• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a process for the production of the same, characterized in that a suspension of spherical terithromycin clusters and terithromycin crystals is prepared and the crystals are gradually crystallized by coating them with a phase insoluble in terithromycin. Spherical terithromycin clusters are used to make microcapsules.
    公开号:KR20020033771A
    申请号:KR1020027002404
    申请日:2000-08-28
    公开日:2002-05-07
    发明作者:진-이브 고다드；발레리 록농-라보
    申请人:크리스티앙 쥘랭, 장-끌로드 비에이으포스；아벤티스 파마 소시에떼아노님；
    IPC主号:
    专利说明:

    Spherical Telithromycin Clusters, Method for the Production and Use Thereof in the Preparation of Pharmaceutical Forms}
    [1] The present invention relates to spherical aggregates of terithromycin, methods for their preparation and their use in the preparation of pharmaceutical forms.
    [2] Territhromycin or 11,12-dideoxy-3-dec ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy of the formula ) -6-O-methyl-3-oxo-12,11- (oxycarbonyl ((4- (4- (3-pyridinyl) -1H-imidazol-1-yl) butyl) imino))- Erythromycin is a product with antibiotic properties, described and claimed in European Patent No. 60967.
    [3]
    [4] Preferred dosage forms of this product are the oral route. Some patients, especially children, have difficulty swallowing tablets and capsules, so it is desirable to use other dosage forms, for example, oral suspensions that can be taken immediately or prepared immediately upon taking.
    [5] Territomycin is an active ingredient with an unpleasant taste. Therefore, the herbal form should be prepared to eliminate the unpleasant taste of the product but to maintain good bioavailability.
    [6] The physicochemical properties of terithromycin are such that it is possible to finely encapsulate, ie coat the active ingredient with a polymer or polymer mixture.
    [7] Microencapsulation can be carried out by spraying the polymer or by interfacial polymerization or coacervation. In order to achieve good microencapsulation, the spherical particles of the active ingredient should not be too small or large when the particle size is too small, no agglomeration occurs between the particles, and when too large, the dissolution takes place too slowly, The coating of the active ingredient is accurate and must be spherical so that the active ingredient has good release kinetics.
    [8] It is an object of the present invention to provide spherical aggregates of terithromycin.
    [9] Spherical aggregates can be obtained by directly modifying the crystals into spherical agglomerates as shown below.
    [10] For general spherical aggregates, see Frederica Guillaume and Anne-Marie Guyot-Hermann, Il Farmaco XLVIII 1993 pages 473 et seq.
    [11] The agglomerates of the present invention allow for good microencapsulation, and an object of the invention is the use of spherical agglomerates, in particular characterized by enclosing the spherical agglomerates with a polymer layer to obtain the desired herbal form, for example a microcapsule.
    [12] An object of the present invention is a spherical aggregate of terrythromycin characterized by a particle size of 30 to 400 microns.
    [13] A very particular object of the present invention is a spherical aggregate of terrythromycin characterized in that the average particle size is between 80 and 150 microns, in particular that the average particle size is close to 100 microns, i.e. half the particle size of the aggregate is less than 100 microns. A spherical aggregate of terthromycin characterized by the above-mentioned.
    [14] It is also an object of the present invention to prepare a spherical aggregate which is characterized in that a suspension of terithromycin crystals is prepared, which is then gradually crystallized by coating the crystals with a phase insoluble in the terithromycin.
    [15] It is an object of the present invention, in particular, to a process for the production of territhromycin in acetone.
    [16] A more particular object of the present invention is a production process wherein crystallization takes place in an acetone / isopropyl ether mixture.
    [17] In a preferred embodiment, crystallization is carried out at -5 to -15 ° C. The size of the spherical aggregates was controlled by adjusting the stirring speed.
    [18] The following examples illustrate but do not limit the invention.
    [19] a) preparation of acetone solution
    [20] 64 g of terithromycin and 128 mL of pure anhydrous acetone were introduced under nitrogen.
    [21] It was stirred under slight overpressure of nitrogen at 19 ° C. to 21 ° C. and it was confirmed that all were dissolved.
    [22] If necessary, a quantitative amount of water (0.26 mL of deionized water) was added to give 2.9% product.
    [23] b) crystallization
    [24] Under nitrogen, 640 mL of isopropyl ether and 12.8 mL of pure anhydrous acetone were introduced into a double case reactor equipped with a mechanical stirrer, temperature probe and nitrogen inlet.
    [25] The temperature was stabilized between 19 ° C and 21 ° C.
    [26] 5% by mass of acetone solution was introduced with stirring at 350 rpm.
    [27] The crystallization was then initiated with 0.96 g of micronized terithromycin suspended by sonication in 3.2 mL of isopropyl ether with continued stirring at 350 rpm.
    [28] Crystallization proceeded immediately after initiation.
    [29] After stirring for 15 minutes at 20 ± 1 ° C., the suspension was cooled to −10 ± 1 ° C. over 30 minutes.
    [30] 157.2 g of acetone solution of terithromycin was introduced into the remaining acetone solution.
    [31] Stirred at -10 ° C for 1 hour.
    [32] c) isolation
    [33] Dried, clarified and washed twice with 64 mL of isopropyl ether each time.
    [34] It was dried in an oven at 40 ° C. under vacuum and then cooked into a 500 μm grid.
    [35] 50.4 g of terithromycin spherical aggregates were obtained.
    [36] Particle size analysis
    [37] Particle size was measured by laser diffraction using a HELOS SYMPATEC® model particle size analyzer.
    [38] The results obtained are as follows:
    [39] 10% of the particles have a diameter of <77 microns.
    [40] 50% of the particles have a diameter of <107 microns.
    [41] 90% of the particles have <166 microns.
    [42] Figure 1 shows the aggregates obtained by operation as indicated above, where the unit is 1 cm = 150 microns.
    [43] Usage
    [44] The product of the above example was used to prepare microcapsules for the preparation of oral suspensions prepared immediately by simple coacervation or by direct spraying of a suitable polymer.
    [45] The suspension prepared is acceptable to children and possesses good release kinetics.
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] Spherical Aggregates of Terriritomycin.
    [2" claim-type="Currently amended] The spherical aggregate of terrythromycin according to claim 1, wherein the particle size is 30 to 400 microns.
    [3" claim-type="Currently amended] The spherical aggregate of terrythromycin according to claim 2, wherein the average particle size is 80 to 150 microns.
    [4" claim-type="Currently amended] The spherical aggregate of terthromycin according to any one of claims 1 to 3, characterized in that the average particle size is close to 100 microns.
    [5" claim-type="Currently amended] 5. The process according to claim 1, wherein a suspension of terithromycin crystals is prepared and subsequently crystallized by coating the crystals with a phase insoluble in terithromycin. .
    [6" claim-type="Currently amended] The production method according to claim 5, wherein a solution of terithromycin in acetone is used.
    [7" claim-type="Currently amended] 7. Process according to claim 5 or 6, characterized in that the crystallization takes place in an acetone / isopropyl ether mixture.
    [8" claim-type="Currently amended] 8. The process according to claim 5, wherein the crystallization is carried out at −5 ° C. to −15 ° C. 9.
    [9" claim-type="Currently amended] Use of the spherical aggregate according to any one of claims 1 to 4, characterized in that the spherical aggregate is surrounded by a polymer layer to obtain the desired herbal form.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-08-26|Priority to FR9910810A
    1999-08-26|Priority to FR99/10810
    2000-08-28|Application filed by 크리스티앙 쥘랭, 장-끌로드 비에이으포스, 아벤티스 파마 소시에떼아노님
    2002-05-07|Publication of KR20020033771A
    2007-05-15|Application granted
    2007-05-15|Publication of KR100718222B1
    优先权:
    申请号 | 申请日 | 专利标题
    FR9910810A|FR2797875B1|1999-08-26|1999-08-26|Spherical telithromycin agglomerates, process for their preparation and their application in the preparation of pharmaceutical forms|
    FR99/10810|1999-08-26|
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