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WO2017220050A2 - Composition pharmaceutique d'azithromycine et son utilisation médicale pour soulager la toux - Google Patents

Composition pharmaceutique d'azithromycine et son utilisation médicale pour soulager la toux Download PDF

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Publication number
WO2017220050A2
WO2017220050A2 PCT/CN2017/097788 CN2017097788W WO2017220050A2 WO 2017220050 A2 WO2017220050 A2 WO 2017220050A2 CN 2017097788 W CN2017097788 W CN 2017097788W WO 2017220050 A2 WO2017220050 A2 WO 2017220050A2
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WO
WIPO (PCT)
Prior art keywords
compound
azithromycin
group
ethanol
eluted
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Ceased
Application number
PCT/CN2017/097788
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English (en)
Chinese (zh)
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WO2017220050A3 (fr
Inventor
崔坤峰
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Individual
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Publication of WO2017220050A3 publication Critical patent/WO2017220050A3/fr
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Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/888—Araceae (Arum family), e.g. caladium, calla lily or skunk cabbage
    • A61K36/8884—Arisaema, e.g. Jack in the pulpit

Definitions

  • the invention belongs to the field of biomedicine and relates to a new use of azithromycin, in particular to a pharmaceutical composition of azithromycin and a medical use thereof for relieving cough.
  • Azithromycin is a second-generation macrolide drug used primarily for the treatment of respiratory and reproductive tract infections. It can treat respiratory infections in children and adults caused by various pathogens, genital chlamydia trachomatis infection, etc., and is recommended by the medical guidelines of many countries and regions as the first-line treatment for the above infections (such as the United States, Japan, China, the United States and China CDC).
  • Azithromycin is suitable for the following infections caused by sensitive bacteria: bronchitis, pneumonia and other lower respiratory tract infections; skin and soft tissue infections; acute otitis media; sinusitis, pharyngitis, tonsillitis and other upper respiratory tract infections (penicillin is commonly used in the treatment of pyogenic streptococcal pharyngitis Medicine is also a common drug for preventing rheumatic fever; azithromycin can effectively remove oropharyngeal streptococcus, but there is no data on the efficacy of azithromycin treatment and prevention of rheumatic fever.
  • Azithromycin can be used for simple genital infections caused by Chlamydia trachomatis in male and female sexually transmitted diseases.
  • Azithromycin can also be used for simple genital infections caused by non-multi-drug-resistant gonococcal bacteria and soft chancres caused by Haemophilus ducrei (removal of syphilis spp.).
  • a pharmaceutical composition of azithromycin comprising azithromycin, a compound (I) as described above, and a pharmaceutically acceptable carrier.
  • the preparation method of the compound (I) as described above comprising the following steps: (a) drying the dried tubers of the genus Crushed, extracted with 65 ⁇ 75% ethanol under reflux, combined with extract, concentrated to non-alcoholic flavor, extracted with petroleum ether, ethyl acetate and water-saturated n-butanol to obtain petroleum ether extract and ethyl acetate extract respectively. And n-butanol extract; (b) the n-butanol extract in step (a) is removed with macroporous resin, first eluted with 20% ethanol in 9 column volumes, and then eluted with 65% column volume with 65% ethanol.
  • step (b) The 65% eluate was collected and concentrated under reduced pressure to obtain a 65% ethanol eluting concentrate;
  • step (c) the 65% ethanol eluting concentrate in step (b) was separated by normal phase silica gel, and the volume ratio was 65:1, 35 in sequence. :1, 15:1 and 7:1 gradient elution of dichloromethane-methanol to obtain 4 components;
  • step (d) component 4 is further separated by normal phase silica gel in a volume ratio of 12: 1.
  • step (d) component 2 is separated by octadecylsilane-bonded reversed phase silica gel, The aqueous solution of 58% by volume was eluted isocratically, and 11 to 15 column volumes of the eluate were collected, and the eluate was concentrated under reduced pressure to give the compound (I).
  • step (a) is carried out by hot reflux extraction with 70% ethanol, and the extracts are combined.
  • the macroporous resin is a D101 type macroporous adsorption resin.
  • the pharmaceutical composition of azithromycin provided by the invention comprises azithromycin and a novel natural product isolated from the dried tubers of Araceae, and the azithromycin and the natural product have anti-inflammatory and antitussive effects when they act alone;
  • the anti-inflammatory and anti-cough effects are further improved and can be developed into anti-inflammatory and anti-cough drugs.
  • the present invention has outstanding substantial features and significant advances over the prior art.
  • the concentrate was concentrated by pressure to obtain a concentrate of 65% ethanol;
  • the 65% ethanol eluted concentrate in step (b) was separated by normal phase silica gel in a volume ratio of 65:1 (9 column volumes), 35:1. (10 column volumes), 15:1 (8 column volumes) and 7:1 (8 column volumes) of dichloromethane-methanol gradient elution to give 4 components;
  • Group (c) The fraction 4 was further separated by normal phase silica gel, and the volume ratio was 12:1 (6 Column volume), 7:1 (7 column volumes) and 1:1 (6 column volumes) of dichloromethane-methanol gradient elution to give 3 components;
  • the eluate was concentrated under reduced pressure to give a compound (I. (4
  • Infrared spectroscopy indicated that the compound contained a hydroxyl group (3478 cm -1 ), a carbonyl group (1760 cm -1 ), a double bond (1663 cm -1 ) and a geminal dimethyl (1380 cm -1 ) group.
  • the 13 C-NMR, DEPT, and HSQC spectra show 30 carbon signals, including eight methyl groups, seven methylene groups, seven methine groups (one oxycarbon and one olefin carbon), and eight quaternary carbons. (Two carbonyl groups, one olefinic quaternary carbon), the above functional structure combined with the number of unsaturation indicates that the compound is a pentacyclic triterpene structure.
  • the data indicates that the compound is a ursane-type triterpenoid.
  • Azithromycin was purchased from the China National Institute for the Control of Pharmaceutical and Biological Products.
  • the compound (I) was prepared by itself, and the preparation method is shown in Example 1.
  • Glacial acetic acid produced by Nanning Chemical Reagent Factory in Guangxi
  • xylene produced by Shanghai Chemical Reagent Company of China Pharmaceutical Group
  • Evanslan produced by Shanghai Chemical Reagent Purchasing and Supply Station.
  • Aspirin tablets (100mg/tablet), produced by Bayer Pharmaceuticals; Guilong Kechuanning Capsule, produced by Shanxi Guilong Pharmaceutical Co., Ltd.; Tanghong Granules, produced by Nanchang Kangzheng De Pharmaceutical Co., Ltd.
  • mice There were 90 Kunming mice, weighing (20 ⁇ 2) g, half male and half female; 60 Wistar rats, weighing (200 ⁇ 20) g, male and female, were provided by Hubei Experimental Animal Center.
  • mice Fifty mice were randomly divided into 5 groups, 10 in each group: saline group, aspirin group (300 mg/kg), azithromycin group (80 mg/kg), and compound (I) group (80 mg/kg). , azithromycin and compound (I) composition group [40 mg/kg azithromycin + 40 mg/kg compound (I)] Each group was administered at the corresponding dose, and the physiological saline group was administered with the same amount of physiological saline. Each group was intragastrically administered once a day for 5 days. After the last administration for 1 h, the right ear of each group was coated with xylene 0.05 ml/head, and the left ear was not coated as a blank control.
  • the cervical dislocation of the mouse was dislocated and the discs of the same part of the left and right ears were punched with a hole punch with an inner diameter of 6 mm, and the masses were respectively weighed.
  • the difference between the mass of the right ear and the mass of the left ear was the degree of swelling. The degree of swelling of each group.
  • mice Fifty mice were taken, grouped and administered the same as 1.4.1. Each group was given the drug once a day for 3 consecutive days. One hour after the last administration, the mice were injected with 0.5% Evans blue saline 0.1 ml/10 g in the tail vein, and then intraperitoneally injected with 0.2% acetic acid 0.2 ml/mouse. After 20 min, the mice were sacrificed by decapitation. The abdominal cavity was washed 3 times with 5 ml of physiological saline, and the washing liquid was collected, centrifuged (1000 rpm) for 5 min, and the absorbance (OD value) was measured at 590 nm of a 721 spectrophotometer.
  • mice Fifty mice were randomly divided into 5 groups, 10 in each group, namely, saline group, azithromycin group (80 mg/kg), compound (I) group (80 mg/kg), azithromycin and compound (I) composition group. [40mg/kg azithromycin + 40mg/kg compound (I)], Guilong Kechuanning group (5g/kg). Each group was administered according to the corresponding dose, and the normal saline group was administered with the same amount of normal saline once a day for 7 days. One hour after the last administration, the mice were placed in a 500 ml jar, and SO 2 6 ml was introduced to induce cough. The mice showed obvious mouth wheezing as a cough index, and the mice were observed and recorded in a bottle until coughing occurred. The incubation period and the number of coughs within 3 minutes.
  • Wistar rats were randomly divided into 5 groups, 10 in each group, namely saline group, azithromycin group (80 mg/kg), compound (I) group (80 mg/kg), azithromycin and compound (I) composition.
  • Each group was administered according to the corresponding dose, and the normal saline group was administered with the same amount of normal saline once a day for 7 days. Before the experiment, the rats were fasted for 12 hours. After 30 minutes of the last administration, they were anesthetized with sodium pentobarbital 30 mg/kg, fixed in the supine position, and the neck was cut open.
  • the trachea was separated and placed in the middle of the lower cartilage of the thyroid cartilage. A small hole was made with an injection needle, and then a capillary of a known mass (G1) having a diameter of 0.5 ml was inserted, which was 10 cm long. Make the capillary tube just touch the surface of the trachea to absorb the sputum in the trachea. If a tube is full, immediately change a tube, collect the sputum for 60min, and collect it with the electronic scale.
  • the weight of the glass tube of sputum (G2), G2-G1 is the amount of sputum excretion in rats for 60 min, and the number of mg of drainage at 60 min/100 g is calculated as an index of sputum.
  • the azithromycin and the compound (I) composition group and the Guilong Kechuanning group can reduce the number of coughing caused by SO 2 in mice and prolong the cough latency, the difference is statistically significant (P ⁇ 0.01).
  • the azithromycin group and the compound (I) group also reduced the number of coughs and prolonged the cough latency (P ⁇ 0.05). The results are shown in Table 2.
  • the mg number of the 60 min/100 g drainage in the azithromycin group, the compound (I) group and the orange red granule group was 3.21 ⁇ 0.57, 3.25 ⁇ 0.37 and 3.28 ⁇ 0.42, which were higher than the saline group (2.24 ⁇ 0.43), and the difference was statistically significant (P ⁇ 0.05), the composition of the azithromycin and the compound (I) was 3.54 ⁇ 0.68, which was significantly higher than that of the physiological saline group (P ⁇ 0.01).
  • azithromycin and compound (I) have anti-inflammatory and anti-cough effects when they act alone; when combined, the anti-inflammatory and anti-cough effects are further improved, and an anti-inflammatory and anti-cough drug can be developed.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique d'azithromycine et son utilisation médicale pour soulager la toux. La composition pharmaceutique d'azithromycine contient de l'azithromycine et un composé de produit naturel (I) séparé du rhizoma arariématitis séché et ayant une nouvelle structure. Lorsqu'ils sont utilisés individuellement, l'azithromycine et le composé de produit naturel (I) ont un effet anti-inflammatoire et de soulagement de la toux. Lorsqu'ils sont utilisés ensemble, les deux composés améliorent en outre l'effet anti-inflammatoire et de soulagement de la toux, peuvent être développés sous la forme d'un médicament anti-inflammatoire et de soulagement de la toux, et ont des caractéristiques significatives importantes et représentent un progrès notable par rapport à l'état de la technique.
PCT/CN2017/097788 2016-06-23 2017-08-17 Composition pharmaceutique d'azithromycine et son utilisation médicale pour soulager la toux Ceased WO2017220050A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610463311.0A CN106146601A (zh) 2016-06-23 2016-06-23 阿奇霉素的药物组合物及其止咳的医药用途
CN201610463311.0 2016-06-23

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WO2017220050A2 true WO2017220050A2 (fr) 2017-12-28
WO2017220050A3 WO2017220050A3 (fr) 2018-02-15

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CN (1) CN106146601A (fr)
WO (1) WO2017220050A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105837449A (zh) * 2016-04-18 2016-08-10 镇江高海生物药业有限公司 一种l-叔亮氨酸的药物组合物及其在生物医药中的应用
CN105884741A (zh) * 2016-04-23 2016-08-24 徐挺 一种富马酸比索洛尔的药物组合物及其医药用途
CN106146601A (zh) * 2016-06-23 2016-11-23 崔坤峰 阿奇霉素的药物组合物及其止咳的医药用途
CN106045835A (zh) * 2016-06-23 2016-10-26 崔坤峰 盐酸苄丝肼的药物组合物及其降血糖的医药用途

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CN104107358A (zh) * 2014-07-21 2014-10-22 河南科技大学第一附属医院 一种用于止咳化痰的药丸及其制备方法
CN105837449A (zh) * 2016-04-18 2016-08-10 镇江高海生物药业有限公司 一种l-叔亮氨酸的药物组合物及其在生物医药中的应用
CN105663138A (zh) * 2016-04-23 2016-06-15 贺玉皓 一种氯硝西泮的药物组合物及其医药用途
CN105884741A (zh) * 2016-04-23 2016-08-24 徐挺 一种富马酸比索洛尔的药物组合物及其医药用途
CN106146601A (zh) * 2016-06-23 2016-11-23 崔坤峰 阿奇霉素的药物组合物及其止咳的医药用途

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CN106146601A (zh) 2016-11-23

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