WO2020187019A1 - 润肠通便的中药组合物、其制备方法及应用 - Google Patents

润肠通便的中药组合物、其制备方法及应用 Download PDF

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WO2020187019A1
WO2020187019A1 PCT/CN2020/077631 CN2020077631W WO2020187019A1 WO 2020187019 A1 WO2020187019 A1 WO 2020187019A1 CN 2020077631 W CN2020077631 W CN 2020077631W WO 2020187019 A1 WO2020187019 A1 WO 2020187019A1
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chinese medicine
traditional chinese
medicine composition
extraction
extract
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PCT/CN2020/077631
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English (en)
French (fr)
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杜成强
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清华德人西安幸福制药有限公司
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Priority to US17/440,758 priority Critical patent/US20220193173A1/en
Priority to EP20774006.9A priority patent/EP3943095A4/en
Priority to JP2021532176A priority patent/JP7157253B2/ja
Priority to KR1020217034030A priority patent/KR20210141649A/ko
Publication of WO2020187019A1 publication Critical patent/WO2020187019A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • 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
    • 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)
    • A61K36/886—Aloeaceae (Aloe family), e.g. aloe vera
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • 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
    • 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
    • A61K2236/37—Extraction at elevated pressure or temperature, e.g. pressurized solvent extraction [PSE], supercritical carbon dioxide extraction or subcritical water extraction
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to the technical field of traditional Chinese medicine, in particular to a traditional Chinese medicine composition for moisturizing the intestines and laxative, its preparation method and application.
  • Constipation is a common clinical symptom, which mainly refers to a decrease in the frequency of bowel movements, a decrease in stool volume, dry stool, and laborious defecation. When two or more of the above symptoms are present, it can be diagnosed as symptomatic constipation. It is usually based on the reduction of defecation frequency, generally defecation once every 2 to 3 days or longer (or ⁇ 3 times a week) is constipation.
  • the present invention aims to provide a traditional Chinese medicine composition for moisturizing the bowel and laxative, its preparation method and application, so as to reduce the risk of side effects after taking the medicine.
  • a Chinese medicinal composition for moisturizing the bowel and laxative is provided.
  • the active ingredient of the traditional Chinese medicine composition is made from the extract of the raw material medicine, and the raw material medicine is composed of aloe and citrus aurantium with a mass ratio of 2-5:1-10.
  • the raw material medicine is composed of aloe and citrus aurantium with a mass ratio of 5:7.
  • the traditional Chinese medicine composition also includes pharmaceutically acceptable excipients.
  • the dosage forms of the Chinese medicine composition are tablets, granules, capsules, pills, suppositories, powders, ointments, drops, aerosols, powder mists, solutions, suspensions, syrups, mixtures, wines Medicine, tea, lozenge, freeze-dried powder injection, or emulsion.
  • the traditional Chinese medicine composition is prepared by the following steps: S1, taking aloe vera and citrus aurantium with a mass ratio of 2-5:1-10 in an extraction tank for water extraction, and the vapor pressure of extraction is 0.25-0.35MPa , The temperature is 70 ⁇ 90°C, the extract is obtained after the extraction is completed; S2, the extract is concentrated under reduced pressure, the vacuum degree of the reduced pressure concentration is -0.08 ⁇ -0.06MPa, the vapor pressure is 0.25 ⁇ 0.35MPa, The temperature is 60-70°C to obtain a clear ointment; and S3, the clear ointment is used as an active ingredient to prepare a traditional Chinese medicine composition for moisturizing and laxative.
  • the extraction is carried out in 2 or more times.
  • the leaching includes: adding 6-10 times the amount of water for the first time, leaching for 4 hours; and the second time 4-8 times the amount of water, leaching for 3 hours; the first leaching obtained from the first leaching
  • the extract and the second extract obtained from the second extraction are combined and filtered to obtain the extract.
  • S3 also includes drying and pulverizing the clear ointment to obtain a dry ointment powder, and then preparing it as an effective ingredient into a traditional Chinese medicine composition for laxative and laxative.
  • a method for preparing the above-mentioned traditional Chinese medicine composition includes the following steps: S1, taking aloe vera and citrus aurantium with a mass ratio of 2 ⁇ 5:1 ⁇ 10 into an extraction tank for water extraction, the vapor pressure of extraction is 0.25 ⁇ 0.35MPa, and the temperature is 70 ⁇ At 90°C, the extract is obtained after the extraction is completed; S2, the extract is concentrated under reduced pressure, the vacuum degree of the reduced pressure concentration is -0.08 ⁇ -0.06MPa, the vapor pressure is 0.25 ⁇ 0.35MPa, and the temperature is 60 ⁇ 70 °C to obtain a clear ointment; and S3, the clear ointment is used as an active ingredient to prepare a laxative Chinese medicine composition; preferably, the extraction is carried out in 2 or more times; more preferably, the extraction includes: the first time Add 6-10 times the amount of water and extract for 4 hours; and for the second time 4-8 times the amount of water, extract for 3 hours
  • the composition of the traditional Chinese medicine composition for moisturizing and laxative bowel movement is simple, and the active ingredients are extracted from aloe vera and citrus aurantium, avoiding excessive reactions between the components of complex ingredients, and significantly reducing medication There is a risk of side effects afterwards, and it has a good laxative effect.
  • a Chinese medicinal composition for moisturizing the intestines and laxative is provided.
  • the active ingredients of the Chinese medicinal composition are made of extracts of raw materials, and the mass ratio of the raw materials is 2 ⁇ 5:1 ⁇ 10. Composed of aloe vera and citrus aurantium.
  • the raw material medicine is composed of aloe and Fructus Aurantii with a mass ratio of 5:7.
  • the traditional Chinese medicine composition further includes pharmaceutically acceptable auxiliary materials.
  • the dosage form of the traditional Chinese medicine composition is tablet, granule, capsule, pill, suppository, powder, ointment, drops, aerosol Medicine, powder mist, solution, suspension, syrup, mixture, wine, tea, lozenge, lyophilized powder injection, or emulsion. It can be ordinary formulations, sustained-release formulations, controlled-release formulations, and various particle delivery systems.
  • the pharmaceutical carrier familiar to those skilled in the art can be used to prepare the traditional Chinese medicine pharmaceutical composition of the present invention containing an effective dose.
  • oral preparations such as tablets, capsules, solutions or suspensions
  • injectable preparations such as injectable solutions or suspensions, or injectable dry powders. Add water for injection immediately before injection use).
  • the carrier in the pharmaceutical composition includes: binders used in oral preparations (such as starch, usually corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone), diluents (Such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycerin), lubricants (such as silicon dioxide, talc, stearic acid or its salts, usually magnesium stearate or hard Calcium fatty acid, and/or polyethylene glycol), and if necessary, also containing disintegrating agents, such as starch, agar, alginic acid or its salts, usually sodium alginate, and/or effervescent mixtures, co-solvents, Stabilizers, suspending agents, non-coloring, flavoring agents, etc., preservatives, solubilizers, stabilizers, etc.
  • binders used in oral preparations such as starch
  • compositions can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.
  • the phrase "effective dose" of the Chinese medicine pharmaceutical composition of the present invention refers to a compound in a sufficient amount to treat a disorder with a reasonable effect/risk ratio suitable for any medical treatment and/or prevention.
  • the total daily dosage of the traditional Chinese medicine composition of the present invention must be determined by the attending physician within the scope of reliable medical judgment.
  • the specific therapeutically effective dose level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; The age, weight, general health, gender, and diet of the patient; the time of administration, route of administration and excretion rate of the specific compound used; duration of treatment; drugs used in combination or concurrently with the specific compound used; and Similar factors well known in the medical field.
  • the dosage of the traditional Chinese medicine composition starts from a level lower than the level required to obtain the desired therapeutic effect, and gradually increases the dosage until the desired effect is obtained.
  • the dosage of the Chinese medicinal composition of the present invention for mammals, especially humans can range from 3.6 to 109 mg/kg ⁇ day (60 kg for adults).
  • the traditional Chinese medicine composition is prepared by the following steps: S1, taking aloe vera and citrus aurantium with a mass ratio of 2-5:1-10 in an extraction tank for water extraction,
  • the vapor pressure is 0.25 ⁇ 0.35MPa, the temperature is 70 ⁇ 90°C, the leaching liquid is obtained after the extraction is completed;
  • S2 the leaching liquid is concentrated under reduced pressure, and the vacuum degree of the vacuum concentration is -0.08 ⁇ -0.06MPa.
  • the pressure is 0.25-0.35 MPa and the temperature is 60-70°C to obtain a clear ointment; and S3, the clear ointment is used as an active ingredient to prepare a laxative Chinese medicine composition.
  • the extraction is carried out in two or more times. More preferably, the leaching includes: adding 6-10 times the amount of water for the first time, leaching for 4 hours; and the second time 4-8 times the amount of water, leaching for 3 hours; The extract and the second extract obtained from the second extraction are combined and filtered to obtain the extract.
  • S3 further includes drying and pulverizing the clear ointment to obtain a dry ointment powder, and then using the dry ointment powder as an active ingredient to prepare a laxative Chinese medicine composition. This is more convenient for the storage and industrial production of effective ingredients.
  • a method for preparing the above-mentioned traditional Chinese medicine composition includes the following steps: S1, taking aloe vera and citrus aurantium with a mass ratio of 2 ⁇ 5:1 ⁇ 10 into an extraction tank for water extraction, the vapor pressure of extraction is 0.25 ⁇ 0.35MPa, and the temperature is 70 ⁇ At 90°C, the extract is obtained after the extraction is completed; S2, the extract is concentrated under reduced pressure, the vacuum degree of the reduced pressure concentration is -0.08 ⁇ -0.06MPa, the vapor pressure is 0.25 ⁇ 0.35MPa, and the temperature is 60 ⁇ 70 °C to obtain a clear ointment; and S3, the clear ointment is used as an active ingredient to prepare a laxative Chinese medicine composition; preferably, the extraction is carried out in 2 or more times; more preferably, the extraction includes: the first time Add 6-10 times the amount of water and extract for 4 hours; and for the second time 4-8 times the amount of water, extract for 3
  • the compound diphenoxylate was given by oral gavage to establish a mouse small intestinal peristalsis inhibition model, calculate the ink advance rate of the small intestine within a certain period of time, and judge the gastrointestinal peristalsis function of the model mice.
  • the medium dose is 2.40ml/20ml/kg, take 2.40ml stock solution and add distilled water to 20ml.
  • mice The administration volume of mice is 20ml/kg, once a day.
  • Compound diphenoxylate tablets each containing 2.5mg compound diphenoxylate tablets, take 25mg (10 tablets) of compound diphenoxylate tablets, grind with a mortar to form a powder, add water to 100ml, and prepare before use.
  • mice 60 Kunming male mice weighing 18-22 g were purchased from the Experimental Animal Center of Xi'an Jiaotong University.
  • mice According to the weight of the mice, they were randomly divided into blank control group, model control group, and 1# sample small, medium and high-dose groups, a total of 5 groups, each with 12 mice.
  • the blank control group and the model control group were given distilled water by gavage, and the test sample was given in the same way.
  • the administration volume was 20ml/Kg, once a day for 10 consecutive days.
  • mice After the mice were given gastric administration for 10 days, the mice in each group were fasted without water for 16 hours.
  • the model control group and each dose group of the samples were given compound diphenoxylate (5mg/kg BW) by gavage, and the blank control group was given distilled water.
  • the dose groups were given the ink containing the corresponding test sample (containing 5% activated carbon powder, 10% gum arabic) by intragastric administration, and the blank and model control groups were given ink.
  • the animal was killed by removing the cervical vertebrae immediately, opening the abdominal cavity to separate the mesentery, cutting the upper end of the intestine from the pylorus, lower end to the ileocecal, and placing it on the tray, gently pulling the small intestine into a straight line, and measuring the length of the intestine as "total length of small intestine" , From the pylorus to the ink preface is "the length of ink advancing".
  • the data can be counted using the analysis of variance and the pairwise comparison of the means of multiple experimental groups and a control group. See Table 1 below for details.
  • the ink advancing rate of the model control group was extremely statistically significant (P ⁇ 0.01), indicating that the model preparation was established.
  • the ink advancing rate of each dose group of sample 1# has significant or extremely significant statistical significance
  • the model drug compound diphenoxylate was administered orally orally to establish a mouse model of constipation.
  • the time of the first black stool, the number of black stools and the weight of black stool discharged in 6 hours were measured to reflect the small size of the model. The defecation of the mouse.
  • Sample #1 Provided by Tsinghua Deren Xi'an Fortune Pharmaceutical Co., Ltd. (Aloe-Fructus Aurantii is fed at 5:7, decocted with an appropriate amount of water, and concentrated to 500ml). Each 1ml is equivalent to 0.4152g of total crude drug.
  • the medium dose is 2.40ml/20ml/kg, take 2.40ml stock solution and add distilled water to 20ml.
  • mice The administration volume of mice is 20ml/kg, once a day.
  • Compound diphenoxylate tablets each containing 2.5mg of compound diphenoxylate tablets, take 50mg (20 tablets) of compound diphenoxylate tablets, grind in a mortar and add distilled water to 100ml, and prepare before use.
  • mice 60 Kunming male mice weighing 18-22 g were purchased from the Experimental Animal Center of Xi'an Jiaotong University.
  • mice According to the weight of the mice, they were randomly divided into blank control group, model control group, and 1# sample small, medium, and high-dose groups, a total of 5 groups, each with 12 mice.
  • the blank control group and the model control group were given distilled water by gavage, and the test sample was given in the same way.
  • the administration volume was 20ml/Kg, once a day for 10 consecutive days.
  • mice After the mice were given gastric administration for 10 days, the mice in each group were fasted without water for 16 hours.
  • the model control group and 1# sample each dose group were given compound diphenoxylate (5mg/kg BW) by gavage, and the blank control group was given distilled water.
  • mice in the negative control group and the model control group were gavaged with ink, and the dose group was given the ink containing the test sample.
  • the animals were raised in single cages and drank and ate normally.
  • the data can be counted by the analysis of variance and the pairwise comparison of the means of multiple experimental groups and a control group. See Table 2, Table 3, and Table 4 for details.
  • the model control group's first black stool time has extremely significant statistical significance (P ⁇ 0.01), indicating that the model preparation is established.
  • P ⁇ 0.01 the time of first defecation of melena in each dose group of 1# sample was shortened, but it was not statistically significant (P>0.05).
  • the test result can be determined as positive.
  • the 1# sample has significant or extremely significant statistical significance on small intestinal peristalsis and defecation of mice (P ⁇ 0.05 or P ⁇ 0.01).
  • mice The model drug compound diphenoxylate was given by oral gavage to establish a mouse small intestinal peristalsis inhibition model, calculate the ink advancement rate of the small intestine within a certain period of time, and judge the gastrointestinal peristalsis function of the model mice.
  • mice defecation experiment The model drug compound diphenoxylate was given by oral gavage to establish a mouse model of constipation, and the time of the first defecation of the mice, the number of black defecation and black defecation within 6 hours were measured The weight reflects the defecation of the model mice.
  • Proportion I sample Aloe-Fructus Aurantii is fed at a ratio of 5:1, add appropriate amount of water to decoct and extract, and concentrate to 500ml, which is called the original liquid I. Each 1ml is equivalent to 0.4152g of the total crude drug.
  • Proportion II sample Aloe-Fructus Aurantii is fed at a ratio of 5:7, and an appropriate amount of water is added to decocting and extracting, and then concentrating to 500ml, which is called original liquid II. Each 1ml is equivalent to 0.4152g of the total crude drug.
  • Proportion III sample Aloe-Fructus Aurantii is fed at a ratio of 1:5, decocted and extracted with an appropriate amount of water, and concentrated to 500ml, which is called the original solution III. Each 1ml is equivalent to 0.4152g of the total crude drug.
  • the original solution I, the original solution II, and the original solution III are prepared according to the small, medium and large doses respectively.
  • the method is as follows:
  • mice The administration volume of mice is 20ml/kg, once a day.
  • compound diphenoxylate solution take 10 compound diphenoxylate tablets (each tablet contains 2.5mg compound diphenoxylate), grind in a mortar and add distilled water to 100ml, and prepare before use.
  • compound diphenoxylate solution take 20 compound diphenoxylate tablets (each tablet contains 2.5 mg compound diphenoxylate), grind with a mortar and add distilled water to 100ml, and prepare before use.
  • the blank control group and the model control group were given distilled water by gavage, and the test sample was given in the same way.
  • the administration volume was 20ml/Kg, once a day for 10 consecutive days.
  • mice After the mice were given gastric administration for 10 days, the mice in each group were fasted without water for 16 hours.
  • the model control group and each dose group of the sample were given 0.025% compound diphenoxylate solution (5mg/kg BW) by gavage, and the blank control group was given distilled water.
  • the dose groups were given the ink containing the corresponding test sample (containing 5% activated carbon powder, 10% gum arabic) by intragastric administration, and the blank and model control groups were given ink.
  • the animal was killed by removing the cervical vertebrae immediately, opening the abdominal cavity to separate the mesentery, cutting the upper end of the intestine from the pylorus, lower end to the ileocecal, and placing it on the tray, gently pulling the small intestine into a straight line, and measuring the length of the intestine as "total length of small intestine" , From the pylorus to the ink preface is "the length of ink advancing".
  • the data was calculated by analysis of variance, a pairwise comparison method of the means of multiple experimental groups and a control group. See Table 5 below for details.
  • the ink advancing rate of the model control group was extremely statistically significant (P ⁇ 0.01), indicating that the model preparation was established.
  • the ink advancing rate of each dose group of the sample is increased.
  • the medium and high dose group of the proportion I sample, the small, medium and high dose group of the proportion II sample, the medium and high dose group of the proportion III sample, the ink advancing The rates were all statistically significant (P ⁇ 0.05).
  • the blank control group and the model control group were given distilled water by gavage, and the test sample was given in the same way.
  • the administration volume was 20ml/Kg, once a day for 10 consecutive days.
  • mice After the mice were given gastric administration for 10 days, the mice in each group were fasted without water for 16 hours.
  • the model control group and each dose group of the samples were given 0.05% compound diphenoxylate solution (5mg/kg BW) by gavage, and the blank control group was given distilled water.
  • the data can be counted using the analysis of variance and the pairwise comparison of the means of multiple experimental groups and a control group. For details, see Table 6, Table 7 and Table 8.
  • the model control group's first black stool time has extremely significant statistical significance (P ⁇ 0.01), indicating that the model preparation is established.
  • P ⁇ 0.01 the proportion of samples I, II, and III samples in the middle-dose group and the high-dose group shortened the time of first defecation, but there was no statistical significance.
  • the test result can be determined as positive.
  • the ratio I (5:1), the ratio II (5:7), and the ratio III (1:5) all have a certain degree of laxative effect.
  • the intestinal laxative effect is ratio II (5:7)> ratio I (3:1)> ratio III (1:5).
  • the proportion of aloe should be appropriately reduced, so the ratio II (5:7) is the optimal ratio.
  • Aloe-Fructus Aurantii Chinese medicinal composition (sample 1 in Example 1), Aloe-Angelica-Ophiopogon japonicus-Fructus Aurantii Chinese medicinal composition (for the preparation method see patent: A Chinese medicinal composition for improving gastrointestinal function and Its preparation, patent number: ZL201110317780.9) has been confirmed by mouse functional experiments that the medium and large doses of each composition have the effect of moisturizing and laxative.
  • the daily intake of crude drugs in each group of mice (calculated as 20g) was calculated and counted (see Table 9). From the results, it can be seen that the daily intake of mice in the Aloe-Fructus Aurantii group The amount of imported medicines was lower than the aloe-angelica-Ophiopogon-Fructus Aurantii group.
  • Aloe vera accounted for 41.7% in the Aloe-Fructus Aurantii Chinese medicinal composition, and 50.9% of the Aloe Vera-Angelica-Ophiopogon-Fruit Chinese medicinal composition. Reduce the risk of side effects after taking the medicine.

Abstract

一种润肠通便的中药组合物、其制备方法及应用，所述中药组合物由质量比为2～5:1～10的芦荟和枳壳经提取制成。

Description

润肠通便的中药组合物、其制备方法及应用 技术领域
本发明涉及中药技术领域，具体而言，涉及一种润肠通便的中药组合物、其制备方法及应用。
背景技术
便秘是临床常见症状，主要是指排便次数减少、粪便量减少、粪便干结、排便费力等。上述症状同时存在2种以上时，可诊断为症状性便秘。通常以排便频率减少为主，一般每2～3天或更长时间排便一次(或每周＜3次)即为便秘。
现代人的生活方式较前发生了很大的变化，不少人久坐不动，饮食测试食不厌精，摄入的纤维素越来越少，有的人过度饮酒，种种原因导致消化功能失常，大肠秘结是最常见的现象，给不少人带来难言之苦，影响了身体的健康。
目前，市场上存在不少润肠通便的中药组合物，但是通常药物组分多，成分复杂，常言道“是药三分毒”，这在某种程度上增加了服药后产生副作用的风险。
发明内容
本发明旨在提供一种润肠通便的中药组合物、其制备方法及应用，以减低服药后产生副作用的风险。
为了实现上述目的，根据本发明的一个方面，提供了一种润肠通便的中药组合物。该中药组合物的有效成分由原料药的提取物制成，原料药由质量比为2～5：1～10的芦荟和枳壳组成。
进一步地，原料药由质量比为5：7的芦荟和枳壳组成。
进一步地，中药组合物还包括药学上可接受的辅料。
进一步地，中药组合物的剂型为片剂、颗粒剂、胶囊剂、丸剂、栓剂、散剂、膏剂、滴剂、气雾剂、粉雾剂、溶液剂、混悬剂、糖浆剂、合剂、酒剂、茶剂、口含片、冻干粉针剂、或乳剂。
进一步地，中药组合物通过以下步骤制备得到：S1，取质量比为2～5：1～10的芦荟和枳壳置于提取罐中进行加水浸提，浸提的汽压为0.25～0.35MPa，温度为70～90℃，浸提完成后得到浸提液；S2，将浸提液进行减压浓缩，减压浓缩的真空度为-0.08～-0.06MPa，汽压为0.25～0.35MPa，温度为60～70℃，得到清膏；以及S3，将清膏作为有效成分制备成润肠通便的中 药组合物。
进一步地，浸提分2次或多次进行。
进一步地，浸提包括：第一次加6～10倍量水，浸提4小时；以及第二次4～8倍量水，浸提3小时；将第一次浸提得到的第一浸提液与第二次浸提得到的第二浸提液合并过滤后得到浸提液。
进一步地，S3还包括，将清膏干燥、粉碎，得干膏粉，然后将作为有效成分制备成润肠通便的中药组合物。
根据本发明的另一方面，提供了一种上述中药组合物的制备方法。该制备方法包括以下步骤：S1，取质量比为2～5：1～10的芦荟和枳壳置于提取罐中进行加水浸提，浸提的汽压为0.25～0.35MPa，温度为70～90℃，浸提完成后得到浸提液；S2，将浸提液进行减压浓缩，减压浓缩的真空度为-0.08～-0.06MPa，汽压为0.25～0.35MPa，温度为60～70℃，得到清膏；以及S3，将清膏作为有效成分制备成润肠通便的中药组合物；优选的，浸提分2次或多次进行；更优选的，浸提包括：第一次加6～10倍量水，浸提4小时；以及第二次4～8倍量水，浸提3小时；将第一次浸提得到的第一浸提液与第二次浸提得到的第二浸提液合并过滤后得到浸提液；进一步优选的，S3还包括，将清膏干燥、粉碎，得干膏粉，然后将干膏粉作为有效成分制备成润肠通便的中药组合物。
根据本发明的另一方面，提供了一种上述润肠通便的中药组合物在制备润肠通便的药物中的应用。
应用本发明的技术方案，润肠通便的中药组合物成分简单，有效成分从芦荟和枳壳中提取，避免了复杂成分之间组分之间可能存在的过多反应，明显的降低了服药后产生副作用的风险，并且具有良好的润肠通便效果。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
现有市场上存在的润肠通便的中药组合物，但是通常药物组分多，成分复杂，这在某种程度上增加了服药后产生副作用的风险。为了降低这种风险，本发明的发明人对润肠通便的中药组合物进行了深入的研究。在研究过程中意外发现，仅仅芦荟和枳壳按照特定的比例进行配置作为原料药的提取物就能够达到良好的效果，这样就可以避免复杂成分之间组分之间可能存在的过多反应，明显的降低了服药后产生副作用的风险，可以说是取得了预料不到的效果。
根据本发明一种典型的实施方式，提供一种润肠通便的中药组合物，中药组合物的有效成分由原料药的提取物制成，原料药由质量比为2～5:1～10的芦荟和枳壳组成。
考虑到芦荟-枳壳组合物安全性问题，优选的，原料药由质量比为5：7的芦荟和枳壳组成。
根据本发明一种典型的实施方式，中药组合物还包括药学上可接受的辅料，中药组合物的剂型为片剂、颗粒剂、胶囊剂、丸剂、栓剂、散剂、膏剂、滴剂、气雾剂、粉雾剂、溶液剂、混悬剂、糖浆剂、合剂、酒剂、茶剂、口含片、冻干粉针剂、或乳剂。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。
运用本领域技术人员熟悉的药物载体可以制备成含有效剂量的本发明的中药药物组合物。例如，口服制剂(如片剂、胶囊剂、溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末，在注射前加入注射水可立即使用)。药物组合物中载体包括：口服制剂使用的粘合剂(如淀粉，通常是玉米、小麦或米淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮)，稀释剂(如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素，和/或甘油)，润滑剂(如二氧化硅、滑石、硬脂酸或其盐，通常是硬脂酸镁或硬脂酸钙，和/或聚乙二醇)，以及如果需要，还含有崩解剂，如淀粉、琼脂、海藻酸或其盐，通常是藻酸钠，和/或泡腾混合物，助溶剂、稳定剂、悬浮剂、无色素、矫味剂等，可注射的制剂使用的防腐剂、加溶剂、稳定剂等；局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可以将其配制成肠衣片剂。
词语“有效剂量”的本发明中药药物组合物指以适用于任何医学治疗和/或预防的合理效果/风险比治疗障碍的足够量的化合物。但应认识到，本发明的中药药物组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者，具体的治疗有效剂量水平须根据多种因素而定，所述因素包括所治疗的障碍和该障碍的严重程度；所采用的具体化合物的活性；所采用的具体组合物；患者的年龄、体重、一般健康状况、性别和饮食；所采用的具体化合物的给药时间、给药途径和排泄率；治疗持续时间；与所采用的具体化合物组合使用或同时使用的药物；及医疗领域公知的类似因素。例如，本领域的做法是，中药药物组合物的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。一般说来，本发明中药药物组合物用于哺乳动物特别是人的剂量可以介于3.6～109mg/kg·天(成人以60kg计)。
根据本发明一种典型的实施方式，中药组合物通过以下步骤制备得到：S1，取质量比为2～5：1～10的芦荟和枳壳置于提取罐中进行加水浸提，浸提的汽压为0.25～0.35MPa，温度为70～90℃，浸提完成后得到浸提液；S2，将浸提液进行减压浓缩，减压浓缩的真空度为-0.08～-0.06MPa，汽压为0.25～0.35MPa，温度为60～70℃，得到清膏；以及S3，将清膏作为有效成分制备成润肠通便的中药组合物。
尽管不能明确上述步骤所得清膏中的所有组分及其含量，但是发明人发现，通过上述步骤值得的中药组合物具有较好的疗效，同时，因为原始原料成分简单，因为可能产生的副作用风险也得到了极大的降低。
为了使有效成分得到充分的浸提，优选的，浸提分2次或多次进行。更优选的，浸提包括：第一次加6～10倍量水，浸提4小时；以及第二次4～8倍量水，浸提3小时；将第一次浸提得到的第一浸提液与第二次浸提得到的第二浸提液合并过滤后得到浸提液。
根据本发明一种典型的实施方式，S3还包括，将清膏干燥、粉碎，得干膏粉，然后将干膏粉作为有效成分制备成润肠通便的中药组合物。这样更方便有效成分的储存和工业化生产。
根据本发明一种典型的实施方式，提供了一种上述中药组合物的制备方法。该制备方法包括以下步骤：S1，取质量比为2～5：1～10的芦荟和枳壳置于提取罐中进行加水浸提，浸提的汽压为0.25～0.35MPa，温度为70～90℃，浸提完成后得到浸提液；S2，将浸提液进行减压浓缩，减压浓缩的真空度为-0.08～-0.06MPa，汽压为0.25～0.35MPa，温度为60～70℃，得到清膏；以及S3，将清膏作为有效成分制备成润肠通便的中药组合物；优选的，浸提分2次或多次进行；更优选的，浸提包括：第一次加6～10倍量水，浸提4小时；以及第二次4～8倍量水，浸提3小时；将第一次浸提得到的第一浸提液与第二次浸提得到的第二浸提液合并过滤后得到浸提液；进一步优选的，S3还包括，将清膏干燥、粉碎，得干膏粉，然后将作为有效成分制备成润肠通便的中药组合物。
尽管不能明确上述步骤所得清膏中的所有组分及其含量，但是发明人发现，通过上述步骤值得的中药组合物具有较好的疗效，同时，因为原始原料成分简单，因为可能产生的副作用风险也得到了极大的降低。
根据本发明一种典型的实施方式，提供了一种上述润肠通便的中药组合物在制备润肠通便的药物中的应用。
下面将结合实施例进一步说明本发明的有益效果。
实施例1
一、1#样品对小白鼠小肠蠕动的影响
1.原理
经口灌胃给予造模药物复方地芬诺酯，建立小鼠小肠蠕动抑制模型，计算一定时间内小肠的墨汁推进率，判断模型小鼠胃肠蠕动功能。
2.样品和仪器
2.1样品和仪器
2.1.1 1#样品：由清华德人西安幸福制药有限公司提供(芦荟-枳壳以5:7投料，加适量水煎煮提取，浓缩至500ml，称之为原液)，每1ml相当于总生药量0.4152g。
上述原液制备方法如下：
取芦荟、枳壳同时置多功能提取罐中，第1次加6～10倍量水，浸提4小时，第二次4～8 倍量水，浸提3小时，汽压0.25～0.35MPa，温度80℃，滤过，合并滤液，减压浓缩，真空度为-0.06～-0.08MPa，汽压为0.25～0.35MPa，温度为60～70℃，浓缩至500ml，称之为原液。
2.1.2仪器：手术剪、眼科镊、直尺、注射器、活性炭粉、阿拉伯树胶、复方地芬诺酯、量筒、蒸馏水、托盘、计时器。
2.2试剂配制
2.2.1 1#样品的配制
小剂量0.24ml/20ml/kg，取0.24ml原液加蒸馏水至20ml。
中剂量2.40ml/20ml/kg，取2.40ml原液加蒸馏水至20ml。
大剂量7.20ml/20ml/kg，取7.20ml原液加蒸馏水至20ml。
小鼠给药容积均为20ml/kg，每天1次。
2.2.2墨汁的配制
准确称取阿拉伯树胶50g，加水400ml，煮沸至溶液透明，称取活性炭(粉状)25g加至上述溶液中煮沸三次，待溶液凉后加水定容至500ml，于冰箱中4℃保存，用前摇匀。
2.2.3浓度0.025％复方地芬诺酯的配制
复方地芬诺酯片，每片含复方地芬诺酯2.5mg，取复方地芬诺酯片25mg(10片)，用研钵研碎呈粉末后加水至100ml，临用前配制。
3.实验方法
3.1实验动物
昆明雄性小鼠60只，体重18-22g，购自西安交通大学实验动物中心。
3.2实验步骤
3.2.1实验动物分组及给药
按小鼠体重随机分层分为空白对照组、模型对照组、1#样品小、中、大剂量组，共5组，每组12只。空白对照组和模型对照组灌胃给蒸馏水，同样途径给予受试样品，给药容积20ml/Kg，连续10天，每天1次。
3.2.2模型的建立
小鼠灌胃10天后，各组小鼠禁食不禁水16h。模型对照组和样品各剂量组灌胃给予复方地芬诺酯(5mg/kg BW)，空白对照组给蒸馏水。
3.2.3指标测定的具体方法
给复方地芬诺酯0.5小时后，剂量组分别灌胃给予含相应受试样品的墨汁(含5％的活性炭粉、10％阿拉伯树胶)，空白和模型对照组给墨汁。25分钟后立即脱颈椎处死动物，打开腹腔分离肠系膜，剪取上端自幽门、下端至回盲部的肠管，置于托盘上，轻轻将小肠拉成直线，测量肠管长度为“小肠总长度”，从幽门至墨汁前言为“墨汁推进长度”。按下算式计算墨汁推进率(％)：
Figure PCTCN2020077631-appb-000001
4.数据处理
数据可用方差分析，多个实验组和一个对照组均数的两两比较方法进行统计，详见下表1。
表1 1#样品对小鼠小肠蠕动的影响(
Figure PCTCN2020077631-appb-000002
n＝12)
Figure PCTCN2020077631-appb-000003
注：与正常组比较 △P<0.01；与模型组比较 **P<0.01；与模型组比较 *P<0.05.
5.实验结果
与正常对照组比较，模型对照组墨汁推进率具有极显著统计学意义(P＜0.01)，说明模型制备成立。与模型对照组比较，1#样品各剂量组墨汁推进率具有显著或极显著统计学意义
(P＜0.05或P＜0.01)。
二、1#样品对小白鼠排便的影响
1.原理
经口灌胃给予造模药物复方地芬诺酯，建立小鼠便秘模型，测定小鼠的首粒排黑便的时间、6小时内排黑便粒数和排黑便重量，来反应模型小鼠的排便情况。
2.样品和仪器
2.1样品和仪器
2.1.1 1#样品：由清华德人西安幸福制药有限公司提供(芦荟-枳壳以5:7投料，加适量水煎煮提取，浓缩至500ml)，每1ml相当于总生药量0.4152g。
上述原液制备方法如下：
取芦荟、枳壳同时置多功能提取罐中，第1次加6～10倍量水，浸提4小时，第二次4～8倍量水，浸提3小时，汽压0.25～0.35MPa，温度80℃，滤过，合并滤液，减压浓缩，真空度为-0.06～-0.08MPa，汽压为0.25～0.35MPa，温度为60～70℃，浓缩至500ml，称之为原液。
2.1.2仪器：手术剪、眼科镊、直尺、注射器、活性炭粉、阿拉伯树胶、复方地芬诺酯、量筒、蒸馏水、托盘、计时器。
2.2试剂配制
2.2.1 1#样品的配制
小剂量0.24ml/20ml/kg，取0.24ml原液加蒸馏水至20ml。
中剂量2.40ml/20ml/kg，取2.40ml原液加蒸馏水至20ml。
大剂量7.20ml/20ml/kg，取7.20ml原液加蒸馏水至20ml。
小鼠给药容积均为20ml/kg，每天1次。
2.2.2墨汁的配制
准确称取阿拉伯树胶50g，加水400ml，煮沸至溶液透明，称取活性炭(粉状)25g加至上述溶液中煮沸三次，待溶液凉后加水定容至500ml，于冰箱中4℃保存，用前摇匀。
2.2.3浓度0.05％复方地芬诺酯的配制
复方地芬诺酯片，每片含复方地芬诺酯2.5mg,取复方地芬诺酯片50mg(20片)，用研钵研碎后加蒸馏水至100ml，临用前配制。
3.实验方法
3.1实验动物
昆明雄性小鼠60只，体重18-22g，购自西安交通大学实验动物中心。
3.2实验步骤
3.2.1实验动物分组及给药
按小鼠体重随机分层分为空白对照组、模型对照组、1#样品小、中、大剂量组，共5个组，每组12只。空白对照组和模型对照组灌胃给蒸馏水，同样途径给予受试样品，给药容积20ml/Kg，连续10天，每天1次。
3.2.2模型的建立
小鼠灌胃10天后，各组小鼠禁食不禁水16h。模型对照组和1#样品各剂量组灌胃给予复方地芬诺酯(5mg/kg BW)，空白对照组给蒸馏水。
3.2.3指标测定的具体方法
给复方地芬诺酯0.5小时后，阴性对照组和模型对照组小鼠用墨汁灌胃，剂量组给予含受试样品的墨汁，动物均单笼饲养，正常饮水进食。
从灌墨汁开始，记录每只动物首粒排黑便时间、6小时内排黑便粒数及重量。
4.数据处理及结果判定
数据可用方差分析，多个实验组和一个对照组均数的两两比较方法进行统计，详见下表2、表3和表4。
表2 1#样品对小鼠首粒排黑便时间的影响(
Figure PCTCN2020077631-appb-000004
n＝12)
Figure PCTCN2020077631-appb-000005
注：与正常组比较 △P<0.01；与模型组比较 **P<0.01；与模型组比较 *P<0.05.
与正常对照组比较，模型对照组首粒排黑便时间具有极显著统计学意义(P＜0.01)，说明模型制备成立。与模型对照组比较，1#样品各剂量组首粒排黑便时间缩短，但无统计学意义(P＞0.05)。
表3 1#样品对小鼠排黑便粒数的影响(
Figure PCTCN2020077631-appb-000006
n＝12)
Figure PCTCN2020077631-appb-000007
注：与正常组比较 △P<0.05；与模型组比较 **P<0.01；与模型组比较 *P<0.05.
与正常对照组比较，模型对照组排黑便粒数具有显著统计学意义(P＜0.05)，说明模型制备成功。与模型对照组比较，1#样品各剂量组均具有显著统计学意义(P＜0.05)。
表4 1#样品对小鼠排黑便重量的影响(
Figure PCTCN2020077631-appb-000008
n＝12)
Figure PCTCN2020077631-appb-000009
Figure PCTCN2020077631-appb-000010
注：与正常组比较 △P<0.01；与模型组比较 **P<0.01；与模型组比较 *P<0.05.
与正常对照组比较，模型对照组的排黑便重量增加，但无统计学差异(P＞0.05)，与模型对照组比较，1#样品各剂量组排黑便重量具有显著统计学意义(P＜0.05)。
5.结果判定：
根据小肠运动实验和排便时间任一项结果阳性，同时6小时内排黑便重量和粒数任一项结果阳性，可判定该项实验结果阳性。
上述结果表明，与模型对照组比较，1#样品各剂量组墨汁推进率具有显著或极显著统计学意义(P＜0.05或P＜0.01)；1#样品各剂量组排黑便粒数具有显著统计学意义(P＜0.05)。
6.结论
1#样品对小白鼠小肠蠕动和排便作用具有显著或极显著统计学意义(P＜0.05或P＜0.01)。
实施例2
不同比例的中药组合物对润肠通便作用的影响
1原理：通过小鼠胃肠蠕动实验、小鼠排便实验结果本发明中中药组合物(芦荟和枳壳)比例的有益效果。
1.1小鼠胃肠蠕动实验：经口灌胃给予造模药物复方地芬诺酯，建立小鼠小肠蠕动抑制模型，计算一定时间内小肠的墨汁推进率，判断模型小鼠胃肠蠕动功能。
1.2小鼠排便实验：经口灌胃给予造模药物复方地芬诺酯，建立小鼠便秘模型，测定小鼠的首粒排黑便的时间、6小时内排黑便粒数和排黑便重量，反应模型小鼠的排便情况。
2样品和仪器
2.1样品和仪器
2.1.1样品来源：清华德人西安幸福制药有限公司提供。
2.1.2样品制备
(1)比例Ⅰ样品：芦荟-枳壳以5：1投料，加适量水煎煮提取，浓缩至500ml，称之为原液Ⅰ。每1ml相当于总生药量的0.4152g。
(2)比例Ⅱ样品：芦荟-枳壳以5：7投料，加适量水煎煮提取，浓缩至500ml，称之为原液Ⅱ。每1ml相当于总生药量的0.4152g。
(3)比例Ⅲ样品：芦荟-枳壳以1：5投料，加适量水煎煮提取，浓缩至500ml，称之为原液Ⅲ。每1ml相当于总生药量的0.4152g。
2.1.2仪器：手术剪、眼科镊、直尺、注射器、活性炭粉、阿拉伯树胶、复方地芬诺酯、量筒、蒸馏水、托盘、计时器。
2.2试剂配制
2.2.11给药剂量设置
原液Ⅰ、原液Ⅱ、原液Ⅲ分别按照小、中、大剂量进行配制，方法如下：
(1)小剂量：0.24ml/20ml/kg，取0.24ml原液加蒸馏水至20ml。
(2)中剂量：2.40ml/20ml/kg，取2.40ml原液加蒸馏水至20ml。
(3)大剂量：7.20ml/20ml/kg，取7.20ml原液加蒸馏水至20ml。
小鼠给药容积均为20ml/kg，每天1次。
2.2.2墨汁的配制
准确称取阿拉伯树胶50g，加水400ml，煮沸至溶液透明，称取活性炭(粉状)25g加至上述溶液中煮沸三次，待溶液凉后加水定容至500ml，于冰箱中4℃保存，用前摇匀。
2.2.3复方地芬诺酯溶液的配制
(1)0.025％复方地芬诺酯溶液：取复方地芬诺酯片10片(每片含复方地芬诺酯2.5mg)，用研钵研碎后加蒸馏水至100ml，临用前配制。
(2)0.05％复方地芬诺酯溶液：取复方地芬诺酯片20片(每片含复方地芬诺酯2.5mg)，用研钵研碎后加蒸馏水至100ml，临用前配制。
3小鼠胃肠蠕动实验
3.1实验方法
3.1.1实验动物
昆明雄性小鼠132只，体重18～22g，购自西安交通大学实验动物中心。
3.1.2实验步骤
3.1.2.1实验动物分组及给药
按小鼠体重随机分层分为空白对照组、模型对照组、比例Ⅰ样品小、中、大剂量组、比例Ⅱ样品小、中、大剂量组、比例Ⅲ样品小、中、大剂量组，共11组，每组12只。空白对照组和模型对照组灌胃给蒸馏水，同样途径给予受试样品，给药容积20ml/Kg，连续10天，每天1次。
3.1.2.2模型的建立
小鼠灌胃10天后，各组小鼠禁食不禁水16h。模型对照组和样品各剂量组灌胃给予0.025％复方地芬诺酯溶液(5mg/kg BW)，空白对照组给蒸馏水。
3.1.2.3指标测定的具体方法
给复方地芬诺酯0.5小时后，剂量组分别灌胃给予含相应受试样品的墨汁(含5％的活性炭粉、10％阿拉伯树胶)，空白和模型对照组给墨汁。25分钟后立即脱颈椎处死动物，打开腹腔分离肠系膜，剪取上端自幽门、下端至回盲部的肠管，置于托盘上，轻轻将小肠拉成直线，测量肠管长度为“小肠总长度”，从幽门至墨汁前言为“墨汁推进长度”。按下算式计算墨汁推进率(％)：
Figure PCTCN2020077631-appb-000011
3.2数据处理
数据用方差分析，多个实验组和一个对照组均数的两两比较方法进行统计，详见下表5。
表5 不同比例中药组合物对小鼠小肠蠕动的影响(
Figure PCTCN2020077631-appb-000012
n＝12)
Figure PCTCN2020077631-appb-000013
注：与正常组比较 △P<0.01；与模型组比较 **P<0.01；与模型组比较 *P<0.05.
3.3实验结果
与正常对照组比较，模型对照组墨汁推进率具有极显著统计学意义(P＜0.01)，说明模型制备成立。与模型对照组比较，样品各剂量组墨汁推进率增大，比例Ⅰ样品的中、大剂量组，比例Ⅱ样品的小、中、大剂量组，比例Ⅲ样品的中、大剂量组，墨汁推进率均具有显著统计学意义(P＜0.05)。
4小鼠排便实验
4.1实验方法
4.1.1实验动物
昆明雄性小鼠132只，体重18～22g，购自西安交通大学实验动物中心。
4.1.2实验步骤
4.1.2.1实验动物分组及给药
按小鼠体重随机分层分为空白对照组、模型对照组、比例Ⅰ样品小、中、大剂量组、比例Ⅱ样品小、中、大剂量组、比例Ⅲ样品小、中、大剂量组，共11个组，每组12只。空白对照组和模型对照组灌胃给蒸馏水，同样途径给予受试样品，给药容积20ml/Kg，连续10天，每天1次。
4.1.2.2模型的建立
小鼠灌胃10天后，各组小鼠禁食不禁水16h。模型对照组和，样品各剂量组灌胃给予0.05％复方地芬诺酯溶液(5mg/kg BW)，空白对照组给蒸馏水。
4.1.2.3指标测定的具体方法
给复方地芬诺酯0.5小时后，空白对照组和模型对照组小鼠用墨汁灌胃，剂量组给予含受试样品的墨汁，动物均单笼饲养，正常饮水进食。
从灌墨汁开始，记录每只动物首粒排黑便时间、6小时内排黑便粒数及重量。
4.2数据处理及结果判定
数据可用方差分析，多个实验组和一个对照组均数的两两比较方法进行统计，详见下表6、表7和表8。
表6 不同比例中药组合物对小鼠首粒排黑便时间的影响(
Figure PCTCN2020077631-appb-000014
n＝12)
Figure PCTCN2020077631-appb-000015
Figure PCTCN2020077631-appb-000016
注：与正常组比较 △P<0.01；与模型组比较 **P<0.01；与模型组比较 *P<0.05.
与正常对照组比较，模型对照组首粒排黑便时间具有极显著统计学意义(P＜0.01)，说明模型制备成立。与模型对照组比较，比例Ⅰ、Ⅱ、Ⅲ样品中剂量组和高剂量组首粒排黑便时间缩短，但无统计学意义。
表7 不同比例中药组合物对小鼠排黑便粒数的影响(
Figure PCTCN2020077631-appb-000017
n＝12)
Figure PCTCN2020077631-appb-000018
注：与正常组比较 △P<0.05；与模型组比较 **P<0.01；与模型组比较 *P<0.05.
与正常对照组比较，模型对照组排黑便粒数具有显著统计学意义(P＜0.05)，说明模型制备成功。与模型对照组比较，比例Ⅰ、Ⅱ、Ⅲ样品各剂量组排黑便粒数明显增加，中剂量组和大剂量组具有显著统计学意义(P＜0.05)。
表8 不同比例中药组合物对小鼠排黑便重量的影响(
Figure PCTCN2020077631-appb-000019
n＝12)
Figure PCTCN2020077631-appb-000020
Figure PCTCN2020077631-appb-000021
注：与正常组比较 △P<0.01；与模型组比较 **P<0.01；与模型组比较 *P<0.05.
与正常对照组比较，模型对照组排黑便重量增加，但无统计学差异(P＞0.05)。与模型对照组比较，比例Ⅰ、Ⅱ、Ⅲ样品各剂量组排黑便重量具有统计学意义(P＜0.05)。
4.3实验结果
根据小肠运动实验和排便时间任一项结果阳性，同时6小时内排黑便重量和粒数任一项结果阳性，可判定该项实验结果阳性。
上述结果表明，与模型对照组比较，比例Ⅰ、Ⅱ、Ⅲ样品各剂量组墨汁推进率具有显著或极显著统计学意义(P＜0.05或P＜0.01)；比例Ⅰ、Ⅱ、Ⅲ样品各剂量组排黑便粒数具有显著统计学意义(P＜0.05)。
5结论
通过小鼠胃肠蠕动实验、小鼠排便实验结果可知，比例Ⅰ(5:1)、比例Ⅱ(5:7)、比例Ⅲ(1:5)均具有一定的润肠通便作用，其润肠通便作用强弱为比例Ⅱ(5:7)＞比例Ⅰ(3:1)＞比例Ⅲ(1:5)。
另外，考虑到芦荟-枳壳组合物安全性问题，应适当降低芦荟的占比，故比例Ⅱ(5:7)为最优比例。
实施例3
中药组合物关于润肠通便作用的优势对比
1.芦荟-枳壳中药组合物(实施例1中的1#样品)、芦荟-当归-麦冬-枳壳中药组合物(制备方法参见专利：一种改善胃肠道功能的中药组合物及其制备，专利号：ZL201110317780.9)通过小鼠功能学实验证实，各组合物的中、大剂量均具有润肠通便功效。将各组样品的小鼠(以20g计)日摄入生药量计算统计(见表9)，由结果可知，在发挥润肠通便作用的前提下，芦荟-枳壳组的小鼠日摄入生药量低于芦荟-当归-麦冬-枳壳组。
表9 小鼠日摄入生药量(g)
Figure PCTCN2020077631-appb-000022
Figure PCTCN2020077631-appb-000023
2.芦荟-枳壳中药组合物中芦荟占比41.7％，芦荟-当归-麦冬-枳壳中药组合物中芦荟占比50.9％，芦荟的使用比例明显减少，提高了组合物的安全性，降低服药后产生副作用的风险。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种润肠通便的中药组合物，其特征在于，所述中药组合物的有效成分由原料药的提取物制成，所述原料药由质量比为2～5:1～10的芦荟和枳壳组成。
  2. 根据权利要求1所述的中药组合物，其特征在于，所述原料药由质量比为5：7的芦荟和枳壳组成。
  3. 根据权利要求1所述的中药组合物，其特征在于，所述中药组合物还包括药学上可接受的辅料。
  4. 根据权利要求3所述的中药组合物，其特征在于，所述的中药组合物的剂型为片剂、颗粒剂、胶囊剂、丸剂、栓剂、散剂、膏剂、滴剂、气雾剂、粉雾剂、溶液剂、混悬剂、糖浆剂、合剂、酒剂、茶剂、口含片、冻干粉针剂、或乳剂。
  5. 根据权利要求1至4中任一项所述的中药组合物，其特征在于，所述的中药组合物通过以下步骤制备得到：
    S1，取质量比为2～5:1～10的芦荟和枳壳置于提取罐中进行加水浸提，所述浸提的汽压为0.25～0.35MPa，温度为70～90℃，浸提完成后得到浸提液；
    S2，将所述浸提液进行减压浓缩，所述减压浓缩的真空度为-0.08～-0.06MPa，汽压为0.25～0.35MPa，温度为60～70℃，得到清膏；以及
    S3，将所述清膏作为有效成分制备成所述润肠通便的中药组合物。
  6. 根据权利要求5所述的中药组合物，其特征在于，所述浸提分2次或多次进行。
  7. 根据权利要求5所述的中药组合物，其特征在于，所述浸提包括：
    第一次加6～10倍量水，浸提4小时；以及
    第二次4～8倍量水，浸提3小时；
    将第一次浸提得到的第一浸提液与第二次浸提得到的第二浸提液合并过滤后得到所述浸提液。
  8. 根据权利要求5所述的中药组合物，其特征在于，所述S3还包括，将所述清膏干燥、粉碎，得干膏粉，然后将所述干膏粉作为有效成分制备成所述润肠通便的中药组合物。
  9. 一种如权利要求1至8中任一项所述的中药组合物的制备方法，其特征在于，包括以下步骤：
    S1，取质量比为2～5:1～10的芦荟和枳壳置于提取罐中进行加水浸提，所述浸提的汽压为0.25～0.35MPa，温度为70～90℃，浸提完成后得到浸提液；
    S2，将所述浸提液进行减压浓缩，所述减压浓缩的真空度为-0.08～-0.06MPa，汽压为0.25～0.35MPa，温度为60～70℃，得到清膏；以及
    S3，将所述清膏作为有效成分制备成所述润肠通便的中药组合物；
    优选的，所述浸提分2次或多次进行；
    更优选的，所述浸提包括：第一次加6～10倍量水，浸提4小时；以及第二次4～8倍量水，浸提3小时；将第一次浸提得到的第一浸提液与第二次浸提得到的第二浸提液合并过滤后得到所述浸提液；
    进一步优选的，所述S3还包括，将所述清膏干燥、粉碎，得干膏粉，然后将所述作为有效成分制备成所述润肠通便的中药组合物。
  10. 根据权利要求1至8中任一项所述的润肠通便的中药组合物在制备润肠通便的药物中的应用。
PCT/CN2020/077631 2019-03-21 2020-03-03 润肠通便的中药组合物、其制备方法及应用 WO2020187019A1 (zh)

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JP2021532176A JP7157253B2 (ja) 2019-03-21 2020-03-03 潤腸便通の漢方薬組成物、その調製方法及びその用途
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