Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • 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
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

• the present invention relates to a process for preparing an oral formulation of products belonging to the class of quinolones.
• quinolone class products are widely known antibacterial agents, which have been described in particular in the following references: BE 870 576; US 4,448,962; DE 3,142,854 EP 047,005; EP 206,283; BE 887 574; EP 221,463; EP 140,116 EP 131,839; EP 154,780; EP 078,362; EP 310,849; EP 520,240 US 4,499,091; US 4,704,459; US 4,795,751; US 4,668,784.
• the products of the quinolone class can be chosen from the products of general formula:
• R- j is an alkyl radical containing 1 to 4 carbon atoms, fluoroethyl, cyclopropyl, methylamino or difluorophenyl
• R2 is a hydrogen atom, or may represent an amino radical, if R 7 is a fluorine atom
• R3 is a hydrogen atom, a 2,8-diaza bicyclo [4.3.0] non-8-yl radical or a radical of structure:
• R 4 , R and Rg are identical or different and represent hydrogen atoms or methyl radicals, or their pharmaceutically acceptable salts.
• pefloxacin a compound which is more particularly interesting
• sparfloxacin a compound which is more particularly interesting
• ciprofloxacin a compound having a high degree of sensitivity
• ofloxacin levofloxacin
• enoxacin a compound having a high degree of fluorescence
• norfloxacin a compound having a high degree of fluorescence
• fleroxacin a compound having a high degree of the quinolone
• lomefloxacin a compound which are more particularly interesting are pefloxacin, sparfloxacin, ciprofloxacin, ofloxacin, levofloxacin, enoxacin, norfloxacin, fleroxacin, lomefloxacin, temafloxacin, amiflox tosufloxacin, flumequine, rufloxacin, clinafloxacin, Bay-y-3118, or PD 131 628.
• compacting is carried out by subjecting the product to mechanical densification under a low force, then grinding the agglomerates thus obtained on a grid in order to obtain a mixture having a particle size of 50 ⁇ m to 1 mm. and preferably greater than 100 ⁇ m, thus allowing good flow and good regularity in the dosages.
• Mechanical densification can be carried out under a force ranging from 1 to 12 kg.N / cm. Preferably under a force of 1 to 5 kg.N / cm.
• the grid on which the grinding is carried out is such that it is possible to ensure the obtaining of the particle size stated above.
• the excipients used are those which are usually recommended for the direct compression of a mixture of powders.
• the excipients are chosen in particular from cohesion agents, disintegrating agents, flow agents and lubricating agents.
• the cohesion agents can be microcrystalline cellulose, lactose, dicalcium phosphate or mixtures of these excipients
• the disintegrating agents can be corn starch, wheat starch, L-hydroxypropylcellulose, sodium carboxymethyl starch, crosslinked sodium carboxymethylcellulose or mixtures of these excipients
• the flow agents can be colloidal silica, talc or mixtures of these excipients
• the lubricating agents can be magnesium stearate, stearic acid, glycerol tribehenate or mixtures of these excipients.
• the compression operation following compaction and grinding is carried out under a force which can range from 6 to 10 kN (measurement at the level of the compression roller) and preferably of the order of 8 to 9 kN.
• This compression operation is preferably preceded by pre-compression under a force which can range from 0.5 to 2.5 kN.
• High compression speeds can be achieved by the method according to the invention, without altering the quality of the tablets. It is in particular possible to reach speeds greater than 150,000 tablets / hour, without causing cleavage.
• the tablets thus obtained have a disintegration time of less than 1 minute and generally of the order of 30 seconds.
• Their residual humidity levels are generally around 2.4% and can vary from 2.1 to 3%.
• the tablets obtained at the end of the process according to the invention can optionally be film-coated according to the usual methods.
• the filming operation is facilitated by the fact that no cleavage occurs during the operation.
• the method according to the invention thus provides access to an oral form in which the cleavage is eliminated, for which the tablets have a gain in homogeneity of hardness and the mixture of which is used in the final compression, after compaction and grinding, has a gain in cohesion.
• magnesium stearate After sieving on a 0.5 mm grid, 133.33 g of magnesium stearate are added and then mixed again for 5 minutes at the speed of 12 rotations per minute.
• the yield of the operation is approximately 80 kg / hour.
• the compression is carried out on a Courtoy ⁇ R190 rotary machine equipped with 24 punches with a diameter of 8 mm and a radius of curvature 10 mm.
• the pre-compression is carried out under a force of 250 kg and the compression is carried out under a force of 780 kg.
• the production speed is 1000 tablets of unit mass: 150 mg per minute.
• Figure 1 attached in appendix on plate n ° I shows the absence of cleavage zones (magnification: 7.5).
• magnesium stearate After sieving on a 0.5 mm grid, 800 g of magnesium stearate are added and then mixed again for 5 minutes at the speed of 12 rotations per minute.
• the yield of the operation is approximately 80 kg / hour.
• the compression is carried out on a Courtoy v - R190 rotary machine equipped with 24 punches with a diameter of 8 mm and a radius of curvature 10 mm.
• the pre-compression is carried out under a force of 160 kg and the compression is carried out under a force of 800 kg.
• the production speed is 1500 tablets of 150 mg per minute. A good flow of the powder is observed, a good resistance of the weights and a correct hardness of the tablets. There are no cleavage zones.
• Figure 2 attached in appendix on plate n ° I shows the absence of cleavage zones (magnification: 7.5).
• FETTE PT2080 (* D R) equipped with 43 punches with a diameter of 10 mm and a radius of curvature 12 mm.
• the pre-compression is carried out under a force of 1.5 kN and the compression is carried out under a force of 8.5 kN.
• the production speed is 80,000 300 mg tablets per hour.
• FIG. 4 attached as an appendix on Plate II shows the absence of cleavage zones.
• FIG. 4 annexed to plate No. II, shows a cleavage zone on a tablet prepared in the same proportions as those of Example 3, but by direct compression of the powder mixture (magnification: 7.5).

Landscapes

• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

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• 1993
  • 1993-10-21 FR FR9312550A patent/FR2711524B1/fr not_active Expired - Fee Related
• 1994
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  • 1994-10-19 WO PCT/FR1994/001211 patent/WO1995011022A1/fr not_active Application Discontinuation
  • 1994-10-19 GR GR940100472A patent/GR1002181B/el unknown
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  • 1994-10-19 CZ CZ961136A patent/CZ113696A3/cs unknown
  • 1994-10-19 DZ DZ940108A patent/DZ1818A1/fr active
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  • 1994-10-19 AT AT0905894A patent/ATA905894A/de unknown
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  • 1994-10-19 BE BE9400944A patent/BE1007326A3/fr not_active IP Right Cessation
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  • 1994-10-19 GB GB9608316A patent/GB2297908B/en not_active Expired - Fee Related
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  • 1994-10-19 EE EE9600050A patent/EE9600050A/xx unknown
  • 1994-10-19 CA CA002174444A patent/CA2174444A1/fr not_active Abandoned
  • 1994-10-19 AU AU79970/94A patent/AU7997094A/en not_active Abandoned
  • 1994-10-19 EP EP94931613A patent/EP0724442A1/fr not_active Withdrawn
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• 1996
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