WO2016041462A1 - 一种治疗打呼的药物组合物及其制备方法和用途 - Google Patents

一种治疗打呼的药物组合物及其制备方法和用途 Download PDF

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WO2016041462A1
WO2016041462A1 PCT/CN2015/089333 CN2015089333W WO2016041462A1 WO 2016041462 A1 WO2016041462 A1 WO 2016041462A1 CN 2015089333 W CN2015089333 W CN 2015089333W WO 2016041462 A1 WO2016041462 A1 WO 2016041462A1
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parts
uncaria
pharmaceutical composition
cinnamon
water
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PCT/CN2015/089333
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English (en)
French (fr)
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郭小雪
严晓玲
钟莉沙
张弘
钟雨禅
黄泽祥
谭名湘
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四川圣棠湖生物科技有限公司
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Priority to US15/527,612 priority Critical patent/US20180296625A1/en
Publication of WO2016041462A1 publication Critical patent/WO2016041462A1/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)
    • A61K36/74—Rubiaceae (Madder family)
    • 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)
    • A61K36/428—Trichosanthes
    • 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
    • A61K36/482—Cassia, e.g. golden shower 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)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • 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)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • 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)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1664—Compounds of unknown constitution, e.g. material from plants or 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for treating snoring, a preparation method and use thereof.
  • Snoring (medical terminology for snoring, snoring, sleep apnea syndrome) is a ubiquitous sleep phenomenon that most people think is commonplace now, and it is not a problem, and some people regard snoring as a sleepy scent. Performance.
  • snoring People generally divide snoring into multiple categories, ranging from mild snoring to severe snoring, including hypopnea (during which the person's breathing may become Abnormally slow and shallow) and suffocation events (breathing stops during this period). The latter of these cases is characteristic of obstructive sleep apnea (OSP) involving a complete airway closed airway closure.
  • OSP obstructive sleep apnea
  • the methods of treating snoring mainly include surgical treatment, medical treatment and physical device treatment.
  • Surgical treatment It is necessary to select different surgical methods according to the plane of obstruction, perform nasal surgery or pharyngealplasty, etc. It is the most commonly used surgical method for treating snoring and sleep apnea. Its success depends on the choice of the surgical patient, and the treatment process is painful.
  • Medication At present, there are many drugs used to treat snoring at home and abroad. For example, acetazolamide and thyroxine tablets can promote metabolism and have certain effects. During the medication, the snoring can be relieved to a certain extent, but it cannot be cured. Some physical devices such as nose clips and tongue pads that have appeared in recent years have gradually faded out of the market because of their unsatisfactory results.
  • the present invention provides a pharmaceutical composition for treating snoring, the drug substance of which contains the following components by weight:
  • the present inventors have unexpectedly discovered in the study that after the combination of Uncaria and Cinnamon, the therapeutic effect on snoring is significantly better than that of Uncaria, indicating that the present invention combines the two to produce a synergistic effect; Unexpectedly, cinnamon and cassia twig are the different sites of the same plant. There is no research report on the relationship between snoring and treatment. However, the present invention combines cinnamon with genus After use, the therapeutic effect on snoring was significantly better than that of the combination of Uncaria and Guizhi.
  • Uncaria rhynchophylla (Miq.) ex Havil. is a dry, hooked stem of the genus Uncaria rhynchophylla (Miq.) ex Havil. It is sweet, slightly bitter, and slightly cold. It is used to clear the heat and calm the liver; Modern pharmacological studies have confirmed that Uncaria can improve nasal discharge, treat high blood pressure, and regulate nerve machines. Can be dysfunctional, treat children with convulsions, dizziness and so on.
  • Cinnamon is the dry bark of Cinnamomum cassia Presl, which is spicy and hot. Used to supplement Yuanyang, warm spleen and stomach, in addition to cold, blood and so on. Modern pharmacological studies have confirmed that Uncaria can treat bronchial asthma and regulate the central nervous system.
  • the drug substance contains the following components by weight:
  • the weight fraction of Uncaria and Cinnamon used is 25 parts of Uncaria and 15 parts of Cinnamon.
  • the present invention further provides a kind of In the composition, the raw material medicine further contains the following components by weight:
  • the trichosanthes is the root of Trichosanthes kirilowii Maxim. It is sweet, slightly bitter and slightly cold. For fever, polydipsia, lung heat dry cough, internal heat and thirst, sore swollen poison. Modern pharmacological studies have confirmed that trichosanthin has anti-early pregnancy, anti-cancer, immune-enhancing, antibacterial and anti-viral effects.
  • Reed rhizomes are fresh or dried rhizomes of the Phragmites communis Trin., sweet and cold. For fever, polydipsia, stomach heat vomiting, lung heat cough, lung phlegm and pus, hot dripping pain. Modern pharmacological studies have confirmed that reed rhizomes have an inhibitory effect on skeletal muscle and have a relaxing effect on isolated guinea pig intestines.
  • Turmeric is a dry root of the perennial herb turmeric (Curcuma longa L.) of the family Zingiberaceae and Curcuma. It has a bitter taste and warmth. For chest and abdominal pain, dysmenorrhea and limb pain. Modern pharmacological studies have confirmed that turmeric has hypolipidemic, anti-tumor, anti-inflammatory and anti-pathogenic agents. The role of choleretic and the improvement of the cardiovascular system.
  • the drug substance contains the following components by weight:
  • Uncaria 15 parts of cinnamon, 18 parts of trichosanthin, 20 parts of reed rhizome, and 12 parts of turmeric.
  • a preparation form prepared from a powder of a drug substance, an aqueous extract or/and an alcohol extract as an active ingredient, and a pharmaceutically acceptable auxiliary or auxiliary ingredient.
  • the pharmaceutically acceptable excipient of the present invention refers to a substance contained in a dosage form other than the active ingredient, including but not limited to a filler (diluent), a lubricant (glidant or anti-adhesive), a dispersing agent, Wetting agents, binders, conditioners, solubilizers, antioxidants, bacteriostatic agents, emulsifiers, disintegrators, and the like.
  • the binder comprises syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose and derivatives thereof (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose) , gelatin paste, syrup, starch slurry or polyvinylpyrrolidone; fillers include lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, phosphoric acid Hydrogen calcium, precipitated calcium carbonate, etc.), sorbitol or glycine; the lubricant comprises micronized silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; the disintegrant comprises starch and Derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch,
  • the pharmaceutically acceptable auxiliary component has a certain physiological activity, but the addition of the component does not change the dominant position of the above compound or derivative in the course of the disease treatment, but only plays an auxiliary effect, and the auxiliary effects are only
  • the use of known activity of this component is an adjuvant treatment that is commonly used in the medical field. If the above auxiliary ingredients are combined with the present hair The use of the compounds in combination is still within the scope of protection of the present invention.
  • the dosage form is a transgastrointestinal absorption dosage form; the dosage form is selected from the group consisting of a wine, an oral solution, a beverage, a granule, a powder, a pill, a tablet or a capsule.
  • the invention also provides a preparation method of the above pharmaceutical composition, which comprises the following steps:
  • the aqueous extract may be added to a pharmaceutically acceptable auxiliary or auxiliary ingredient preparation.
  • the water is extracted into boiling or ultrasonic.
  • the water extract or the medicine powder is used in traditional Chinese medicine. After water extraction, due to the wide range of water dissolution, most of the active ingredients can be dissolved, so that the medicine is more easily absorbed by the body and the effect is faster, such as decoction.
  • the dosage form is the same as the original powder; the surface area of the powder is larger, which is also beneficial to the absorption of the active ingredients in the medicine, but the active ingredient is still extracted and reabsorbed in the body, and the effect is relatively high. It is slower, but it also weakens the toxic side effects caused by harmful components in the medicine. It is suitable for long-term use, such as preparation of the original powder into pellets.
  • ethanol is used as a solvent to extract the drug, which is also one of the most common extraction methods.
  • Ethanol is a semi-polar solvent, and its solubility is between polar and non-polar solvents, which can dissolve water-soluble one.
  • Some ingredients can also dissolve some components dissolved in non-polar solvents, usually with ethanol extraction instead of decoction, thus avoiding the dissolution of a large number of ineffective ingredients, increasing the concentration of active ingredients and extraction efficiency, but the price of ethanol is more expensive than water, in modern In the large-scale production of the pharmaceutical industry, in order to save production costs, it is usually based on water decoction.
  • water extract, raw powder, alcohol extraction or a combination thereof may be optionally used to prepare a specific dosage form. .
  • the invention also provides the use of the above pharmaceutical composition for the preparation of a snoring drug.
  • the invention provides a two-flavored traditional Chinese medicine Uncaria sinensis, cinnamon, and a combination thereof with traditional Chinese medicine Tianhua powder, reed rhizome and turmeric, and has the effects of improving or inhibiting the symptoms of snoring, and the curative effect is remarkable. No side effects, avoiding the risk of surgery and providing new options for clinical treatment.
  • Formulation ratio 15 parts of Uncaria and 5 parts of cinnamon.
  • the invention provides a preparation method of the above traditional Chinese medicine material and plant extract composition, the main steps of which are as follows:
  • the above concentrated liquid is spray-dried by a high-speed centrifugal spray dryer to prepare a dry extract powder of 80-120 mesh;
  • the dry extract powders are weighed according to the formula ratio, and then added into suitable tablets to prepare ordinary tablets.
  • Formulation ratio 20 parts of Uncaria and 10 parts of cinnamon.
  • the invention provides a preparation method of the above traditional Chinese medicine material and plant extract composition, the main steps of which are as follows:
  • the above concentrated liquid is spray-dried by a high-speed centrifugal spray dryer to prepare a dry extract powder of 80-120 mesh;
  • the dry extract powders are weighed according to the formula ratio, and then added into suitable capsules to prepare capsules.
  • Formulation ratio 25 parts of Uncaria and 15 parts of cinnamon.
  • the invention provides a preparation method of the above traditional Chinese medicine material and plant extract composition, the main steps of which are as follows:
  • the above concentrated liquid is spray-dried by a high-speed centrifugal spray dryer to prepare a dry extract powder of 80-120 mesh;
  • the dry extract powders are weighed according to the formula ratio, and then added into suitable auxiliaries to prepare granules.
  • Formulation ratio 15 parts of Uncaria, 5 parts of cinnamon, 12 parts of trichosanthin, 12 parts of reed rhizome, and 6 parts of turmeric.
  • the invention provides a preparation method of the above traditional Chinese medicine material and plant extract composition, the main steps of which are as follows:
  • the above concentrated liquid is spray-dried by a high-speed centrifugal spray dryer to prepare a dry extract powder of 80-120 mesh;
  • the dry extract powder is evenly mixed according to the formula ratio, and then added with suitable excipients to prepare ordinary tablets.
  • Formulation ratio 20 parts of Uncaria, 10 parts of cinnamon, 15 parts of trichosanthin, 17 parts of reed rhizome, and 9 parts of turmeric.
  • the invention provides a preparation method of the above traditional Chinese medicine material and plant extract composition, and the main method thereof The steps are as follows:
  • the above concentrated liquid is spray-dried by a high-speed centrifugal spray dryer to prepare a dry extract powder of 80-120 mesh;
  • the dry extract powder is uniformly mixed according to the formula ratio, and then added into suitable capsules to prepare capsules.
  • Formulation ratio 25 parts of Uncaria, 15 parts of cinnamon, 18 parts of trichosanthin, 20 parts of reed rhizome, and 12 parts of turmeric.
  • the invention provides a preparation method of the above traditional Chinese medicine material and plant extract composition, the main steps of which are as follows:
  • the above concentrated liquid is spray-dried by a high-speed centrifugal spray dryer to prepare a dry extract powder of 80-120 mesh;
  • the doses were calculated in terms of the amount of crude drug equivalent to the corresponding extracted raw material g/kg.
  • Example 3 of the present invention was used in the following experiment.
  • mice were given 50 g (raw drug)/kg of the test preparation once a day, and no animal died during the test period. It can be determined that the maximum tolerated dose of the mouse once administered is 50 g (raw drug)/kg, which is equivalent to clinical
  • the daily dosage of the person is 125 times (in terms of 60 kg per person, 2 capsules per capsule, once a day, each containing 12 g of crude drug, 24 g per person, 0.4 g/kg/day).
  • Rats were continuously intragastrically administered at a dose of 20 g/kg for 14 weeks. Compared with the distilled water of the control group, no general clinical symptoms, weight gain, hematology, blood biochemical examination indicators, and related organ systems were observed. Pathological tissue toxicity changes. After 4 weeks of withdrawal, the remaining items of the above-mentioned items were not examined for the delayed toxicity of the test article. It is indicated that the composition of the present invention has no obvious side effects by continuous oral administration.
  • Example 1 of the composition of the present invention was a test sample of the composition of the present invention.
  • the dry extract powder was weighed and mixed according to 15 parts of Uncaria, and then added into a suitable tablet to prepare a common tablet, and the test sample of Uncaria was obtained.
  • the method of administration is 2 tablets before bedtime, each tablet is 0.25 g (each tablet is equivalent to 12 g of crude drug); 240 cases of sleep are counted. Treatment of patients with apnea syndrome.
  • the main manifestations of sleep apnea syndrome are:
  • the disease level is divided into mild, moderate and severe.
  • the number of mild apneas is 30-50 times / seven hours, each timeout is 10-30 seconds;
  • Moderate condition apnea is 50-100 times / seven hours, each timeout is 30-60 seconds;
  • the number of severe apneas is 100-200 times/seven hours, and each pause time is greater than 60 seconds.
  • Treatment Warm clothes every night before going to bed, seven days for a course of treatment.
  • Cure normal sleep, snoring disappeared, all kinds of complications caused by snoring disappeared, headache, dizziness and drowsiness disappeared completely, and there was spirit during the day, feeling clear thinking, enhanced memory and complete recovery.
  • the traditional Chinese medicine composition provided by the invention has good curative effect, rapid effect and no side effects, and has significant curative effect on snoring.
  • mice were administered with 50 g (raw drug)/kg of the pharmaceutical composition prepared in Example 1 and Example 2 in a single intragastric administration, and no animal died during the test period, and the maximum tolerance of the mouse in one administration was determined.
  • the amount is 50g (raw drug) / kg, which is equivalent to 125 times of the daily dose of the clinical provider (based on 60kg per person, 2 capsules per capsule, once a day, each containing 12g of medicine, daily dosage of 24g, 0.4g / kg / day).
  • Example 1 and Example 2 of the present invention The pharmaceutical composition prepared in Example 1 and Example 2 of the present invention was continuously administered intragastrically at a dose of 20 g/kg for 14 weeks. Compared with the distilled water of the control group, no general clinical symptoms, weight gain, and hematology were observed in the animals. , indicators of blood biochemical examination, toxicity changes related to organ systems and pathological tissues. After 4 weeks of withdrawal, the remaining items of the above-mentioned items were not examined for the delayed toxicity of the test article. It is indicated that the composition of the present invention has no obvious side effects by continuous oral administration.
  • the dry extract powder was weighed and mixed according to 15 parts of Uncaria, and then added into a suitable tablet to prepare a common tablet, and the test sample of Uncaria was obtained.
  • the taking method is 2 pieces before bedtime, each piece is 0.25 g (each piece is equivalent Including the amount of crude drug (12g); statistics on the treatment of 320 patients with sleep apnea syndrome.
  • the main manifestations of sleep apnea syndrome are:
  • the disease level is divided into mild, moderate and severe.
  • the number of mild apneas is 30-50 times / seven hours, each timeout is 10-30 seconds;
  • Moderate condition apnea is 50-100 times / seven hours, each timeout is 30-60 seconds;
  • the number of severe apneas is 100-200 times/seven hours, and each pause time is greater than 60 seconds.
  • 320 patients 240 were male and 80 were female, aged 36-82 years. There were 160 patients with mild disease, 120 patients with moderate disease, and 40 patients with severe disease. In the experiment, it is divided into four groups, that is, the composition group obtained in the second embodiment of the present invention, the composition group prepared in the third embodiment of the composition, the nectarine group and the hook vine group, each group 80 people, 60 males and 20 females, including 40 mild patients in each group, 30 moderate patients, and 10 severe patients
  • Treatment Warm clothes every night before going to bed, seven days for a course of treatment.
  • Cure normal sleep, snoring disappeared, all kinds of complications caused by snoring disappeared, headache, dizziness and drowsiness disappeared completely, and there was spirit during the day, feeling clear thinking, enhanced memory and complete recovery.
  • the traditional Chinese medicine composition for treating snoring provided by the second embodiment and the third embodiment of the present invention has good curative effect, rapid effect and no side effects, and has remarkable curative effect on snoring.
  • mice were given 50 g (raw drug)/kg of the test preparation once a day, and no animal died during the test period. It can be determined that the maximum tolerated dose of the mouse once administered is 50 g (raw drug)/kg, which is equivalent to clinical Provides 125 times the daily dose (based on 60kg per person, taking capsules each time) 2 capsules, once a day, each containing 12g of crude drug, daily dosage of 24g, 0.4g / kg / day).
  • Rats were continuously intragastrically administered at a dose of 20 g/kg for 14 weeks. Compared with the distilled water of the control group, no general clinical symptoms, weight gain, hematology, blood biochemical examination indicators, and related organ systems were observed. Pathological tissue toxicity changes. After 4 weeks of withdrawal, the remaining items of the above-mentioned items were not examined for the delayed toxicity of the test article. It is indicated that the composition of the present invention has no obvious side effects by continuous oral administration.
  • composition of the present invention (Example 4) was taken as 2 tablets before bedtime, 0.25 g per tablet (each tablet corresponds to a crude drug amount of 12 g); and the treatment of 120 patients with sleep apnea syndrome was counted.
  • the main manifestations of sleep apnea syndrome are:
  • the disease level is divided into mild, moderate and severe.
  • the number of mild apneas is 30-50 times / seven hours, each timeout is 10-30 seconds;
  • Moderate condition apnea is 50-100 times / seven hours, each timeout is 30-60 seconds;
  • the number of severe apneas is 100-200 times/seven hours, and each pause time is greater than 60 seconds.
  • Treatment Warm clothes every night before going to bed, seven days for a course of treatment.
  • Cure normal sleep, snoring disappeared, all kinds of complications caused by snoring disappeared, headache, dizziness and drowsiness disappeared completely, and there was spirit during the day, feeling clear thinking, enhanced memory and complete recovery.
  • the therapeutic effect shows that the traditional Chinese medicine composition for treating snoring provided by the invention has good curative effect, rapid effect and no side effect, and has remarkable curative effect on snoring.
  • the cure rate of the five-drug combination for one course of mild, moderate and severe patients was 88.3%, 70% and 45%, respectively.
  • the cure rates of the two courses were 95%, 87.5% and 70% respectively.
  • the cure rate of the combination of Uncaria and Cinnamon for the treatment of mild, moderate and severe patients was 80%, 60% and 30%, respectively.
  • the cure rates of the two courses were 90%, 83.3% and 60% respectively. Therefore, the therapeutic effect of the combination of Wuwei and Cinnamon is obviously better than that of the combination of Uncaria and Cinnamon.
  • Example 4 The products prepared in Example 4 and Example 5 of the present invention were used in the following tests.
  • the pharmaceutical composition prepared in Example 4 and Example 5 was administered to the mice by a single intragastric administration. 50g (raw drug) / kg, no animal death during the test period, it can be determined that the maximum tolerated dose of a mouse in one dose is 50g (raw drug) / kg, equivalent to 125 times the daily dose of the clinical provider (per For a person weighing 60 kg, take 2 capsules each time, once a day, each containing 12 g of crude drug, and the daily dose is 24 g, 0.4 g/kg/day.
  • Example 4 and Example 5 of the present invention were continuously administered intragastrically at a dose of 20 g/kg for 14 weeks. Compared with the distilled water of the control group, no general clinical symptoms, weight gain, and hematology were observed in the animals. , indicators of blood biochemical examination, toxicity changes related to organ systems and pathological tissues. After 4 weeks of withdrawal, the remaining items of the above-mentioned items were not examined for the delayed toxicity of the test article. It is indicated that the composition of the present invention has no obvious side effects by continuous oral administration.
  • composition of the present invention (Example 5 and Example 6) was taken as 2 tablets before bedtime, 0.25 g per tablet (each tablet corresponds to a crude drug amount of 12 g); and the treatment of 240 patients with sleep apnea syndrome was counted.
  • the main manifestations of sleep apnea syndrome are:
  • the disease level is divided into mild, moderate and severe.
  • the number of mild apneas is 30-50 times / seven hours, each timeout is 10-30 seconds;
  • Moderate condition apnea is 50-100 times / seven hours, each timeout is 30-60 seconds;
  • the number of severe apneas is 100-200 times/seven hours, and each pause time is greater than 60 seconds.
  • the 240 patients there were 160 males and 80 females, aged 36-82 years. There were 120 patients with mild disease, 80 patients with moderate disease, and 40 patients with severe disease.
  • the experiment is divided into two groups, namely, the pharmaceutical composition group prepared in the fifth embodiment of the present invention and the pharmaceutical composition group prepared in the sixth embodiment of the present invention, each group of 120 persons, 80 males and 40 females, among which mild There were 60 patients, 40 patients with moderate disease, and 20 patients with severe disease.
  • Treatment Warm clothes every night before going to bed, seven days for a course of treatment.
  • Cure normal sleep, snoring disappeared, all kinds of complications caused by snoring disappeared, headache, dizziness and drowsiness disappeared completely, and there was spirit during the day, feeling clear thinking, enhanced memory and complete recovery.
  • the therapeutic effect shows that the traditional Chinese medicine composition for treating snoring provided by the fifth embodiment and the sixth embodiment of the present invention has good curative effect, rapid effect and no side effect, and has remarkable curative effect on snoring.
  • the cure rate of the five-drug combination provided in Example 5 was 91.6%, 70%, and 50% for one course of mild, moderate, and severe patients, respectively, and the cure rates for the two courses were 95%, 90%, and 70%, respectively.
  • the cure rate of the five-drug combination provided in Example 6 was 91.6%, 72.5%, and 50% for one course of mild, moderate, and severe patients, respectively, and the cure rates for the two courses were 96.7%, 90%, and 70%, respectively. .
  • the cure rate of the combination of Uncaria and Cinnamon for the treatment of mild, moderate and severe patients was 80%, 60% and 30%, respectively.
  • the cure rates of the two courses were 90%, 83.3% and 60% respectively. Therefore, the therapeutic effects of the combination of the five herbs provided in Example 5 and Example 6 are significantly better than the therapeutic effects of the combination of Uncaria and Cinnamon.

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Abstract

一种治疗打鼾的药物组合物，其原料药含有如下重量份的组分：钩藤15-25份，肉桂5-15份。该药物组合物的原料药还可以含有如下重量份的组分：天花粉12-18份，芦根12-20份，姜黄6-12份。该药物组合物的制备方法及其用途。该药物组合物具有抑制或改善打鼾症状的作用。

Description

一种治疗打呼的药物组合物及其制备方法和用途
本申请要求于2014年9月16日提交中国专利局、申请号为201410473010.7、发明名称为“一种治疗打呼的药物组合物及其制备方法和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种治疗打呼的药物组合物及其制备方法和用途。
背景技术
打呼(医学术语为鼾症、打呼噜、睡眠呼吸暂停综合症)是一种普遍存在的睡眠现象，目前大多数人认为这是司空见惯的，而不以为然，还有人把打呼噜看成睡得香的表现。
但是一些调查报告表明至少有20％的人睡觉打呼噜，其实打呼噜是健康的大敌，由于打呼噜使睡眠呼吸反复暂停，造成大脑、血液严重缺氧，形成低血氧症，而诱发高血压、脑心病、心率失常、心肌梗死、心绞痛。夜间呼吸暂停时间超过120秒容易在凌晨发生猝死。
通过医学研究证明，打呼噜主要是由于以下3种原因引起：
1.中枢性方面的疾病引起；
2.阻塞性方面的疾病引起；
3.混合性方面的疾病引起。
一般而言，成年人以混合性原因为多，未成年人则以阻塞性的问题为多。通过深入研究，已经鉴定了多种风险因子，包括吸烟、酒精、肥胖、多种生理学原因(例如，鼻中隔弯曲以及内部鼻结构的其他异常、慢性鼻充血、喉组织的充血、适合度以适能(fitness)及肌肉张力的缺乏、扁桃体或腺样体的肥大、以及舌肿大)。药物治疗(例如，苯并二氮杂卓类(benzodazines)以及镇静剂类)还可能导致肌肉松弛，由此增加了打鼾的风险或倾向。人们一般将打鼾分成多个种类，范围从轻度打鼾到重度打鼾，包括呼吸不足(在此期间人的呼吸可能变得 异常地慢和浅)以及窒息事件(在此期间呼吸停止)。这些情况中的后者是阻塞性睡眠呼吸暂停(OSP)的特征，涉及完全的气路封闭气道闭合。
目前治疗打呼的手段主要有手术治疗、药物治疗和物理器械治疗等方法。手术治疗：要根据阻塞的平面选择不同的手术方法，进行鼻部的手术或者腭咽成形术等，它是目前治疗打鼾及睡眠呼吸暂停最常用的手术方法。它的成功与否决定于手术病人的选择，且治疗过程痛苦较大。药物治疗：目前国内外用来治疗打呼噜的药物很多，如乙酰唑胺、甲状腺素片，能促进新陈代谢，具有一定功效，服药期间可以一定程度缓解打呼，但不能治愈。近年来出现的一些物理器械如鼻夹、舌托等，都因为效果不理想，而渐渐淡出市场。
而应用中医药治疗打呼已有多年历史，同时具有疗效显著、副作用小、应用广泛等特点。
发明内容
本发明的目的在于提供一种治疗打呼的药物组合物。本发明的另一目的在于提供该组合物的制备方法和用途。
具体地，本发明提供了一种治疗打呼的药物组合物，其原料药含有如下重量份的组分：
钩藤15—25份、肉桂5—15份。
本发明在研究中意外地发现，将钩藤与肉桂联合使用后，其对打呼的治疗作用显著优于钩藤单味药，表明本发明将两者组合使用产生了协同增效作用；更令人意料不到的是，肉桂与桂枝为同一植物的不同用药部位，当前并未有研究报道称两者之间对打呼治疗作用的优劣关系，然而本发明将肉桂与钩藤联合使用后，对打呼的治疗作用却明显优于钩藤与桂枝联用组。
钩藤为茜草科植物钩藤(Uncaria rhynchophylla(Miq.)ex Havil.)的干燥带钩茎枝，味甘、微苦，性微寒。用于清热平肝；熄风止痉。现代药理研究证实钩藤能够改善鼻衄不止、治疗高血压、调节神经机 能失调、治疗小儿惊热、头晕目眩等。
肉桂为樟科植物肉桂(Cinnamomum cassia Presl)的干燥树皮，味辛，性热。用于补元阳，暖脾胃，除积冷，通血脉等。现代药理研究证实钩藤能够治疗支气管哮喘、调节中枢神经系统等。
进一步地，提供的组合物中，其原料药含有如下重量份的组分：
钩藤15份、肉桂5份；
钩藤20份、肉桂10份；
钩藤25份、肉桂15份。
本发明一个具体实施方式中，使用的钩藤和肉桂重量份为：钩藤25份、肉桂15份。
本发明进一步研究发现，在钩藤和肉桂的基础上，加入天花粉、肉桂和姜黄，能够增强对打呼的治疗活性，同等生药剂量下的药效活性明显提高，因此，本发明进一步提供的一种组合物中，其原料药中还含有如下重量份的组分：
天花粉12—18份、芦根12—20份、姜黄6—12份。
其中:
天花粉为葫芦科植物栝蒌(Trichosanthes kirilowii Maxim.)的根，味甘、微苦，性微寒。用于热病烦渴，肺热燥咳，内热消渴，疮疡肿毒。现代药理研究证实天花粉具有抗早孕、抗癌、提高免疫力、抗菌及抗病毒等作用。
芦根为禾本科芦苇(Phragmites communis Trin.)的新鲜或干燥根茎，味甘，性寒。用于热病烦渴、胃热呕吐、肺热咳嗽、肺痈吐脓、热淋涩痛。现代药理研究证实芦根对骨骼肌有抑制作用、对离体豚鼠肠管有松弛作用。
姜黄为姜科、姜黄属多年生草本植物姜黄(Curcuma longa L.)的干燥块根，味辛苦，性温。用于气滞血瘀的胸腹痛、痛经及肢体疼痛等。现代药理研究证实姜黄具有降血脂、抗肿瘤、抗炎、抗病原。利胆作用以及改善心血管系统等作用。
更进一步地，其原料药含有如下重量份的组分：
钩藤15份、肉桂5份、天花粉12份、芦根12份、姜黄6份；
钩藤20份、肉桂10份、天花粉15份、芦根17份、姜黄9份；
钩藤25份、肉桂15份、天花粉18份、芦根20份、姜黄12份。
其中，它是由原料药的药粉、水提物或/和醇提物为活性成分，加上药学上常用的辅料或辅助性成分制备而成的剂型。
本发明所述药学上可接受的辅料，是指除活性成分以外包含在剂型中的物质，包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包含糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮等；填充剂包含乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等；润滑剂包含微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等；崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等；湿润剂包含十二烷基硫酸钠、水或醇等；抗氧剂包含亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等；抑菌剂包含0.5％苯酚、0.3％甲酚、0.5％三氯叔丁醇等；调节剂包含盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠及缓冲剂(包括磷酸二氢钠和磷酸氢二钠)等；乳化剂包含聚山梨酯-80、脂肪酸山梨坦、普流罗尼克F-68，卵磷酯、豆磷脂等；增溶剂包含吐温-80、胆汁、甘油等。
所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述化合物或衍生物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发 明化合物配合使用，仍然应属于本发明保护的范围。
进一步地，所述剂型为经胃肠道吸收剂型；所述剂型选自酒剂、口服液、饮料、颗粒剂、散剂、丸剂、片剂或胶囊剂。
本发明还提供了上述药物组合物的制备方法，它包括如下操作步骤：
(1)按配比称取原料药；
(2)取各原料药，合并水提，所得水提物备用；或者，取原料药，分别水提，所得各药材水提物备用；
(3)将水提物加上药学上常用的辅料或辅助性成分制剂，即可。
进一步地，步骤(2)中，所述水提为煎煮或超声。
水提物或以药粉入药，均是中药传统使用方式，水提后，由于水的溶解范围广，能够将大部分有效成分溶出，使药物更容易被人体吸收，起效更快，例如汤剂等给药形式；以原粉入药，药粉的表面积较大，也有利于药材中有效成分在体内的吸收，但药材未经提取，有效成分仍需在体内溶出再吸收，其起效相对水提物较慢，但也同时削弱了药材中有害成分对人体造成的毒副反应，适合于长期服用，如将原粉制备成丸剂等给药形式。目前在制药过程中，乙醇作为溶剂对药物进行提取，也是最为常见的提取方式之一，乙醇为半极性溶剂，溶解性能界于极性与非极性溶剂之间，可以溶解水溶性的某些成分，也能溶解非极性溶剂溶解的一些成分，通常用乙醇提取代替水煎，从而避免大量无效成分的溶出，提高有效成分的浓度和提取效率，不过乙醇的价格较水贵，在现代制药工业大生产中，为了节省生产成本，通常还是以水煎为主。在本发明已知组合物的水提物具有生理活性的情况下，为了适应各种生产和使用时的需求，可以任选水提、原粉、醇提或它们的组合方法来制备具体的剂型。
本发明还提供了上述药物组合物在制备打呼的药物中的用途。
本发明提供了两味中药钩藤、肉桂，及其与中药天花粉、芦根、姜黄配伍的组合物，具有改善或抑制打呼症状的作用，且疗效显著， 无副作用，可避免外科手术风险，为临床治疗提供新的选择。
具体实施方式
实施例1本发明药物组合物的制备方法
配方比例：钩藤15份、肉桂5份。
本发明提供了上述中药材及植物提取物组合物的制备方法，其主要步骤如下：
1.分别取钩藤、肉桂，加水煎煮三次。第一次加入其重量6倍量的水，浸泡1小时，然后煎煮2小时；第二次加其重量5倍量水，煎煮1小时；第三次加其重量4倍水，煎煮1小时，滤过，合并滤液，加热浓缩至在60-65℃下相对密度为1.10-1.12；
2.将上述浓缩液通过高速离心喷雾干燥机喷雾干燥，制备成80-120目干浸膏粉；
3.根据钩藤、肉桂单味药材提取率，按照配方比例称取各干浸膏粉混合均匀，再加入合适辅料制备成普通片剂。
实施例2本发明药物组合物的制备方法
配方比例：钩藤20份、肉桂10份。
本发明提供了上述中药材及植物提取物组合物的制备方法，其主要步骤如下：
1.分别取钩藤、肉桂，加水煎煮三次。第一次加入其重量6倍量的水，浸泡1小时，然后煎煮2小时；第二次加其重量5倍量水，煎煮1小时；第三次加其重量4倍水，煎煮1小时，滤过，合并滤液，加热浓缩至在60-65℃下相对密度为1.10-1.12；
2.将上述浓缩液通过高速离心喷雾干燥机喷雾干燥，制备成80-120目干浸膏粉；
3.根据钩藤、肉桂单味药材提取率，按照配方比例称取各干浸膏粉混合均匀，再加入合适辅料制备成胶囊剂。
实施例3本发明药物组合物的制备方法
配方比例：钩藤25份、肉桂15份。
本发明提供了上述中药材及植物提取物组合物的制备方法，其主要步骤如下：
1.分别取钩藤、肉桂，加水煎煮三次。第一次加入其重量6倍量的水，浸泡1小时，然后煎煮2小时；第二次加其重量5倍量水，煎煮1小时；第三次加其重量4倍水，煎煮1小时，滤过，合并滤液，加热浓缩至在60-65℃下相对密度为1.10-1.12；
2.将上述浓缩液通过高速离心喷雾干燥机喷雾干燥，制备成80-120目干浸膏粉；
3.根据钩藤、肉桂单味药材提取率，按照配方比例称取各干浸膏粉混合均匀，再加入合适辅料制备成颗粒剂。
实施例4
配方比例：钩藤15份、肉桂5份、天花粉12份、芦根12份、姜黄6份。
本发明提供了上述中药材及植物提取物组合物的制备方法，其主要步骤如下：
3.分别取钩藤、天花粉、肉桂、芦根和姜黄，加水煎煮三次。第一次加入其重量6倍量的水，浸泡1小时，然后煎煮2小时；第二次加其重量5倍量水，煎煮1小时；第三次加其重量4倍水，煎煮1小时，滤过，合并滤液，加热浓缩至在60-65℃下相对密度为1.10-1.12；
4.将上述浓缩液通过高速离心喷雾干燥机喷雾干燥，制备成80-120目干浸膏粉；
3.根据钩藤、天花粉、肉桂、芦根和姜黄单味药材提取率，按照配方比例称取各干浸膏粉混合均匀，再加入合适辅料制备成普通片剂。
实施例5
配方比例：钩藤20份、肉桂10份、天花粉15份、芦根17份、姜黄9份。
本发明提供了上述中药材及植物提取物组合物的制备方法，其主 要步骤如下：
3.分别取钩藤、天花粉、肉桂、芦根和姜黄，加水煎煮三次。第一次加入其重量6倍量的水，浸泡1小时，然后煎煮2小时；第二次加其重量5倍量水，煎煮1小时；第三次加其重量4倍水，煎煮1小时，滤过，合并滤液，加热浓缩至在60-65℃下相对密度为1.10-1.12；
4.将上述浓缩液通过高速离心喷雾干燥机喷雾干燥，制备成80-120目干浸膏粉；
3.根据钩藤、天花粉、肉桂、芦根和姜黄单味药材提取率，按照配方比例称取各干浸膏粉混合均匀，再加入合适辅料制备成胶囊剂。
实施例6
配方比例：钩藤25份、肉桂15份、天花粉18份、芦根20份、姜黄12份。
本发明提供了上述中药材及植物提取物组合物的制备方法，其主要步骤如下：
1.分别取钩藤、天花粉、肉桂、芦根和姜黄，加水煎煮三次。第一次加入其重量6倍量的水，浸泡1小时，然后煎煮2小时；第二次加其重量5倍量水，煎煮1小时；第三次加其重量4倍水，煎煮1小时，滤过，合并滤液，加热浓缩至在60-65℃下相对密度为1.10-1.12；
2.将上述浓缩液通过高速离心喷雾干燥机喷雾干燥，制备成80-120目干浸膏粉；
3.根据钩藤、天花粉、肉桂、芦根和姜黄单味药材提取率，按照配方比例称取各干浸膏粉混合均匀，再加入合适辅料制备成颗粒剂。以下通过试验例具体说明本发明的有益效果：
各试验药物中，剂量均为以相当于对应提取原料的生药量g/kg计算。
试验例1钩藤与肉桂两味药组合后的安全性及药效评价
一、安全性评价
下述实验使用本发明组合物实施例3所制备产品。
1、急性毒性试验
小鼠连续一次灌胃给予受试制剂50g(生药)/kg，在试验期内未见动物死亡，可确定其小鼠一次给药的最大耐受量为50g(生药)/kg，相当于临床提供人日用量的125倍(以每人60kg体重计，每次服用胶囊2粒，每日1次，每粒含生药12g，人日用量为24g，计0.4g/kg/日)。
2、长期毒性试验
以20g/kg剂量给大鼠连续灌胃给药14周，与对照组蒸馏水比较，未见动物出现一般临床症状、体重增长、血液学、血液生化学检查的各项指标、有关脏器系统和病理组织的毒性改变。停药4周后，留存动物上述相同项目检查也未见该受试药的迟缓性毒性。说明本发明组合物经口服连续给药无明显毒副作用。
上述实验证明，本发明实施例3所制备的药物组合物安全性良好。
二、临床统计
取本发明组合物实施例1所制得产品为本发明组合物受试样品。
取钩藤、桂枝，分别加水煎煮三次。第一次加入其重量6倍量的水，浸泡1小时，然后煎煮2小时；第二次加其重量5倍量水，煎煮1小时；第三次加其重量4倍水，煎煮1小时，滤过，合并滤液，加热浓缩至在60-65℃下相对密度为1.10-1.12；将上述浓缩液通过高速离心喷雾干燥机喷雾干燥，制备成80-120目干浸膏粉；根据钩藤、桂枝单味药材提取率，按照钩藤15份、桂枝5份称取各干浸膏粉混合均匀，再加入合适辅料制备成普通片剂，得钩藤与桂枝配伍使用受试样品。
另按照钩藤15份称取干浸膏粉混合均匀，再加入合适辅料制备成普通片剂，得钩藤受试样品。
通过服用本发明组合物、钩藤与桂枝配伍使用、及单用钩藤进行对比，服用方法为睡前2片，每片0.25g(每片相当于含生药量12g)；统计240例睡眠呼吸暂停综合症患者的治疗情况。
睡眠呼吸暂停综合症的主要表现为:
白天:临床症状嗜睡、疲劳、记忆力减退、工作效率下降、胸闷气短、激动易怒，晨起头痛、头晕口干、咽喉疼痛。标准症状以睡眠呼吸暂停次数和暂停时间监测为确诊方法。
夜间:临床症状打鼾，频繁发生呼吸暂停，睡眠动作异常；失眠、多梦、憋气、多尿、遗尿。
病情等级分为轻度、中度和重度。
其中，轻度病情呼吸暂停次数为30-50次/七小时，每次暂停时间为10-30秒；
中度病情呼吸暂停次数为50-100次/七小时，每次暂停时间为30-60秒；
重度病情呼吸暂停次数为100-200次/七小时，每次暂停时间大于60秒。
240例患者中有男180例，女60例，年龄为36-82岁。其中轻度患者120例，中度患者90例，重度患者30例。实验中分为三组，即本发明产品组、钩藤桂枝组和钩藤组，每组80人，男性60例，女20例，其中每组轻度患者40例，中度患者30例，重度患者10例
治疗方法:每晚睡前温服，七天为一个疗程。
疗效评价标准:
有效:鼾声降低，睡眠时常反复憋醒的次数减少，疲乏无力睡眠不宁消失，白天精神变好，头晕乏力消失；
显效:鼾声降低，口舌干燥消失，不再憋醒，头痛眩晕减轻，白天不再打瞌睡了
治愈:睡眠正常，鼾声消失，打呼噜造成的各种并发症消失了，头痛、头晕困倦现象彻底消失，白天有精神，感觉思维清晰、记忆力增强，完全康复。
治疗效果对比:
Figure PCTCN2015089333-appb-000001
治疗过程中均未发现其它副作用。
与服用钩藤桂枝组、钩藤组比较，本发明所提供的治疗打呼的中药组合物疗效好，显效快速且无副作用，对打呼有显著疗效。
试验例2钩藤与肉桂两味药组合后的安全性及药效评价
一、安全性评价
下述实验使用本发明组合物实施例1和实施例2所制备产品。
1、急性毒性试验
小鼠连续一次灌胃给予本发明实施例1和实施例2所制备的药物组合物50g(生药)/kg，在试验期内未见动物死亡，可确定其小鼠一次给药的最大耐受量为50g(生药)/kg，相当于临床提供人日用量的125倍(以每人60kg体重计，每次服用胶囊2粒，每日1次，每粒含生 药12g，人日用量为24g，计0.4g/kg/日)。
2、长期毒性试验
以20g/kg剂量给大鼠连续灌胃给药本发明实施例1和实施例2所制备的药物组合物14周，与对照组蒸馏水比较，未见动物出现一般临床症状、体重增长、血液学、血液生化学检查的各项指标、有关脏器系统和病理组织的毒性改变。停药4周后，留存动物上述相同项目检查也未见该受试药的迟缓性毒性。说明本发明组合物经口服连续给药无明显毒副作用。
上述实验证明，本发明实施例1和实施例2所制备的药物组合物安全性良好。
二、临床统计
另取本发明组合物实施例2和实施例3所制得产品为本发明组合物受试样品。
取钩藤、桂枝，分别加水煎煮三次。第一次加入其重量6倍量的水，浸泡1小时，然后煎煮2小时；第二次加其重量5倍量水，煎煮1小时；第三次加其重量4倍水，煎煮1小时，滤过，合并滤液，加热浓缩至在60-65℃下相对密度为1.10-1.12；将上述浓缩液通过高速离心喷雾干燥机喷雾干燥，制备成80-120目干浸膏粉；根据钩藤、桂枝单味药材提取率，按照钩藤15份、桂枝5份称取各干浸膏粉混合均匀，再加入合适辅料制备成普通片剂，得钩藤与桂枝配伍使用受试样品。
另按照钩藤15份称取干浸膏粉混合均匀，再加入合适辅料制备成普通片剂，得钩藤受试样品。
通过服用本发明实施例2和实施例3所制得的组合物、钩藤与桂枝配伍使用、及单用钩藤进行对比，服用方法为睡前2片，每片0.25g(每片相当于含生药量12g)；统计320例睡眠呼吸暂停综合症患者的治疗情况。
睡眠呼吸暂停综合症的主要表现为:
白天:临床症状嗜睡、疲劳、记忆力减退、工作效率下降、胸闷气短、激动易怒，晨起头痛、头晕口干、咽喉疼痛。标准症状以睡眠呼吸暂停次数和暂停时间监测为确诊方法。
夜间:临床症状打鼾，频繁发生呼吸暂停，睡眠动作异常；失眠、多梦、憋气、多尿、遗尿。
病情等级分为轻度、中度和重度。
其中，轻度病情呼吸暂停次数为30-50次/七小时，每次暂停时间为10-30秒；
中度病情呼吸暂停次数为50-100次/七小时，每次暂停时间为30-60秒；
重度病情呼吸暂停次数为100-200次/七小时，每次暂停时间大于60秒。
320例患者中有男240例，女80例，年龄为36-82岁。其中轻度患者160例，中度患者120例，重度患者40例。实验中分为四组，即本发明实施例2所制得的组合物组、所制得的组合物实施例3所制得的组合物组、钩藤桂枝组和钩藤组，每组80人，男性60例，女20例，其中每组轻度患者40例，中度患者30例，重度患者10例
治疗方法:每晚睡前温服，七天为一个疗程。
疗效评价标准:
有效:鼾声降低，睡眠时常反复憋醒的次数减少，疲乏无力睡眠不宁消失，白天精神变好，头晕乏力消失；
显效:鼾声降低，口舌干燥消失，不再憋醒，头痛眩晕减轻，白天不再打瞌睡了
治愈:睡眠正常，鼾声消失，打呼噜造成的各种并发症消失了，头痛、头晕困倦现象彻底消失，白天有精神，感觉思维清晰、记忆力增强，完全康复。
治疗效果对比:
Figure PCTCN2015089333-appb-000002
治疗过程中均未发现其它副作用。
与服用钩藤桂枝组、钩藤组比较，本发明实施例2和实施例3所提供的治疗打呼的中药组合物疗效好，显效快速且无副作用，对打呼有显著疗效。
试验例3五味药组合后的安全性和药效评价
一、安全性评价
下述试验使用本发明组合物实施例6制备的产品
1、急性毒性试验
小鼠连续一次灌胃给予受试制剂50g(生药)/kg，在试验期内未见动物死亡，可确定其小鼠一次给药的最大耐受量为50g(生药)/kg，相当于临床提供人日用量的125倍(以每人60kg体重计，每次服用胶囊 2粒，每日1次，每粒含生药12g，人日用量为24g，计0.4g/kg/日)。
2、长期毒性试验
以20g/kg剂量给大鼠连续灌胃给药14周，与对照组蒸馏水比较，未见动物出现一般临床症状、体重增长、血液学、血液生化学检查的各项指标、有关脏器系统和病理组织的毒性改变。停药4周后，留存动物上述相同项目检查也未见该受试药的迟缓性毒性。说明本发明组合物经口服连续给药无明显毒副作用。
二、临床统计
取本发明组合物(实施例4)，服用方法为睡前2片，每片0.25g(每片相当于生药量12g)；统计120例睡眠呼吸暂停综合症患者的治疗情况。
睡眠呼吸暂停综合症的主要表现为:
白天:临床症状嗜睡、疲劳、记忆力减退、工作效率下降、胸闷气短、激动易怒，晨起头痛、头晕口干、咽喉疼痛。标准症状以睡眠呼吸暂停次数和暂停时间监测为确诊方法。
夜间:临床症状打鼾，频繁发生呼吸暂停，睡眠动作异常；失眠、多梦、憋气、多尿、遗尿。
病情等级分为轻度、中度和重度。
其中，轻度病情呼吸暂停次数为30-50次/七小时，每次暂停时间为10-30秒；
中度病情呼吸暂停次数为50-100次/七小时，每次暂停时间为30-60秒；
重度病情呼吸暂停次数为100-200次/七小时，每次暂停时间大于60秒。
120例患者中有男80例，女40例，年龄为36-82岁。其中轻度患者60例，中度患者40例，重度患者20例。
治疗方法:每晚睡前温服，七天为一个疗程。
疗效评价标准:
有效:鼾声降低，睡眠时常反复憋醒的次数减少，疲乏无力睡眠不宁消失，白天精神变好，头晕乏力消失；
显效:鼾声降低，口舌干燥消失，不再憋醒，头痛眩晕减轻，白天不再打瞌睡了；
治愈:睡眠正常，鼾声消失，打呼噜造成的各种并发症消失了，头痛、头晕困倦现象彻底消失，白天有精神，感觉思维清晰、记忆力增强，完全康复。
治疗效果:
Figure PCTCN2015089333-appb-000003
治疗过程中均未发现其它副作用。
治疗效果显示，本发明所提供的治疗打呼的中药组合物疗效好，显效快速且无副作用，对打呼有显著疗效。且五味药组合对轻、中、重度患者1个疗程的治愈率分别为88.3％、70％、45％，2个疗程的治愈率分别为95％、87.5％、70％。而钩藤肉桂两味药组合对轻、中、重度患者1个疗程的治愈率分别为80％、60％、30％，2个疗程的治愈率分别为90％、83.3％、60％。故五味药组合的治疗效果明显好于钩藤和肉桂两味药组合的治疗效果。
试验例4五味药组合后的安全性和药效评价
一、安全性评价
下述试验使用本发明组合物实施例4和实施例5制备的产品
1、急性毒性试验
小鼠连续一次灌胃给予实施例4和实施例5所制备的药物组合物 50g(生药)/kg，在试验期内未见动物死亡，可确定其小鼠一次给药的最大耐受量为50g(生药)/kg，相当于临床提供人日用量的125倍(以每人60kg体重计，每次服用胶囊2粒，每日1次，每粒含生药12g，人日用量为24g，计0.4g/kg/日)。
2、长期毒性试验
以20g/kg剂量给大鼠连续灌胃给药本发明实施例4和实施例5所制备的药物组合物14周，与对照组蒸馏水比较，未见动物出现一般临床症状、体重增长、血液学、血液生化学检查的各项指标、有关脏器系统和病理组织的毒性改变。停药4周后，留存动物上述相同项目检查也未见该受试药的迟缓性毒性。说明本发明组合物经口服连续给药无明显毒副作用。
上述实验证明，本发明实施例4和实施例5所制备的药物组合物安全性良好。
二、临床统计
取本发明组合物(实施例5和实施例6)，服用方法为睡前2片，每片0.25g(每片相当于生药量12g)；统计240例睡眠呼吸暂停综合症患者的治疗情况。
睡眠呼吸暂停综合症的主要表现为:
白天:临床症状嗜睡、疲劳、记忆力减退、工作效率下降、胸闷气短、激动易怒，晨起头痛、头晕口干、咽喉疼痛。标准症状以睡眠呼吸暂停次数和暂停时间监测为确诊方法。
夜间:临床症状打鼾，频繁发生呼吸暂停，睡眠动作异常；失眠、多梦、憋气、多尿、遗尿。
病情等级分为轻度、中度和重度。
其中，轻度病情呼吸暂停次数为30-50次/七小时，每次暂停时间为10-30秒；
中度病情呼吸暂停次数为50-100次/七小时，每次暂停时间为 30-60秒；
重度病情呼吸暂停次数为100-200次/七小时，每次暂停时间大于60秒。
240例患者中有男160例，女80例，年龄为36-82岁。其中轻度患者120例，中度患者80例，重度患者40例。实验中分为二组，即本发明实施例5所制备的药物组合物组和本发明实施例6所制备的药物组合物组，每组120人，男80例，女40例，其中轻度患者60例，中度患者40例，重度患者20例。
治疗方法:每晚睡前温服，七天为一个疗程。
疗效评价标准:
有效:鼾声降低，睡眠时常反复憋醒的次数减少，疲乏无力睡眠不宁消失，白天精神变好，头晕乏力消失；
显效:鼾声降低，口舌干燥消失，不再憋醒，头痛眩晕减轻，白天不再打瞌睡了；
治愈:睡眠正常，鼾声消失，打呼噜造成的各种并发症消失了，头痛、头晕困倦现象彻底消失，白天有精神，感觉思维清晰、记忆力增强，完全康复。
治疗效果:
Figure PCTCN2015089333-appb-000004
治疗过程中均未发现其它副作用。
治疗效果显示，本发明实施例5和实施例6所提供的治疗打呼的中药组合物疗效好，显效快速且无副作用，对打呼有显著疗效。且实施例5所提供的五味药组合对轻、中、重度患者1个疗程的治愈率分别为91.6％、70％、50％，2个疗程的治愈率分别为95％、90％、70％。而实施例6所提供的五味药组合对轻、中、重度患者1个疗程的治愈率分别为91.6％、72.5％、50％，2个疗程的治愈率分别为96.7％、90％、70％。而钩藤肉桂两味药组合对轻、中、重度患者1个疗程的治愈率分别为80％、60％、30％，2个疗程的治愈率分别为90％、83.3％、60％。故实施例5和实施例6所提供的五味药组合的治疗效果明显好于钩藤和肉桂两味药组合的治疗效果。

Claims (9)

  1. 一种治疗打呼的药物组合物，其特征在于：其原料药含有如下重量份的组分：
    钩藤15—25份、肉桂5—15份。
  2. 根据权利要求1所述的药物组合物，其特征在于：其原料药含有如下重量份的组分：
    钩藤15份、肉桂5份；
    钩藤20份、肉桂10份；
    钩藤25份、肉桂15份。
  3. 根据权利要求1所述的药物组合物，其特征在于：其原料药中还含有如下重量份的组分：
    天花粉12—18份、芦根12—20份、姜黄6—12份。
  4. 根据权利要求3所述的药物组合物，其特征在于：其原料药由如下重量份的组分组成：
    钩藤15份、肉桂5份、天花粉12份、芦根12份、姜黄6份；
    钩藤20份、肉桂10份、天花粉15份、芦根17份、姜黄9份；
    钩藤25份、肉桂15份、天花粉18份、芦根20份、姜黄12份。
  5. 根据权利要求1～4任意一项所述的药物组合物，其特征在于：它是由原料药的药粉、水提物或/和醇提物为活性成分，加上药学上常用的辅料或辅助性成分制备而成的剂型。
  6. 根据权利要求5所述的药物组合物，其特征在于：所述剂型为经胃肠道吸收剂型。
  7. 权利要求1～6任意一项所述药物组合物的制备方法，其特征在于：它包括如下操作步骤：
    (1)按配比称取原料药；
    (2)取各原料药，合并，水提，所得水提物备用；或者，取原料药，分别水提，所得各药材水提物备用；
    (3)将水提物加上药学上常用的辅料或辅助性成分制剂，即可。
  8. 根据权利要求7所述的制备方法，其特征在于：步骤(2)中，所述水提为煎煮或超声。
  9. 权利要求1～6任意一项所述药物组合物在制备治疗打呼的药物中的用途。
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