WO2020010904A1 - 一种降三高含片及其制备方法 - Google Patents

一种降三高含片及其制备方法 Download PDF

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WO2020010904A1
WO2020010904A1 PCT/CN2019/085147 CN2019085147W WO2020010904A1 WO 2020010904 A1 WO2020010904 A1 WO 2020010904A1 CN 2019085147 W CN2019085147 W CN 2019085147W WO 2020010904 A1 WO2020010904 A1 WO 2020010904A1
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parts
luo han
lozenge
powder
han guo
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French (fr)
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张芝庭
张涛涛
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贵州神奇药业有限公司
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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)
    • A61K36/46—Eucommiaceae (Eucommia family), e.g. hardy rubber tree
    • 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)
    • A61K36/42—Cucurbitaceae (Cucumber family)
    • 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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to a lozenge and a manufacturing method thereof, in particular to a Jiangsan high lozenge and a preparation method thereof.
  • Ilex kudingcha contains more than 200 ingredients such as Ilex saponin, amino acids, vitamin C, polyphenols, flavonoids, caffeine, and protein. It can regulate the metabolism of the body in two ways, enhance the immune function of the human body, significantly reduce the serum total cholesterol, triglycerides and low-density lipoproteins of patients with hyperlipidemia. It has the functions of clearing throat and clearing throat, clearing heat and detoxifying, protecting the liver and wine, and reducing inflammation and convenience. It also has obvious prevention and cure effect on hypertension, hyperlipidemia, arteriosclerosis, diabetes, obesity, colitis, constipation, hemorrhoids and various oral inflammations.
  • Eucommia ulmoides leaves are slightly bitter, warm, and mainly contain Eucommia chlorogenic acid, eucommia gum and so on. It has the effects of nourishing liver and kidney, strengthening bones and bones, lowering blood pressure, regulating blood lipids, preventing and treating osteoporosis, lowering blood sugar, sedating and soothe the nerves, anti-fatigue, analgesic, improving immunity, anti-inflammatory, promoting glucose metabolism, anti-aging, and inhibiting uterine excitement.
  • eucommia chlorogenic acid has pharmacological effects such as antibacterial, anti-inflammatory, detoxification, choleretic, lowering blood pressure and increasing white blood cells, significantly increasing gastrointestinal motility and promoting gastric secretion, and has strong effects on E. coli, Staphylococcus aureus, pneumococcus and virus. Inhibitory effect.
  • Eucommia ulmoides double-lowering foaming agent is made of Eucommia ulmoides leaves and Kuding tea. It is included in the Twelfth Book of Chinese Medicine Formulations of the Ministry of Health. It is used to lower blood pressure and blood lipids, but the existing products are prepared by boiling in water. The preparation process is only boiling water, and the kuding tea is partially crushed and directly used as medicine. This simple processing results in the bitterness of Eucommia ulmoides leaves and the thickness of Eucommia ulmoides.
  • a kuding tea sugar-free buccal tablet and its preparation method disclose Kuding tea, Eucommia ulmoides leaves and Lozenges made from nine kinds of medicinal materials, such as pueraria root, castor leaf, gypenoside, salvia miltiorrhiza, osmanthus, etc., but the preparation process of this product only uses simple water extraction and alcohol precipitation.
  • the patent introduces that the product focuses on clearing away heat and reducing heat, Shengjinzhike, anti-aging and other effects, but its actual effect is unknown.
  • Luo Han Guo contains Luo Han Guo glycosides, a variety of amino acids and vitamins and other medicinal ingredients. It treats lung heat, phlegm, fire, cough, sore throat, tonsillitis, acute gastritis, and constipation. Mogroside is also known as sweetener 300 times sweeter than sucrose. Because of its high sweetness and low calorie, it is widely used as a sweetener and is the best substitute for sucrose. It is often used as a substitute sugar for obese people and diabetic patients. It has significant effects on bronchitis, hypertension and other diseases, and still plays a role in preventing and treating coronary heart disease, vascular sclerosis and obesity. Therefore, using Luo Han Guo as a sweetener and sugar in oral preparations is an ideal substitute for auxiliaries such as mannitol, which is not only beneficial to the three high populations, but also exerts its own effects.
  • auxiliaries such as mannitol
  • the present invention provides a series of Jiang San Gao Tablets and a method for preparing the same after a large number of formula screening and verification, which is suitable for patients with hypertension, hyperlipidemia, and hyperglycemia. Play a role in relieving symptoms.
  • the present invention provides the following technical solutions:
  • a type of Jiang San Gao lozenge characterized in that by weight parts, it consists of 400-600 parts of Eucommia ulmoides leaves, 150-250 parts of Kuding tea, 5-15 parts of Luo Han Guo extract, 2.5-7.5 parts of Luo Han Huo powder, paste 10-20 parts of refined, 3-7 parts of isomalt, 2-6 parts of CMS-Na, 1-4 parts of magnesium stearate.
  • 450 parts of Eucommia ulmoides leaves 200 parts of Kuding tea, 10 parts of Luo Han Guo extract, 5 parts of Luo Han Huo powder, 15 parts of dextrin, 5 parts of isomalt, 5 parts of CMS-Na, hard Made from 2 parts of magnesium stearate.
  • the invention also provides a method for preparing Jiangsan high lozenges including the following steps: pretreatment of Luo Han Guo, Kuding tea, Eucommia ulmoides leaves, and the preparation steps of lozenges.
  • the Luo Han Guo pretreatment includes the following steps:
  • the pretreatment of Kudingcha and Eucommia leaves is that the Kudingcha and Eucommia leaves are washed, dried, and mixed separately.
  • the mixed raw materials are crushed and added with 10-15 times water. After boiling, they are extracted at 90-100 ° C for 3-4 hours. After centrifugation at 4500-5000r / min for 10-20min, take the supernatant, obtain the filter residue, repeat the extraction and filtration twice in the same steps, combine the supernatants, and concentrate the combined supernatants to the original mixed extract volume 1 / 10-1 / 20, the concentrated liquid is spray-dried to obtain a mixed extract powder.
  • the preparation of the tablet includes the following steps:
  • spray drying granulation uses an aqueous solution of sodium carboxymethyl starch as a binder, the solution concentration is 2% to 6%, the liquid supply rate is 10 to 30ml / min, the bed temperature is 40 to 70 ° C, and the compression pressure is 0.15 ⁇ 0.25MPa, spray granulation time is 40-80min.
  • the granulation process is as follows: adding all the components together into a spray-drying granulator, fluidizing and realizing powder mixing, the spraying device is started, and the mist drops on the powder during the continuous spraying process of 40-80min The process of agglomeration and growth occurs in vivo until the desired particle size stops spraying. Finally, all the granulated products are continuously fluidized and dried in the same container to obtain a granulated end product.
  • the husk powder obtained by the pretreatment of Luo Han Guo is placed under a microwave condition with a power of 100-200W for 5-10s, and then X-rays are irradiated for 5-10s.
  • the Luo Han Guo extract obtained by pre-treatment of Luo Han Guo is placed in a reactor, and a mixed gas is charged into the reactor at a flow rate of 5-8 mol / min for 120-180 s; wherein the mixed gas is nitrogen monoxide and nitrogen
  • the molar ratio is 1: (2-4).
  • the pretreatment product of Kuding tea and Eucommia ulmoides leaves is pumped to a pulse electric field processing chamber at a flow rate of 80-100 mL / min through a peristaltic pump with an electric field intensity of 200-228 V / cm, a pulse frequency of 30-40 Hz, The pulse time is 4-6s.
  • the beneficial effects of the present invention are as follows: 1.
  • the present invention replaces Luo Han Guo extract and Luo Han Huo powder with sucrose, honey, mannitol and other sweeteners that are not suitable for the three high populations, and reduces the use of dextrin, making the product suitable for use. Food for the elderly, pregnant women, people with three highs, etc. 2.
  • using repeated extraction and centrifugation of Eucommia ulmoides leaves and Kuding tea to fully extract the active ingredients increase the content of active ingredients in lozenges, strengthen the lozenges to relieve hypertension, hyperlipidemia, arteriosclerosis, diabetes, The efficacy of obesity, and the preparation method also effectively avoids the bitterness and stickiness of Eucommia ulmoides. 3.
  • the buccal tablets provided by the present invention have good mouthfeel and good patient compliance. On the basis of the original dosage form, it also has a hypoglycemic function, which expands the indications of the product; the added Luo Han Guo extract and Shell powder has the dual functions of excipients and main medicines, which can improve the taste while taking into account the curative effect, and achieve the dual purpose.
  • the invention treats Luo Han Guo pretreatment product, Kuding tea and Eucommia ulmoides leaf pretreatment product before the preparation of lozenges, which not only plays a bactericidal effect, but also stimulates the activity of the material.
  • Microwave and X-ray are used to process Luo Han Guo Husk powder.
  • the microstructure of the material is improved, so that the flavonoids are fixed in the structure, and at the same time, trace element ions such as manganese ions, iron ions, and molybdenum ions are stimulated at the outer end of the macromolecules, which helps improve the absorption rate of active ingredients.
  • Using a mixed gas of nitric oxide and nitrogen to treat the extract of Luo Han Guo kernels can help to stimulate the activity of Luo Han Guo, reduce the activity of D-mannitol, not only improve the taste of lozenges, make lozenges more suitable for the three high population; use pulse Electric field treatment of Kudingcha and Eucommia ulmoides leaf pretreatment concentrated solution not only improves the activity of chlorogenic acid, kubutin, amino acids, vitamin C, polyphenols, flavonoids, caffeine, protein and other components, but also improves Eucommia ulmoides
  • the water absorption and solubility of the glue make the disintegration rate of the lozenges in an acidic environment increase, which is more conducive to absorption by the human body.
  • Lo Han Guo pretreatment Wash and dry the Lo Han Guo fruit and separate the shell and the core; crush the shell and sieve it with a 60-mesh sieve to obtain Lo Han Guo shell powder for future use; add the core to 10 times the mass fraction of water, After boiling for 2 hours, use a double-layer gauze to filter the large-scale filter residue. The filtrate is centrifuged at 4500 r / min for 10 minutes. The supernatant is taken and the double-layer gauze is used to obtain the filter residue. The same steps are repeated for extraction and filtration, and combined. Supernatant, the combined supernatant is concentrated to 1/10 of the volume of the original mixed extract, and then used.
  • Eucommia ulmoides leaves and Kuding tea pretreatment 150g Kuding tea and 600g Eucommia leaves were washed, dried and mixed. The mixed raw materials were crushed and added with 10 times water. After boiling, it was leached at 90 ° C for 4h and then 5000r / min. Centrifuge for 10min, take the supernatant, filter with double-layer gauze to obtain the filter residue, repeat the extraction and filtration twice in the same steps, combine the supernatants, and concentrate the combined supernatants to 1/10 of the volume of the original mixed extract. The concentrated liquid was spray-dried to obtain a mixed extract powder for use.
  • Lo Han Guo pretreatment Wash and dry the Lo Han Guo fruit and separate the shell and the core; crush the shell and sieve it with a 70-mesh sieve to obtain Lo Han Guo shell powder for future use; add the core to 15 times the mass fraction of water, After boiling for 3 hours, use a double-layer gauze to filter the large-scale filter residue. The filtrate is centrifuged at 5000r / min for 15min. The supernatant is taken and the double-layer gauze is used to obtain the filter residue. Repeat the extraction and filtration twice. The supernatant was concentrated, and the combined supernatant was concentrated to 1/15 of the volume of the original mixed extract, and then used.
  • Eucommia ulmoides leaves and Kuding tea pretreatment 250g Kuding tea and 400g Eucommia leaves were washed, dried and mixed. The mixed raw materials were crushed and 15 times water was added. After boiling, it was leached at 100 ° C for 3h and then 4500r / min. Centrifuge for 20min, take the supernatant, filter through double-layer gauze to obtain the filter residue, repeat the extraction and filtration twice in the same steps, combine the supernatants, and concentrate the combined supernatants to 1/20 of the volume of the original mixed extract. The concentrated liquid was spray-dried to obtain a mixed extract powder for use.
  • Lo Han Guo pretreatment Wash and dry the Lo Han Guo fruit and separate the shell and the core; crush the shell and sieve it with an 80-mesh sieve to obtain Lo Han Guo shell powder for future use; add the core to 20 times the mass fraction of water, After boiling for 2.5 hours, use a double-layer gauze to filter the large-scale filter residue. The filtrate is centrifuged at 4500 r / min for 20 minutes. The supernatant is taken and the double-layer gauze is used to obtain the filter residue. Repeat the extraction and filtration twice. Combine Supernatant, the combined supernatant was concentrated to 1/20 of the volume of the original mixed extract, and then used.
  • Pretreatment of Eucommia ulmoides leaves and Kuding tea 200g Kuding tea and 450g Eucommia leaves were washed, dried and mixed. The mixed raw materials were crushed and added 13 times water. After boiling, it was leached at 95 ° C for 3.5h, and then at 4500r / Centrifuge for 15 min, take the supernatant, filter through double-layer gauze to obtain the filter residue, repeat the extraction and filtration twice in the same steps, combine the supernatants, and concentrate the combined supernatants to 1/15 of the volume of the original mixed extract. , The concentrated liquid is spray-dried to obtain a mixed extract powder for use.
  • Lo Han Guo pretreatment Wash and dry the Lo Han Guo fruit and separate the shell and the core; crush the shell and sieve it with an 80-mesh sieve to obtain Lo Han Guo shell powder for future use; add the core to 20 times the mass fraction of water, After boiling for 2 hours, use a double-layer gauze to filter the large-scale filter residue. The filtrate is centrifuged at 5000r / min for 15min. The supernatant is taken and the double-layer gauze is used to obtain the filter residue. Repeat the extraction and filtration twice, and combine them. The supernatant was concentrated, and the combined supernatant was concentrated to 1/20 the volume of the original mixed extract, and then used.
  • Eucommia ulmoides leaves and Kuding tea pretreatment 220g Kuding tea and 550g Eucommia leaves were washed, dried and mixed. The mixed raw materials were crushed and added with 12 times water. After boiling, it was leached at 95 ° C for 4h and then 5000r / min. Centrifuge for 18min, take the supernatant and filter through double gauze to obtain the filter residue. Repeat the extraction and filtration twice in the same steps. Combine the supernatants and concentrate the combined supernatants to 1/15 of the volume of the original mixed extract. The concentrated liquid was spray-dried to obtain a mixed extract powder for use.
  • spray drying granulation uses an aqueous solution of sodium carboxymethyl starch as a binder, a solution concentration of 2%, a liquid supply rate of 10 ml / min, a bed temperature of 40 ° C, a compressed air pressure of 0.15 to 0.25 MPa, and spray granulation.
  • the time is 40min.
  • Eucommia ulmoides leaves and Kudingcha mixed extract powder are obtained in Examples 1-4, 15g of Luo Han Guo extract, 2.5 g of Luo Han Huo powder, 10 g of dextrin, 7 g of isomalt, 6 g of CMS-Na, and magnesium stearate 4g.
  • spray-drying granulation uses an aqueous solution of sodium carboxymethyl starch as a binder, a solution concentration of 6%, a liquid supply rate of 30 ml / min, a bed temperature of 70 ° C, a compressed air pressure of 0.15 to 0.25 MPa, and spray granulation.
  • the time is 80min.
  • Eucommia ulmoides leaves and Kudingcha mixed extract powder are obtained in Examples 1-4, Luo Han Guo extract 10 g, Luo Han Huo powder 5 g, dextrin 15 g, isomalt 5 g, CMS-Na 5 g, magnesium stearate 2 g .
  • spray-drying granulation uses an aqueous solution of sodium carboxymethyl starch as a binder, a solution concentration of 5%, a liquid supply rate of 20 ml / min, a bed temperature of 60 ° C, a compressed air pressure of 0.15 to 0.25 MPa, and spray granulation.
  • the time is 60min.
  • Example 7 The difference from Example 7 is that the following operations are also included before the preparation of the tablet:
  • the Luo Han Guo extract obtained from the pretreatment of Luo Han Guo was placed in a reactor, and the reactor was filled with a mixed gas at a flow rate of 5-8 mol / min for 120-180 s; wherein the mixed gas was nitric oxide and nitrogen at a molar ratio of 1 :( 2-4) composition;
  • the pretreatment product of Kudingcha and Eucommia ulmoides leaves was pumped to a pulsed electric field processing chamber at a flow rate of 80-100 mL / min through a peristaltic pump with an electric field intensity of 200-228V / cm, a pulse frequency of 30-40Hz, and a pulse time of 4-6s.
  • the eucommia ulmoides leaves and kuding tea are extracted by the original standard in methods 1 and 2.
  • the remaining methods 3-7 are extracted by the method of the present invention, and then spray-dried with other auxiliary materials to granulate and tablet.
  • Comparative group 1 Eucommia ulmoides double-dropping foaming agent, the original standard prepared as a foaming agent, the daily dosage is 3 bags.
  • Comparative group 2 The prescription of Method 2 in Test Example 1 was selected and prepared according to the manufacturing process of Example 7 of the present invention.
  • SHR primary hypertensive rats
  • Blank negative control group eat basic feed and drink freely
  • Captopril was fed daily at 25 mg / kg, basic feed was fed, and water was free to drink;
  • Test group Test group 1-4 uses the product of Example 5-8; test group 5-6 uses the product of comparison group 1-2, and drinks freely, the amount of which is 5 times the human daily use amount.
  • Blood pressure was measured once a week for 4 weeks of continuous use.
  • Eighty SD male rats (180-220g) were selected for the experiment and randomly divided into a normal control group, a model control group and 6 test groups.
  • the model control group and the test group were modeled for one month and fed with high-fat diet daily and drinking water freely. After modeling is completed:
  • Normal control group eat basic feed and drink freely
  • Model control group eating high-fat feed and drinking freely
  • Test group Test group 1-4 uses the product of Example 5-8; test group 5-6 uses the product of comparison group 1-2, and drinks freely.
  • the formula of high-fat feed is based on the basic feed, adding 1.5g / 100g cholesterol, 1.5g / 100g egg yolk powder, 1.5g / 100g lard, 0.25g / 100g bile salt.
  • TC cholesterol
  • LDL-C low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • mice (25-30 g) were selected for the experiment and randomly divided into a normal control group, a model control group and 6 test groups.
  • the model control group and the test group were continuously modeled with tetraoxopyrin for 15 days, and the mice were injected intraperitoneally with 45 mg / kg of freshly prepared tetraoxopyrimidine daily. After modeling is completed:
  • Normal control group eat basic feed and drink freely
  • Model control group eat basic feed and drink freely
  • Test group Test group 1-4 uses the product of Example 5-8; test group 5-6 uses the product of comparison group 1-2, and drinks freely, the amount of which is 5 times the human daily use amount.
  • Table 1 show that the blood pressure value of the blank negative control group has remained stable and has no obvious rise or decline trend; the blood pressure value (mmHg) of the positive control group has decreased significantly in the first week, and the blood pressure value in the subsequent continued positions has remained stable.
  • the blood pressure value (mmHg) of the test group 1-3 and 5SHR also decreased significantly in the first week, and the blood pressure value of the subsequent continued position remained stable.
  • Test group 5 had a slightly lower effect.
  • Test group 4 stabilized after a slight decrease, but the difference compared with the blank negative control group was not as significant as that of test group 1-3. It shows that the formula and process steps of the invention are reasonable, and the effects of reducing and stabilizing blood pressure and reducing the amount of the original medicinal materials are achieved.
  • test group TC (mmol / L) HDL-C (mmol / L) LDL-C (mmol / L) Normal control group 1.91 ⁇ 3.09 a 1.48 ⁇ 2.14 a 0.29 ⁇ 3.19 a Model control group 3.13 ⁇ 3.19 c 2.67 ⁇ 3.41 c 0.52 ⁇ 2.53 c Test group 1 2.39 ⁇ 1.39 ab 1.53 ⁇ 3.31 ab 0.31 ⁇ 1.51 ab Test group 2 2.23 ⁇ 3.02 ab 1.58 ⁇ 2.13 ab 0.33 ⁇ 2.28 ab Test group 3 2.45 ⁇ 2.24 ab 1.61 ⁇ 2.35 ab 0.32 ⁇ 2.33 ab Test group 4 2.58 ⁇ 2.09 a 1.66 ⁇ 2.72 ab 0.34 ⁇ 1.97 b
  • Test group 5 3.10 ⁇ 1.65 c 2.69 ⁇ 2.34 c 0.54 ⁇ 2.19 c
  • Test group 6 3.01 ⁇ 1.05 c 2.32 ⁇ 1.23 c 0.50 ⁇ 1.92 c
  • Table 2 show that the cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) values of the test groups 1-3 and 5 are slightly higher than the normal group, but significant. It is lower than the model control group, but the test group 5 has a slightly lower effect. The values of each index of test group 4 were lower than those of the model control group, but the differences compared with the model group were not as obvious as those of the test group 1-3. It shows that the formula and process steps of the invention are reasonable, and the effects of reducing blood lipids and reducing the amount of raw materials used are achieved.
  • test group Fasting blood glucose (mmol / L) Normal control group 8.56 ⁇ 2.31 a Model control group 20.56 ⁇ 3.30 c Test group 1 13.22 ⁇ 2.51 ab Test group 2 12.43 ⁇ 2.31 ab Test group 3 13.51 ⁇ 3.01 ab Test group 4 12.37 ⁇ 1.81 bc Test group 5 21.55 ⁇ 3.33 c Test group 6 18.05 ⁇ 2.30 c
  • Control group the concentrated solution obtained from Kudingcha and Eucommia ulmoides leaves prepared in Example
  • Test group 1 The pretreatment products of Kudingcha and Eucommia ulmoides leaves were pumped to a pulsed electric field processing chamber at a flow rate of 100mL / min by a peristaltic pump with an electric field intensity of 220V / cm, a pulse frequency of 35Hz, and a pulse time of 5s;
  • Test group 2 After pretreatment of Kudingcha and Eucommia ulmoides leaves under microwave conditions with a power of 100W for 10s, immediately irradiate them with X-rays for 5s;
  • Test group 3 Put the Kuding tea and Eucommia ulmoides leaves pretreatment product into the reactor, and fill the reactor with a mixed gas at a flow rate of 6mol / min for 150s; where the mixed gas is nitric oxide and nitrogen with a molar ratio of 1 : 3 composition;
  • Test group 4 The pretreatment products of Kudingcha and Eucommia ulmoides leaves were pumped to a pulsed magnetic field processing chamber by a peristaltic pump at a flow rate of 100mL / min, with a magnetic field intensity of 1A / m and a frequency of 8MHz;
  • Formula of artificial saliva KCl11200mg / L, NaCl6700mg / L, Na 2 HPO 4 260mg / L, KH 2 PO 4 200mg / L, KNHCO 3 1500mg / L, KSCN330mg / L, add 1000mL distilled water, adjust pH to 7.0, configure After completion, put artificial saliva in a constant temperature water bath (37 ° C), stir well and set aside;
  • the sample is constant: all the prepared samples are ultrasonically cleaned in distilled water for 10 minutes, then sterilized at 303.975 kPa and 121 ° C for 20 minutes, and then stored in a desiccator at (37 ⁇ 1) ° C for 24 hours, and then moved to room temperature Store in a desiccator for 30 min, and then weigh all samples, accurate to 0.01 mg; Repeat the measurement until a constant mass is obtained, and record it as m1; During continuous weighing, the mass loss between 2 measurements is not greater than 0.02 mg;
  • Dissolution percentage (%) 100% * (m1-m3) / m1
  • Example 7 In terms of activity, the tablet-containing group of Example 7 is better than the non-added group;
  • liver and kidney organs were dissected to observe the changes of the liver and kidney organs.
  • the liver and kidney lesions of the group containing Example 7 were not significant, but the lesions of the non-added group showed significant lesions. , Liver cirrhosis is obvious;
  • the lozenge has the effect of alleviating and protecting heart and brain function, liver and kidney function, and can maintain normal metabolism and physical balance of the animal body.

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Abstract

本发明提供了一种降三高含片及其制备方法，所述降三高含片由苦丁茶、杜仲叶为原料制成，并将罗汉果提取物及罗汉果壳粉代替白砂糖、蜂蜜等不适宜三高人群食用的甜味剂，使含片适合老人、孕妇、患有三高人群等食用。同时加入的杜仲叶、苦丁茶混合提取有效成分使含片具缓解高血压、高血脂、动脉硬化、糖尿病、肥胖症等功效。

Description

一种降三高含片及其制备方法 技术领域
本发明涉及一种含片及其制作方法，特别是涉及一种降三高含片及其制备方法。
背景技术
苦丁茶中含有苦丁皂甙、氨基酸、维生素C、多酚类、黄酮类、咖啡碱、蛋白质等200多种成分。能双向调节机体代谢，增强人体免疫功能，明显降低高脂血症患者的血清总胆固醇、甘油三酯及低密度脂蛋白，具有清咽利喉、清热解毒、护肝解酒、消炎利便等功效；还对高血压、高血脂、动脉硬化、糖尿病、肥胖症、结肠炎、便秘、痔疮和各类口腔炎症等有明显的防治作用。
杜仲叶微辛，温，主要含有杜仲绿原酸、杜仲胶等。具有补肝肾、强筋骨、降血压、调节血脂、防治骨质疏松、降血糖、镇静安神、抗疲劳、镇痛、提高免疫力、消炎、促进糖代谢、抗衰老、抑制子宫兴奋等功效。其中杜仲绿原酸具有抗菌、消炎、解毒、利胆、降压和升高白细胞及显著增加胃肠蠕动和促进胃液分泌等药理作用，对大肠杆菌、金色葡萄球菌、肺炎球菌和病毒有较强的抑制作用。
我公司现有产品杜仲双降袋泡剂由杜仲叶和苦丁茶制成，收载于卫生部药品标准中药成方制剂第十二册61页，具有降压，降脂的功效，主要用于降血压和降血脂，但现有产品是通过开水泡服，制备工艺中仅是水煎煮、其中苦丁茶部分粉碎直接入药，这样的简单加工，杜仲叶的苦涩、杜仲胶的粘稠感不易被苦丁茶掩盖，容易造成茶汤入口的不适感；简单水煎煮提取、部分的粗颗粒直接冲泡也会造成有效成分溶出不完全的缺陷。因此，对现有产品进行工艺上的优化、以及剂型上的拓展，是本公司研究人员的主要研究方向。
在对产品的研究过程中，发明人员发现，利用罗汉果与苦丁茶、杜仲叶进行搭配，筛选出合理的辅料，制成口含片，不仅提高了原药材活性成分的溶出，且口含片含糖量低，非常适合与三高人群服用，还解决了现有袋泡剂冲泡口感不够理想、携带不方便等问题。目前针对杜仲叶和苦丁茶制成的产品中，还尚未有口含片的报道，CN201410047527.X一种苦丁茶无糖口含片及其制备方法公开的是苦丁茶、杜仲叶与葛根、蓖麻叶、绞股蓝、丹参、枳实等九种药材制成的含片， 但该产品的制备工艺仅采用简单的水提醇沉，另外在专利中虽然介绍了产品侧重于清热消暑、生津止渴、抗衰老等功效，但其实际作用效果未知。
罗汉果含有罗汉果甜苷、多种氨基酸和维生素等药用成分，主治肺热痰火咳嗽、咽喉炎、扁桃体炎、急性胃炎、便秘等。罗汉果甜甙又称为甜味素比蔗糖甜300倍，因其甜度高、热量低而作为甜味剂广泛使用，是蔗糖的最佳替代品。常作为肥胖者和糖尿病患者的代用糖，对支气管炎、高血压等疾病有显著疗效，还是起到防治冠心病、血管硬化、肥胖症的作用。因此，用罗汉果作为口服制剂中的甜味剂和糖分，是理想的甘露醇等辅料的替代产品，不仅有益于三高人群，且本身的作用效果也得到发挥。
发明内容
本发明为了克服现有技术的不足，经过大量的配方筛选及验证，提供了一种降三高含片及其制备方法，适宜患有高血压、高血脂、高血糖病的患者食用同时还可以起到缓解病症的功效。
具体地，本发明提供了如下的技术方案：
一种降三高含片，其特征在于：按重量份计算，由杜仲叶400-600份、苦丁茶150-250份、罗汉果提取物5-15份、罗汉果壳粉2.5-7.5份、糊精10-20份、异麦芽糖醇3-7份、CMS-Na 2-6份、硬脂酸镁1-4份制成。
优选的，按重量份计算，由杜仲叶450份、苦丁茶200份、罗汉果提取物10份、罗汉果壳粉5份、糊精15份、异麦芽糖醇5份、CMS-Na 5份、硬脂酸镁2份制成。
本发明还提供了降三高含片的制备方法包括以下步骤：罗汉果、苦丁茶、杜仲叶预处理，含片制备步骤。
所述罗汉果预处理包括以下步骤：
(1)将罗汉果洗净、晾干后果壳和果核分离；
(2)将果壳进行粉碎后用60-80目筛网进行过筛后得罗汉果果壳粉备用；
(3)将果核加入质量分数10-20倍水，煮沸后小火熬制2-3h，采用双层纱布过滤大型滤渣，滤液于4500-5000r/min离心分离10-20min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/10-1/20后备用。
所述苦丁茶、杜仲叶预处理为将苦丁茶、杜仲叶分别洗净、晾干再混合，混合原材料粉碎后加入10-15倍水，煮沸后于90-100℃浸提3-4h，后于4500-5000r/min离心分离10-20min，取上清液，得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/10-1/20，将浓缩液进行喷雾干燥获得混合提取物粉末。
所述含片制备包括以下步骤：
(1)取处方量罗汉果提取物、罗汉果壳粉备用；
(2)取预处理得到的苦丁茶、杜仲叶合提取物粉末，处方量糊精、异麦芽糖醇、硬脂酸镁备用；
(3)采用一步制粒法，将前述准备的所有组分加到一起置入喷雾干燥制粒机中，喷雾干燥造粒，制成粒径为40目的粒状粉料，然后利用压片机压片成型，得到重量在0.4～1.0g/片的降三高口含片。
其中，喷雾干燥造粒是以羧甲基淀粉钠的水溶液为粘合剂，溶液浓度为2％～6％，供液速度为10～30ml/min，床层温度40～70℃，压缩气压0.15～0.25MPa，喷雾制粒时间为40-80min。
所述造粒过程为：将所有组分加到一起置入喷雾干燥制粒机中，进行流化并实现粉体混合，喷雾装置开动，在40-80min的连续喷雾过程中，雾滴在粉体上发生凝聚和长大过程，直到所需颗粒尺寸停止喷雾。最后，所有颗粒产物在同一容器内继续进行流化干燥，从而得到制粒的终产物。
本发明含片制备前，将罗汉果预处理所得的果壳粉置于功率为100-200W的微波条件下处理5-10s后，即刻用X射线照射5-10s。
本发明含片制备前，将罗汉果预处理所得的罗汉果提取物置于反应器中，以5-8mol/min的流速向反应器中充入混合气体120-180s；其中混合气体是一氧化氮与氮气按摩尔比为1：(2-4)组成。
本发明含片制备前，将苦丁茶、杜仲叶预处理所得物以80-100mL/min流速经蠕动泵泵送至脉冲电场处理室，电场强度200-228V/cm、脉冲频率30-40Hz、脉冲时间4-6s。
本发明的有益效果为：1、本发明将罗汉果提取物及罗汉果壳粉代替蔗糖、蜂蜜、甘露醇等不适宜三高人群食用的甜味剂，并减少了糊精的使用量，使产品 适合老人、孕妇、患有三高人群等食用。2、对杜仲叶、苦丁茶采取反复浸提、离心的方式，使有效成分得到充分提取，提高了含片中有效成分含量，加强了含片缓解高血压、高血脂、动脉硬化、糖尿病、肥胖症的功效，并且该制备方法还有效避免了杜仲的苦涩、粘稠问题。3、本发明所提供的口含片，口感好，患者顺应性好，在原有剂型降脂降压的基础上还兼具降糖的功能，扩展了产品的适应症；加入的罗汉果提取物和壳粉兼具辅料和主药的双重作用，可以在改善口感的同时兼顾疗效，达到双重目的。
本发明在含片制备前对罗汉果预处理所得物、苦丁茶和杜仲叶预处理所得物进行处理，不仅起到了杀菌作用，还激发了物料活性；利用微波以及X射线处理罗汉果果壳粉，改善了物料微观结构，使得黄酮被固定于结构内，同时激发了大分子外端的微量元素离子，如锰离子、铁离子、钼离子等，有助于提高有效成分的吸收率。利用一氧化氮和氮气混合气体处理罗汉果果核提取物，有助于激发罗汉果甙活性，降低D-甘露醇的活性，不仅改善了含片口味，使得含片更适用于三高人群；利用脉冲电场处理苦丁茶和杜仲叶预处理所得的浓缩液，不仅提高了绿原酸、苦丁皂甙、氨基酸、维生素C、多酚类、黄酮类、咖啡碱、蛋白质等成分的活性，还改善了杜仲胶的吸水性与溶解性，使得含片在酸性环境中崩解速度增加，更有利于人体吸收。
具体实施方式：
下面结合实施例对本发明的具体实施方式作进一步详细的描述。
实施例1：原材料的预处理
罗汉果预处理：将罗汉果洗净、晾干后果壳和果核分离；将果壳进行粉碎后用60目筛网进行过筛后得罗汉果果壳粉备用；将果核加入质量分数10倍水，煮沸后小火熬制2h，采用双层纱布过滤大型滤渣，滤液于4500r/min离心分离10min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/10后备用。
杜仲叶、苦丁茶预处理：将苦丁茶150g、杜仲叶600g分别洗净、晾干再混合，混合原材料粉碎后加入10倍水，煮沸后于90℃浸提4h，后于5000r/min离心分离10min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/10，将浓缩液进行喷 雾干燥获得混合提取物粉末备用。
实施例2：原材料的预处理
罗汉果预处理：将罗汉果洗净、晾干后果壳和果核分离；将果壳进行粉碎后用70目筛网进行过筛后得罗汉果果壳粉备用；将果核加入质量分数15倍水，煮沸后小火熬制3h，采用双层纱布过滤大型滤渣，滤液于5000r/min离心分离15min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/15后备用。
杜仲叶、苦丁茶预处理：将苦丁茶250g、杜仲叶400g分别洗净、晾干再混合，混合原材料粉碎后加入15倍水，煮沸后于100℃浸提3h，后于4500r/min离心分离20min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/20，将浓缩液进行喷雾干燥获得混合提取物粉末备用。
实施例3：原材料的预处理
罗汉果预处理：将罗汉果洗净、晾干后果壳和果核分离；将果壳进行粉碎后用80目筛网进行过筛后得罗汉果果壳粉备用；将果核加入质量分数20倍水，煮沸后小火熬制2.5h，采用双层纱布过滤大型滤渣，滤液于4500r/min离心分离20min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/20后备用。
杜仲叶、苦丁茶预处理：将苦丁茶200g、杜仲叶450g分别洗净、晾干再混合，混合原材料粉碎后加入13倍水，煮沸后于95℃浸提3.5h，后于4500r/min离心分离15min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/15，将浓缩液进行喷雾干燥获得混合提取物粉末备用。
实施例4：原材料的预处理
罗汉果预处理：将罗汉果洗净、晾干后果壳和果核分离；将果壳进行粉碎后用80目筛网进行过筛后得罗汉果果壳粉备用；将果核加入质量分数20倍水，煮沸后小火熬制2h，采用双层纱布过滤大型滤渣，滤液于5000r/min离心分离15min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/20后备用。
杜仲叶、苦丁茶预处理：将苦丁茶220g、杜仲叶550g分别洗净、晾干再混合，混合原材料粉碎后加入12倍水，煮沸后于95℃浸提4h，后于5000r/min离心分离18min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/15，将浓缩液进行喷雾干燥获得混合提取物粉末备用。
实施例5：含片的制备
配方：杜仲叶、苦丁茶混合提取物粉末为实施例1-4获得量，罗汉果提取物5g、罗汉果壳粉7.5g、糊精20g、异麦芽糖醇3g、CMS-Na 2g、硬脂酸镁1g。
工艺：(1)取处方量罗汉果提取物、罗汉果壳粉备用；
(2)取实施例1-4任一方法预处理得到的苦丁茶、杜仲叶合提取物粉末，处方量糊精、异麦芽糖醇、硬脂酸镁备用；
(3)采用一步制粒法，将前述准备的所有组分加到一起置入喷雾干燥制粒机中，喷雾干燥造粒，制成粒径为40目的粒状粉料，然后利用压片机压片成型，得到重量在1.0g/片的降三高口含片100片。
其中，喷雾干燥造粒是以羧甲基淀粉钠的水溶液为粘合剂，溶液浓度为2％，供液速度为10ml/min，床层温度40℃，压缩气压0.15～0.25MPa，喷雾制粒时间为40min。
实施例6：含片的制备
配方：杜仲叶、苦丁茶混合提取物粉末为实施例1-4获得量，罗汉果提取物15g、罗汉果壳粉2.5g、糊精10g、异麦芽糖醇7g、CMS-Na 6g、硬脂酸镁4g。
工艺：(1)取处方量罗汉果提取物、罗汉果壳粉备用；
(2)取预处理得到的苦丁茶、杜仲叶合提取物粉末，处方量糊精、异麦芽糖醇、硬脂酸镁备用；
(3)采用一步制粒法，将前述准备的所有组分加到一起置入喷雾干燥制粒机中，喷雾干燥造粒，制成粒径为40目的粒状粉料，然后利用压片机压片成型，得到重量在0.4g/片的降三高口含片250片。
其中，喷雾干燥造粒是以羧甲基淀粉钠的水溶液为粘合剂，溶液浓度为6％，供液速度为30ml/min，床层温度70℃，压缩气压0.15～0.25MPa，喷雾制粒时间为80min。
实施例7：含片的制备
配方：杜仲叶、苦丁茶混合提取物粉末为实施例1-4获得量，罗汉果提取物10g、罗汉果壳粉5g、糊精15g、异麦芽糖醇5g、CMS-Na 5g、硬脂酸镁2g。
工艺：(1)取处方量罗汉果提取物、罗汉果壳粉备用；
(2)取预处理得到的苦丁茶、杜仲叶合提取物粉末，处方量糊精、异麦芽糖醇、硬脂酸镁备用；
(3)采用一步制粒法，将前述准备的所有组分加到一起置入喷雾干燥制粒机中，喷雾干燥造粒，制成粒径为40目的粒状粉料，然后利用压片机压片成型，得到重量在0.5g/片的降三高口含片200片。
其中，喷雾干燥造粒是以羧甲基淀粉钠的水溶液为粘合剂，溶液浓度为5％，供液速度为20ml/min，床层温度60℃，压缩气压0.15～0.25MPa，喷雾制粒时间为60min。
实施例8
与实施例7的区别在于：在含片制备前还包括以下操作：
将罗汉果预处理所得的果壳粉置于功率为100-200W的微波条件下处理5-10s后，即刻用X射线照射5-10s；
将罗汉果预处理所得的罗汉果提取物置于反应器中，以5-8mol/min的流速向反应器中充入混合气体120-180s；其中混合气体是一氧化氮与氮气按摩尔比为1：(2-4)组成；
将苦丁茶、杜仲叶预处理所得物以80-100mL/min流速经蠕动泵泵送至脉冲电场处理室，电场强度200-228V/cm、脉冲频率30-40Hz、脉冲时间4-6s。
试验例1：
本发明的配方是经过筛选的，简述如下：
按照表1中的配方准备口含片的原料，其配方是按照质量份数进行配比：
  方法1 方法2 方法3 方法4 方法5 方法6 方法7
杜仲叶 700 700 450 350 600 450 450
苦丁茶 300 300 200 100 250 200 200
罗汉果提取物 - 10 10 20 15 - -
罗汉果壳粉 - 5 5 10 - - -
甜叶菊 20 - - - - 15 20
甘露醇 10 - - - - - 14
糊精 - 15 15 20 20 15 -
异麦芽糖醇 - 5 5 3 5 - -
CMS-Na - 5 5 3 3 - 5
淀粉浆 10 - -- - - 10 -
滑石粉 3 - -- 2 - 1 -
硬脂酸镁 - 1 2 - 3 - 2
以上制成100片，每片重约1.0-1.5g。具体制法为：
方法1、2中杜仲叶和苦丁茶采用原标准提取，其余方法3-7采用本发明方法提取，然后同其他辅料喷雾干燥制粒、压片，即可。
将上述七个筛选方法中制成口含片进行感官评价、绿原酸含量测定、脆碎度、崩解时限的检查，结果如表2：
表2降三高含片指标检查结果
Figure PCTCN2019085147-appb-000001
结果表明，采用方法3的原辅料组成和配比，效果良好。
试验例2：
为能进一步的验证本发明创造的疗效，本研究者在本发明创造中，进行如下实验验证：
1、实验组设计
对比组1：杜仲双降袋泡剂，原有标准制备成袋泡剂，每日用量为3袋。
对比组2：选择试验例1中方法2的处方，按本发明实施例7制作工艺制备。
2、检测指标
对实施例5-8和对比组1-2的产品进行大鼠降血压、降血脂、降血糖功能实验。
1)大鼠降血压功能实验
实验选用80只年龄5个月的原发性高血压大鼠(SHR)，随机分为1组空白阴性对照组，1组阳性对照组，7组受试组；
空白阴性对照组：进食基本饲料，自由饮水；
阳性对照组：每日按照25mg/kg喂食卡托普利(captopril)，进食基本饲料，自由饮水；
受试组：受试组1-4使用实施例5-8的产品；受试组5-6使用对比组1-2的产品，自由饮水，用量均为人每日使用量的5倍。
连续使用4周，每周测量一次血压。
2)大鼠降血脂功能实验
实验选用80只SD雄性大鼠(180-220g)，随机分为1组正常对照组，1组模型对照组，6组受试组。将模型对照组和受试组建模一个月每日喂以高脂饲料，自由饮水。建模完成后：
正常对照组：进食基本饲料，自由饮水；
模型对照组：进食高脂饲料，自由饮水；
受试组：受试组1-4使用实施例5-8的产品；受试组5-6使用对比组1-2的产品，自由饮水，用量均为人每日使用量的5倍。
高脂饲料的配方为：以基础饲料为基础，添加1.5g/100g的胆固醇，1.5g/100g的蛋黄粉，1.5g/100g的猪油，0.25g/100g的胆盐。
喂养45d后禁食16h，眼球取血，采用相应试剂盒检测胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)及高密度脂蛋白胆固醇(HDL-C)水平。
3)小鼠降血糖功能实验
实验选用80只小鼠(25-30g)，随机分为1组正常对照组，1组模型对照组，6组受试组。将模型对照组和受试组用四氧嘧啶连续建模15天，每日给小鼠腹腔注射45mg/kg新鲜配制的四氧嘧啶。建模完成后：
正常对照组：进食基本饲料，自由饮水；
模型对照组：进食基本饲料，自由饮水；
受试组：受试组1-4使用实施例5-8的产品；受试组5-6使用对比组1-2的产品，自由饮水，用量均为人每日使用量的5倍。
喂养45d后，禁食3h，眼眶取血，分离得到血清，用血糖试剂盒检测空腹血 糖值。
3、检测结果
1)大鼠降血压功能实验
表1 SHR血压值(mmHg)变化结果
实验组 给药前 1周 2周 3周 4周
空白阴性对照组 125.1±2.0 a 124.3±4.2 a 121.5±2.3 a 125.6±3.2 a 126.1±2.7 a
阳性对照组 122.9±2.5 a 91.8±4.1 bc 89.4±3.8 c 88.6±2.9 c 85.7±3.6 c
受试组1 123.1±3.4 a 103.2±3.9 b 99.8±3.1 b 97.2±2.8 bc 92.7±1.9 bc
受试组2 127.3±1.8 a 105.3±1.3 b 102.8±3.2 b 98.6±2.8 b 93.5±3.1 b
受试组3 124.5±2.3 a 101.2±1.5 b 98.1±3.9 bc 96.8±3.2 bc 91.8±1.4 bc
受试组4 123.6±1.9 a 96.4±2.2 b 92.5±2.7 c 89.9±1.6 bc 87.5±3.1 b
受试组5 121.2±3.9 a 115.4±4.0 a 110.2±5.1 a 108.5±4.2 a 106.2±5.3 a
受试组6 124.2±4.1 a 108.5±3.2 a 105.0±4.5 a 101.9±3.9 a 95.1±5.1 a
表1结果显示：空白阴性对照组血压值一直保持平稳未有明显上升或下降趋势；阳性对照组血压值(mmHg)第一周明显下降，后续继续位置血压值保持平稳。受试组1-3、5SHR血压值(mmHg)第一周也明显下降，后续继续位置血压值保持平稳，虽与阳性对照组还存在一点差异但较空白阴性对照组血压值明显下降，且受试组5效果略低。受试组4略有下降后趋于平稳，但与空白阴性对照组比较的差异没有受试组1-3明显。说明本发明的配方及工艺步骤合理，达到降低、稳定血压且原药材用量降低的效果。
2)小鼠降血脂功能实验
表2大鼠胆固醇值变化结果
实验组 TC(mmol/L) HDL-C(mmol/L) LDL-C(mmol/L)
正常对照组 1.91±3.09 a 1.48±2.14 a 0.29±3.19 a
模型对照组 3.13±3.19 c 2.67±3.41 c 0.52±2.53 c
受试组1 2.39±1.39 ab 1.53±3.31 ab 0.31±1.51 ab
受试组2 2.23±3.02 ab 1.58±2.13 ab 0.33±2.28 ab
受试组3 2.45±2.24 ab 1.61±2.35 ab 0.32±2.33 ab
受试组4 2.58±2.09 a 1.66±2.72 ab 0.34±1.97 b
受试组5 3.10±1.65 c 2.69±2.34 c 0.54±2.19 c
受试组6 3.01±1.05 c 2.32±1.23 c 0.50±1.92 c
表2结果显示：受试组1-3、5的胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)及高密度脂蛋白胆固醇(HDL-C)值虽比正常组稍高，但显著低于模型对照组，但受试组5效果略低。受试组4的各项指标数值比模型对照组低，但与模型组比较的差异没有受试组1-3明显。说明本发明的配方及工艺步骤合理，达到降低血脂且原材料使用量降低的效果。
3)小鼠降血糖功能实验
表3小鼠空腹血糖值变化结果
实验组 空腹血糖值(mmol/L)
正常对照组 8.56±2.31 a
模型对照组 20.56±3.30 c
受试组1 13.22±2.51 ab
受试组2 12.43±2.31 ab
受试组3 13.51±3.01 ab
受试组4 12.37±1.81 bc
受试组5 21.55±3.33 c
受试组6 18.05±2.30 c
表3结果显示，受试组1-3、4的空腹血糖值虽比正常组稍高，但显著低于模型对照组。受试组6的各项指标数值与模型组比较的差异没有受试组1-3明显。说明本发明的配方及工艺步骤合理，达到降低血糖且原材料使用量降低的效果。
试验例3
取实施例7制得苦丁茶和杜仲叶预处理所得的浓缩液5份，每份100mL，1个对照组，4份试验组，然后将每组各取50mL置入人工唾液或蒸馏水中7d，检测样品吸水性与溶解性；
1、实验组设计
对照组：实施例7制得苦丁茶和杜仲叶预处理所得的浓缩液
试验组1：将苦丁茶、杜仲叶预处理所得物以100mL/min流速经蠕动泵泵送至脉冲电场处理室，电场强度220V/cm、脉冲频率35Hz、脉冲时间5s；
试验组2：将苦丁茶、杜仲叶预处理所得物置于功率为100W的微波条件下处理10s后，即刻用X射线照射5s；
试验组3：将苦丁茶、杜仲叶预处理所得物置于反应器中，以6mol/min的流速向反应器中充入混合气体150s；其中混合气体是一氧化氮与氮气按摩尔比为1：3组成；
试验组4：将苦丁茶、杜仲叶预处理所得物以100mL/min流速经蠕动泵泵送至脉冲磁场处理室，磁场强度为1A/m，频率为8MHz；
人工唾液的配方：KCl11200mg/L、NaCl6700mg/L、Na 2HPO 4260mg/L、KH 2PO 4200mg/L、KNHCO 31500mg/L、KSCN330mg/L，加入1000mL蒸馏水，调节pH值至7.0，配置完成后将人工唾液放入恒温水浴(37℃)中，搅拌均匀，备用；
2、检测方法
试样的恒定：将制备好的所有样品在蒸馏水中超声清洗10min，然后在303.975kPa、121℃条件下消毒20min，然后放在(37±1)℃的干燥器中贮存24h，后移至室温的干燥器中贮存30min，然后称量所有组别试样，精确到0.01mg；多次测量，直到获得恒定质量，记录为m1；在连续称量时，2次测量之间质量损失不大于0.02mg；
试样的浸水：分别将各组试样分别放入(37±1)℃的蒸馏水和人工唾液中贮存7d±2h、30d±2h。然后分别将试样从水中取出，用吸水纸轻轻拭干肉眼可见的水渍，在空气中晾干15s，在从水中取出1min左右时，称质量(精确到0.01mg)，记录为m2。试样再恒定：将试样再次放入干燥器中，当质量再次恒定时，记录为m3。再恒定条件同于第1次干燥过程；
吸水百分率(％)＝100％*(m2-m3)/m1
溶解百分率(％)＝100％*(m1-m3)/m1
3、实验结果
表4各组在不同介质中的吸水率和溶解率
Figure PCTCN2019085147-appb-000002
Figure PCTCN2019085147-appb-000003
试验例4降三高含片对心脑、肝肾功能的影响
1、实验组设计
取30只大小、体重相近的已通过高脂高糖膳食诱导的大鼠，将其均分为两组，记录两组大鼠的血压、血脂等心脑功能测试数值以及解毒、排尿等肝肾功能测试数值，对其中一组在日常饲料中添加实施例7的含片进行喂养，另一组采用日常饲料喂养，连续喂养6周后，再一次对大鼠的相关数值进行测试、记录；
2、实验结果
2.1活动量方面，添加实施例7含片组优于未添加组；
2.2心脑功能方面，添加实施例7含片组数据低于未添加组；
2.3每组随机选取5只进行断头处理后，解剖尸体观察肝肾器官变化：添加实施例7含片组肝脏、肾脏病变不显著，而未添加组出现明显病变，肝脏周五组织脂肪堆积多、肝硬化现象明显；
2.4排尿代谢方面，添加实施例7含片组尿液含量及频率正常，而未添加组排尿频繁，每次尿液含量较少；
2.5体重方面，添加实施例7含片组实验前后体重无明显变化，而未添加组体重明显减轻。
3、结果分析
该含片对心脑功能、肝肾功能有缓解和保护的作用，可维持动物体正常代谢和体质平衡。
效果例1
1、研究对象
自2015年始，选择老年2型糖尿病患者50例，男女各半，年龄60-80岁，体重50-80kg，糖尿病病程1-20年，所有患者均符合WHO糖尿病诊断标准；
2、治疗方法
每日2次，每次100mg，餐后半小时内服用；
3、观察指标
所有患者在治疗前、后12h测定FPG、HbAlc及血脂，并观察有无不良反应发生；
4、统计学方法
用SPSS12.0统计软件进行分析
5、结果
5.1治疗前后FPG、HBASlc水平比较
  FPG(mmol/L) HbAlc(％)
治疗前 9.3±1.7 13.4±2.6
治疗后12h 6.2±1.5 * 9.0±1.6 *
与治疗前比较：*P＜0.05
5.2治疗前后血脂水平比较
  LDL HDL TC TG
治疗前 3.1±1.1 0.85±0.11 6.0±1.2 3.8±1.2
治疗后12h 2.3±0.7 * 0.85±0.08 * 5.1±0.9 * 3.2±0.8 *
5.3不良反应
患者出现恶心、腹泻，症状较轻，持续时间短的有2例，无低血糖反应、猝死、心绞痛、心肌梗塞等事件。

Claims (7)

  1. 一种降三高含片，其特征在于：按重量份计算，由杜仲叶400-600份、苦丁茶150-250份、罗汉果提取物5-15份、罗汉果壳粉2.5-7.5份、糊精10-20份、异麦芽糖醇3-7份、CMS-Na 2-6份、硬脂酸镁1-4份制成。
  2. 如权利要求1所述的降三高含片，其特征在于：按重量份计算，由杜仲叶450份、苦丁茶200份、罗汉果提取物10份、罗汉果壳粉5份、糊精15份、异麦芽糖醇5份、CMS-Na 5份、硬脂酸镁2份制成。
  3. 如权利要求1或2所述的降三高含片的制备方法，其特征在于，包括罗汉果、苦丁茶、杜仲叶预处理，含片制备步骤。
  4. 如权利要求3所述的降三高含片的制备方法，其特征在于，所述罗汉果预处理包括以下步骤：
    (1)将罗汉果洗净、晾干后果壳和果核分离；
    (2)将步骤(1)果壳进行粉碎后，用60-80目筛网进行过筛后得罗汉果果壳粉备用；
    (3)将步骤(1)果核加入质量分数10-20倍水，煮沸后小火熬制2-3h，采用双层纱布过滤大型滤渣，滤液于4500-5000r/min离心分离10-20min，取上清液，采用双层纱布过滤得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/10-1/20后备用。
  5. 如权利要求3所述的降三高含片的制备方法，其特征在于，所述苦丁茶、杜仲叶预处理为：将处方量苦丁茶、杜仲叶分别洗净、晾干再混合，混合原材料粉碎后加入10-15倍水，煮沸后于90-100℃浸提3-4h，后于4500-5000r/min离心分离10-20min，取上清液，得到滤渣以相同步骤重复浸提、过滤2次，合并上清液，将合并的上清液浓缩至原混合提取液体积的1/10-1/20，将浓缩液进行喷雾干燥获得混合提取物粉末。
  6. 如权利要求3所述的降三高含片的制备方法，其特征在于，所述含片制备包括以下步骤：
    (1)取处方量罗汉果提取物、罗汉果壳粉备用；
    (2)取预处理得到的苦丁茶、杜仲叶合提取物粉末，处方量糊精、异麦芽糖醇、硬脂酸镁备用；
    (3)采用一步制粒法，将前述准备的所有组分加到一起置入喷雾干燥制粒机中，喷雾干燥造粒，制成粒径为40目的粒状粉料，然后利用压片机压片成型，得到重量在0.4～1.0g/片的降三高口含片。
  7. 如权利要求6所述的降三高含片的制备方法，其特征在于：所述步骤(3)中喷雾干燥造粒是以羧甲基淀粉钠的水溶液为粘合剂，溶液浓度为2％～6％，供液速度为10～30ml/min，床层温度40～70℃，压缩气压0.15～0.25MPa，喷雾制粒时间为40-80min。
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