WO2020150930A1 - Nouvel agent auxiliaire médicinal à base de mannitol microcristallin - Google Patents

Nouvel agent auxiliaire médicinal à base de mannitol microcristallin Download PDF

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Publication number
WO2020150930A1
WO2020150930A1 PCT/CN2019/072849 CN2019072849W WO2020150930A1 WO 2020150930 A1 WO2020150930 A1 WO 2020150930A1 CN 2019072849 W CN2019072849 W CN 2019072849W WO 2020150930 A1 WO2020150930 A1 WO 2020150930A1
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mannitol
pharmaceutical excipient
microcrystalline
novel
novel microcrystalline
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谭淞文
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    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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

Definitions

  • the invention relates to the technical field of pharmaceutical excipients, in particular to a novel microcrystalline mannitol pharmaceutical excipient.
  • the molecular formula of mannitol is C 6 H 14 O 6 , the molecular weight is 182, and it is easily soluble in water. It is a kind of pharmaceutical excipient, often used as a sweetener, adhesive, excipient, tablet or capsule filler, and inhalation compound ⁇ etc. "Why is mannitol becoming more and more popular as a pharmaceutical excipient in solid dosage forms" published by H.
  • mannitol prepared by the prior art
  • mannitol often needs to be mixed with other pharmaceutical excipients to meet the requirements of preparations.
  • the "a pharmaceutical excipient and its preparation method” (application number CN200910052769.7) and "a rapidly disintegrating pharmaceutical excipient and its preparation method” (application number CN201010184193.2) recorded in the prior art are all mixed Mannitol, lactose and crospovidone are used to obtain compound pharmaceutical excipients, which have good fluidity, disintegration, taste and physical strength, and can be used in various oral solid preparations.
  • a freeze-dried powder formulation of human relaxin-2 Relaxin for injection (application number CN201110062557.4) illustrates that mannitol can also interact with trehalose, polyvinylpyrrolidone, dodecyl- ⁇ -D-maltoside, and hydroxy
  • trehalose polyvinylpyrrolidone
  • dodecyl- ⁇ -D-maltoside dodecyl- ⁇ -D-maltoside
  • hydroxy One or more of propyl- ⁇ -cyclodextrin, calcium phosphate and zinc carbonate are used in combination as a compound pharmaceutical excipient.
  • mannitol medicinal excipients to obtain improved, practical, and novel physical and chemical properties of mannitol has positive significance for the innovation of pharmaceutical preparations.
  • An improved mannitol excipient can be used in thousands of pharmaceutical preparations that use mannitol to upgrade the entire line.
  • the purpose of the present invention is to provide a new type of microcrystalline mannitol pharmaceutical excipients, on the basis of the original traditional mannitol pharmaceutical excipients, a substantial and innovative upgrade and transformation, so as to apply to medicines In preparation.
  • the present invention provides a novel microcrystalline mannitol pharmaceutical excipient, characterized in that: the novel microcrystalline mannitol pharmaceutical excipient is composed of 50-80% ⁇ -mannitol and 20-50% ⁇ -mannitol
  • the composite mannitol polycrystal composed of solid powder is fibrous or filamentous in microscopic form. It is a porous structure material.
  • the nitrogen adsorption specific surface area is 2-9m 2 /g. It can reach up to 300mL/g for organic solvents under the action of capillary phenomenon.
  • the adsorption capacity of g, and the DSC melting point peak is 167 ⁇ 1 degrees.
  • the new microcrystalline mannitol pharmaceutical excipient is prepared by the following steps: prepare a 0.5g/mL mannitol aqueous solution and heat it to completely dissolve; mix the configured mannitol aqueous solution with ethanol at a ratio of 1:50 to 300; leave it for 15 Filter after ⁇ 30 minutes; dry the filtered solid to obtain the product.
  • the concentration of the mannitol aqueous solution can be appropriately increased, but should not exceed 0.5g/mL, otherwise it needs to be heated until the water is near boiling to completely dissolve all the mannitol solutes, and the boiling causes excessive water loss, and the amount of loss has Uncertainty; At the same time, the concentration of the mannitol aqueous solution can be reduced, but excessive water molecules will affect the subsequent mixing process with ethanol, and adversely affect crystallization and subsequent ethanol recovery and purification.
  • the mixing ratio of the configured mannitol aqueous solution and ethanol is particularly important for the crystallization process.
  • the target mannitol product in the form of fibers or filaments, because the speed of crystallization affects the ⁇ -mannitol Conversion and co-crystallization between alcohol and delta-mannitol.
  • the time of standing filtration can also be adjusted according to the actual situation. It should not be too short, otherwise the crystals will not form stably, and it should not be too long, otherwise ⁇ -mannitol and ⁇ -mannitol may slowly be converted into more stable ⁇ -mannitol.
  • FTIR scanning is a way to monitor the content of functional groups of chemical substances
  • XRD scanning is a method to detect the crystalline characteristics of substances.
  • the ratio of ⁇ -mannitol and ⁇ -mannitol involved in the patent of the present invention is based on their values at 928 ⁇ 1cm -1 and 952 ⁇ 1cm -1 FTIR peak ratio is calculated, or calculated based on the ratio of ⁇ -mannitol XRD characteristic peak at 13.7 ⁇ 0.1 degrees or 17.3 ⁇ 0.1 degrees reduced.
  • a new type of microcrystalline mannitol pharmaceutical excipient invented in this patent is most distinctive in that its microscopic form is fibrous or filamentous. It is the world’s first invention.
  • the fibrous or filamentous mannitol particles are intertwined and are porous.
  • Structural material properties, BET measurement shows that its nitrogen adsorption specific surface area is 2-9m 2 /g, with a micro-medium-macroporous nanostructure.
  • the novel microcrystalline mannitol pharmaceutical excipient can be added to the tablet as an excipient.
  • the new type of microcrystalline mannitol pharmaceutical excipient has a fibrous or filamentous structure, and its microscopic shape is similar to paper.
  • the product of the present invention can be pressed into medical paper, and the prepared paper sheet is easily soluble in water but insoluble Most organic solvents (chemical properties are the same as mannitol), and similarly, they can adsorb 0-300mL/g organic solvents under the action of capillary phenomenon.
  • Figure 1 is a scanning electron microscope picture of the novel microcrystalline mannitol described in Example 1 of the present invention and commercially available ordinary mannitol.
  • Figure 2 is a flow chart of the preparation process of the novel microcrystalline mannitol described in Example 1 of the present invention.
  • Figure 3 is a comparison diagram of FTIR scanning spectra of the novel microcrystalline mannitol, mannitol, and block mannitol described in Example 2 of the present invention.
  • Figure 4 is a scanning electron micrograph of the novel microcrystalline mannitol prepared in Example 3 of the present invention.
  • Figure 5 is a scanning electron microscope picture of the novel microcrystalline mannitol prepared in Example 4 of the present invention.
  • Fig. 6 is a scanning electron microscope picture of the novel microcrystalline mannitol prepared in Example 5 of the present invention.
  • Figure 7 is a scanning electron microscope picture of the novel microcrystalline mannitol prepared in Example 6 of the present invention.
  • Fig. 8 is a comparison diagram of FTIR scanning spectra of novel microcrystalline mannitol products prepared by using different ratios of solution and ethanol in Examples 3, 4, 5, and 6 of the present invention.
  • Fig. 9 is a scanning electron microscope picture of block mannitol prepared in Example 7 of the present invention.
  • Figure 10 is a scanning electron micrograph of the novel microcrystalline mannitol prepared in Example 8 of the present invention.
  • Figure 11 is a graph of the desorption and adsorption pore size distribution of the novel microcrystalline mannitol measured in Example 9 of the present invention.
  • Figure 12 is a DSC melting point peak position map of the novel microcrystalline mannitol measured in Example 10 of the present invention.
  • Fig. 13 is an XRD comparison chart of the novel microcrystalline mannitol, ⁇ -mannitol, and commercially available ordinary mannitol measured in Example 11 of the present invention.
  • Fig. 14 is a front and back photograph of the novel microcrystalline mannitol paper prepared in Example 12 of the present invention.
  • This embodiment provides a novel microcrystalline mannitol pharmaceutical excipient, characterized in that: the novel microcrystalline mannitol pharmaceutical excipient is composed of 50-80% ⁇ -mannitol and 20-50% ⁇ -mannitol
  • the composite mannitol polycrystal composed of solid powder is fibrous or filamentous in microscopic form. It is a porous structure material.
  • the nitrogen adsorption specific surface area is 2-9m 2 /g. It can reach up to 300mL/g for organic solvents under the action of capillary phenomenon.
  • the adsorption capacity of g, and the DSC melting point peak is 167 ⁇ 1 degrees.
  • Figure 1 is a comparison of scanning electron micrographs of the novel microcrystalline mannitol described in Example 1 of the present invention and commercially available ordinary mannitol (scale bar: 50 microns), which clearly shows that the mannitol of the present invention has the world's first fibrous or filamentary shape. Structure;
  • the present invention designs a preparation process, as shown in Figure 2, including the following steps:
  • the concentration of the mannitol aqueous solution can be appropriately increased, but should not exceed 0.5g/mL, otherwise it needs to be heated until the water is near boiling to completely dissolve all the mannitol solutes, and the boiling causes excessive water loss, and the amount of loss has Uncertainty; At the same time, the concentration of the mannitol aqueous solution can be reduced, but excessive water molecules will affect the subsequent mixing process with ethanol, and adversely affect crystallization and subsequent ethanol recovery and purification.
  • the mixing ratio of the configured mannitol aqueous solution and ethanol is particularly important for the crystallization process.
  • the target mannitol product in the form of fibers or filaments, because the speed of crystallization affects the ⁇ -mannitol Conversion and co-crystallization between alcohol and delta-mannitol.
  • the time of standing filtration can also be adjusted according to the actual situation. It should not be too short, otherwise the crystals will not form stably, and it should not be too long, otherwise ⁇ -mannitol and ⁇ -mannitol may be slowly converted into more stable ⁇ -mannitol.
  • This embodiment provides a novel microcrystalline mannitol, and its preparation method is as follows:
  • This embodiment also provides a block of mannitol.
  • the conditions of the preparation process do not meet the range defined by the method for preparing novel microcrystalline mannitol.
  • the preparation method is as follows:
  • FIG. 3 is a comparison diagram of the FTIR scanning spectra of the novel microcrystalline mannitol, mannitol (commercially available common), and massive mannitol described in Example 2 of the present invention.
  • the preparation process of the novel microcrystalline mannitol and the bulk mannitol only differs in the ratio of the aqueous solution and ethanol. Because the bulk mannitol has a higher concentration of mannitol during the crystallization process, the crystallization During the process, the nucleation and crystallization speed is relatively fast, so a mannitol crystal body different from the novel microcrystalline mannitol is obtained.
  • This embodiment provides a novel microcrystalline mannitol, and its preparation method is as follows:
  • Figure 4 is a scanning electron micrograph of the novel microcrystalline mannitol prepared in Example 3 of the present invention (scale bar: 50 microns).
  • a small part of the prepared mannitol has a fibrous or filamentous structure (Ie the target product), most of the prepared mannitol has a rod-like or needle-like structure (ie a non-target product), indicating that the ratio of aqueous solution to ethanol should not be less than 1:300, otherwise the mannitol concentration is too low and crystallized The speed is too slow, which will affect the crystal form.
  • This embodiment provides a novel microcrystalline mannitol, and its preparation method is as follows:
  • Figure 5 is a scanning electron micrograph of the novel microcrystalline mannitol prepared in Example 4 of the present invention (scale bar: 50 microns). As shown in Figure 5, the prepared mannitol has a fibrous or filamentous structure, which conforms to Product expectations.
  • This embodiment provides a novel microcrystalline mannitol, and its preparation method is as follows:
  • Figure 6 is a scanning electron micrograph of the novel microcrystalline mannitol prepared in Example 5 of the present invention (scale bar: 50 microns). As shown in Figure 6, the prepared mannitol has a fibrous or filamentous structure, which conforms to Product expectations.
  • This embodiment provides a novel microcrystalline mannitol, and its preparation method is as follows:
  • Figure 7 is a scanning electron micrograph of the new microcrystalline mannitol prepared in Example 6 of the present invention (scale bar: 50 microns). As shown in Figure 7, most of the prepared mannitol has a fibrous or filamentous structure (Ie the target product), very few of the prepared mannitol has a needle-like structure (ie, non-target product), indicating that the ratio of aqueous solution and ethanol should not be higher than 1:50, otherwise the water content in the mixed solution is too high and the mannitol If the alcohol concentration is too high, the crystallization speed is too fast, which will affect the crystal form.
  • the ratio of ⁇ -mannitol and ⁇ -mannitol is calculated based on the ratio of FTIR peaks at 928 ⁇ 1cm -1 and 952 ⁇ 1cm -1 .
  • FTIR Scanning is a way to monitor the content of functional groups of chemical substances
  • XRD scanning is a method to detect the crystalline characteristics of substances.
  • Figure 8 is a comparison diagram of FTIR scanning spectra of the novel microcrystalline mannitol products prepared by using different ratios of solutions and ethanol in Examples 3, 4, 5, and 6 of the present invention.
  • the results show that the 1:300 solution and When the ethanol ratio is used, the mannitol crystals formed are almost ⁇ -mannitol. However, when other solutions and ethanol ratios are used in Examples 4, 5, and 6, the mannitol crystals formed are mixed crystals of ⁇ -mannitol and ⁇ -mannitol.
  • the ratio of solution to ethanol should be between 1:300 to 1:50.
  • the novel microcrystalline mannitol pharmaceutical excipient is composed of 50-80% ⁇ -mannitol and 20-50% ⁇ -mannitol. Composed of compound mannitol polycrystals. It should be noted that the composite mannitol polycrystal composed of 50-80% ⁇ -mannitol and 20-50% ⁇ -mannitol is the target product prepared according to the method of the present invention.
  • This embodiment provides a novel microcrystalline mannitol, and its preparation method is as follows:
  • Figure 9 is a scanning electron micrograph of the block mannitol prepared in Example 7 of the present invention (scale bar: 50 microns).
  • the prepared mannitol has a rod-like or needle-like structure (that is, a non-target product). ), further indicating that the ratio of the aqueous solution and ethanol should not be higher than 1:50, otherwise the crystallization speed is too fast due to the high water content and the high mannitol concentration in the mixed liquid, which will affect the crystal form and product morphology.
  • This embodiment provides a novel microcrystalline mannitol, and its preparation method is as follows:
  • Figure 10 is a scanning electron micrograph of the new microcrystalline mannitol prepared in Example 8 of the present invention (scale bar: 50 microns).
  • part of the prepared new microcrystalline mannitol is fibrous Or filamentous structure (ie the target product), indicating that other organic solvents that cannot dissolve mannitol can also achieve production goals, but take into account safety, actual production conditions (cost, processing technology, etc.) and subsequent organic solvent recycling and other factors , Ethanol is preferred as the solvent; the surface of this example, on the premise that no innovative invention is made, the new microcrystalline mannitol pharmaceutical excipient is obtained by simply changing the solvent, which should belong to those skilled in the art to simply apply this patent In the range.
  • the new microcrystalline mannitol prepared by the patented invention was subjected to BET nitrogen desorption and adsorption measurement, and the nitrogen adsorption specific surface area obtained from multiple measurements was 2-9m 2 /g, which is a porous structural material.
  • a new type of microcrystalline mannitol pharmaceutical excipient invented in this patent is most distinctive in that its microscopic form is fibrous or filamentous. It is the world’s first invention.
  • the fibrous or filamentous mannitol particles are intertwined to form Porous structure material.
  • the pore size distribution map was obtained using the BJH model, as shown in FIG. 11, which is the desorption and adsorption pore size distribution map of the novel microcrystalline mannitol measured in Example 9 of the present invention, and has a micro-medium-macroporous nanostructure.
  • Figure 12 is the DSC melting point peak of the novel microcrystalline mannitol measured in Example 10 of the present invention.
  • Location map, the new microcrystalline mannitol prepared under different conditions is slightly different in the ratio of ⁇ -mannitol to ⁇ -mannitol, and the measured DSC melting point peak is 167 ⁇ 1 degrees.
  • This embodiment provides a novel microcrystalline mannitol, and its preparation method is as follows:
  • This embodiment also provides a kind of ⁇ -mannitol whose preparation process conditions do not meet the range defined by the method for preparing novel microcrystalline mannitol, and its preparation method is as follows:
  • XRD scanning is a method for detecting the crystallization characteristics of substances.
  • Figure 13 shows the new microcrystalline mannitol and ⁇ -mannitol measured in Example 11 of the present invention.
  • the ratio of ⁇ -mannitol and ⁇ -mannitol involved in the patent of the present invention can also be reduced according to the ratio of the XRD characteristic peak of ⁇ -mannitol at 13.7 ⁇ 0.1 degrees or 17.3 ⁇ 0.1 degrees (double angle) Calculated.
  • Figure 13 calculated based on the XRD peak value at 13.7 ⁇ 0.1 degrees, the content of ⁇ -mannitol in this product (the new microcrystalline mannitol) is 54.7%.
  • the product The content of the novel microcrystalline mannitol) ⁇ -mannitol is 75.3%, which is within the range of 50-80% ⁇ -mannitol measured by FTIR, corresponding to 20-50% of ⁇ -mannitol.
  • FIG. 14 is a front and back photo of the novel microcrystalline mannitol paper sheet prepared in Example 12 of the present invention , The surface is smooth and the inner surface is rough. Because mannitol is a single molecule, the prepared paper sheet material is easily soluble in water and insoluble in most organic solvents (chemical properties are the same as mannitol). It has a fibrous or filamentous structure, and Under the action of capillary phenomenon, it can absorb 0 ⁇ 300mL/g organic solvent.
  • This embodiment provides a preparation process, in which the novel microcrystalline mannitol pharmaceutical excipient provided by the present invention is added as an excipient to a tablet.
  • the implementation process is that 0.5 g of the mixed powder containing the novel microcrystalline mannitol is compressed at 32-320 MPa, and the compressed tablet has a fracture force of 80-180 N, which meets the required physical strength of the tablet.

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Abstract

L'invention concerne un nouvel agent auxiliaire médicinal à base de mannitol microcristallin, comprenant un polycristal composite à base de mannitol composé de 50 % à 80 % d'α-mannitol et de 20 % à 50 % de δ-mannitol, la forme microscopique d'une poudre solide correspondante étant fibreuse ou filamenteuse, chacun des granules de mannitol fibreux ou filamenteux s'imbriquant les uns dans les autres, formant un matériau à structure poreuse présentant une surface spécifique d'adsorption d'azote gazeux de 2 à 9 m2/g et, sous les effets d'une action capillaire, présentant une quantité d'adsorption de solvant organique allant jusqu'à 300 ml/g. Grâce à l'agent auxiliaire médicinal à base de mannitol, le mannitol obtient des propriétés physiques et chimiques pratiques améliorées et il peut être appliqué dans des milliers ou des dizaines de milliers de préparations pharmaceutiques utilisant du mannitol, pour une amélioration correspondante à tous les niveaux. De plus, la structure fibreuse correspondante du matériau permet à celui-ci d'être transformé en un papier de qualité pharmaceutique soluble dans l'eau pour des applications dans la pratique médicale réelle.
PCT/CN2019/072849 2019-01-23 2019-01-23 Nouvel agent auxiliaire médicinal à base de mannitol microcristallin Ceased WO2020150930A1 (fr)

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Cited By (1)

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WO2024088560A1 (fr) * 2022-10-28 2024-05-02 Roquette Freres Composé pour formuler des principes actifs sensibles à l'humidité

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CN115671053A (zh) * 2022-11-09 2023-02-03 江西中医药大学 一种含有多孔甘露醇的载药粉末的制备方法
CN116617406A (zh) * 2023-06-16 2023-08-22 齐鲁理工学院 一种微晶甘露醇药用辅料、硬胶囊及其制备方法

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EP1967211A1 (fr) * 2005-12-28 2008-09-10 Takeda Pharmaceutical Company Limited Procede de production de preparation solide se desintegrant dans la cavite orale
CN101920018A (zh) * 2009-06-09 2010-12-22 吴江迪星科技有限公司 一种药用辅料及其制备方法
CN103371978A (zh) * 2012-04-28 2013-10-30 天津金耀集团有限公司 采用含乙醇溶剂制备的冻干粉针剂
CN103432586A (zh) * 2013-08-24 2013-12-11 江苏神华药业有限公司 一种药用辅料黄原胶及其制备方法
CN104645336A (zh) * 2015-01-04 2015-05-27 深圳市药品检验所 一种复合辅料及其制备方法和用途
CN108815531A (zh) * 2018-07-23 2018-11-16 深圳市优普惠药品股份有限公司 一种新型药用辅料及其制备方法

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Publication number Priority date Publication date Assignee Title
EP1967211A1 (fr) * 2005-12-28 2008-09-10 Takeda Pharmaceutical Company Limited Procede de production de preparation solide se desintegrant dans la cavite orale
CN101920018A (zh) * 2009-06-09 2010-12-22 吴江迪星科技有限公司 一种药用辅料及其制备方法
CN103371978A (zh) * 2012-04-28 2013-10-30 天津金耀集团有限公司 采用含乙醇溶剂制备的冻干粉针剂
CN103432586A (zh) * 2013-08-24 2013-12-11 江苏神华药业有限公司 一种药用辅料黄原胶及其制备方法
CN104645336A (zh) * 2015-01-04 2015-05-27 深圳市药品检验所 一种复合辅料及其制备方法和用途
CN108815531A (zh) * 2018-07-23 2018-11-16 深圳市优普惠药品股份有限公司 一种新型药用辅料及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024088560A1 (fr) * 2022-10-28 2024-05-02 Roquette Freres Composé pour formuler des principes actifs sensibles à l'humidité

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