Note: Descriptions are shown in the official language in which they were submitted.
CA 02227314 1998-01-16
Hoechst Aktiengesellschaft HOE 97/F 012 Dr. RU/St
Description
S Preparalion of concealed taste preparations of antih~cterially active quinolone
derivatives
The present invention relates to a process for the production of co"cealed taste oral
10 pharmaceutical preparations of antibacterially active quinolone derivatives.
It is known that antibacterially active inhibitors of the bacterial gyrase from the
quinolones substance group are distinguished by a highly bitter intrinsic taste. This
intrinsic taste! must be concealed to attain adequate patient acceptance on
15 administration of oral preparations of the sl Ihst~nces. As a rule, this is carried out by
film-coating tlhe tablets. For therapy with antibaclerially active quinolone derivatives,
individual doses of 100 mg to 1000 mg of the pharl"aceutical are necessary. The
taking of ~dequ~tely large-volume solid pharmaceutical forms by swallowing
presents great difficulties to elderly and also dysphagic patients and children, so
20 that there is a need for an oral phar",aceutical form which is acceptal,le as regards
taste, which does not have to be swallowed as a whole in solid form, but which can
be taken either suspended in liquid or by chewing.
The technologically most simple way of covering up an unpleasant taste is the
25 addition of suitable flavors to a solution of the pharmaceutical. In the case of the
antibacterially active quinolone derivatives, this measure, however, is inadequate,
so that further steps are necessary for the concealment or neutralization of the bitter
taste.
The processles known until now are aimed at preventing or at least decreasing the
3() dissolution of the mainly highly soluble antibacterially active quinolone derivatives in
the solvent used and in the saliva.
In EP-A-0551 820, this is carried out by microencapsulation of the anhydrate of the
base form of these substances. As coating materials, water-insoluble neutral methyl
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and/or ethyl ester compounds or quaternary ammonium compounds of
polymethacrylic acid or mixtures thereof or ethylcellulose are used.
Biol. Pharm. Bull. (1993), 16 (2), 172-7 describes a microencapsulation of fine
5 granules of sparfloxacin and hydroxypropylcellulose with a low degree of
substitution using ethylcellulose and hydroxypropylmethylcellulose as coating
materials.
A similar process for the microencapsulation of particles of pyridonecarboxylic acid
1 () antibacterial agents (especially enoxacin) and water-swellable agents with mixtures
of ethylcellulose and water-soluble polymers is described in EP-A- 409 254.
In these proc esses for microencapsulation, the coating materials are applied byspraying on solutions thereof. It is disadvantageous here that expensively
15 constructed equipment is necess~ry and that a practical lower limit is placed on the
utilizable particle size of the granules to be coated - on the one hand due to the
more than proportionally increasing need for coating with decreasing particle size
and on the other hand to the increasing cohesiveness with decreasing particle size,
which technically restricts the possibilities for coating by means of spraying on
20 account of increasing tendencies to agglomerate.
Thus EP-A-0551 820 mentions 100 - 500 ,um as a prefer~ed range for the
microcapsules obtained. Particles of 500 ,um, applied as a suspension, however,
can definitely produce an unpleasant sandy feeling in the mouth of the patient. In
25 addition, the time needed for the coating of fine particles by spraying is high.
JP 63 150220 describes a process which may also afford a product similar to a
microencapsulation. Powdered pharmaceutical (e.g. enoxacin) is mixed with
powdered coating material, e.g. with waxy substances, such as paraffin, stearic
acid, beeswax, etc. or with polymeric substances capable of film formation, such as
3() methacrylic acid copolymer, ethylcellulose, polystyrene, etc. The mixture is treated
with organic solvents in order to dissolve the coating materials. After removing the
solvent, a powder is again obtained. A disadvantage of this process is the use of
solvents which are flammable, injurious to health or ecologically questionable, which
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have to be recovered or to be disposed of by expensive means. A residual amount
moreover remains in the product.
Use of liquicl vehicles as a medium for the dissolution or dispersion of the coating
5 materials is common to all processes described until now for the coating of active
con",ound particles or granules of antimicrobially active quinolone derivatives.
The invention was based on the object of making available a process for the
preparation of orally administrable concealed taste pharmaceutical preparations
10 having rapid release of active compound for antibacle, ially active quinolonederivatives, which does not have the described disadvanlages of the processes
known from Ithe literature and which moreover avoids use of liquid vehicles as
medium for the dissolution or dispersion of the coating materials.
Rapid releas;e of active compound is understood as meaning an at least 80%
release of an individual dose after 30 minutes in 900 ml of 0.1 N HCI.
Surprisingly, it has now been found that concealment of taste even without use of
liquid vehicles is possible if antimicrobially active quinolone derivatives are mixed
with higher fatty acids and, if appropriate, further additives, the mixture is heated
2t) and, after cooling, comminuted to a powder or granules. Even after pulverization,
the product still has an ~dequ~te concealment of taste. The heating of the mixtures
can be carried out according to conventional processes. From the process
technology point of view, the use of a heating mixer with a high speed of rotation
(such as, for example, Henschel Fluid Mixer FM4 or FM10) is prefened, in which the
2'; mixtures are heated by frictional heat and which in the same unit offers thepossibility of comminution after cooling. High speed of rotation is understood as
meaning a slpeed of rotation of at least 3000 rpm. The mixtures are heated to 30~C
to 140~C, preferably 40~C to 1 20~C, particularly preferably to 50~C to 85~C.
30 The invention furthermore relates to preparations which can be prepared by this
method.
Higher fatty acids are understood as meaning fatty acids having at least 10 carbon
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atoms.
Suitable higher fatty acids are those having 10 to 22 carbon atoms, fatty acids
having 12 to 18 carbon atoms being particularly suitable for the process described.
Mixtures of latty acids can also be employed advanlageously.Thus, for example,
5 co",i"ercially available stearic acid, which is a mixture of approximately equal
amounts of stearic acid and palmitic acid, can be readily employed. A suitable
further additive is, for example, highly disperse silica.
As an essential structural feature, the antibacterially active quinolone derivatives
10 have 1-ethyl-4-oxopyridine-3-carboxylic acid (see Auterhoff, Knabe, Holtje,
Lehrbuch der Pharmazeutischen Chemie [Textbook of Pharmaceutical Chemistry],
13th Edition, 1994, page 788). Levofloxacin, ofloxacin, ciprofloxacin, norfloxacin,
sparfloxacin and enoxacin are preferred. Levofloxacin and ofloxacin are particularly
preferred.
The weight ratio of quinolone derivative(s) to fatty acid(s) is preferably from 1:0.3 to
1:4, particularly preferably 1:1 to 1:2.
The heat-treated and subsequently comminuted preparations of antimicrobially
20 active quinolone derivative and higher fatty acid according to the invention can be
further processed to give pharmaceuticals, such as, for example, to give sachets,
chewable tablets or soluble tablets.
1. Soluble tablets
A soluble talblet is a pharmaceutical form which is intended to disintegrate in a glass
of water within at most 3 minutes with stirring and to form a suspension which can
30 pass through a sieve of 0.715 mm mesh width.
Soluble tablets offer themselves as a pharmaceutical form for pharmaceuticals
which are to be administered in a high dose, which as a conventional tablet would
be difficult to swallow on account of their large volume. The particular mode of
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administration of the soluble tablets in suspension or solution form requires anadequate concealment of the taste of badly tasting pharmaceuticals.
Soluble tablets can be formulated with auxiliaries which are also used for
conventional tablets. Typically, flavorings, sweete"er~ and possibly colorants are
~i additionally added. Utilizable product technologies are moist granulation, dry
granulation alnd direct tableting.
2. Sachets
1 Cl Sachets are bags which usually contain one individual dose of a pharmaceutical as
a power or granules. For administration, the conte"t of a bag is suspended or
dissolved in .3 glass of water. In addition to sugars and sugar substitutes, suitable
additives are viscosity-increasing auxiliaries, flow regulators, flavorings, colorants
and possibly buffer substances.
3. Chewable tablets
Chewable tablets are tablets which are chewed before swallowing. In the case of the
high-dose antibacterially active quinolone derivatives, reasons for the use of this
2C pharmaceutical form are likewise problems which certain groups of patients have
with the swallowability of conventional tablets, film-coated tablets, capsules or
coated tablets. In addition to other customary tableting auxiliaries, chewable tablets
usually mainly contain sugars or sugar substitutes and also flavorings.
2S The release of active compound is measured in a USP paddle apparatus, as is
described in USP23, page 1792, Section 711, Figure 2.
Working Examples
3() Example 1
shows the preparation of a concealed taste base mixture of levofloxacin
hemihydrate.
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Levofloxacin hemihydrate 256.23 mg
Stearic acid 211.00 mg
Levofloxacin hemihydrate and stearic acid are mixed for 3 minutes at a speed of
5 rotation of 1 CI00 rpm in a heating mixer. The speed of rotation is then increas~d to
5500 rpm and further mixing is carried out until the temperalLJre of the mixed
material reaches 75~C and the material has assumed a granular structure. The
mixture is cooled to room temperature by jacket cooling and the material is thencomminuted Iby further mixing over a period of 4 x 0.5 minutes at 5500 rpm with
10 further cooling. A powder having a neutral taste is obtained.
The active cc""pound release determinations in a USP paddle apparalus afforded
the following results:
Release medium
15, 900 ml of water 900 ml of 0.1 N
hydrochloric acid
after 5 minutes 34.2 % 91.2 %
after 15 minutes 47.1 % 97,9 %
after 30 minutes 55.7 % 97,4 %
Example 2
shows the fulther processing of the concealed taste base mixture from Example 1 to
give a soluble tablet
Levofloxacin hemihydrate/stearic acid mixture 467.23 mg
Corn starch 243.77 mg
Microcrystalline cellulose 200.00 mg
Crospovidone, micronized 50.00 mg
Polyvinylpyrrolidone 5.00 mg
Levofloxacin hemihydrate/stearic acid mixture, corn starch, microcrystalline
cellulose, crospovidone, micronized and polyvinylpyrrolidone are mixed, granulated
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with water, dried, pressed through a sieve of mesh width 1.2 mm and tableted using
an eccentric tableting machine.
The bitter intrinsic taste of active compound is largely conce~ed in the suspension
5 of the soluble tablets in 100 ml of mains water at room temperature.
The active compound release determinations in a USP paddle apparatus arrorded
the following results:
Release medium
900 ml of water 900 ml of 0.1 N
hydrochloric acid
after 5 minutles 32.2 % 96.4 %
after 15 minutes 47.4 % 100 %
after 30 minutes 58.9 % 100 %
Example 3
shows the production of a levofloxacin hemihydrate soluble tablet with palmitic acid
as a taste-concealing higher fatty acid, which was prepared by the process
2() according to the invention:
Levofloxacin hemihydrate 512.46 mg
Palmitic acid 422.00 mg
Microcrystalline cellulose 457.54 mg
Crospovidone 150.00 mg
Raspberry flavor 30.00 mg
Aspartame 60.00 mg
Levofloxacin hemihydrate and palmitic acid are processed as described in Example30 1 to give a concealed taste base mixture.
Microcrystalline cellulose, crospovidone, raspberry flavor and aspartame are
admixed and the total mixture is compacted and dry-granulated through a 1.0 mm
sieve. The dry granules are processed to give soluble tablets.
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The active compound release determinations in a USP paddle apparatus afforded
the following results:
Release medium
900 ml of water 900 ml of 0.1 N
hydrochloric acid
after 5 minutes 43.5 % 100 %
after 15 minutes 58.9 % 100 %
after 30 minutes 73.9 % 100 %
1()
Example 4
shows the preparation of a norfloxacin soluble tablet by the process according to the
invention witlh stearic acid as a taste-concealing higher fatty acid. Norfloxacin is an
example of a pharmaceutical having lower solubility than levofloxacin.
1 cj
Norfloxacin 500.00 mg
Stearic acid 600.00 mg
Corn starch 711.46 mg
Microcrystalline cellulose 638.32 mg
Crospovidone 146.22 mg
Highly disperse silica 14.00 mg
Peach flavor 30.00 mg
Aspartame 40.00 mg
Acesulfam K 20.00 mg
Norfloxacin zlnd stearic acid are processed, analogously to Example 1, to give aconcealed taste base mixture. Corn starch, microcrystalline cellulose, crospovidone,
highly disperse silica, peach flavor, aspartame and acesulfam K are admixed to the
base mixture. The total mixture is tableted using an eccentric tableting machine.
3~)
The active compound release determinations in a USP paddle apparatus afforded
the following results:
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Release medium
900 ml of water 900 ml of 0.1 N
hydrochloric acid
after 5 minutes 7.6 % 94.9 %
after 15 minutes 16.5 % 99.5%
after 30 minutes 24 % 100 %
Example 5
10 shows the preparation of an of loxacin soluble tablet by the process according to the
invention with stearic acid as a taste-concealing higher fatty acid.
Orfloxacin 500.00 mg
Stearic acid 600.00 mg
1 L; Corn starch 711.46 mg
Microcrystalliine cellulose 638.32 mg
Crospovidonle 146.22 mg
Highly disperse silica 14.00 mg
Peach flavor 30.00 mg
Aspartame 40.00 mg
Acesulfam K 20.00 mg
Ofloxacin and stearic acid are processed, analogously to Example 1, to give a
concealed taste base mixture. Corn starch, microcrystalline cellulose, crospovidone,
25 highly disperse silica, peach flavor, aspartame and acesulfam K are added to the
base mixture, the total mixture is compacted, granulated through a 1.0 mm sieve
and tableted using an eccentric tableting machine.
The active compound release determinations in a USP paddle apparatus afforded
30 the following results:
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Release medium
900 ml of water 900 ml of 0.1 N
hydrochloric acid
after 5 minutes 6.8 % 87.3 %
after 15 minutes 14.4 % 100 %
after 30 minutes 20.6 % 100 %
Examples 6, 7, 8 and 9
10 show the preparation of levofloxacin hemihydrate soluble tablets using various waxy
substances as taste-concealing agents.
C~dlllF'e 9 10 11 12
Le~o~c~~~cin 512.45 mg 512.45 m~ 512.45 mg 512.45 mg
1 5 hemihydrate
Stearic acid 422.00 mg - - -
Stearyl alcohol -- 422.00 mg
Hy~ogen-- ~ - - 422.00 mg
castor oil
2() Glycerol mono- -- -- -- 422.00 mg
stearate
Poly~:lone 25000 10.00 mg 10.00 mg 10.00 mg 10.00 mg
Corn starch 487.55 mg 487.55 mg 487.55 mg 487.55 mg
MiCrOCrystallilll' 400.00 mg 400.00 mg 400.00 mg 400.00 mg
cell ~'Dse
CrosFIovidone, 100.00 mg 100.00 mg 100.00 mg 100.00 mg
,., :ofii~ed
Levofloxacin hemihydrate and stearic acid or stearyl alcohol or hydrogenated castor
30 oil or glycerol monostearate are triturated in a mortar and heated at 80~C for 1 hour
in a drying oven. The mixture is allowed to cool, and is pulverized and mixed with
Polyvidone 25000, corn starch, microcrystalline cellulose and crospovidone,
micronized. The mixture is granulated with water, dried, pAsseci through a sieve of
mesh width l mm and the granules are compressed to give tablets.
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The active c:ompound release determinations in a USP paddle apparatus afforded
the followin~ results:
Example 9 10 11 12
Release medium Water
after 5 minutes33.5 % 64.3 % 51.9 % 61.6 %
after15minutes46.4% 81.7% 76.1 % 74.4%
1 0 a~ter 30 minutes 63.4 % 90.6 % 89.3 % 81.5 %
Release medium 0.1 N hy~ueh'oric acid
after5 minute's 95.3% 91.6 % 81.2% 85.1 %
a~ter 15 minutes 100 % 99.4 % 94.0 % 93.8 %
after 30 minutles 100 % 100% 100 % 98.6 %
After suspending the soluble tablets from Examples 9 to 12 in 100 ml each of mains
water and A<;sessment of the taste, an adequate concealment of taste resulted only
for the solublle tablets from Example 9.
20 Comparison Example 1
shows the preparation of a levofloxacin hemihydrate soluble tablet with palmitic acid
as a higher latty acid and which was not prepared by the process according to the
invention.
Levofloxacin hemihydrate 512.46 mg
Palmitic acicl 422.00 mg
Microcrystallline cellulose 807.54 mg
Crospovidone 150.00 mg
Raspberry flavor 30.00 mg
Aspartame 60.00 mg
Levofloxacin hemihydrate, palmitic acid, microcrystalline cellulose, crospovidone,
raspberry flavor and aspartame are mixed, compacted and dry-granulated through a35 1.0 mm sieve. The dry granules are processed to give soluble tablets.
The active compound release determinations in a USP paddle apparatus arrorded
the following results:
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Release medium
900 ml of water 900 ml of 0.1 N
hydrochloric acid
after 5 minut:es 89.9 % 98 %
after 15 minutes 100 % 100 %
after 30 minutes 100 % 100 %
The bitter int.rinsic taste of the pharmaceutical is far more strongly deteclable after
10 suspending l:he soluble tablet in 100 ml of water than with the soluble tablets from
Example 3.
Comparison Example 2
15 shows the preparalion of a norfloxacin soluble tablet which was not prepared by the
process according to the invention and was also without use of a higher fatty acid.
Norfloxacin 500.00 mg
Corn starch 711.46 mg
Microcrystallinecellulose 638.32 mg
Crospovidone 146.22 mg
Highly disperse silica 14.00 mg
Peach flavor 30.00 mg
Aspartame 40.00 mg
2S Acesulfam K 20.00 mg
Norfloxacin, corn starch, microcrystalline cellulose, crospovidone, highly disperse
silica, peach flavor, aspartame and acesulfam K are mixed and compressed to givetablets.
The active compound release determinations in a USP paddle apparatus afforded
the following results:
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Release medium
900 ml of water 900 ml of 0.1 N
hydrochloric acid
after5 minutes 40.1 % 98.2 %
after 15 minutes 62.2 % 100 %
after 30 minutes 73.2 % 100 %
After suspension of the soluble tablets from Example 4 and Comparison Example 2
10 in 100 ml eac h of mains water, the following results follow from the taste testing: the
preparation from Example 4 having active compound with taste concealed by the
process according to the invention did not have a bitter taste, whereas the
preparation not according to the invention according to Comparison Example 2
allowed the bitter intrinsic taste of the compound to be identified clearly.
Comparison IExample 3
shows the preparation of an ofloxacin soluble tablet which was not prepared by the
process according to the invention and also without use of a higher fatty acid.
Ofloxacin 500.00 mg
Corn starch 711.46 mg
Microcrystalliine cellulose 638.32 mg
Crospovidone 146.22 mg
Highly disperse silica 14.00 mg
Peach flavor 30.00 mg
Aspartame 40.00 mg
Acesulfam K 20.00 mg
30 Of loxacin, corn starch, crospovidone, highly disperse silica, peach flavor, aspartame
and acesulfam K are mixed and compressed to give tablets.
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The active c:ompound release determinations in a USP paddle apparatus afforded
the following results:
Release medium
900 ml of water 900 ml of 0.1 N
hydrochloric acid
after 5 minultes 89.9 % 95.4 %
after 15 minutes 100 % 97.4 %
after 30 minutes 100 % 100 %
After suspension of the soluble tablets from Example 5 and Comparison Example 3
in 100 ml each of mains water, the following results followed from taste testing: The
preparation lFrom Example 5 having active compound with taste concealed by the
process aca~rding to the invention no longer had a bitter taste, whereas the
15 preparation rlot according to the invention according to Comparison Example 3allowed the unpleasant bitter intrinsic taste of the active compound to be identified
clearly.
