WO2019039836A2 - Composition de formulation complexe pour le traitement d'une maladie neurodégénérative - Google Patents

Composition de formulation complexe pour le traitement d'une maladie neurodégénérative Download PDF

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WO2019039836A2
WO2019039836A2 PCT/KR2018/009601 KR2018009601W WO2019039836A2 WO 2019039836 A2 WO2019039836 A2 WO 2019039836A2 KR 2018009601 W KR2018009601 W KR 2018009601W WO 2019039836 A2 WO2019039836 A2 WO 2019039836A2
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disease
treatment
sustained
inhibitor
present
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PCT/KR2018/009601
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English (en)
Korean (ko)
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WO2019039836A3 (fr
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홍지만
임태성
최문희
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아주대학교산학협력단
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to a combination formulation for the treatment of neurodegenerative disorders, and more particularly to a composition for the treatment of neurodegenerative disorders of the degenerative nature comprising cholinesterase inhibitor, scopolamine butyl bromide and a pharmaceutically acceptable salt thereof. Compositions and sustained release formulations thereof.
  • Dementia is a type of degenerative brain disease that is characterized by a complex cognitive disorder characterized by memory loss, degenerative changes in intelligence, changes in personality, and behavioral disorders. This symptom is a gradual depletion of neurons in the central nervous system that cause degenerative diseases, resulting in irreversible dysfunctions in the neural network and ultimately leading to permanent loss of the human function.
  • choline acetyltransferase which synthesizes acetylcholine (ACh), a neurotransmitter
  • ChAT choline acetyltransferase
  • ACh acetylcholine
  • a drug using an inhibitor that inhibits choline esterase (ChE), an enzyme that hydrolyzes acetylcholine has been developed as an indirect treatment method.
  • Choline esterase has two forms: acetylcholinesterase (AChE) and butylcholinesterase (BuChE).
  • the above-mentioned acetylcholine esterase is an enzyme that hydrolyzes acetylcholine, which is one of neurotransmitters that mediate the activity of parasympathetic nerves in the body, into choline and acetate, and is formed in the endoplasmic reticulum membrane and moves to the cell membrane to perform its function .
  • These enzymes are most widely distributed in the cholinergic nerve and its surroundings, especially in the muscle nerve junction, and are important enzymes found in plasma, liver and other tissues.
  • acetylcholinesterase inhibitors are the most commonly used drugs for the treatment of dementia, and some drugs simultaneously inhibit acetylcholinesterase and butylcholinesterase inhibitors. Examples include Donepezil, Rivastigmine, Galantamine, Tacrine and the like. These drugs have the ability to reversibly inhibit acetylcholine esterase and / or butylcholinesterase, thereby increasing acetylcholine in the brain of a patient suffering from Alzheimer ' s Dementia, Activates the nervous system and, as a result, alleviates or slows down the symptoms of dementia.
  • a cholinesterase inhibitor drug is not only effective in preventing or treating Alzheimer's dementia, but also has a serious side effect as an oral agent.
  • oral administration of acetylcholinesterase inhibitors has been reported to cause side effects such as liver dysfunction, sneezing, digestive tract disorders such as nausea, vomiting, diarrhea and abdominal pain.
  • the cause of such side effects is that it is generally impossible to avoid the primary transit effect to the liver, and as a result, it is easy to affect the liver function, and it is present in high concentration in the digestive tract, and side effects are likely to appear in the digestive tract .
  • Scopolamine butylbromide also known as Buscopan, is a drug that has an anticholinergic action and has an antimicrobial effect. Although it is not a mechanism to eliminate pain itself, it can calm the overactive active smooth muscle to calm the cause of pain, and it can be used for various diseases such as spastic cramps, menstrual cramps, and digestive system abnormalities. In addition, since quaternary ammonium of scopolamine butylbromide is charged, it does not pass through the blood-brain barrier (BBB), so that it has an advantage that there is almost no side effect of the central nervous system (CNS). However, there have been no reports of co-administration with dementia drugs.
  • BBB blood-brain barrier
  • the present inventors have made intensive efforts to develop a method for sustaining the effect of the drug for a long time while reducing the side effects of the choline esterase inhibitor, and have completed the present invention.
  • the present invention provides a pharmaceutical composition for treating a degenerative neurological disease comprising a cholinesterase inhibitor, scopolamine butyl bromide and a pharmaceutically acceptable salt thereof, for solving the above-mentioned problems.
  • the present invention also provides a sustained release formulation for treating a degenerative neurological disease comprising a cholinesterase inhibitor and scopolamine butyl bromide.
  • the sustained-release formulation of the present invention is characterized in that it has a double-layer structure including a slow release layer and a slow release layer in the body including a immediate release layer and a hydrophilic matrix.
  • the immediate-release layer is characterized by releasing all active ingredients immediately or at least within one hour after the administration of the drug.
  • a pharmaceutically acceptable salt, carrier or excipient . ≪ / RTI >
  • the sustained-release layer gradually releases the active ingredient from the body for 12 hours to 36 hours after administration of the drug, and includes a hydrophilic matrix for the drug release effect.
  • the hydrophilic matrix may include a sustained-release polymer.
  • the sustained-release polymer may be selected from HPMC (Hydroxypropyl methylcellulose), but is not limited to a carrier or an excipient capable of slowly releasing a drug in the body for 12 to 36 hours .
  • the inventors of the present invention found that the combined use of acetylcholinesterase inhibitors donepezil and scopolamine butyl bromide increased the level of acetylcholine in the brain, and at the same time, the symptoms such as sore throat and abdominal pain, which are side effects of the digestive system, Thereby completing the present invention.
  • Another embodiment of the present invention relates to a method for treating a neurodegenerative disease, comprising administering to a patient having the disease a combined administration of a cholinesterase inhibitor and scopolaminebutyl bromide.
  • the cholinesterase inhibitor of the present invention may be an acetylcholine esterase inhibitor or a butylcholinesterase inhibitor and specifically includes donepezil, rivastigmin, galantamine, but are not limited to, at least one selected from the group consisting of mimopezil, ladostigil, huperzine, and tacrine.
  • the pharmaceutically acceptable salts of the present invention are acid addition salts of non-toxic acids.
  • the salts may be formed with organic acids such as, for example, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, Salts formed from malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p- aminobenzoic acid, glutamic acid, benzenesulfonic acid, theophylline acetic acid, , E. G. 8-bromo theophylline.
  • the salts may also be made from inorganic salts such as hydrochloric acid, hydrobromic acid, sulfuric acid,
  • the combined administration of the cholinesterase inhibitor and scopolaminebutyl bromide may take the form of a co-administration.
  • the cholinesterase inhibitor and scopolaminebutyl bromide are administered to the patient in the form of one dosage form containing both active ingredients at essentially the same time, or in separate dosage forms,
  • the combined administration of the cholinesterase inhibitor and scopolaminebutyl bromide involves the disparity between the administration of the two active ingredients.
  • either the choline esterase inhibitor or scopolamine butyl bromide may be administered initially.
  • the synergistic effect depends on whether a pharmacologically effective amount of both the cholinesterase inhibitor and scopolaminebutyl bromide is present in the body at the same time. This gives the upper limit of the time difference between administration of the cholinesterase inhibitor and scopolaminebutyl bromide.
  • &quot half-life " herein is the time required for the plasma level of the pharmaceutically active ingredient to reach 50% of the initial value of the ingredient.
  • the combined administration of donepezil and scopolaminebutyl bromide as cholinesterase inhibitors increases the level of acetylcholine in the brain and produces a synergistic effect.
  • similar characteristics were observed by the combination of donepezil and other cholinesterase inhibitors and scopolaminebutyl bromide.
  • the approved maintenance dosage (FDA) for the choline esterase inhibitor is 10 mg or 23 mg per day at an initial dose of 5 mg.
  • the present invention provides a method of treating a donepezil, comprising scophoramine butyl bromide administered at 1 mg, 5 mg, 15 mg or 20 mg per day, wherein the donepezil is at least 1 mg per day, for example, 2 mg Or more, for example, 5 mg or more, for example, 10 mg or more.
  • Specific examples include 5 mg to 10 mg of donepezil, together with 5 mg to 20 mg of scopolamine butyl bromide, for example 10 mg or 15 mg per day.
  • Specific examples include 10 mg to 25 mg of donepezil, for example 23 mg of donepezil, together with 5 mg to 20 mg of scopolamine butyl bromide per day, for example 10 mg or 15 mg.
  • the active pharmaceutical ingredients used in the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, either as single compounds or as multiple doses, as pure compounds .
  • the pharmaceutical compositions according to the present invention may be formulated with pharmaceutically acceptable carriers or diluents as well as conventional techniques such as those described in Remington: The Science and Practice of Pharmacy, 21 Edition, Hauber, Ed., Lippincott Williams & , ≪ / RTI > and other excipients and excipients.
  • compositions of the present invention may be used in the manufacture of a medicament for the treatment and / or prophylaxis of the diseases or disorders mediated by any particular route, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, , Intra-vertebral, intravenous and intradermal) routes, and oral routes are preferred. It will be appreciated that the preferred route may vary depending upon the overall condition and age of the subject to be treated, the nature of the condition to be treated, and the active ingredient selected.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders, and granules. Where appropriate, the solid dosage forms may be prepared with the coatings thereon.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or emulsions, as well as sterile injectable solutions or sterile powders to be reconstituted in a dispersion prior to use.
  • Suitable dosage forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, and the like.
  • solutions of the compounds of the present invention in a sterile aqueous solution aqueous propylene glycol, aqueous vitamin E or sesame oil or peanut oil may be used.
  • aqueous solutions should be suitably buffered if necessary, and the liquid diluent should initially be isotonic with sufficient saline or glucose.
  • Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed can all be readily obtained by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers are lower alkyl ethers of lactose, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • Formulations of the present invention suitable for oral administration may each be presented as discrete units, such as capsules or tablets, containing a predetermined amount of the active ingredient and containing suitable excipients.
  • the orally administrable formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation When the solid carrier is used for oral administration, the preparation may be in the form of tablets, for example, in hard gelatine capsules, in the form of powders or pellets, or in the form of trochinose lozenges.
  • the amount of solid carrier may vary, but will generally be from about 25 mg to about 1 g.
  • the preparation When a liquid carrier is used, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule or a sterile injectable solution, for example an aqueous or nonaqueous liquid suspension or solution.
  • Tablets may be prepared by mixing the active ingredient with conventional excipients and / or diluents and then compressing the mixture in a conventional tablet machine.
  • adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gum and the like. Any other adjuvants or additives generally used for purposes such as coloring, flavoring and preserving may be used, but these are those which are miscible with the active ingredients.
  • the compounds of the present invention are administered as unit dosage forms containing cholinesterase inhibitor and scopolamine butyl bromide in an amount of about 1 mg to 100 mg, each.
  • the unit dose of scopolamine butyl bromide is 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg
  • the unit dose of the cholinesterase inhibitor is 1 mg, 2 mg, 5 mg, 10 mg, 20 mg or 25 mg.
  • the degenerative neurodegenerative diseases of the present invention are useful for the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, immune system abnormal brain dysfunction, progressive neurodegenerative disease, metabolic brain disease, Dementia due to cerebral hemorrhage, but not limited to, diseases caused by degeneration of the central nervous system.
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, immune system abnormal brain dysfunction, progressive neurodegenerative disease, metabolic brain disease, Dementia due to cerebral hemorrhage, but not limited to, diseases caused by degeneration of the central nervous system.
  • a " therapeutically effective amount " of a compound in the present invention means an amount sufficient to cure, alleviate or partially delay the clinical manifestations of a given disease and complications thereof in therapeutic intervention involving administration of the compound.
  • An amount sufficient to achieve this is defined as a " therapeutically effective amount ".
  • the quantities effective for each purpose will vary depending on the severity of the disease or injury, as well as the body weight and overall condition of the subject.
  • the terms " treating " and " treating &quot refer to the management and care of a patient for the purpose of preventing a condition, e.g., a disease or disorder.
  • the term encompasses the full range of treatment for any condition for which the patient is suffering, e. G., Relieving the symptoms or complications, delaying / delaying the progression of the condition, or administering the active compound to heal or eliminate the condition .
  • the patient to be treated is preferably a mammal, particularly a human.
  • sustained release formulations for the treatment of neurodegenerative disorders of the present invention not only significantly reduce the adverse effects of the central nervous system due to digestive system adverse effects or sudden increase in blood concentration inevitably caused by oral administration of choline esterase inhibitors, It is possible to maintain an effective blood concentration and thus to provide an agent effective for the treatment of highly degenerative neurological diseases or cognitive diseases.
  • scopolamine butylbromide used in the present invention has an advantage that it acts only in the small intestine mucosa and is not absorbed into the body, thereby minimizing the burden on the stomach.
  • combination formulation or sustained-release preparation of the present invention can be applied as a composition for relieving hangover, since it has the effect of eliminating digestive-related abnormalities such as swelling and vomiting without causing side effects of the central nervous system.
  • FIG. 1 is a schematic view showing the structure of a sustained-release preparation according to an embodiment of the present invention.
  • FIG. 1 shows the structure of a sustained release formulation according to one embodiment of the present invention.
  • the sustained-release preparation according to one embodiment of the present invention may be formulated so as to reduce the adverse side effects of acetylcholinesterase inhibitor, and to prevent side effects of scopolamine butyl bromide, Of double - layer structure. More specifically, the immediate-release layer can be rapidly eluted within 30 minutes by using the immediate-release tablets, and the slow-release layer can be slowly eluted for 24 hours using the hydrophilic matrix-type tablets. According to one embodiment of the present invention, the sustained-release preparation can be optimized to be administered once a day by the double-stranded structure as described above.
  • the cholinesterase inhibitor drug acts by increasing the active concentration of the central and peripheral cholines. Therefore, the side effects that are generally observed when the cholines increase may appear.
  • the combination therapy significantly reduced side effects of digestive system such as vomiting and sore throat as compared with the conventional administration of choline esterase inhibitor alone.
  • adverse side effects of the digestive system which occurred more than 50% initially in the conventional single administration method, occurred only in 7% of the examples of the present invention. There were no side effects at all.
  • all 33 patients in the experimental group showed rapid cognitive dysfunction and no other central and peripheral anticholinergic side effects.
  • choline esterase inhibitors such as donepezil alone at a high dose (23 mg / day) is more effective in improving behavioral and cognitive impairment than low doses (10 mg / day), but it is also effective in reducing digestive disorders such as nausea, vomiting, diarrhea, There are serious side effects.
  • Table 1 when the combination administration method of the present invention is applied, even when a low-dose choline esterase inhibitor is used, no adverse effects such as deterioration of cognitive function are produced at all, The use of inhibitors can also significantly reduce adverse gastrointestinal side effects such as vomiting and tingling, which can be effective in treating highly degenerative neurological or cognitive diseases.

Abstract

La présente invention concerne une composition de formulation complexe pour le traitement d'une maladie neurodégénérative. Plus spécifiquement, la présente invention concerne une composition pharmaceutique pour le traitement d'une maladie neurodégénérative, où la composition pharmaceutique contient un inhibiteur de cholinestérase, du butylbromure de scopolamine, et un sel pharmaceutiquement acceptable de celui-ci, et une préparation à libération prolongée la contenant. Une formulation à libération prolongée pour le traitement d'une maladie neurodégénérative selon la présente invention permet non seulement de réduire remarquablement les effets secondaires du système digestif inévitablement provoqués par l'administration par voie orale d'un inhibiteur de cholinestérase ou les effets secondaires du système nerveux central dus à une augmentation rapide du taux de médicament dans le sang, mais peut également maintenir un niveau efficace de médicament dans le sang sur une longue période de temps, et fournir ainsi une préparation qui est efficace dans le traitement d'une maladie neurodégénérative ou cognitive de stade élevée. La composition de formulation complexe ou la préparation à libération prolongée selon la présente invention a en outre pour effet de résoudre les symptômes anormaux du système digestif, tels que nausée et vomissements, tout en ne provoquant aucun effet secondaire du système nerveux central, et peut donc être appliquée à titre de composition pour soulager la gueule de bois.
PCT/KR2018/009601 2017-08-22 2018-08-21 Composition de formulation complexe pour le traitement d'une maladie neurodégénérative WO2019039836A2 (fr)

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CN113880899A (zh) * 2020-10-30 2022-01-04 杭州拉林智能科技有限公司 黄酮苷-有机胺类神经激动剂复盐化合物及其制备方法和应用

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JP4012689B2 (ja) * 1998-10-01 2007-11-21 ノバルティス アクチエンゲゼルシャフト 新規徐放性経口製剤
CN1520818A (zh) * 2003-02-09 2004-08-18 山东绿叶天然药物研究开发有限公司 治疗老年性痴呆的胆碱酯酶抑制剂药物组合物
TW201422254A (zh) * 2012-11-21 2014-06-16 Ferring Bv 用於速釋及延釋的組成物
US8999393B1 (en) * 2013-01-09 2015-04-07 Edgemont Pharmaceuticals Llc Sustained release formulations of lorazepam
KR101811700B1 (ko) * 2016-10-13 2017-12-22 한국유나이티드제약 주식회사 레보드로프로피진 함유 서방정 및 이의 제조방법

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* Cited by examiner, † Cited by third party
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CN113880899A (zh) * 2020-10-30 2022-01-04 杭州拉林智能科技有限公司 黄酮苷-有机胺类神经激动剂复盐化合物及其制备方法和应用
CN113880899B (zh) * 2020-10-30 2023-06-23 杭州拉林智能科技有限公司 黄酮苷-有机胺类神经激动剂复盐化合物及其制备方法和应用

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