Process for the preparation of oral compositions containing quinolones

Method for the preparation of an improved oral formulation of active ingredients belonging to the class of quinolones. The method is characterized by an intermediate compacting and grinding stage, before compression of the mixture of the active ingredient and excipients.

The present invention relates to a process for the preparation of an oral 
formulation of products belonging to the quinolone family. 
The products of the quinolone family are widely known antibacterial agents, 
which have been described in particular in the following references: BE 
870 576; U.S. Pat. No. 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; U.S. Pat. No. 4,499,091; U.S. Pat. No. 4,704,459; 
U.S. Pat. No. 4,795,751; U.S. Pat. No. 4,668,784. 
The preparation of fine granules by a wet granulation process has been 
described in the publication by Y. Shirai et al., Biol. Pharm. Bull. 
16(2), 172 (1993). 
A process for the direct compression of the mixture of a quinolone with 
excipients, without the prior addition of mixing water, has been described 
in Patent EP 189,114. 
However, the previously known processes have drawbacks which lead, most 
often, to an imperfect result. Indeed, the processes which make use of wet 
granulation have a tendency to slow down the dissolution and to promote 
the formation of hydrates, which are less soluble or more difficult to 
disperse when compared with the corresponding anhydrous form. This results 
in a delay in the dissolution and the release of the active principle, 
which may be a nuisance in the use of antimicrobial medicinal products. 
Moreover, methods for the direct compression of a mixture of the 
excipients in powder form has the advantage of avoiding the formation of 
hydrates, but the quality of the tablets obtained is not always consistent 
and satisfactory insofar as cleavage problems arise, thus rendering some 
batches of tablets unsuitable for marketing. Industrial losses, which may 
prove to be considerable, are thereby incurred. 
It has now been found that oral formulations of active principles belonging 
to the quinolone family, having no problems of overly slow solubilization 
or any cleavage problems, could be prepared by incorporating an 
intermediate step of compacting and then of grinding. Namely, by 
dry-mixing the said active principle with the suitable excipients for an 
oral formulation, followed by a compacting, a grinding and then 
compression of the granules thus obtained. The new step of compacting and 
grinding makes it possible to carry out the direct compression of a powder 
of much coarser particle size and leads to tablets having no cleavage 
problems. The industrial risks due to batch-to-batch variations were thus 
able to be reduced, or even eliminated. 
According to the invention, the products of quinolone family may be chosen 
from the products of general formula: 
##STR1## 
in which R.sub.1 is an alkyl radical containing 1 to 4 carbon atoms or a 
fluoroethyl, cyclopropyl, methylamino or difluorophenyl radical, X 
represents a nitrogen atom or a group .dbd.CR.sub.7 -- in which R.sub.7 is 
a hydrogen, chlorine or fluorine atom or alternatively R.sub.7 forms, with 
the radical R.sub.1 and the atoms to which they are attached, a 6-membered 
heterocycle which is substituted with a methyl radical and which 
optionally contains an oxygen or sulphur atom, R.sub.2 is a hydrogen atom 
or may represent an amino radical if R.sub.7 is a fluorine atom, and 
R.sub.3 is a hydrogen atom, a 2,8-diazabicyclo4.3.0!non-8-yl radical or a 
radical of structure: 
##STR2## 
in which R.sub.4, R.sub.5 and R.sub.6 are identical or different and 
represent hydrogen atoms or methyl radicals, or the pharmaceutically 
acceptable salts thereof. 
More especially advantageous among the quinolones mentioned above are 
pefloxacin, sparfloxacin, ciprofloxacin, ofloxacin, levofloxacin, 
enoxacin, norfloxacin, fleroxacin, lomefloxacin, temafloxacin, 
amifloxacin, tosufloxacin, flumequine, rufloxacin, clinafloxacin, 
Bay-y-3118 and PD 131 628. 
According to the process of the invention, the compacting is carried out by 
subjecting the product to a mechanical densification at a rather low 
force, followed by grinding the agglomerates thus obtained on a grid, in 
order to obtain a mixture having a particle size of 50 .mu.m to 1 mm and 
preferably greater than 100 .mu.m, thus allowing a good flow and good 
uniformity in the doses. 
The mechanical densification may be carried out at a force ranging from 1 
to 12 kg N/cm. Preferably at 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 that the 
abovementioned particle size is obtained. 
The excipients used are generally those which are usually recommended for 
the direct compression of a mixture of powders. By way of example, the 
excipients are chosen in particular from cohesion agents, cleaving agents, 
flow agents and lubricants. 
More precisely, and without any limitation being implied, the cohesion 
agents may be microcrystalline cellulose, lactose, calcium hydrogen 
phosphate or mixtures of these excipients; the cleaving agents may be corn 
starch, wheat starch, L-hydroxypropyl cellulose, sodium carboxymethyl 
starch, crosslinked sodium carboxymethyl cellulose or mixtures of these 
excipients; the flow agents may be colloidal silica, talc or mixtures of 
these excipients; the lubricants may be magnesium stearate, stearic acid, 
glycerol tribehenate or mixtures of these excipients. 
According to the invention, the compression operation which follows the 
compacting and the grinding is carried out at a force which may range from 
6 to 10 kN (measured at the compression roller) and preferably of the 
order of 8 to 9 kN. This compression operation is preferably preceded by a 
precompression at a force which may range from 0.5 to 2.5 kN. 
High compression rates may be achieved by virtue of the process according 
to the invention, without, however, detrimentally affecting the quality of 
the tablets. It is in particular possible to reach rates higher than 
150,000 tablets/hour, without causing any cleavage. 
The tablets thus obtained have a disintegration time of less than 1 minute 
and generally of the order of 30 seconds. Their residual moisture content 
is generally in the region of 2.4% and may vary from 2.1 to 3%. 
It is understood that the tablets obtained on conclusion of the process 
according to the invention may optionally be film-coated according to the 
usual methods. The film-coating operation is facilitated by the fact that 
no cleavage occurs during the operation. 
The process according to the invention makes it thus possible to gain 
access to an oral form in which cleavage is suppressed, in which the 
tablets show increased homogeneity of hardness and in which the mixture 
used in the final compression, after the compacting and the grinding, 
shows increased cohesion. 
The absence of cleavage zones was demonstrated in particular in the 
following test: An interchangeable ground drill bit, rotating at a steady 
speed set at 500 revolutions per minute, penetrates vertically into the 
tablet which is mounted on a holder which rises steadily and continuously 
(1 mm/minute). Simultaneously, a detector connected to a strain gauge 
placed under the tablet holder records the forces which oppose the 
advancement of the bit into the tablet. The sudden variations in the 
forces recorded indicate the presence of a cleavage zone. In the tests 
carried out on the tablets of Examples 1 to 3, no cleavage was observed.

EXAMPLE 1 
1) The constituents intended for the initial mixture, comprising: 
______________________________________ 
sparfloxacin 6,666.67 g 
microcrystalline cellulose 
1,566.67 g 
corn starch 1,000.00 g 
L-hydroxypropyl cellulose 
333.33 g 
colloidal silica 100.00 g 
______________________________________ 
are screened through a 1 mm grid and then mixed in a 30-liter tank for 15 
minutes at a speed of 12 rotations per minute (rpm). 
After screening through a 0.5 mm grid, 133.33 g of magnesium stearate are 
added, following by mixing for a further 5 minutes at a speed of 12 
rotations per minute. 
2) The powder mixture is compacted and then ground on a Gerteis.RTM. 
compactor (3W Polygran type) set to the following parameters: 
a) compacting: 
pressure on the rollers: 2.4 kN/cm 
thickness of the compact: 3.0 mm 
roller speed: 12 rpm 
% of briquette: 90% 
b) grinding: 
compactor equalizing grid: 1.00 mm 
speed of the equalizing rotor: 40 rpm 
amplitude of the equalizing rotor: 60.degree.. 
The yield of the operation is approximately 80 kg/hour. 
After mixing the ground material for 10 minutes, 100 g of L-hydroxypropyl 
cellulose, screened beforehand through a 0.5 mm grid, are added. Mixing is 
continued for 10 minutes at the speed of 12 rpm, and 100 g of magnesium 
stearate, screened beforehand through a 0.5 mm grid, are then added. 
Mixing is continued for a further 5 minutes at the speed of 12 rpm. 
3) The compression is carried out on a Courtoy.RTM. R190 rotary machine 
equipped with 24 punches of 8 mm diameter and of a 10 mm radius of 
curvature. The precompression is carried out at a force of 250 kg and the 
compression is carried out at a force of 780 kg. The production rate is 
1000 tablets of unit mass: 150 mg per minute. 
Good flow of the powder, good weight behaviour and a correct hardness of 
the tablets are observed. There is no presence of cleavage zones. 
FIG. 1 shows the absence of cleavage zones (magnification: 7.5). 
EXAMPLE 2 
1) The constituents intended for the initial mixture, comprising: 
______________________________________ 
sparfloxacin 40,000 g 
microcrystalline cellulose 
9,400 g 
corn starch 6,000 g 
L-hydroxypropyl cellulose 
2,000 g 
colloidal silica 600 g 
______________________________________ 
are screened through a 1 mm grid and then mixed in a 30-liter tank for 15 
minutes at the speed of 12 rotations per minute (rpm). 
After screening through a 0.5 mm grid, 800 g of magnesium stearate are 
added, followed by mixing for a further 5 minutes at the speed of 12 
rotations per minute. 
2) The mixture of powders is compacted and then ground on a Gerteis.RTM. 
compacter (3W Polygran type) set to the following parameters: 
a) compacting: 
pressure on the rollers: 2.4 kN/cm 
thickness of the compact: 3.0 mm 
roller speed: 12 rpm 
% of briquette: 90% 
b) grinding: 
compactor equalizing grid: 1.00 mm 
speed of the equalizing rotor: 40 rpm 
amplitude of the equalizing rotor: 60.degree. 
The yield of the operation is approximately 80 kg/hour. 
After mixing the ground material for 10 minutes, 600 g of L-hydroxypropyl 
cellulose, screened beforehand through a 0.5 mm grid, are added. Mixing is 
continued for 10 minutes at the speed of 12 rpm, and 600 g of magnesium 
stearate, screened beforehand through a 0.5 mm grid, are then added. 
Mixing is continued for a further 5 minutes at the speed of 12 rpm. 
3) The compression is carried out on a Courtoy.RTM. R190 rotary machine 
equipped with 24 punches of 8 mm diameter and of a 10 mm radius of 
curvature. The precompression is carried out at a force of 160 kg and the 
compression is carried out at a force of 800 kg. The production rate is 
1500 tablets of 150 mg per minute. 
Good flow of the powder, good weight behaviour and a correct hardness of 
the tablets are observed. There is no presence of cleavage zones. 
FIG. 2 shows the absence of cleavage zones (magnification: 7.5). 
EXAMPLE 3 
1) The constituents intended for the initial mixture, comprising: 
______________________________________ 
sparfloxacin 166.667 kg 
microcrystalline cellulose 
39.167 kg 
corn starch 25.000 kg 
L-hydroxypropyl cellulose 
8.333 kg 
colloidal silica 2.500 kg 
______________________________________ 
are placed in a 600-liter tank feeding a screener fitted with a 0.24 cm 
grid. After screening, the powders are collected in another 600-liter 
mixer tank. The powders are mixed for 15 minutes at a speed of 8 rotations 
per minute. After screening through a 0.11 cm grid, 3.333 kg of magnesium 
stearate are added, followed by continued stirring of the mixture for 5 
minutes at the speed of 8 rotations per minute. 
2) The mixture of powders is compacted and then ground on a Gerteis.RTM. 
compacter (3W Polygran type) set to the following parameters: 
a) compacting: 
pressure on the rollers: 2.4 kN/cm 
thickness of the compact: 3.0 mm 
roller speed: 12 rpm 
% of briquette: 90% 
b) grinding: 
compactor equalizing grid: 1.00 mm 
speed of the equalizing rotor: 50 rpm 
amplitude of the equalizing rotor: 90.degree. 
The yield of the operation is approximately 80 kg/hour. 
After mixing the ground material for 2 minutes, 2.500 kg of L-hydroxypropyl 
cellulose, screened beforehand through a 0.11 cm grid, are added. Mixing 
is continued for a further 5 minutes at the speed of 8 rpm. 
3) The compression is carried out on a Fette PT2080.RTM. rotary machine 
equipped with 43 punches of 10 mm diameter and of a 12 mm radius of 
curvature. The precompression is carried out at a force of 1.5 kN and the 
compression is carried out at a force of 8.5 kN. The production rate is 
80,000 tablets of 300 mg per hour. 
Good flow of the powder, good weight behaviour and a correct hardness of 
the tablets are observed. There is no presence of cleavage zones. 
FIG. 3 shows the absence of cleavage zones. FIG. 4 shows a cleavage zone on 
a tablet prepared in identical proportions to those of Example 3, but by 
direct compression of the powder mixture (magnification: 7.5).