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WO2019011350A1 - 芬乐胺晶g型、制备方法和其组合物与用途 - Google Patents

芬乐胺晶g型、制备方法和其组合物与用途 Download PDF

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Publication number
WO2019011350A1
WO2019011350A1 PCT/CN2018/104574 CN2018104574W WO2019011350A1 WO 2019011350 A1 WO2019011350 A1 WO 2019011350A1 CN 2018104574 W CN2018104574 W CN 2018104574W WO 2019011350 A1 WO2019011350 A1 WO 2019011350A1
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Prior art keywords
fenolamine
solid material
crystalline
crystal
type
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PCT/CN2018/104574
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English (en)
French (fr)
Inventor
吕扬
杨世颖
刘耕陶
张丹
鲍秀琦
谢平
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Institute of Materia Medica of CAMS and PUMC
Shijiazhuang Yiling Pharmaceutical Co Ltd
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Institute of Materia Medica of CAMS and PUMC
Shijiazhuang Yiling Pharmaceutical Co Ltd
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Application filed by Institute of Materia Medica of CAMS and PUMC, Shijiazhuang Yiling Pharmaceutical Co Ltd filed Critical Institute of Materia Medica of CAMS and PUMC
Priority to KR1020207003749A priority Critical patent/KR20210042042A/ko
Priority to EP18831950.3A priority patent/EP3653603A4/en
Priority to JP2020501362A priority patent/JP2020528881A/ja
Priority to US16/629,950 priority patent/US11236041B2/en
Publication of WO2019011350A1 publication Critical patent/WO2019011350A1/zh
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a crystalline G-type solid state state form in which the form of fentonamine is present in a solid state; relates to a method for preparing a crystal G-type; and relates to the invention of a G-type containing fentanyl and a crystal of any ratio G a pharmaceutical composition of a mixed crystal form; the present invention also relates to a crystalline substance of fentanyl as a pharmaceutical active ingredient, in the preparation of Parkinson's disease (PD), improvement of learning and memory disorders, treatment of memory loss and Al Application in the prevention and treatment of Alzheimer's disease (AD).
  • PD Parkinson's disease
  • AD Alzheimer's disease
  • Fenolamine (chemical name: trans-2-(2,5-dimethoxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)-N-(4-hydroxyphenethyl)
  • the molecular structure of acrylamide is as follows:
  • Fenolamine is a derivative of lycopene amide, and its compound structure has been disclosed in Chinese Patent No. CN1445211 (Publication No.), which describes the "new lycopene amide derivative” invented by the Institute of Materia Medica, Chinese Academy of Medical Sciences and its preparation method. And its pharmaceutical composition and use” [1] , wherein in the embodiment 24, a method for synthesizing farnamine is disclosed, wherein the fentonide is obtained by recrystallization from a chloroform solvent.
  • the present invention finds a novel Fenolamine G-type solid substance state and preparation method different from the above-mentioned patent or literature research report, and finds that the Fenolamine G-type solid substance is absorbed in the blood after oral absorption.
  • the characteristics of the substance and the concentration of the blood drug were found to be good in the stability of the G-type solid substance of the Fenolamine crystal.
  • the research object of the present invention is to start from the research on the existence state of the crystalline solid substance of fentanyl, and to find and discover the existence type of the crystalline solid substance on the raw material level of the active ingredient of the medicine through the crystal type screening technology and the crystal type biological activity evaluation technology.
  • Combining with the state characteristics, the combination of crystalline materials and pharmacodynamic studies provides basic scientific data for the discovery, discovery, and development of the best medicinal crystalline solids with the best clinical efficacy of Fenolamine.
  • Based on the raw materials of Lejin solid pharmaceutical materials it provides a scientific basis for applying for national or international intellectual property invention patent protection.
  • the technical problem to be solved by the present invention is to provide a new solid matter state and characterization mode of fenlocamine, namely, Fenolamine crystal form G.
  • the second technical problem to be solved by the present invention is to provide a method for preparing a Fenolamine crystal G-type solid substance.
  • the third technical problem to be solved by the present invention is to provide a solid drug containing a pure form of Fenolamine crystal G or a mixed crystal form containing a crystal form of any ratio G and a composition thereof.
  • the fourth technical problem to be solved by the present invention is to provide a pharmaceutical composition using a Fenolamine Form G solid substance as a pharmaceutically active ingredient, which has a daily dose of 10 to 3000 mg.
  • the pharmaceutical composition includes a tablet, a capsule, a pill, an injection, a sustained release or a controlled release preparation.
  • Fenolamine crystal G-type solid substance is prepared for preventing and treating Parkinson's disease (PD), improving learning and memory disorders, treating memory loss and Alzheimer's disease (Alzheimer's disease) , AD) for the application of drugs.
  • PD Parkinson's disease
  • AD Alzheimer's disease
  • the present invention relates to a Fenolamine G-type solid material, wherein the crystalline G-type solid material is a hydrate of fentanyl, when the powder X-ray diffraction analysis is carried out using CuK ⁇ radiation experimental conditions, the diffraction peak position 2-Theta Value (°) or d value
  • the diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) has the following table (Table 1, Fig. 1).
  • the present invention relates to a Fenolamine G-type solid material, wherein the crystalline G-type solid material contains a crystalline water component, and when analyzed by thermogravimetric analysis, a weight loss peak exists in the range of 40 to 150 ° C. The weight loss is 3.0% to 5.0% (Fig. 2); when Karl Fischer moisture analysis is used, the water content is 3.0% to 5.0%.
  • the present invention relates to a Fenolamine G-type solid material, wherein when analyzed by differential scanning calorimetry, it exhibits a temperature in the range of 30 to 150 ° C and a heating rate of 3 ° C per minute, in the DSC spectrum. There is one endothermic peak at a temperature of 96 °C ⁇ 3 °C (Fig. 3).
  • the present invention relates to a Fenolamine Form G solid material, wherein 3375, 2937, 2836, 1643, 1591, 1580, 1525, 1509, 1498, 1466, 1453, 1425, 1412, 1370, 1261, 1220, 1181 There are infrared spectral characteristic peaks at 1166, 1121, 1071, 1042, 1033, 1019, 944, 923, 895, 851, 817, 788, 774, 755, 732, 711, 693 cm -1 , wherein the allowable deviation of the characteristic peaks of the infrared spectrum It is ⁇ 2cm -1 ( Figure 4).
  • a fenoxamine mixed crystalline solid material comprising any of the non-zero ratios of the Fenolamine G-type solid matter component according to any one of the present invention.
  • the farnesamine mixed crystalline solid material of the present invention is a Fenolamine crystalline G-type component obtained by the above method, and is mixed with other fentanyl crystalline solid materials according to any ratio and a conventional method.
  • composition containing a crystalline component of fentanyl, dosage characteristics and pharmaceutical use:
  • a pharmaceutical composition according to the invention comprising a fentanyl G form and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition according to the invention comprising a farnamine mixed crystal solid material and a pharmaceutically acceptable carrier.
  • the daily dose of fentanyl is in the range of 10 to 3000 mg.
  • composition according to the present invention wherein the pharmaceutical composition is various tablets, capsules, pills, powder injections, sustained release preparations or controlled release preparations, and is a solid dosage form.
  • the present invention relates to the application of Fenolamine crystal form G in the preparation of a drug for preventing and treating Parkinson's disease (PD), improving learning and memory disorders, treating memory loss and Alzheimer's disease (AD) .
  • PD Parkinson's disease
  • AD Alzheimer's disease
  • the present invention relates to a mixture of crystalline material of Fenolamine containing any proportion of Fenolamine G, in the preparation of Parkinson's disease (PD), improvement of learning and memory disorders, treatment of memory loss and Alzheim Application in the treatment of Alzheimer's disease (AD).
  • PD Parkinson's disease
  • AD Alzheimer's disease
  • the invention relates to a pharmaceutical composition for use in the preparation of a medicament for preventing and treating Parkinson's disease (PD), improving learning and memory disorders, treating memory loss and Alzheimer's disease (AD).
  • PD Parkinson's disease
  • AD Alzheimer's disease
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the novel form of the Fenolamine Form G of the present invention and the solid substance of the present invention.
  • the pharmaceutical composition can be prepared according to methods well known in the art. It can be prepared by combining the Finlayamine G-type component of the present invention, the Fenolamine mixed crystalline solid material of the present invention, with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. Any dosage form used in humans or animals.
  • the content of the Fenolamine Form G composition of the present invention and the farnamine mixed crystalline solid material of the present invention is usually from 0.1 to 95% by weight in the pharmaceutical composition.
  • the compound of the present invention may be administered in a unit dosage form, and the administration route may be intestinal or parenteral, such as oral administration, intravenous administration, or a pharmaceutical composition containing the same according to the present invention.
  • intestinal or parenteral such as oral administration, intravenous administration, or a pharmaceutical composition containing the same according to the present invention.
  • Injection intramuscular, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.
  • the administration form of the present invention is preferably a solid dosage form.
  • the solid dosage form may be a tablet (including a common tablet, an enteric tablet, a lozenge tablet, a dispersible tablet, a chewable tablet, an effervescent tablet, an orally disintegrating tablet), a capsule (including a hard capsule, a soft capsule, an enteric capsule), and a granule.
  • the Fenolamine G-type component of the present invention and the farnamine mixed crystalline solid material of the present invention can be prepared into a common preparation, a sustained release preparation, a controlled release preparation, a targeted preparation, and various microparticle delivery systems.
  • the G-type component of the Fenolamine, and the solid substance of the present invention the mixture of the crystalline form of the Fenolamine can be widely used, and various excipients known in the art, including a diluent, a binder, and a wetting agent, can be widely used. , disintegrants, lubricants, and flow aids.
  • the diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.;
  • the wetting agent may be water, ethanol, or different Propyl alcohol, etc.;
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group Cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinyl pyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium hydrogencarbonate and citric acid, polyoxyethylene sorb
  • Tablets may also be further formulated into coated tablets such as sugar coated tablets, film coated tablets, enteric coated tablets, or double layered tablets and multilayer tablets.
  • the active ingredient of the present invention may be a mixture of the Fenolamine G-type component, the present Fenloramine mixed crystalline solid material, a diluent, a glidant, and the mixture directly placed in a hard capsule. Or in a soft capsule.
  • the active ingredient of the present invention may be a granule or a pellet of a farnamine crystal form-type solid component of the present invention, and a mixture of a diluent, a binder and a disintegrating agent, and then placed in a hard capsule or a soft capsule. In the capsule.
  • the present invention can also be used for preparing various types of diluents, binders, wetting agents, disintegrating agents and glidants.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the dosage of the Fenolamine G-type component of the present invention, the fargentamine mixed crystalline solid substance pharmaceutical composition of the present invention, according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the administration route and The dosage form and the like can have a wide range of changes.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the Fenolamine Form G composition of the present invention, the farnamine mixed crystalline solid substance or composition of the present invention may be administered alone or in combination with other therapeutic drugs or symptomatic drugs.
  • the Glyceramide G-type component of the present invention and the Fenolamine mixed crystalline solid material of the present invention have synergistic effects with other therapeutic drugs, the dosage thereof should be adjusted according to actual conditions.
  • the Fenolamine G-type solid material of the present invention has good stability. Influential factors The experimental results show that the F-type solid material of Fenolamine crystals remains stable under high temperature, high humidity and light conditions.
  • the Fenolamine G-type solid material of the invention does not contain any toxic and harmful crystallization solvent, only contains crystal water, and has the advantages of good safety and medicine.
  • Figure 1 is a powder X-ray diffraction pattern of a Fenlocamine G-type sample
  • Figure 3 is a DSC spectrum of a Fenolamine G-type sample
  • Figure 4 is an infrared absorption spectrum of a Fenolamine G-type sample.
  • a solid sample of farnamine recrystallized from an ethanol solvent was added to 50 mL of distilled water, placed at a constant temperature of 40 ° C, and the ambient humidity was 30%, stirred at a constant rate for 6 hours, filtered, and dried under reduced pressure for 2 hours.
  • the solid sample was analyzed by powder X-ray diffraction (Fig. 1), indicating that the obtained sample was a crystalline G-type solid substance, and its thermograviogram, DSC pattern, and infrared spectrum are shown in Fig. 2 to Fig. 4.
  • amorphous form of fentanyl solid sample was added to 150 mL of distilled water, placed at a constant temperature of 50 ° C, and the ambient humidity was 40%, stirred at a constant rate for 10 hours, filtered, and dried under reduced pressure for 24 hours to obtain a solid.
  • the sample was analyzed by powder X-ray diffraction, and its spectrum was consistent with FIG. 1.
  • the thermograviogram, DSC spectrum, and infrared spectrum were consistent with those shown in FIG. 2 to FIG. 4, indicating that the obtained sample was a crystalline G-type solid substance.
  • the crystal G-type samples of fenlocamine were placed in open clean surface plates, and placed at high temperature 60 ° C, high temperature 40 ° C, 25 ° C, relative humidity 90% ⁇ 5%, 45001 x ⁇ 5001 x illuminance for 10 days, and Samples were taken on day 0, day 5 and day 10, and analyzed by powder X-ray diffraction (the obtained spectrum is consistent with Fig. 1) and gas chromatography. The results show that the form of Fenolamine G is under high temperature, high humidity and light conditions. Both are stable, indicating that the crystalline G-type solid material has good stability. All of the products of Example 1 were subjected to this test to achieve the same effect.
  • a preparation method of a combined pharmaceutical tablet which is characterized in that a pure substance of Fenolamine crystal G type or a mixed crystal solid substance containing any ratio of crystal G type is used as a raw material drug for a combined drug, and several excipients are used as a preparation.
  • the auxiliary ingredients of the combined drug tablets are prepared into a tablet sample containing 50 to 500 mg per tablet according to a certain ratio, and Table 2 gives the tablet formulation ratio:
  • the method of preparing the Fenolamine crystal G type pure product or the mixed crystal raw material containing the crystal form G of any ratio is prepared by mixing several excipients with the raw material medicine and adding 1% hydroxymethyl cellulose.
  • the sodium solution is made into a soft material, sieved and granulated, dried by wet granules, sieved and sized, and mixed with magnesium stearate and talc powder to form a uniform tablet.
  • a preparation method of a combined pharmaceutical capsule which is characterized in that a pure substance of Fenolamine crystal G type or a mixed crystal solid substance containing any ratio of crystal G type is used as a raw material drug for a combined drug, and several excipients are used as a preparation combination.
  • the auxiliary ingredients of the drug capsules are prepared according to a certain ratio of capsules containing 50-500 mg of each capsule. Table 3 gives the ratio of capsule formula:
  • the method of preparing the Fenolamine crystal G type pure product or the mixed crystal raw material containing the crystal form G of any ratio is prepared by mixing several excipients with the raw material medicine and adding 1% hydroxymethyl cellulose.
  • the amount of sodium solution is made into wet granules, dried and sifted into granules, added with magnesium stearate and uniformly mixed, and inserted into capsules; or without granulating step, and directly with fenlocamine crystal G-type drug substance and several kinds of
  • the excipients are uniformly mixed, and after being sieved, they are directly prepared by capsules.
  • the present invention relates to a farnesoid crystalline form of the pharmaceutical composition which has a number of factors in the dosage of the active ingredient to be administered, for example, the use of the agent for the prevention and treatment varies depending on the amount of the daily dose;
  • the nature of the disease is different from the severity of the disease, resulting in a difference in the daily dose;
  • the difference in the sex, age, body surface area, the route of administration, the number of doses, and the purpose of treatment cause different daily doses;
  • the difference in absorption and blood concentration between the crystalline samples also results in a daily suitable dosage range of 0.01 to 300 mg/kg body weight, preferably 1 to 50 mg/kg body weight, in the present invention using the farnesene crystal form component.
  • different dosage regimens of G-type active ingredients of Fenolamine should be formulated and can be divided into multiple or one-time administration.

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Abstract

公开了芬乐胺晶G型、制备方法和其组合物与用途，具体是公开了芬乐胺化合物(化学名：反式-2-(2，5-二甲氧基苯基)-3-(4-羟基-3-甲氧基苯基)-N-(4-羟苯乙基)丙烯酰胺)的晶G型、其制法和其组合物与用途。具体而言，公开了在固体状态下芬乐胺存在晶G型固体物质；晶G型固体物质的制备方法；利用芬乐胺晶G型固体物质作为药物活性成分在制备抗帕金森氏病(Parkinson's disease，PD)、改善学习记忆障碍、治疗记忆能力减退及阿尔兹海默病(Alzheimer's disease，AD)的防治药物中的应用。

Description

芬乐胺晶G型、制备方法和其组合物与用途 技术领域
本发明涉及发现了芬乐胺在固体状态下存在的一种晶G型固体物质状态形式；涉及发明了晶G型的制备方法；涉及发明了含有芬乐胺晶G型及含任意比例晶G型的混合晶型的药物组合物；本发明还涉及芬乐胺晶型物质作为药物有效成分，在制备抗帕金森氏病(Parkinson’s disease，PD)、改善学习记忆障碍、治疗记忆能力减退及阿尔兹海默病(Alzheimer’s disease，AD)的防治药物中的应用。
背景技术
芬乐胺(化学名：反式-2-(2，5-二甲氧基苯基)-3-(4-羟基-3-甲氧基苯基)-N-(4-羟苯乙基)丙烯酰胺)分子结构式如下：
Figure PCTCN2018104574-appb-000001
芬乐胺是番荔枝酰胺的衍生物，其化合物结构已在中国专利CN1445211(公开号)中公开，该专利记载了中国医学科学院药物研究所发明的“新的番荔枝酰胺衍生物及其制法和其药物组合物与用途” [1]，其中在实施例24中涉及了芬乐胺的合成方法，其中芬乐胺采用氯仿溶剂重结晶获得。
通过文献检索到17篇芬乐胺相关文章 [2-19]，但这些文献报道均是关于芬乐胺的药理学作用或药代动力学研究等方面，未涉及制备方法及晶型物质。
经国内外专利与文献检索，未发现有关芬乐胺的其它晶型专利或文献报道。
本发明发现了与上述专利或文献研究报道内容不同的一种新芬乐胺晶G型固体物质状态和制备方法，发现了芬乐胺晶G型固体物质经口服给药吸收后在血液中晶型物质和血药浓度变化特征，发现芬乐胺晶G型固体物质的稳定性良好。
本发明的研究目的是从芬乐胺的晶型固体物质存在状态研究入手，通过晶型筛选技术、晶型生物活性评价技术，在药物的有效成分原料层面上寻找、发现晶型固体物质存在种类与状态特征，将晶型物质与药效学研究相结合，为寻找、发现、开发具有最佳临 床疗效的芬乐胺的优势药用晶型固体物质提供基础科学数据；同时，也为从芬乐胺固体药物原料物质基础上申请国家或国际的知识产权发明专利保护提供科学依据。
发明内容
本发明要解决的技术问题是，提供一种芬乐胺新的固体物质存在状态和表征方式，即芬乐胺晶G型。
本发明要解决的技术问题之二：提供芬乐胺晶G型固体物质的制备方法。
本发明要解决的技术问题之三：提供含有芬乐胺晶G型纯品、或含有任意比例晶G型的混合晶型的固体药物及其组合物。
本发明要解决的技术问题之四：提供使用芬乐胺晶G型固体物质作为药物活性成分的药物组合物，其每日用药剂量在10～3000mg范围内。所述的药物组合物包括片剂、胶囊、丸剂、针剂、缓释或控释制剂药物。
本发明要解决的技术问题之五：芬乐胺晶G型固体物质在制备防治帕金森氏病(Parkinson’s disease，PD)、改善学习记忆障碍、治疗记忆能力减退及阿尔兹海默病(Alzheimer’s disease，AD)的药物中的应用。
为解决上述技术问题，本发明采用如下技术方案：
1.芬乐胺的晶G型样品形态特征：
1.1本发明涉及的芬乐胺晶G型固体物质，其中，晶G型固体物质是芬乐胺的水合物，当使用粉末X射线衍射分析采用CuK α辐射实验条件时，衍射峰位置2-Theta值(°)或d值
Figure PCTCN2018104574-appb-000002
衍射峰相对强度峰高值(Height％)或峰面积值(Area％)具有如下表所示(表1，图1)。
表1 芬乐胺晶G型样品的粉末X射线衍射峰值
Figure PCTCN2018104574-appb-000003
Figure PCTCN2018104574-appb-000004
1.2本发明涉及的芬乐胺晶G型固体物质，其中，晶G型固体物质中含有结晶水成分，当使用热重技术分析时，表现为在40～150℃范围内存在1个失重峰，失重量为3.0％～5.0％(图2)；当使用卡尔费休水分分析时，其含水量在3.0％～5.0％。
1.3本发明涉及的芬乐胺晶G型固体物质，其中，使用差示扫描量热技术分析时，表现为在30～150℃范围内并且升温速率为每分钟3℃时，其DSC图谱中在96℃±3℃温度处存在1个吸热峰(图3)。
1.4本发明涉及的芬乐胺晶G型固体物质，其中，3375、2937、2836、1643、1591、1580、1525、1509、1498、1466、1453、1425、1412、1370、1261、1220、1181、1166、1121、1071、1042、1033、1019、944、923、895、851、817、788、774、755、732、711、693cm -1处存在红外光谱特征峰，其中红外光谱特征峰的允许偏差为±2cm -1(图4)。
1.5一种芬乐胺混合晶型固体物质，其中，含有任意非零比例的本发明任一项所述的芬乐胺晶G型固体物质成分。
2.芬乐胺晶G型样品和混晶的制备方法特征：
2.1本发明涉及的芬乐胺B型固体物质的制备方法，其中，将芬乐胺固体物质混悬于水中，在环境温度4℃～80℃、环境湿度10％～80％、常压条件下搅拌1～24小时，经抽滤减压干燥1～24小时制备获得芬乐胺的晶G型固体物质。
2.2本发明的芬乐胺混合晶型固体物质，是将上述方法制备获得的芬乐胺晶G型成分，按照任意比例和常规的方法和其他芬乐胺晶型固体物质混合。
3.含有芬乐胺的晶型成分的药物制剂组合物、给药剂量特征和制药用途：
3.1本发明涉及的药物组合物，含有芬乐胺晶G型和药学上可接受的载体。
3.2本发明涉及的药物组合物，含有芬乐胺混晶固体物质和药学上可接受的载体。
3.3本发明涉及的药物组合物，芬乐胺的每日用药剂量在10～3000mg范围内。
3.4本发明涉及的药物组合物，其中，所述的药物组合物是各种片剂、胶囊、丸剂、粉针剂、缓释制剂或控释制剂，并且是固体剂型。
3.5本发明涉及芬乐胺晶G型在制备防治帕金森氏病(Parkinson’s disease，PD)、改善学习记忆障碍、治疗记忆能力减退及阿尔兹海默病(Alzheimer’s disease，AD)的药物中的应用。
3.6本发明涉及的含有任意比例芬乐胺晶G型的芬乐胺混合晶型固体物质在制备防治帕金森氏病(Parkinson’s disease，PD)、改善学习记忆障碍、治疗记忆能力减退及阿尔兹海默病(Alzheimer’s disease，AD)的药物中的应用。
本发明涉及的药物组合物在制备防治帕金森氏病(Parkinson’s disease，PD)、改善学习记忆障碍、治疗记忆能力减退及阿尔兹海默病(Alzheimer’s disease，AD)的药物中的应用。
本发明涉及以本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质在其药物组合物中的含量通常为0.1-95重量％。
本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
本发明的给药剂型优选是固体剂型。固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等。
本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质可以制成普通制剂、也制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双 层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质片剂的各种稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质的胶囊剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明芬乐胺晶G型成分、本发明芬乐胺混合晶型固体物质与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
4.本发明的有益技术效果
4.1芬乐胺晶G型的稳定性：
本发明的芬乐胺晶G型固体物质具有较好的稳定性。影响因素实验结果表明，芬乐胺晶G型固体物质在高温、高湿、光照条件下均保持稳定。
4.2芬乐胺晶G型的安全性：
本发明的芬乐胺晶G型固体物质不含有任何有毒有害的结晶溶剂，只含有结晶水，具有良好的安全性成药优势。
附图说明
图1芬乐胺晶G型样品的粉末X射线衍射图谱；
图2芬乐胺晶G型样品的TG图谱；
图3芬乐胺晶G型样品的DSC图谱；
图4芬乐胺晶G型样品的红外吸收光谱图。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
实施例1
芬乐胺晶G型样品的制备方法1：
将经乙醇溶剂重结晶的芬乐胺固体样品0.5g加入到50mL蒸馏水中，置于在40℃恒温条件下，环境湿度为30％，匀速搅拌6小时后，过滤，减压干燥2小时后获得固体样品，采用粉末X射线衍射分析(图1)，表明所得样品为晶G型固体物质，其热重图谱、DSC图谱、红外光谱如图2-图4所示。
芬乐胺晶G型样品的制备方法2：
将经丙酮溶剂重结晶的芬乐胺固体样品0.5g加入到100mL蒸馏水中，置于在50℃恒温条件下，环境湿度为50％，匀速搅拌3小时后，过滤，减压干燥4小时后获得固体样品，经粉末X射线衍射分析，其图谱与图1一致，其热重图谱、DSC图谱、红外光谱与图2-图4所示一致，表明所得样品为晶G型固体物质。
芬乐胺晶G型样品的制备方法3：
将经异丙醇溶剂重结晶的芬乐胺固体样品0.5g加入到40mL蒸馏水中，置于在60℃恒温条件下，环境湿度为40％，匀速搅拌8小时后，过滤，减压干燥8小时后获得固体样品，经粉末X射线衍射分析，其图谱与图1一致，其热重图谱、DSC图谱、红外光谱与图2-图4所示一致，表明所得样品为晶G型固体物质。
芬乐胺晶G型样品的制备方法4：
将经氯仿溶剂重结晶的芬乐胺固体样品0.5g加入到80mL蒸馏水中，置于在60℃恒温条件下，环境湿度为40％，匀速搅拌5小时后，过滤，减压干燥12小时后获得固体样品，经粉末X射线衍射分析，其图谱与图1一致，其热重图谱、DSC图谱、红外光谱与图2-图4所示一致，表明所得样品为晶G型固体物质。
芬乐胺晶G型样品的制备方法5：
将经乙酸乙酯溶剂重结晶的芬乐胺固体样品0.5g加入到100mL蒸馏水中，置于在 50℃恒温条件下，环境湿度为40％，匀速搅拌2小时后，过滤，减压干燥6小时后获得固体样品，经粉末X射线衍射分析，其图谱与图1一致，其热重图谱、DSC图谱、红外光谱与图2-图4所示一致，表明所得样品为晶G型固体物质。
芬乐胺晶G型样品的制备方法6：
将无定型态的芬乐胺固体样品0.5g加入到150mL蒸馏水中，置于在50℃恒温条件下，环境湿度为40％，匀速搅拌10小时后，过滤，减压干燥24小时后获得固体样品，经粉末X射线衍射分析，其图谱与图1一致，其热重图谱、DSC图谱、红外光谱与图2-图4所示一致，表明所得样品为晶G型固体物质。
实施例2
芬乐胺晶G型固体物质的稳定性：
将芬乐胺的晶G型样品分别置开口洁净表面皿中，在高温60℃、高温40℃、25℃，相对湿度90％±5％、45001x±5001x照度条件下放置10天，并于第0天、第5天和第10天取样，采用粉末X射线衍射(得到的图谱与图1一致)和气相色谱方法进行分析，结果表明芬乐胺晶G型在高温、高湿、光照条件下均稳定，表明晶G型固体物质具有良好的稳定性。实施例1全部产品进行该测试均取得相同效果。
实施例3
组合药物制剂的制备方法1(片剂)：
一种组合药物片剂的制备方法，其特征是使用芬乐胺晶G型纯品、或含有任意比例晶G型的混晶固体物质作为组合药物的原料药、使用几种赋形剂作为制备组合药物片剂的辅料成分，按照一定比例配比制成每片含药量在50～500mg的片剂样品，表2给出片剂配方比例：
表2 芬乐胺组合药物片剂的制备配方
Figure PCTCN2018104574-appb-000005
Figure PCTCN2018104574-appb-000006
将芬乐胺晶G型纯品或含有任意比例晶G型的混晶原料药制备成片剂制剂的方法是：将几种赋形剂与原料药混合均匀，加入1％羟甲基纤维素钠溶液适量，制成软料，过筛制粒，湿粒烘干，过筛整粒，加入硬脂酸镁和滑石粉混合均匀，压片，即得。
组合药物制剂的制备方法2(胶囊)：
一种组合药物胶囊的制备方法，其特征是使用芬乐胺晶G型纯品、或含有任意比例晶G型的混晶固体物质作为组合药物的原料药、使用几种赋形剂作为制备组合药物胶囊的辅料成分，按照一定比例配比制成每片含药量在50～500mg的胶囊样品，表3给出胶囊配方比例：
表3 芬乐胺组合药物胶囊制剂的原料药和辅料配方
Figure PCTCN2018104574-appb-000007
将芬乐胺晶G型纯品或含有任意比例晶G型的混晶原料药制备成片剂制剂的方法是：将几种赋形剂与原料药混合均匀，加入1％羟甲基纤维素钠溶液适量，制成湿粒烘干过筛整粒，加入硬脂酸镁混合均匀，插入胶囊制得；或不使用制粒步骤，而直接将芬乐胺晶G型原料药与几种赋形剂辅料混合均匀，过筛后，直接装入胶囊制得。
实施例4
芬乐胺晶型组合药物的给药剂量1(片剂)：
使用晶型芬乐胺样品作为药物活性成分制备开发的药物组合物，其特征是使用晶G型芬乐胺作为药物的活性成分，每日给药剂量为10-3000mg，可分别制备成每日1次或每日2次，每次1-6片含活性成分10、100、200、300、500mg的普通片剂类型。
芬乐胺晶型组合药物的给药剂量2(胶囊)：
使用晶型芬乐胺样品作为药物活性成分制备开发的药物组合物，其特征是使用晶G型芬乐胺作为药物的活性成分，每日给药剂量为10-3000mg，可分别制备成每日1次或 每日2次，每次1-6粒含活性成分10、100、200、300、500mg的胶囊。
需要说明的问题：本发明涉及的芬乐胺晶型药物组合物在有效成分的给药剂量上存在有许多因素影响，例如：用于预防和治疗的用途不同而造成每日用药剂量的不同；患病性质与患病严重程度不同而造成每日用药剂量的不同；患者性别、年龄、体表面积的不同，给药途径、给药次数、治疗目的不同而造成每日用药剂量的不同；此外，晶型样品间存在的吸收和血药浓度不同等，亦造成本发明在使用芬乐胺晶型成分的每日合适剂量范围为0.01-300mg/kg体重，优选为1-50mg/kg体重。使用时应根据实际的预防与治疗不同情况需求制定不同的芬乐胺晶G型有效成分总剂量方案，并可分为多次或一次给药方式完成。

Claims (10)

  1. 芬乐胺晶G型固体物质，其特征在于，晶G型固体物质是芬乐胺的水合物，当使用粉末X射线衍射分析采用CuK α辐射实验条件时，衍射峰位置2-Theta值或d值、衍射峰相对强度峰高值或峰面积值具有如下表示：
    Figure PCTCN2018104574-appb-100001
  2. 根据权利要求1所述的芬乐胺晶G型固体物质，其特征在于，晶G型固体物质中含有结晶水成分，当使用热重技术分析时，表现为在40～150℃范围内存在1个失重峰，失重量为3.0％～5.0％；当使用卡尔费休水分分析时，其含水量在3.0％～5.0％。
  3. 根据权利要求1所述的芬乐胺晶G型固体物质，其特征在于，使用差示扫描量热技术分析时，表现为在30～150℃范围内并且升温速率为每分钟3℃时，其DSC图谱中在96℃±3℃温度处存在1个吸热峰。
  4. 根据权利要求1所述的芬乐胺晶G型固体物质，其特征在于，使用衰减全反射傅立叶红外光谱法进行分析时在3375、2937、2836、1643、1591、1580、1525、1509、1498、1466、1453、1425、1412、1370、1261、1220、1181、1166、1121、1071、1042、1033、1019、944、923、895、851、817、788、774、755、732、711、693cm -1处存在红外光谱特征峰，其中红外光谱特征峰的允许偏差为±2cm -1。
  5. 权利要求1-4中任一项所述的芬乐胺晶G型固体物质的制备方法，其特征在于， 将芬乐胺固体物质混悬于水中，在环境温度4℃～80℃、环境湿度10％～80％、常压条件下搅拌1～24小时，经抽滤减压干燥1～24小时制备获得芬乐胺的晶G型固体物质。
  6. 一种芬乐胺混合晶型固体物质，其特征在于，含有权利要求1-4任一项所述的芬乐胺晶G型固体物质的量为1-99.9％，优选为10-99.99％，再优选为50-99.9％，最优选为90-99.9％。
  7. 一种药物组合物，其特征在于，含有有效剂量的权利要求1-4中任一项的芬乐胺晶G型固体物质和药学上可接受的载体；或者含有有效剂量的权利要求6中所述的芬乐胺混合晶型固体物质和药学上可接受的载体。
  8. 根据权利要求7的药物组合物，其特征在于，芬乐胺的每日用药剂量在10mg～3000mg范围内。
  9. 根据权利要求7的药物组合物，其特征在于，所述的组合物的剂型是片剂、胶囊、丸剂、粉针剂、缓释制剂或控释制剂，并且是固体剂型。
  10. 权利要求1-4中任一项所述的芬乐胺晶G型固体物质、或权利要求6所述的芬乐胺混合晶型固体物质、或权利要求7的的药物组合物在制备防治帕金森氏病、改善学习记忆障碍、治疗记忆能力减退及阿尔兹海默病的药物中的应用。
PCT/CN2018/104574 2017-07-11 2018-09-07 芬乐胺晶g型、制备方法和其组合物与用途 Ceased WO2019011350A1 (zh)

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