WO2019011349A1 - 芬乐胺晶b型、制备方法和其组合物与用途 - Google Patents
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- WO2019011349A1 WO2019011349A1 PCT/CN2018/104573 CN2018104573W WO2019011349A1 WO 2019011349 A1 WO2019011349 A1 WO 2019011349A1 CN 2018104573 W CN2018104573 W CN 2018104573W WO 2019011349 A1 WO2019011349 A1 WO 2019011349A1
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- fenolamine
- ethanol
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Images
Classifications
-
- 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
-
- 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
- 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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- 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
-
- 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
-
- 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 B type solid state state form which is found in a solid state of fenlocamide; relates to a method for preparing a crystal B type; and relates to a method comprising the form of fentanyl crystal B and containing any ratio of crystal B 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 Example 24, a method for synthesizing fentanyl is disclosed, wherein fenlocamine is obtained by recrystallization from a chloroform solvent, and the fentanyl solid is confirmed by powder X-ray diffraction analysis. The sample is a crystalline F type containing crystalline chloroform molecules.
- the invention finds a state and preparation method of a novel Fenolamine crystal B type solid substance different from the above-mentioned patent or literature research report, and finds that the Fenolamine crystal B type solid substance is absorbed in the blood after being absorbed by oral administration.
- the characteristics of the substance and the concentration of the blood drug were found to be good for the stability of the solid substance of the Fenolamine Form B.
- 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, fenlocamine crystal form B.
- Fenolamine Form B is an ethanolate formed from fentonide and ethanol, and it belongs to a special solvate, a non-stoichiometric solvate.
- the crystal B type is a crystal group containing a series of subtypes.
- the same or similar spatial lattice arrangement exists between different subtypes, but there are differences in the amount of crystalline ethanol, and crystal forms containing different amounts of crystalline ethanol.
- the crystal B 1 type, the crystal B 2 type, the crystal B 3 type, and the crystalline B n type are distinguished.
- the second technical problem to be solved by the present invention is to provide a method for preparing a solid substance of Fenolamine crystal B type.
- the third technical problem to be solved by the present invention is to provide a solid drug containing a pure crystalline form of Fenolamine Form B or a mixed crystal form containing any non-zero ratio Form B, 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 B 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.
- the fifth problem to be solved by the present invention is that Fenolamine crystal B type solid substance is used for preparing and preventing 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
- Figure 1 shows the form of fenlocamine crystal B.
- Figure 2 shows the theoretical powder diffraction pattern of crystalline B-type solid matter obtained by single crystal data calculation, and the theoretical powder diffraction of crystalline B-type solid matter containing different amounts of crystalline ethanol, respectively, shown in Fig. 3 to Fig. 4 Map.
- the present invention relates to a Fenolamine crystalline Form B solid material, wherein the crystalline Form B contains a series of subtypes, and the ratio of the farnamine molecule to the crystalline ethanol molecule in the different subtypes is 1:0.5 to 1:0.1, wherein preferably a subtype of a ratio of the molar ratio of the farnamine molecule to the crystalline ethanol molecule of 1:0.5, a subtype of the ratio of the molecule of the farnamine to the crystalline ethanol molecule of 1:0.2, more preferably the ratio of the molecule of the farnamine to the crystalline ethanol is 1:0.2. Subtype.
- the crystal B type of the present invention contains a series of subtypes, which means that there may be multiple subtypes of the crystal B type, wherein the ratio of the farnamine molecule to the crystalline ethanol molecule of each subtype is different;
- the prepared farnamine is composed essentially of one of the subtypes; the subunit may have a mass percentage content of greater than 80%, preferably greater than 85%, more preferably greater than 90%, and even more preferably greater than 95%, preferably more than 99%;
- the prepared farnamine in addition to the subtype, other components of a heterogeneous amount may be contained, and the other components may include other subtypes of the form of Fenolamine Form B other than the subtype. .
- the present invention may also prepare a mixture of fentanyl containing a plurality of subtypes simultaneously, i.e., the prepared fenlocamine is combined with a certain proportion of different subtypes of fentanyl crystal form B.
- the ratio of the farnesamine molecule to the crystalline ethanol molecule in the different subtypes of the present invention is 1:0.5 to 1:0.1, which refers to different subtypes of fentanyl molecules and crystal water molecules.
- the ratios are each independently from 1:0.5 to 1:0.1.
- Fen Butralin invention crystal 1.3 type B solid substance wherein, when analyzed using X-ray powder diffraction using CuK ⁇ radiation conditions, the diffraction peak position of 2-Theta values (°) value or d
- the diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) has the following expression (Fig. 5, Table 1.1).
- the Fenolamine Form B solid matter diffraction peak position 2-Theta value (°) or d value is used when the powder X-ray diffraction analysis is performed using CuK ⁇ radiation experimental conditions.
- the diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) has the following expression (Fig. 6, Table 1.2).
- the present invention relates to a Fenolamine Form B 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 123 °C ⁇ 3 °C and 130 °C ⁇ 3 °C (Fig. 7).
- the present invention relates to a Fenolamine Form B solid material, wherein when analyzed by thermogravimetry, it exhibits a weight loss peak in the range of 100 to 150 ° C, and the weight loss is 1.5% to 5.0% ( FIG. 8 ). .
- the present invention relates to a Fenolamine Form B solid material, wherein the analysis is carried out using attenuated total reflection Fourier infrared spectroscopy at 3392, 3174, 3014, 2937, 2834, 2060, 1864, 1649, 1591, 1514, 1497, 1464, 1428, 1414, 1359, 1287, 1267, 1223, 1171, 1126, 1108, 1046, 952, 933, 907, 896, 857, 819, 773, 735, 710, 688, 643, 629, 562, 541, Infrared spectral characteristic peaks exist at 514, 493, and 452 cm -1 , and the allowable deviation of the characteristic peaks of the infrared spectrum is ⁇ 2em -1 (Fig. 9).
- a Fenlocamine mixed crystal solid material comprising the Fenolamine Form B solid matter component of the present invention in an arbitrary ratio.
- the present invention relates to a method for preparing a Fenlocamine B type solid material, wherein a sample of a fenlocamine is completely dissolved at an ambient temperature of 4 ° C to 80 ° C using a single solvent of ethanol or a mixed solvent containing ethanol. Crystalline B-type solid matter of farnamine is obtained by recrystallization from °C to 80 ° C, ambient humidity of 10% to 75%, atmospheric pressure or vacuum test conditions.
- the Fenolamine mixed crystal solid material of the present invention is a Fenolamine Form B component obtained by the above method, and is mixed with other Fenlocamine crystalline solid materials in an arbitrary 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 form of Formenol Form B 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, injections, sustained release preparations or controlled release preparations.
- the present invention relates to the application of Fenolamine Form B 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 the inclusion of any proportion of fentanyl crystal B-type mixed crystal components in the preparation of 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 pharmaceutical composition
- a pharmaceutical composition comprising the present invention, a Fenolamine Form B component, and a farnamine mixed crystalline solid material of the present invention as an active ingredient.
- the pharmaceutical composition can be prepared according to methods well known in the art. It can be prepared by combining the present invention with the Fenolamine Form B component, the present invention, a farnamine mixed crystalline solid material, and 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 B component 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 unit dosage form, and the route of administration may be intestinal or parenteral, such as oral or intravenous, in the form of a solid substance of the present invention or a pharmaceutical composition containing the same.
- intestinal or parenteral such as oral or intravenous
- 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 Form B component of the present invention and the Fenolamine mixed crystal solid substance 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.
- Fenolamine Form B component of the present invention and the Fenolamine mixed crystalline solid material of the present invention into tablets, various excipients known in the art, including diluents, binders, and wetting agents, 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 formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
- the active ingredient of the present invention may be a mixture of the present invention, a mixture of the present invention, a mixture of a crystalline solid substance of the present invention, a diluent and a glidant, and the mixture is directly placed in a hard capsule. Or in a soft capsule.
- the active ingredient of the present invention may be a hard capsule or a soft capsule or a soft capsule or a soft capsule.
- the solid substance of the present invention may be granulated or pelletized with a diluent, a binder or a disintegrating agent, and then placed in a hard capsule or soft. In the capsule.
- a capsule of the present invention, a Fenolamine Form B component, and a Fenolamine mixed crystalline solid material of the present invention can also be used for preparation.
- 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 farnesamine crystalline Form B component of the present invention, the farnesamine 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 present invention may be used alone or in combination with other therapeutic or symptomatic agents.
- the present invention has a synergistic effect on the compound of the form of the Fenolamine Form B, the mixed crystalline form of the Fenolamine form of the present invention, and other therapeutic agents, the dosage thereof should be adjusted according to the actual situation.
- the Fenolamine Form B solid material of the present invention exhibits a good solubility advantage in six solvent systems which mimic different pH environments in the human body, and is superior to the disclosed crystal F type.
- the crystallizing solvent contained in the solid substance of the Fenolamine crystal form B of the present invention is ethanol, and has substantially no effect on human health, so the solid substance of the Fenolamine crystal B type has the advantage of drug-preserving safety.
- the Fenolamine Form B solid material of the present invention has good stability. Influential factors
- the experimental results show that the solid substance of Fenolamine crystal B is stable under high humidity and light conditions, and changes to a subtype with lower ethanol content under high temperature conditions.
- Figure 1 is a molecular arrangement diagram of a sample of Fenolamine Form B
- Figure 9 is an infrared absorption spectrum of a sample of Fenolamine Form B
- Figure 10 shows the dissolution profile of Fenolamine Form B in six different solvent systems.
- the content of ethanol in the product was determined by gas chromatography to be 2.0%, which is the B-type subtype of Fenolamine crystal containing 1/5 crystal ethanol, and its powder X-ray diffraction pattern, differential scanning calorimetry, thermograviogram, The infrared spectrum is shown in Fig. 5 and Fig. 7 to Fig. 9.
- the sample of fentonamine was completely dissolved at 40 ° C using an anhydrous ethanol solvent, and allowed to stand at a temperature of 4-40 ° C for 1-5 days to obtain a colorless transparent crystal of fenlocamine, which was subjected to single crystal X-ray.
- the unit cell also contains crystalline ethanol molecules.
- the ratio of fentanyl to ethanol molecules is 2:1.
- Fig. 1 powder X-ray diffraction analysis was carried out, and the powder diffraction pattern thereof is shown in Fig. 6.
- the fentanyl sample is completely dissolved at 15-80 ° C using a mixed solvent containing ethanol, such as 40% ethanol, 75% ethanol or 95% ethanol mixed solvent, and allowed to stand at a temperature of 10-20 ° C for 7 days.
- a mixed solvent containing ethanol such as 40% ethanol, 75% ethanol or 95% ethanol mixed solvent
- the fentonamide sample is completely dissolved at 50 ° C, and allowed to stand at a temperature of 20 ° C for 7 days to obtain fentanyl colorless.
- the transparent crystal was subjected to powder X-ray diffraction analysis, and its powder diffraction pattern was consistent with FIG.
- a mixed solvent containing ethanol such as an ethanol: chloroform (1:1) mixed solvent system
- the fenlocamine sample was completely dissolved at 30 ° C, and allowed to stand at a temperature of 10 ° C for 10 days to obtain fentanyl colorless.
- the transparent crystal was subjected to powder X-ray diffraction analysis, and its powder diffraction pattern was consistent with FIG.
- the fenlocamine sample is completely dissolved at 60 ° C, and allowed to stand at a temperature of 40 ° C for 5 days to obtain fentanyl colorless.
- the transparent crystal was subjected to powder X-ray diffraction analysis, and its powder diffraction pattern was consistent with FIG.
- the fenlocamine sample is completely dissolved at 20 ° C, and allowed to stand at a temperature of 4 ° C for 12 days to obtain fentonamine colorless.
- the transparent crystal was subjected to powder X-ray diffraction analysis, and its powder diffraction pattern was consistent with FIG.
- the fentonamide sample was completely dissolved at 20 ° C using a mixed solvent containing ethanol, such as an ethanol:cyclohexane (1:1) mixed solvent system, and allowed to stand at a temperature of 4 ° C for 12 days to obtain fentonamide.
- a colorless transparent crystal was subjected to powder X-ray diffraction analysis, and its powder diffraction pattern was consistent with FIG.
- the mixed solvent containing ethanol means ethanol and methanol, isopropanol, n-propanol, n-butanol, chloroform, dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, pyridine, dioxane, glacial acetic acid.
- a single solvent system such as formic acid, diethyl ether, toluene, benzene, n-hexane, cyclohexane, DMF, petroleum ether or water, mixed solvent mixture in any ratio, wherein the preferred volume ratio of ethanol More than 40%.
- the crystalline solvent contained in the solid substance of Fenolamine crystal is ethanol, which has no effect on human health. Therefore, the solid substance of Fenolamine crystal B has the advantage of drug safety.
- the crystalline B-type sample of Fenolamine (crystalline ethanol content of 2.58%) was placed in an open clean surface dish at a high temperature of 60 ° C, a high temperature of 40 ° C, 25 ° C, a relative humidity of 90% ⁇ 5%, and a temperature of 4500 xx ⁇ 500 lx. After 10 days of storage, samples were taken on days 0, 5, and 10, and analyzed by powder X-ray diffraction and gas chromatography. The results showed that the form of Fenolamine crystal B was stable under high humidity and light conditions at high temperature. Under the conditions, the sub-forms with lower ethanol content were transformed, and the crystalline ethanol content was about 2.1% at 10 days.
- a method for preparing a combined pharmaceutical tablet which comprises using a pure product of Fenolamine Form B or a mixed solid material containing any ratio of Form B as a bulk drug for a combined drug, using several excipients as a preparation
- the auxiliary ingredients of the combined drug tablets are prepared into a tablet sample containing 10 to 500 mg per tablet according to a certain ratio, and Table 4 gives the tablet formulation ratio:
- a method for preparing a tablet preparation by using a pure crystalline form of Fenolamine Form B or a mixed crystal raw material containing any ratio of Form B is: mixing several excipients with the drug substance uniformly, 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 method for preparing a combined pharmaceutical capsule which comprises using a pure product of Fenolamine Form B or a mixed solid material containing any ratio of Form B as a bulk drug for a combined drug, using several excipients as a preparation combination
- the auxiliary ingredients of the drug capsules are prepared according to a certain ratio of capsules containing 10 to 500 mg of each capsule. Table 5 gives the ratio of capsule formula:
- a method for preparing a tablet preparation by using a pure crystalline form of Fenolamine Form B or a mixed crystal raw material containing any ratio of Form B is: mixing several excipients with the drug substance uniformly, 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 directly without granulating step, directly with fenlocamine crystal B-type raw materials 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 different active ingredients of Fenolamine Form B should be formulated and can be divided into multiple or one-time administration.
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Abstract
本发明公开了一种芬乐胺晶B型、制备方法和其组合物与用途，具体是一种芬乐胺化合物(I)(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B型、其制法和其组合物与用途。具体而言，本发明公开了在固体状态下芬乐胺存在晶B型固体物质；晶B型固体物质的制备方法；利用芬乐胺晶B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
本发明涉及发现了芬乐胺在固体状态下存在的一种晶B型固体物质状态形式；涉及发明了晶B型的制备方法；涉及发明了含有芬乐胺晶B型及含任意比例晶B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。
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：
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，经粉末X射线衍射分析证实该芬乐胺固体样品为含有结晶氯仿分子的晶F型。
通过文献检索到18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B型固体物质状态和制备方法，发现了芬乐胺晶B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B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B型。
前期研究发现，芬乐胺在重结晶过程中易与丙酮(晶A型)、乙醇(晶B型)、异丙醇(晶C型)、乙酸乙酯(晶E型)、氯仿(晶F型)等溶剂分子结合形成不同的溶剂合物晶型。本申请涉及的芬乐胺晶B型即为芬乐胺与乙醇形成的乙醇合物，并且其属于特殊的溶剂合物——非化学计量类溶剂合物。这类溶剂合物中化合物分子与溶剂分子的比例往往不是整数比，溶剂分子在晶格中占有一定位置，但溶剂分子数量的增减对晶格排列的影响甚微。因此，晶B型为包含一系列亚型的晶型群，不同亚型之间存在相同或相似的空间点阵排列规律，但其含有结晶乙醇的数量存在差异，含有不同数量结晶乙醇的晶型以晶B
1型、晶B
2型、晶B
3型......晶B
n型进行区分。
进一步地，利用芬乐胺晶B型的单晶X射线衍射数据，可以发现不同结晶乙醇含量对芬乐胺晶型纯品的粉末图谱的影响：随着晶B型样品中结晶乙醇含量的减少，其理论粉末衍射图谱的衍射峰位置基本一致，但衍射峰强度发生变化，其中2θ值为10.5°、16.0°和24.2°的衍射峰的相对强度变化最为显著，随着结晶乙醇含量的降低，2θ值为10.5°的衍射峰强度增加，2θ值为24.2°的衍射峰强度下降。
本发明要解决的技术问题之二：提供芬乐胺晶B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B型纯品、或含有任意非零比例晶B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B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B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B型样品形态特征：
1.1 本发明涉及的芬乐胺晶B型固体物质，其中，当使用单晶X射线衍射结构分析时表现为单斜晶系对称性，空间群为Cc，晶胞参数值
α＝γ＝90°，β＝128.4°，晶胞内分子数Z＝8，晶胞内除含有芬乐胺分子外，还含有结晶乙醇分子，图1所示为芬乐胺晶B型的分子排列图，图2所示为通过单晶数据计算获得晶B型固体物质的理论粉末衍射图谱，图3至图4所示分别为含有不同数量结晶乙醇的晶B型固体物质的理论粉末衍射图谱。
1.2 本发明涉及的芬乐胺晶B型固体物质，其中，晶B型含有系列亚型，不同亚型中芬乐胺分子与结晶乙醇分子的比例为1∶0.5～1∶0.1，其中，优选芬乐胺分子与结晶乙醇分子比例为1∶0.5的亚型、芬乐胺分子与结晶乙醇分子比例为1∶0.2的亚型，更优选芬乐胺分子与结晶乙醇分子比例为1∶0.2的亚型。
其中可以理解的是，本发明所述的晶B型含有系列亚型，是指晶B型可以存在多种亚型，其中每种亚型的芬乐胺分子与结晶乙醇分子的比例不同；
在通常情况下，所制备的芬乐胺基本上是以其中一种亚型组成；该亚型的质量百分比含量可以为大于80％，其中优选大于85％，更优选大于90％，再优选大于95％，又优选大于99％；
其中进一步的，所制备的芬乐胺中，除了该亚型外，还可含有杂质量的其他成分，所述的其他成分可以包含除了该亚型以外的芬乐胺晶B型的其他亚型。
在某些情况下，本发明还可制备包含多种亚型同时存在的芬乐胺混合物，即所制备的芬乐胺是以一定比例的不同亚型的芬乐胺晶B型组合而成。
其中还可以理解的是，本发明所述的不同亚型中芬乐胺分子与结晶乙醇分子的比例为1∶0.5～1∶0.1，是指不同亚型的芬乐胺分子与结晶水分子的比例各自独立的分别为1∶0.5～1∶0.1。
1.3 本发明涉及的芬乐胺晶B型固体物质，其中，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(Height％)或峰面积值(Area％)具有如下表示(图5，表1.1)。
表1.1 芬乐胺晶B型的粉末X射线衍射峰值
根据本发明一些具体实施方案，其中，当使用粉末X射线衍射分析采用CuK
α辐射实验条件时，所述芬乐胺晶B型固体物质衍射峰位置2-Theta值(°)或d值
衍射峰相对强度峰高值(Height％)或峰面积值(Area％)具有如下表示(图6，表1.2)。
表1.2 芬乐胺晶B型的粉末X射线衍射峰值
1.4 本发明涉及的芬乐胺晶B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123℃±3℃和130℃±3℃温度处分别存在1个吸热峰(图7)。
1.5 本发明涉及的芬乐胺晶B型固体物质，其中，使用热重技术分析时，表现为在100～150℃范围内存在1个失重峰，失重量为1.5％～5.0％(图8)。
1.6 本发明涉及的芬乐胺晶B型固体物质，其中，使用衰减全反射傅立叶红外光谱法进行分析时在3392、3174、3014、2937、2834、2060、1864、1649、1591、1514、1497、1464、1428、1414、1359、1287、1267、1223、1171、1126、1108、1046、952、933、907、896、857、819、773、735、710、688、643、629、562、541、514、493、452cm
-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±2em
-1(图9)。
1.7 一种芬乐胺混合晶型固体物质，其中，含有任意比例的本发明所述的芬乐胺晶B型固体物质成分。
2.芬乐胺晶B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，使用乙醇单一溶剂，或含有乙醇的混合溶剂，在15℃～80℃温度下将芬乐胺样品完全溶解并经环境温度4℃～80℃、环境湿度10％～75％、常压或真空实验条件下的重结晶制备获得芬乐胺的晶B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B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B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、针剂、缓释制剂或控释制剂。
3.5 本发明涉及芬乐胺晶B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的芬乐胺晶B型混晶成分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。
3.7 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B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B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B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B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B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B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B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B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B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B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B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B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B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B型体外溶解性优势特征：
本发明的芬乐胺晶B型固体物质在模仿人体体内不同pH环境的6种溶剂系统中均表现出良好的溶解性优势，优于已公开的晶F型。
4.2 芬乐胺晶B型成药安全性优势特征：
本发明的芬乐胺晶B型固体物质中含有的结晶溶剂为乙醇，对人体健康基本无影响，故芬乐胺晶B型固体物质具有成药安全性优势特征。
4.3 芬乐胺晶B型的稳定性：
本发明的芬乐胺晶B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B型固体物质在高湿、光照条件下稳定，在高温条件下向乙醇含量更低的亚型转变。
图1 芬乐胺晶B型样品的分子排列图；
图2 芬乐胺晶B型样品的理论粉末X射线衍射图谱(芬乐胺∶乙醇＝2∶1)；
图3 芬乐胺晶B型样品的理论粉末X射线衍射图谱(芬乐胺∶乙醇＝4∶1)；
图4 芬乐胺晶B型样品的理论粉末X射线衍射图谱(芬乐胺∶乙醇＝2∶0)；
图5 芬乐胺晶B型样品的粉末X射线衍射图谱；
图6 芬乐胺晶B型样品的粉末X射线衍射图谱；
图7 芬乐胺晶B型样品的DSC图谱；
图8 芬乐胺晶B型样品的TG图谱；
图9 芬乐胺晶B型样品的红外吸收光谱图；
图10 芬乐胺晶B型在6种不同溶剂系统中的溶解曲线图。
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B型样品的制备方法1：
将1.46kg芬乐胺溶于7.3L无水乙醇，加热搅拌溶解后趁热压滤至精烘包车间内的结晶釜中，20℃下静置过夜。过滤收集产品，于85℃真空烘至无乙醇味(约48小时，此时产品为1/2结晶乙醇的芬乐胺)。研细，过80目筛后，于100℃，10mmHg的真空下烘96小时左右(每12小时翻料一次)，测乙醇含量，直至乙醇含量为1.7-2.4％为合格，得1.276kg产品。经气相色谱法检测该产品乙醇含量为2.0％，即为含有1/5个结晶乙醇的芬乐胺晶B型亚型，其粉末X射线衍射图谱、差示扫描量热图、热重图、红外光谱图如图5、图7-图9所示。
芬乐胺晶B型样品的制备方法2：
使用无水乙醇溶剂，在40℃下将芬乐胺样品完全溶解，在温度为4-40℃条件下静置1-5天，获得芬乐胺无色透明晶体，对其进行单晶X射线衍射分析，结果表明样品为单斜晶系对称性，空间群为Cc，晶胞参数值
α＝γ＝90°，B＝128.4°，晶胞内分子数Z＝8，晶胞内除含有芬乐胺分子外，还含有结晶乙醇分子，芬乐胺与乙醇分子的比例为2∶1(图1)，对其进行粉末X射线衍射分析，其粉末衍射图谱如图6所示。
芬乐胺晶B型样品的制备方法3：
使用含有乙醇的混合溶剂，如40％乙醇、75％乙醇或95％乙醇混合溶剂系统，在15-80℃下将芬乐胺样品完全溶解，在温度为10-20℃条件下静置7天，获得芬乐胺无色透明晶体，对其进行粉末X射线衍射分析，其粉末衍射图谱与图6一致。
使用含有乙醇的混合溶剂，如乙醇∶甲醇(2∶1)混合溶剂系统，在50℃下将芬乐胺样品完全溶解，在温度为20℃条件下静置7天，获得芬乐胺无色透明晶体，对其进行粉末X射线衍射分析，其粉末衍射图谱与图6一致。
使用含有乙醇的混合溶剂，如乙醇∶氯仿(1∶1)混合溶剂系统，在30℃下将芬乐胺样品完全溶解，在温度为10℃条件下静置10天，获得芬乐胺无色透明晶体，对其进行粉末X射线衍射分析，其粉末衍射图谱与图6一致。
使用含有乙醇的混合溶剂，如乙醇∶乙腈(3∶1)混合溶剂系统，在60℃下将芬乐胺样品完全溶解，在温度为40℃条件下静置5天，获得芬乐胺无色透明晶体，对其进行粉末X射线衍射分析，其粉末衍射图谱与图6一致。
使用含有乙醇的混合溶剂，如乙醇∶丙酮(1∶1)混合溶剂系统，在20℃下将芬乐胺样品完全溶解，在温度为4℃条件下静置12天，获得芬乐胺无色透明晶体，对其进行粉末X射线衍射分析，其粉末衍射图谱与图6一致。
使用含有乙醇的混合溶剂，如乙醇∶环己烷(1∶1)混合溶剂系统，在20℃下将芬乐胺样品完全溶解，在温度为4℃条件下静置12天，获得芬乐胺无色透明晶体，对其进行粉末X射线衍射分析，其粉末衍射图谱与图6一致。
含有乙醇的混合溶剂，是指使用乙醇与甲醇、异丙醇、正丙醇、正丁醇、氯仿、二氯甲烷、乙腈、四氢呋喃、乙酸乙酯、丙酮、吡啶、二氧六环、冰醋酸、甲酸、乙醚、甲苯、苯、正己烷、环己烷、DMF、石油醚或水等单一溶剂系统中的一种或多种，按照任意比例混合制成的混合溶剂，其中优选的乙醇体积比例大于40％。
芬乐胺晶B型样品的制备方法4：
使用乙醇含量为5.3％的芬乐胺晶B型亚型进行干燥，在不同干燥条件下获得含有不同乙醇含量的芬乐胺晶B型亚型物质，如表2所示：
表2
实施例2
芬乐胺晶B型固体物质的成药安全性优势特征：
芬乐胺晶B型固体物质中含有的结晶溶剂为乙醇，对人体健康基本无影响，故芬乐胺晶B型固体物质具有成药安全性优势特征。
实施例3
芬乐胺晶B型固体物质在6种溶剂系统中的溶解性优势特征：
使用结晶乙醇含量为2.0％的芬乐胺晶B型样品(芬乐胺∶乙醇＝1∶0.2)，进行溶解性评价。
溶媒系统的选择：①参考药典附录中溶出度测定法所采用的溶媒系统；②参考生物体内不同器官的消化液pH值；③改善水难溶性药物的溶解性质。根据以上3项参考依据设置了6个pH值的溶媒系统：pH值为1.2的0.1N盐酸溶液；pH值为4.5的醋酸盐缓冲液；pH值为6.5的磷酸盐缓冲液；pH值为6.7的水溶液、pH值为7.0的0.2％SDS溶液；pH值为7.3的0.5％SDS溶液。
参照溶解度测定方法(《普通口服固体制剂溶出度试验技术指导原则(初稿)》，2012.10药品评审中心)测定。利用吸光度数据对样品溶解的质量百分比进行计算，以时间为横坐标，溶解含量为纵坐标分别绘制溶解度曲线，如图10所示，数据如下表3所示：
表3 芬乐胺晶B型在不同溶剂系统中的溶出量数据(％)
实施例4
芬乐胺晶B型固体物质的稳定性：
将芬乐胺的晶B型样品(结晶乙醇含量2.58％)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％、4500lx±500lx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射线衍射和气相色谱方法进行分析，结 果表明芬乐胺晶B型在高湿、光照条件下稳定，在高温条件下向乙醇含量更低的亚型转变，高温10天时结晶乙醇含量约为2.1％。
实施例5
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B型纯品、或含有任意比例晶B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10～500mg的片剂样品，表4给出片剂配方比例：
表4 芬乐胺组合药物片剂的制备配方
将芬乐胺晶B型纯品或含有任意比例晶B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B型纯品、或含有任意比例晶B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10～500mg的胶囊样品，表5给出胶囊配方比例：
表5 芬乐胺组合药物胶囊制剂的原料药和辅料配方
将芬乐胺晶B型纯品或含有任意比例晶B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B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6
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B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B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B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 (13)
- 芬乐胺晶B型固体物质，其特征在于，当使用单晶X射线衍射结构分析时表现为单斜晶系对称性，空间群为Cc，晶胞参数值α＝γ＝90°，β＝128.4°，晶胞内分子数Z＝8，晶胞内除含有芬乐胺分子外，还含有结晶乙醇分子。
- 根据权利要求1所述的芬乐胺晶B型固体物质，其特征在于，晶B型含有系列亚型，不同亚型中芬乐胺分子与结晶乙醇分子的比例为1∶0.5～1∶0.1，其中，优选芬乐胺分子与结晶乙醇分子比例为1∶0.5的亚型、芬乐胺分子与结晶乙醇分子比例为1∶0.2的亚型，更优选芬乐胺分子与结晶乙醇分子比例为1∶0.2的亚型。
- 芬乐胺晶B型固体物质，其特征在于，芬乐胺分子与结晶乙醇分子比例为1∶0.2的亚型，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(Height％)或峰面积值(Area％)具有如下表示：
- 根据权利要求1-3任一项所述的芬乐胺晶B型固体物质，其特征在于，使用热重技术分析时，表现为在100～150℃范围内存在1个失重峰，失重量为1.5％～5.0％。
- 根据权利要求1-3任一项所述的芬乐胺晶B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123℃±3℃和130℃±3℃温度处分别存在1个吸热峰。
- 根据权利要求1-3任一项所述的芬乐胺晶B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3392、3174、3014、2937、2834、2060、1864、1649、1591、1514、1497、1464、1428、1414、1359、1287、1267、1223、1171、1126、1108、1046、952、933、907、896、857、819、773、735、710、688、643、629、562、541、514、493、452cm -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。
- 权利要求1-6中任一项所述的芬乐胺晶B型固体物质的制备方法，其特征在于，使用乙醇单一溶剂，或含有乙醇的混合溶剂，在15℃～80℃温度下将芬乐胺样品完全溶解并经环境温度4℃～80℃、环境湿度10％～75％、常压或真空条件下的重结晶制备获得芬乐胺晶B型固体物质。
- 根据权利要求7所述的制备方法，其特征在于，所述含有乙醇的混合溶剂中的乙醇质量含量大于等于40％；优选所述乙醇的混合溶剂为乙醇和至少一种选自如下溶剂的混合溶剂：甲醇、异丙醇、正丙醇、正丁醇、氯仿、二氯甲烷、乙腈、四氢呋喃、乙酸乙酯、丙酮、吡啶、二氧六环、冰醋酸、甲酸、乙醚、甲苯、苯、正己烷、环己烷、DMF、石油醚或水。
- 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B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％。
- 一种药物组合物，其特征在于，含有有效剂量的权利要求1-6中任一项的芬乐胺晶B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8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。
- 根据权利要求10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。
- 根据权利要求10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、针剂、缓释制剂或控释制剂，并且是固体剂型。
- 权利要求1-6中任一项所述的芬乐胺晶B型固体物质或权利要求9所述的芬乐胺混合晶型固体物质或权利要求10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。
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| Title |
|---|
| JI, . XIAOSHEN ET ET AL.: "Studies . on Total Synthesis of Squamosamide", ACTA PHARMACEUTICA SINICA, vol. 28, no. 6, 30 June 1993 (1993-06-30), pages 428 - 431, XP009518870, ISSN: 0513-4870 * |
| See also references of EP3653601A4 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11236041B2 (en) | 2017-07-11 | 2022-02-01 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | Type-G crystal form of fenolamine, preparation method, composition and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| US11059773B2 (en) | 2021-07-13 |
| JP2020528882A (ja) | 2020-10-01 |
| US20210078939A1 (en) | 2021-03-18 |
| CN109232297A (zh) | 2019-01-18 |
| KR20210042041A (ko) | 2021-04-16 |
| EP3653601A1 (en) | 2020-05-20 |
| EP3653601A4 (en) | 2021-04-28 |
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