重量份    浙贝母5-15重量份
    半夏5-15重量份      木蝴蝶3-9重量份     夏枯草5-15重量份。
  2. 根据权利要求1所述的中药组合物，其特征在于，由如下重量份的中药组分制成：
    黄芪15重量份        白术9重量份         茯苓9重量份
    白芍9重量份         制南星9重量份       浙贝母9重量份
    半夏9重量份         木蝴蝶9重量份       夏枯草9重量份。
  3. 一种由权利要求1-2任意一项所述中药组合物制成的口服药物制剂，其特征在于，所述口服药物制剂为口服液、颗粒剂、微囊、胶囊剂、丸剂或片剂中的一种。
  4. 一种权利要求3所述口服药物制剂的制备方法，其特征在于，包括如下步骤：
    A、称取黄芪、白术、茯苓、白芍、制南星、浙贝母、半夏、木蝴蝶、夏枯草9味原料药材，其中黄芪、白术、茯苓、白芍、制南星净选后切片，浙贝母、半夏粗碎，夏枯草切段，木蝴蝶净选，备用；
    B、取步骤A原料药材饮片，混匀，加6-10倍量的水煎煮2-3次，每次煎煮1-3 h，煎煮液滤过，减压浓缩，得浸膏Ⅰ，备用；
    C、步骤B所得浸膏Ⅰ加入乙醇，静置冷沉，滤过，滤液回收乙醇并浓缩，得浸膏Ⅱ，备用；
    D、取步骤C浸膏Ⅱ，按照常规工艺，加入药学上可接受的辅料制成口服药物制剂。
  5. 根据权利要求4所述的制备方法，其特征在于，步骤B加水煎煮2次，第一次加8-10倍量的水煎煮2-3 h，第二次加6-8倍量的水煎煮1-2 h。
  6. 根据权利要求4所述的制备方法，其特征在于，步骤B煎煮液减压浓缩至50-60 ℃时相对密度为1.12-1.18的浸膏Ⅰ。
  7. 根据权利要求4所述的制备方法，其特征在于，步骤C减压浓缩至50-60 ℃时相对密度为1.20-1.30的浸膏Ⅱ。
  8. 根据权利要求4所述的制备方法，其特征在于，步骤C加乙醇使醇含量达50%-70%，静置冷沉24 -48 h。
  9. 权利要求1所述的中药组合物在制备治疗甲状腺癌疾病的药物用途。
PCT/CN2022/136850 2021-12-16 2022-12-06 一种治疗甲状腺癌的中药组合物及其制备方法 WO2023109574A1 (zh)

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