WO2020168779A1 - Composition de ginkgolide pour maladies de l'oreille - Google Patents

Composition de ginkgolide pour maladies de l'oreille Download PDF

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Publication number
WO2020168779A1
WO2020168779A1 PCT/CN2019/122793 CN2019122793W WO2020168779A1 WO 2020168779 A1 WO2020168779 A1 WO 2020168779A1 CN 2019122793 W CN2019122793 W CN 2019122793W WO 2020168779 A1 WO2020168779 A1 WO 2020168779A1
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WIPO (PCT)
Prior art keywords
ginkgolide
group
composition
yxnz
medicine
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PCT/CN2019/122793
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English (en)
Chinese (zh)
Inventor
肖伟
范小雪
曹泽彧
邓奕
曹亮
王振中
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江苏康缘药业股份有限公司
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Publication of WO2020168779A1 publication Critical patent/WO2020168779A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a ginkgolide composition for ear diseases.
  • Tinnitus and deafness are common diseases in otolaryngology. People with tinnitus consciously hear ringing in their ears, such as the sound of tidal waves, thin or violent, such as the sound of wind and thunder, sometimes light and heavy; deaf people have reduced hearing, hindering conversation, and even hearing loss, not hearing external sounds, affecting daily life. Deafness and tinnitus are a variety of reasons that lead to cochlear and posterior cochlear neuropathy, which makes the patient feel hearing loss, so that the nerve tissue cannot normally receive sound waves from the outside.
  • Sudden tinnitus and deafness refers to sensorineural hearing loss that occurs suddenly and for unknown reasons.
  • the main clinical manifestations are unilateral hearing loss, which may be accompanied by tinnitus, ear blockage, dizziness, nausea, and vomiting.
  • Meniere's disease also known as membrane labyrinth hydrops
  • Meniere's disease is an inner ear disease characterized by episodic vertigo, fluctuating hearing loss and tinnitus caused by inner ear membrane labyrinth edema.
  • the exact cause of Meniere’s disease is still unclear.
  • Its histopathological changes include membrane labyrinth hydrops, swelling and enlargement of the endolymphatic cavity, increased endolymph, and a series of secondary changes. At present, there is no unified plan for the treatment of this disease.
  • Ginkgo biloba extract is currently one of the most widely used traditional Chinese medicine extracts in the world.
  • Ginkgolide is the main pharmacodynamic active ingredient of Ginkgo biloba extract and its preparations. There is no evidence that Ginkgo biloba extract can treat tinnitus and deafness. Related reports on treatment or improvement.
  • the present invention conducts research on the ginkgolide composition in a variety of animal models and some clinical observation experiments, and aims to obtain a ginkgolide composition capable of treating or preventing tinnitus and deafness.
  • the ester can be bilobalide, ginkgolides A, B, C, K, J, L, M and combinations thereof.
  • the present invention also provides a medicine for ear diseases, which is characterized in that the medicine comprises the ginkgolide composition as described above.
  • the drug may also include sodium bicarbonate.
  • the above-mentioned drugs are selected from oral administration dosage forms, injection administration dosage forms, and inhalation administration dosage forms.
  • the above-mentioned drugs can be prepared into capsules, tablets, powder injections, pills, transdermal agents and the like.
  • the present invention also proposes the application of the ginkgolide composition as described in any one of the foregoing in preparing medicines for tinnitus and deafness.
  • the drug for tinnitus and deafness is a drug for treating sudden deafness.
  • the present invention also proposes the application of the ginkgolide composition as described above in the preparation of a medicine for the treatment of Meniere's disease.
  • the medicine for treating Meniere's disease includes sodium bicarbonate.
  • the effective dose of the ginkgolide composition for intravenous drip injection is recommended to be above 0.2-0.8 mg/kg/d. It should be noted that the therapeutically effective amount as the recommended dose does not impose a strict limit on the dosage range. Those skilled in the art can understand that the actual dosage may be lower than the above-mentioned dosage range.
  • the therapeutically effective dose and specific treatment plan for a certain subject can be affected by many factors, including the age, weight, sex, diet, time of administration, disease susceptibility, disease progression, and doctor's judgment of the subject.
  • the ginkgolide composition of the present invention can be used for single or combined treatment of related diseases.
  • the ginkgolide composition can improve related symptoms after drug intervention of the ginkgolide composition.
  • the experimental results show that the ginkgolide composition drug can significantly improve the change of 5-HT levels in the plasma of guinea pigs.
  • the ginkgolide composition Drugs can improve the auditory brainstem response (ABR); and have a certain improvement effect on the intrafosular potential (EP), sine swing test nystagmus (SPVN), and Ca 2+ concentration in the guinea pig model of labyrinthine hydrops ; In addition, it has a certain curative effect on patients with Meniere's disease.
  • the efficacy of various animal models and some clinical efficacy observations have confirmed that the ginkgolide composition has the effect of improving tinnitus, dizziness, hearing loss, and otic labyrinth syndrome, and its effect is to improve ear blood flow and nerve disorders related.
  • Example 1 The effect of ginkgolide composition on 5-HT levels in plasma of guinea pigs with sudden deafness
  • Ginkgolide compositions 1-4 are made by Jiangsu Kangyuan Pharmaceutical Co., Ltd., according to the table One ratio of the combination is 0.114, 0.229, 0.458 mg/ml with physiological saline.
  • Microplate reader molecular devices, spectraMax M2e
  • pipette Eppendorf
  • micro-vibrator Guohua ZW-A
  • multi-tube rack automatic balance centrifuge Shanghai Luxiangyi, D5A-WS
  • palm centrifuge Qilinbeier, LX-100
  • vortex apparatus Qilinbeier, VORTEX-5.
  • each group of guinea pigs were placed in a soundproof box with their heads about 15cm away from the noise source. They were exposed to noise once a day for 5 hours each time. After continuous stimulation for 3 days, each model of guinea pigs was given 0.8 mg adrenaline hydrochloride /kg abdominal subcutaneous injection.
  • model guinea pigs were fed in different cages, weighed, labeled, and randomly divided into model groups.
  • the positive control group was given equivalent prednisone acetate tablets (2.6 mg/kg ⁇ d -1 ) by intragastric administration.
  • the guinea pigs were anesthetized with 2% pentobarbital sodium, and blood was removed from the carotid artery by intubation.
  • the plasma 5-HT content was determined according to the kit operating instructions.
  • ABR Auditory brainstem response
  • the experimental animals were anesthetized by intraperitoneal injection of sodium pentobarbital.
  • each group of guinea pigs except the blank group showed varying degrees of irritability and depression. They did not want to eat, and their body mass growth slowed down. After the experiment, individual guinea pigs were significantly thinner, with dull expressions, and shaggy hair. .
  • the changes in the ABR thresholds of the experimental animals before and after the modeling and administration are shown in Table 3. There was no significant difference in the ABR thresholds of the animals in each group before modeling (P>0.05). After the modeling of the animals in the model group, the ABR of the animals The threshold was significantly increased, and the difference was statistically significant compared with the control group (P ⁇ 0.01), and compared with the model group after administration, there was a significant improvement.
  • Table 4 shows the changes in the latency and interval of each wave of ABR during 60dB nHL acoustic stimulation of animals in each group. It can be seen that the latency of wave I, III, V and the interval of wave I-III, III-V and IV in the model group are all prolonged. Compared with the control group in the same period, the difference was statistically significant (P ⁇ 0.01), and after administration, compared with the model group, there was a significant improvement.
  • Example 2 Effect of ginkgolide composition on guinea pig membrane labyrinth hydrops model
  • the raw materials ginkgolides A (GA), ginkgolides B (GB), and ginkgolides K (GK) ginkgolide compositions 1-4 were made by Jiangsu Kangyuan Pharmaceutical Co., Ltd. for details, see Example 1 for details;
  • ABR Auditory brainstem response
  • SPVN sinusoidal swing test nystagmus
  • the models were made in the left ear. A test hole of 4mm ⁇ 5mm was drilled under the suture of the occipital breast. The endolymphatic sac tube was destroyed under a microscope, and the small niche was ground into a blind end with a diamond drill.
  • Each administration group was YXNZ- 1-low (1.14mg/kg ⁇ d -1 ), YXNZ-1-medium (2.29mg/kg ⁇ d -1 ), YXNZ-1-high (4.58mg/kg ⁇ d -1 ), YXNZ-2- Low (1.14mg/kg ⁇ d -1 ), YXNZ-2-medium (2.29mg/kg ⁇ d -1 ), YXNZ-2-high (4.58mg/kg ⁇ d -1 ), YXNZ-3-low ( 1.14mg/kg ⁇ d -1 ), YXNZ-3-medium (2.29mg/kg ⁇ d -1 ), YXNZ-3-high (4.58mg/kg ⁇ d -1 ), YXNZ-high (.58mg/kg ⁇ d -1 ), YXNZ-3-low ( 1.14mg/kg ⁇ d -1 ), YXNZ-3-medium (2.29mg/kg ⁇
  • the ABR threshold of the simple model was significantly increased (P ⁇ 0.05), and the frequency of SPVN was significantly decreased (P ⁇ 0.05), indicating that the membrane labyrinth fluid caused the damage to the hearing function.
  • the decrease of SPVN frequency in each administration group and positive drug group was inhibited.
  • each drug group and the positive drug group can antagonize the increase of the ABR reaction threshold during labyrinthine to a certain extent.
  • EP changes The EP of the blank group, the positive drug group and each administration group was significantly higher than the model group. Changes in Ca 2+ : Compared with the model group, the concentration of endolymph Ca 2+ in the positive drug group, each administration group and the blank group was significantly lower.
  • Example 3 Observation of curative effect of ginkgolide composition on Meniere's disease
  • 78 patients were divided into a control group and an experimental group, with 38 people in the control group and 40 people in the experimental group, including 34 males and 44 females; 17 patients aged 20-30, >30 21 cases were ⁇ 40 years old, 32 cases were more than 40-50 years old, and 8 cases were more than 50 years old; the shortest course was 3 months and the longest was 2 years.
  • the patients were not accompanied by numbness of face and limbs, limb weakness, speech disorder and other symptoms during the onset of vertigo.
  • the patients were randomly divided into 2 groups.
  • the number of patients in the treatment group was 40, including 17 males and 23 females; aged 20-56 years; course of disease was 3-24 months, with an average of 9.2 months.
  • dizziness coefficient (average number of attacks one week of treatment/average number of attacks one month before treatment) ⁇ 100%, if the dizziness coefficient is 0, it means complete control, and 1%-40% is markedly effective , 41% ⁇ 80% is effective, >80% is invalid.
  • the specific experimental results are as follows:
  • 300 g of the ginkgolide composition, 31 g of starch, 5 g of low-substituted hydroxypropyl cellulose, 4.3 g of micronized silica gel, 1.6 g of magnesium stearate, and an appropriate amount of 10% starch slurry were mixed and filled into capsules to obtain 1000 capsules. 3 times a day, 1 capsule each time.
  • 300 g of ginkgolide composition, 1000 g of sucrose and 500 g of dextrin were mixed, and 1000 packets of granules were prepared according to a conventional method. 3 times a day, 1 bag each time.
  • 200 g of the ginkgolide composition, 12 g of soybean phospholipids for injection, 23 g of glycerin for injection, and water for injection are dilute to 1000 mL, and 1000 injections are prepared according to conventional methods. Once a day, 1 bottle each time, at least 250mL 5% glucose injection diluted by intravenous drip.

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

Abstract

L'invention concerne une composition de ginkgolide pour maladies de l'oreille, caractérisée en ce qu'elle comprend ginkgolide A : ginkgolide B : ginkgolide K, le rapport pondéral de ginkgolide A : ginkgolide B : ginkgolide K étant (20-40) : (50-75) : (0,2-5). Au moyen de multiples modèles animaux et de certaines expériences pharmacologiques d'observation d'efficacité clinique, la composition de ginkgolide s'est avérée avoir des effets d'amélioration de l'acouphène, du vertige, de la perte auditive et du syndrome du labyrinthe.
PCT/CN2019/122793 2019-02-21 2019-12-03 Composition de ginkgolide pour maladies de l'oreille WO2020168779A1 (fr)

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CN201910130443.5A CN109908132A (zh) 2019-02-21 2019-02-21 一种用于耳部疾病的银杏内酯组合物
CN201910130443.5 2019-02-21

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Publication number Priority date Publication date Assignee Title
CN109908132A (zh) * 2019-02-21 2019-06-21 江苏康缘药业股份有限公司 一种用于耳部疾病的银杏内酯组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102078343A (zh) * 2010-12-21 2011-06-01 上海信谊百路达药业有限公司 银杏叶总内酯在制备预防或治疗耳聋耳鸣药物中的应用
WO2017146286A1 (fr) * 2016-02-26 2017-08-31 에스케이케미칼주식회사 Composition pharmaceutique à base d'extrait de feuille de ginkgo biloba utilisant une matrice de polymère hydrophile pour libération prolongée, et préparation à libération prolongée utilisant cette dernière
CN109908132A (zh) * 2019-02-21 2019-06-21 江苏康缘药业股份有限公司 一种用于耳部疾病的银杏内酯组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102078343A (zh) * 2010-12-21 2011-06-01 上海信谊百路达药业有限公司 银杏叶总内酯在制备预防或治疗耳聋耳鸣药物中的应用
WO2017146286A1 (fr) * 2016-02-26 2017-08-31 에스케이케미칼주식회사 Composition pharmaceutique à base d'extrait de feuille de ginkgo biloba utilisant une matrice de polymère hydrophile pour libération prolongée, et préparation à libération prolongée utilisant cette dernière
CN109908132A (zh) * 2019-02-21 2019-06-21 江苏康缘药业股份有限公司 一种用于耳部疾病的银杏内酯组合物

Non-Patent Citations (3)

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Title
ANON,: "EGb 761: Ginkgo biloba extract, ginkor,", DRUGS R&D, vol. 4, no. 3, 31 December 2003 (2003-12-31), pages 188 - 193, XP009101388, ISSN: 1174-5886, DOI: 20200212111942A *
KRAUSS, P. ET AL.: "Therapeutic value of Ginkgo biloba extract EGb 761 in an animal model (Meriones unguiculatus) for noise trauma induced hearing loss and tinnitus，", PLOS ONE, vol. 11, no. 6, 17 June 2016 (2016-06-17), pages e0157574-1 - e0157574-16, XP055730758, ISSN: 1932-6203, DOI: 10.1371/journal.pone.0157574 *
LI, JUN-PING: "Clinical Observation of Ginkgo Biloba Extract on the Protective Effect of Diabetes Deafness", DIABETES NEW WORLD, no. 9, 31 May 2015 (2015-05-31), CN, pages 13 - 14, XP55730754, ISSN: 1672-4062, DOI: 10.16658/j.cnki.1672-4062.2015.09.105 *

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