Note: Descriptions are shown in the official language in which they were submitted.
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Peroral Active Agent Suspension
1. Introduction
The present invention relates to orally administered suspen-
sions of pharmaceutically active substances of the NSAID type
(nonsteroidal-antiinflammatory drugs), but particularly the
antirheumatic agent meloxicam and a process for preparJng them.
2. Statement of Problem
Various pharmaceutical forms are used for oral administration
of drugs. Thus, in addition to solid single-dose forms such as
tablets, hard and soft gelatine capsules, liquid forms such as
solutions and syrups are also given, in which the dose to be
administered can be adjusted by means of the volume given.
Solutions and syrups have the advantage that they can be taken
easily and safely even by patients who have trouble taking so-
lid, single-dose forms (e.g. children and older patients) Li-
quid preparations are advantageously easy to measure out for
veterinary use.
However, it should be borne in mind that even with the same
dosage and the same method of administration, the activity of
the same pharmaceutical substance may vary. These variations
mean that the therapeutic effect clinically demonstrated for a
drug in a specific preparation cannot be achieved with a diffe-
rent preparation of the same drug, and furthermore within a
course of treatment one preparation cannot readily be exchanged
for another. Preparations which are not therapeutically equi-
valent are known as "non-bioeauivalent". For the oral admini-
str c L iorl of pharlTlacEut i cal prepar at i ons , the drug is usually
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absorbed faster from liquid preparations, particularly solu-
tions, than from tablets or capsules and these drugs are conse-
quently not always bioequivalent (Bauer K. H.; Fromming K.-H.;
Fuhrer C., Pharmazeutische Technologie, 5'h Edition 1997,
Gustav Fischer Verlag, Stuttgart, page 213).
Meloxicam is an antirheumatic agent belonging to the NSAID's.
NSAID's are cyclooxygenase inhibitors, whilst meloxicam has
been shown to have a selective inhibitory effect on the isoen-
zyme COX-2 and consequently a reduced risk of undesirable
gastrointestinal side effects. For safe administration of
meloxicam and other active substances, e.g. other NSAID's, a
liquid oral preparation is desirable as an alternative to the
solid form (capsule, tablet), particularly in paediatrics and
in veterinary use.
The complex objective of the present invention was primarily to
produce an orally administered liquid preparation of meloxicam.
The formulation should take effect rapidly when first used in
acute cases. However, the substance is preferably used for
long-term therapy. In such long-term therapy, the liquid oral
formulation should be bioequivalent to other oral formulations
(tablet, capsule) in the steady,state in order to allow therapy
with either a liquid or solid oral formulation as desired. At
the same time, the liquid preparation should have a pleasant
flavour in order to be acceptable to children and thus ensure
that it is taken as specified and the treatment is ensured. In
addition, the liquid preparation should preferably not contain
any ethanol, since the possibility of ethanol having a harmful
effect even in physiologically acceptable, non-toxic concentra-
tions cannot be ruled out completely, particularly in children.
Moreover, when ethanol is used, there is the risk of abuse by
alcohol-dependent patients or relapse on the part of formerly
alcohol-dependent patients. The suitability of the formulation
for diabetic patients should also be taken into account. To
ensure exact dosage of a liquid oral preparation of ineloxicam,
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the preparation should also be homogeneous over a sufficient
length of time during its removal from the primary packaging.
In addition, the preparation should also be suitable for use in
animals. The veterinary formulation should also have a smell
and flavour which are suitable for numerous types of animals
which can be treated with antirheumatic drugs, particularly
various species of mammals, to ensure that the course of treat-
ment is completed and the therapy is guaranteed, on the basis
of good acceptance.
3. Specification of the Invention
One obvious way of preparing a liquid oral formulation of a
pharmaceutically active substance is to dissolve the substance
in physiologically inert solvents (especially pharmaceutical
grade water). However, this approach is unsuitable in many
cases. To ensure the desired pleasant taste of a liquid oral
formulation, e.g. meloxicam, it is not possible to use solu-
tions, since the substance in the dissolved state has an un-
pleasant taste of its own. This taste is apparent in all the
solvents which can be used for the oral administration of so-
lutions and cannot be adequately masked even by the addition of
flavour correcting agents such as flavourings and sweeteners.
However, meloxicam does not have a noticeable flavour of its
own when the substance is suspended in a physiologically inert
dispersion medium for a liquid oral preparation and the solubi-
lity of meloxicam in the dispersion medium used is very slight.
This provided a suitable approach to solving the problem. This
approach can be applied analogously to other active substances
of the NSAID category. Since a clearly noticeable unpleasant
taste is present even at a concentration of over 500 g/ml of
dissolved meloxicam, the solubility of this active substance in
the dispersion media used must be below this threshold.
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When a suspension of active substance is used there is the pro-
blem that the homogeneity of the suspension has to be ensured
for a sufficient length of time during removal from the primary
packaging (e.g. glass bottle, 100 ml) to ensure accurate do-
sing. However, the sedimentation of solids dispersed in liquid
media cannot be prevented but only delayed for a greater or
lesser period. One conventional approach to delaying sedimen-
tation is, for example, by increasing the viscosity of the dis-
persing medium by the addition of suitable substances, e.g.
organic hydrocolloid forming agents, e.g. cellulose ether, or
silicon dioxide as a thickener. Increasing the viscosity of
the dispersing agent does, however, have the serious disadvan-
tage that it makes it considerably more difficult to redisperse
the sediment formed, to the extent that if the suspension is
too viscous it is impossible to reconstitute the suspension at
all. Moreover, the caking caused by contact of the individual
particles under the effects of gravity during storage of the
suspension must be avoided. It is known from the literature to
prevent caking by, for example, controlled flocculation of such
systems by the adsorption of potential-determining ions (Sucker
H., Fuchs P., Speiser P., Pharmazeutische Technologie, 5th Edi-
tion 1991, Georg Thieme Verlag, Stuttgart, p. 423). The in-
dustrial manufacture of stable suspensions by controlled
flocculation is subject to limitations, since it is difficult
to reproduce the optimum properties of suspension systems of
this kind owing to the variability of the suspended solid and
the stability of the suspension is considerably affected by the
adjuvants used.
Surprisingly, the suspension of a pharmaceutically active sub-
stance of the NSAID type can be stabilised by the addition of
small amounts of highly dispersed silicone dioxide in the pre-
sence of small amounts of hydrophilic polymers. Because of the
low concentration of highly dispersed silicon dioxide and hy-
drophilic polymer in the dispersion medium, the viscosity is
low; unwanted increased in viscosity, which will prevent
reconstitution of the suspension, caused by gel-like thickening
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of the dispersion medium does not occur if at the same time
small amounts of hydrophilic polymer which are soluble in the
dispersion medium are added to the medium and the silicon di-
oxide is added to the suspension with the aid of high shear
forces. Suitably high shear forces can be produced with a
suitable shear-intensive homogenising mixer, e.g. with mixers
of the series "Becomix" made by Messrs. A. Berents GmbH & Co.
KG, Henleinstr. 19, D-28816 Stuhr, which comprise rapidly ro-
tating homogenisers working on the rotor-stator principle. A
circumferential rotor speed of about 25 to 27 m/s is particu-
larly suitable for generating sufficiently high shear forces
and is used to introduce the highly dispersed silicon dioxide
into the dispersing agent for about 10 - 15 minutes, e.g. using
the mixers Becomix RW 15/RW 60/RW 1000. This produces a spe-
cial siloid structure which consists of a spongy three-dimen-
sional structure of hydratised highly dispersed silicon dioxide
shot through with cavities, the active substance being adsorbed
onto said structure.
Suitablc highly disperePd silicon dioxiL3e lias a specific cur-
tace area of aL least 50 m'/g, preferably 100 to 400 m2/g, for
cxample, whilst a specitic surface dLCa vf about 200 m2/g is
particularly preferred (e.g. AerosilO 200).
The invetiLion relateo to a suspension nf a pharmaceutically
acti.ve substanna ot the NS11ID type wil:h a euspendable particle
size apectrum in a phyciologically 7nart dispersion medium in
which the ant-ive substance Ildd very little eolubility, so thaY
the euspension hao no perceptible t-aate of its own, fvr oial
adminiqt-ration, characteribcc3 in that the ouapexlsion contiainA a
small anlount of highly dispersed si 1 i c on dioxide for stabilisa-
tion by fiorming a three-ditursasional siloid otructure, the
three-dimen3ional siloid sstr.iic,t13r.e being produced by adding the
silir.nn dioxide to the dibpersion medium under the action of
high shcar forces, and the G>>spension additiorlally contains a
small amount of hydrupliilic polymer which ie soluble in the
disper3ion medium_
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According to one aspect of the present invention,
there is provided a pharmaceutical composition for oral
administration which is a suspension comprising a) a non
steroidal anti-inflammatory drug (NSAID) selected from the
group consisting of propionic acid derivatives, acetic acid
derivatives, fenamic acid derivatives, biphenylcarboxylic
acid derivatives, acid enolcarboxamides, diaryl-heterocycles
with methylsulphonyl or aminosulphonyl substituents, acid
sulphonamides and the pharmaceutically acceptable salts
thereof, wherein the NSAID has a particle size spectrum in
which at least 90% of the particles are smaller than 50 m,
b) a physiologically inert dispersion medium in which the
NSAID has a solubility of less than 500 g/ml, c) 0.1 to 5%
by weight of highly dispersed silicon dioxide having a
specific surface area of at least 50 mz/g, to stabilise the
suspension by forming a three-dimensional siloid structure,
the three-dimensional siloid structure being produced by
adding the silicon dioxide to the dispersion medium with the
action of high shear forces, and d) 0.05 to 2% by weight of
a pharmaceutical-grade water soluble cellulose ether.
According to another aspect of the present
invention, there is provided a process for preparing a
pharmaceutical composition for oral administration in form
of a liquid preparation of a NSAID in form of a stabilised
suspension, wherein (i) the NSAID is ground in order to
produce a particle size spectrum in which at least 90% of
the particles are smaller than 50 m, (ii) the ground NSAID
is suspended in a physiologically inert dispersion medium in
which the solubility of the NSAID is less than 500 g/ml,
(iii) 0.1 to 5% by weight of highly dispersed silicon
dioxide, based on the weight of the suspension ready for
use, is added to the dispersion medium with the application
of high shear forces, (iv) 0.05 to 2% by weight of a water
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6a
soluble cellulose ether of pharmaceutical grade are added to
the dispersion medium, based on the weight of the suspension
ready for use, and (v) optionally, one or more components
selected from flavourings, sweeteners, excipients and
preservatives are independently of one another added to the
dispersion medium.
The above-mentioned three-dimensional siloid
structure consists of crosslinked, swollen and coherent
strands of Si02 between which can be found fairly large
cavities filled with dispersion medium. The suspended solid
particles of the active substance, e.g. meloxicam, are
adsorbed almost exclusively onto the Si02 strands. In this
way, the suspended particles are rapidly and fully wetted
and agglomeration of the particles of pharmaceutical
substance can be prevented entirely. This results in a
suspension of the active substance of exceptional
homogeneity and dosing precision. The siloid structure
described does not lead to any gel-like thickening of the
dispersion medium but rather produces a low viscosity
pourable suspension.
At the same time, the three-dimensional siloid
structure acts as a sedimentation stabiliser. The structure
described is very bulky and is compressed only slightly and
very slowly even by sedimentation. Thus, even after months
of storage, the volume of the siloid structure decreases by
only about 20%. The reduction in volume caused by
sedimentation does not result in undesirable caking; the
sediment can be easily and quickly redispersed by the use of
extremely slight mechanical forces (e.g. very gentle shaking
of an oral suspension of meloxicam packaged in standard
commercial glass bottles). The slowness of sedimentation
ensures that the user has sufficient time to take
homogeneous single doses of the oral suspension of a
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pharmaceutically active substance according to the invention
out of its primary packaging, thus ensuring accuracy of
dosing.
For example, an active substance suspension
according to the invention contains 0.1 - 5wt.% of highly
dispersed silicon dioxide (e.g. Aerosil 200), preferably
0.5 - 2 wt.%, more particularly 0.5 - 1.5 wt.%.
Suitable soluble hydrophilic polymers are
pharmaceutical grade cellulose ethers such as hydroxyethyl
cellulose (HEC), hydroxy-
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propyl cellulose (HPC) and hydroxypropylmethyl cellulose
(HPMC). Hydroxyethyl cellulose is preferred. For example, a
suspension of active substance according to the invention con-
tains 0.05 - 2 wt.% of water soluble cellulose ether, prefera-
bly 0.05 - 0.5 wt.%, but more particularly 0.05 - 0.1 wt.%.
Most preferably, the active substance suspension according to
the invention contains 0.5 - 1.5 wt.% of highly dispersed si-
licon dioxide and 0.05 - 0.1 wt.% of hydroxyethyl cellulose.
The properties of a liquid oral suspension of active substance
according to the invention are greatly influenced by the par-
ticle size of the suspended active substance. To achieve the
rapid onset of activity which is desirable when the preparation
is taken once, a small particle size is essential, ensuring the
fastest possible dissolution of the active substance in gastro-
intestinal tract. In the particle size spectrum of the active
substance which is suitable for a suspension according to the
invention, therefore, at least 90% of the particles are smaller
than 50 pm, preferably at least 50% of the particles are smal-
ler than 10 m, and most preferably about 90% of the particles
are smaller than 10 m (determined for example by laser dif-
fractometry). A correspondingly finely dispersed grade of
pharmaceutical can easily be achieved by suitably grinding a
coarser grade. Suitable mills for grinding operations of this
kind are the standard commercial jet mills, for example.
The small particle size of the active substance in a suspension
according to the invention as described also have the advantage
of a slow rate of sedimentation of the suspended particles,
which favourably affects the homogeneity of the liquid oral
formulation of the active substance described and correspon-
dingly ensures a high degree of accuracy in measuring the dose.
The solubility of the active substance in suitable physiolo-
gically acceptable dispersion media should be less than
500 g/ml. Preferably, the solubility is not more than
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50 g/ml, most preferably the solubility is not more than
g/ml, but more particularly not more than 0.5 g/ml.
It is readily possible for the skilled person to find, for any
5 given active substance of the NSAID type, a suitable physiolo-
gically acceptable dispersion medium in which the active sub-
stance has the solubility characteristics mentioned above. For
meloxicam, the physiologically acceptable dispersion medium
preferably consists of an aqueous buffer system with a pH in
the range from 2-4.
An orally administered suspension according to the invention
may contain one or more NSAID's as pharmaceutically active
substance. The classic active substance acetylsalicyclic acid
and the active substances of the following categories are men-
tioned as examples of NSAID's:
(1) propionic acid derivatives,
(2) acetic acid derivatives,
(3) fenamic acid derivatives,
(4) biphenylcarboxylic acid derivatives,
(5) acid enolcarboxamides,
(6) diaryl heterocycles with methylsulphonyl or aminosulphonyl
substituents and
(7) acid sulphonamides.
The following active substances are mentioned as examples of
propionic acid derivatives, although this list should not be
regarded as limiting this category of active substance:
ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, keto-
profen, indoprofen, pirprofen, carprofen, oxaprozin, pranopro-
fen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofe-
nic acid and fluprofen or the pharmaceutically acceptable salts
thereof.
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Examples of acetic acid derivatives include the following ac-
tive substances, although the list does not constitute any
restriction of this category of active substance:
indomethacin, sulindac, tolmetin, zomepirac, nabumetone, di-
clofenac, fenclofenac, alclofenac, bromfenac, ibufenac, ace-
clofenac, acemetacin, fentiazac, clidanac, etodolac and oxpinac
or the pharmaceutically acceptable salts thereof.
The following active substances are mentioned as examples of
fenamic acid derivatives, although the list does not constitute
a limitation to this category of active substance:
mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic
acid and tolfenamic acid or the pharmaceutically acceptable
salts thereof.
Examples of biphenylcarboxylic acid derivatives include the
following active substances, although the list does not con-
stitute a limitation of this category of active substance:
diflunisal and flufenisal or the pharmaceutically acceptable
salts thereof.
The following are examples of acid enolcarboxamides (oxicams),
although the list does not constitute a restriction to this
category of active substance:
piroxicam, tenoxicam, lornoxicam and meloxicam or the pharma-
ceutically acceptable salts thereof.
Nimesulide is mentioned by way of example of an acid sulphon-
amide, but should not constitute a restriction to this category
of active substances.
Chemical structures, pharmacological activity, side effects and
information regarding the usual dosage ranges for the above-
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mentioned NSAID's are given for example in Physician's Desk
Reference, 35'h Edition, 1981; The Merck Index, 12th Edition,
Merck and Company, Rahway, New Jersey (1996); Cutting's
Handbook of Pharmacology, 6'h Edition, Ed. T.Z. Czacky, M.D.,
Appleton-Century-Crofts, New York, 1979, Chapter 49:538-550.
A dosage unit for the following NSAID's may be, for example:
100 - 500 mg Diflunisal, 25 - 100 mg Zomepirac sodium, 50 - 400
mg Ibuprofen, 125 - 500 mg Naproxen, 25 - 100 mg Flurbiprofen,
50 - 100 mg Fenoprofen, 10 - 20 mg Piroxicam, 5 - 20 mg Me-
loxicam, 125 - 250 mg Mefenamic acid, 100 - 400 mg Fenbufen and
25 - 50 mg Ketoprofen.
Particularly preferred oral administered suspensions according
to the invention are those which contain as active substance an
acid enolcarboxamide, especially meloxicam.
Meloxicam is an NSAID with the structural type of an enolic
acid and exhibits a distinctly pH-dependent solubility. The
minimum solubility in buffered aqueous systems is found at pH
values from 2-4. The solubility in this pH range is less than
0.5 g/ml (Luger P., Daneck K., Engel W., Trummlitz G., Wagner
K., Structure and physicochemical properties of meloxicam, a
new NSAID, Eur. J. Pharm. Sci. 4 (1996), 175-187).
Suitable dispersion media for a liquid oral suspension of
meloxicam according to the invention are therefore physiolo-
gically acceptable aqueous buffer systems with a pH in the
range from 2-4, mixtures thereof or mixtures thereof with other
physiologically acceptable liquids which are additionally
suitable for improving specific properties of the meloxicam
suspension, especially
= for adjusting the viscosity of the dispersion medium in
order to reduce the rate of sedimentation of the suspended
particles of pharmaceutical,
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= to ensure that the liquid oral preparation has a pleasant
flavour and
= to improve the wetting qualities of the suspended pharmaceu-
tical particles.
Other physiologically acceptable liquids in the sense of the
invention described are preferably glycerol and optionally
aqueous solutions of sugar alcohols such as sorbitol, mannitol
and xylitol, and mixtures thereof. In a suspension according
to the invention these substances have the advantage
= of increasing the viscosity of the dispersion medium and
hence reducing the rate of sedimentation of the suspended
pharmaceutical particles and making it easier to handle when
the liquid formulation is transferred into metering aids
(e.g. standard measuring spoons or special metering systems
such as metering syringes) and when the liquid formulation
is measured out in drops (e.g. standard dropper inserts),
= of their slightly sweet inherent flavour which gives the
liquid oral formulation a pleasant taste,
= of their suitability for diabetic patients and animals which
can be treated with antirheumatic drugs and
= of improving the wetting properties of the suspended pharma-
ceutical particles.
Suitable physiologically acceptable aqueous buffer systems with
a pH in the range from 2-4 include, for example, sodium dihy-
drogen-phosphate dihydrate/citric acid monohydrate buffer, gly-
cine/HC1 (S. P. Sorensen, Biochem. Z., 21, 131 (1909); Biochem.
Z., 22, 352 (1909)), Na-citrate/HC1 (S. P. Srarensen, Biochem.
Z., 21, 131 (1909); Biochem. Z., 22, 352 (1909)), K-hydrogen
phthalate/HC1 (Clark and Lubs, J. Bact., 2, 1 (1917)), citric
acid/phosphate (T. C. McIlvaine, J. Biol. Chem., 49, 183
(1921)), citrate-phosphate-borate/HC1 (Teorell and Stenhagen,
Biochem. Z., 299, 416 (1938)) and Britton-Robinson Buffer
(Britton and Welford, J. Chem. Soc., 1, 1848 (1937)).
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Preferably, a dispersion medium for a liquid oral suspension of
meloxicam according to the invention is based on an aqueous
buffer system with a pH in the range from 2-4 mixed with one or
more of the physiologically acceptable liquids glycerol and
aqueous solutions of the sugar alcohols mannitol, sorbitol and
xylitol.
For example, the dispersion medium of a liquid oral suspension
of ineloxicam according to the invention consists of mixtures of
about 30-50% aqueous buffer system, pH 2-4, preferably aqueous
sodium dihydrogen phosphate dihydrate/citric acid monohydrate
buffer, about 10-20% glycerol, about 10-20% xylitol and about
20-30% sorbitol or mannitol solution (70% sorbitol or mannitol
in water). Glycerol and the above-mentioned sugar alcohols may
be present either individually or in admixture with one another
in the dispersion medium.
The suspension ready for use may contain varying amounts of the
active substance meloxicam, e.g. 0.050 to 3.000 g/118 g, pre-
ferably 0.050 to 2.000 g/118 g, but particularly 0.050 to
1.5 g/118 g, based on the mass of the preparation ready for
use.
To improve the flavour still further, one or more flavourings
and/or one or more sweeteners may be added to a liquid oral
suspension according to the invention.
Suitable flavourings include, for example, liquid and powdered,
water soluble natural and nature-identical flavourings. Parti-
cularly preferred are liquid flavourings, particularly rasp-
berry, strawberry and honey.
Suitable sweeteners include, for example, saccharin sodium,
saccharin, cyclamate, acesulfam potassium and taumatin.
Moreover, conventional excipients and/or preservatives effec-
tive in the pH range, i.e. preferably sodium benzoate in the
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case of the active substance meloxicam, may be added to a li-
quid oral suspension according to the invention.
Because of the three-dimensional siloid structure and the ad-
hesion of the suspended solid particles, there is no need to
add any surfactants to improve the wetting qualities. Surfac-
tants may have a negative effect in suspensions since the solu-
bility of the solid in the dispersion medium may be increased
in some cases, leading to an unwanted growth in particle size.
Moreover, surfactants, particularly ionic surfactants, are
frequently allergenic and/or irritant to the mucous membranes.
The invention further relates to a process for producing an
orally administered liquid preparation of a pharmaceutically
active substance of the NSAID type in the form of a stabilised
suspension, characterised in that
(i) the solid active substance is ground in order to pro-
duce a particle size spectrum in which at least 90% of
the particles are smaller than 50 m, preferably at
least 500 of the particles are smaller than 10 m, but
in particular about 90% of the particles are smaller
than 10 m,
(ii) the ground active substance is suspended in a physio-
logically inert dispersion medium in which the solubi-
lity of the active substance is very low,
(iii) small amounts of highly dispersed silicon dioxide are
added to the dispersion medium with the application of
high shear forces,
(iv) small amounts of hydrophilic polymer soluble in the
dispersion medium are added to the dispersion medium
and
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(v) optionally, one or more flavourings, one or more
sweeteners, conventional excipients or one or more
preservatives may, independently of one another, be
added to the dispersion medium, the flavourings pre-
ferably being added during the final stage of manufac-
ture owing to their foam breaking properties.
A preferred embodiment of the process according to the inven-
tion is characterised in that
(i) a particle size spectrum is produced in which about 90%
of the particles are smaller than 10 m,
(ii) the ground active substance is suspended in a physiolo-
gically acceptable, aqueous buffer system at a pH in
the range from 2-4, for example sodium dihydrogen phos-
phate dihydrate/citric acid monohydrate buffer, gly-
cine/HC1, K-hydrogen phthalate/HC1, citric acid/phos-
phate, citrate-phosphate-borate/HC1 or Britton-Robinson
buffer, mixtures thereof with one another or mixtures
thereof with other physiologically acceptable liquids
such as glycerol or optionally aqueous solutions of
sugar alcohols such as qorbitol, mannitol and xylitol,
(iii) with the aid of a mixer by the application of high
shear forces, characterised for example by a circum-
ferential rotor speed of 15-35 m/s, preferably
20-30 m/s, 0.1-5.0 wt.-% of highly dispersed silicon
dioxide, based on the weight of the suspension ready
for use, are added to the dispersion medium,
(iv) water soluble cellulose ethers of pharmaceutical grade
are added to the dispersion medium as hydrophilic po-
lymers in an amount of from 0.05 - 2 wt.-o, based on
the weight of the suspension ready for use, and
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(v) one or more flavourings, one or more sweeteners, con-
ventional excipients or one or more preservatives may
optionally be added independently of one another to the
dispersion medium.
A particularly preferred embodiment of the process according to
the invention is characterised in that
(i) a particle size spectrum is produced in which about 90%
of the particles are smaller than 10 m,
(ii) the ground active substance is suspended in a disper-
sion medium consisting of mixtures of 30 - 50% aqueous
buffer systems with a pH in the range from 2-4, aqueous
sodium dihydrogen phosphate dihydrate/citric acid mono-
hydrate buffer being preferred, 10-20% glycerol, 10-20%
xylitol and 20-30% sorbitol or mannitol solution (70%
sorbitol or mannitol in water), whilst glycerol and the
above-mentioned sugar alcohols may be present in the
dispersion medium either individually or in admixture
with one another,
(iii) 0.5-2.0 wt.-% of highly,dispersed silicon dioxide,
based on the weight of the suspension ready for use,
are added to the dispersion medium with the aid of a
mixer by applying high shear forces, characterised for
example by a circumferential rotor speed of 20 to 30
m/s, preferably about 25 to 27 m/s,
(iv) pharmaceutical grade water-soluble cellulose ethers,
preferably hydroxyethyl cellulose, are added to the
dispersion medium as hydrophilic polymers, in an amount
of from 0.05 - 0.5 wt.-%, based on the weight of the
suspension ready for use, and
(v) one or more flavourings, one or more sweeteners, con-
ventional excipients or one or more preservatives may
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optionally be added to the dispersion medium indepen-
dently of one another.
In all the above-mentioned embodiments of the process, steps
(ii) to (v) are preferably carried out in vacuo since the entry
of air affects the density of the suspension to be produced, as
a result of floating effects or air absorption on the siloid
structure, and inhomogeneities may be produced.
A particularly preferred embodiment of the process according to
the invention is characterised in that the active substance is
an acid enolcarboxamide, particularly meloxicam.
A third object of the invention is the use of an active sub-
stance of the NSAID type, preferably an acid enolcarboxamide,
but particularly meloxicam, for preparing a liquid preparation
of the active substance in the form of a stabilised suspension
with a particle size spectrum wherein at least 90% of the par-
ticles are smaller than 50 m, in a physiologically inert dis-
persion medium in which the active substance has very low solu-
bility, so that the suspension does not have any noticeable
taste, for oral administration, characterised in that the sus-
pension contains a small amount,of highly dispersed silicon di-
oxide for stabilising it by forming a three-dimensional siloid
structure, the three-dimensional siloid structure being pro-
duced by adding the silicon dioxide to the dispersion medium
with the action of high shear forces, and the suspension addi-
tionally contains a small amount of hydrophilic polymer soluble
in the dispersion medium.
5. Example
The following recipe is for the preparation of 100 ml of a li-
quid, orally administered suspension of meloxicam according to
the invention. The formulation makes it possible to take se-
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veral doses of 7.5 mg of meloxicam in a volume of 5 ml from a
suitably sized glass bottle by pouring into standard plastic
measuring spoons. The ingredients which are relevant to the
effectiveness and the formation of the siloid structure accor-
ding to the invention are given quantitatively, whilst all the
other ingredients may be present in the formulation in accor-
dance with the information provided above.
In order to protect it from microbial contamination during use
(multi-dose container) the preparation must be suitably preser-
ved with a preservative (in this case sodium benzoate) adapted
to the pH range of the dispersion medium.
Ingredient Formulation A Formulation B
g/100 ml (= g1118 g) g/100 ml (= g/118 g)
(1) Meloxicam, 0.150 1.500
jet-ground
(2) Silicion dioxide, 1.000 1.500
Highly dispersed
(3) Hydroxyethylcellulose 0.100 0.050
Other ingredients are:
70% sorbitol solution (non-crystalline), 85 s glycerol, xylitol,
sodium dihydrogen phosphate dihydrate, citric acid monohydrate,
saccharin sodium crystals, sodium benzoate and raspberry fla-
vouring D 9599 (formulation A) or honey flavouring 203108 (for-
mulation B). The mixture is made up to a final volume of
100 ml, corresponding to 118.000 g, with purified water.
5.1 Physical/chemical properties of the preparations
Formula _ion A Formulation B
pH: 3.5 - 4.5 3.5 - 4.5
Density: 1.16 - 1.20 g/ml (20 C) 1.16 - 1.20 g/ml (20 C)
Viscosity: 40 - 150 mPas 60 - 200 mPas
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5.2 Pharmacokinetic properties of the preparation
A main objective for developing a liquid oral formulation of
meloxicam was the rapid onset of activity on first use. The
prerequisite for this is the fastest possible flooding of the
drug into the central blood compartment.
In the formulation according to the above Example this is
achieved. In a direct comparison between a suspension ac-
cording to the invention and a capsule containing the same
dose, the time for maximum plasma concentration on a single
dose of meloxicam is t,na, = 2h (1.5 - 5 h; suspension) as
against t,a, = 5h (2 - 6 h; capsule),.
In the steady state, bioequivalence should bc detectable owing
to the desirPd tha.rapp 1-i r. Pqu.ivalents ot the suspension ac_r_nr-
ding to the invention and a solid oral formulation. This has
been shown hy ciirPrr r.omparison of a suspension according to
the invention with a capgulc containing thc came doce. In the
srPady state the maximum plasma levels are at tm"<<õ1 = 5.0 h (5
- 9 hi suspension) and t,,,.. (õ) - 5.0 h (3 - 7 hl capeule) . A
graphic representation of the results of the study is ahowu in
I'i.gure 1.
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27400-193
18a
6. Method of preparation
Suspensions according to the invention can be
prepared by a multi-stage mixing and homogenising process.
The use of shear intensive homogenising mixers which enable
the solid particles of the active substance which are to be
suspended and the highly dispersed silicon dioxide to be
distributed in the dispersion medium within a very short
time is crucial to the production of a homogeneous
suspension having the siloid structure described. Different
sizes of process mixers from the series "Becomix" (made by
Messrs. A. Berents GmbH & Co. KG, Henlein-str. 19, D-28816
Stuhr) have proved particularly suitable for this purpose
and will produce suspensions according to the invention in
batch sizes ranging from 2.5 to 1,000 kg. These mixers
incorporate fast rotating homogenisers working on the rotor-
stator principle which ensure optimum mixing and production
of the three-dimensional siloid structure described above.
Sufficiently high shear forces are generated, for example,
at a circumferential rotor speed of 20 to 30 m/s, preferably
about 25 to 27 m/s. With the mixers Becomix RW 60/RW 1000,
circumferential rotor speeds of about 26 m/s are used for
about 10 - 15 minutes to introduce the highly dispersed
silicon dioxide into the dispersing agent.
Step 1 (Premix)
The active substance and the highly dispersed
silicon dioxide are homogeneously premixed in a suitable
container (e.g. VA container). This premixing is necessary
in order to achieve better wetting properties of the
pharmaceutical substance and lump-free distribution in the
suspension.
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19
Step 2 (Polymer solution)
The majority of the water is placed in a suitable batch con-
tainer (e.g. Becomix mixer) and the HEC is sucked in with
stirring, homogenisation and in vacuo and then the mixture is
stirred for about 10 minutes in vacuo. The HEC is allowed to
swell for about 30 min. at room temperature (RT) before heating
to about 80 C in vacuo and maintaining for about 1 hours at
this temperature and cooling to RT again.
Step 3 (Sodium benzoate solution)
A small amount of the water is placed in a suitable batch con-
tainer (e.g. VA container) and the sodium benzoate is dissolved
therein with stirring.
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Step 4 (Final mixing)
The sodium benzoate solution (see above) and the other ingre-
dients of the composition with the exception of the flavouring
are added to the polymer solution (sucked in under vacuum).
The mixture is then homogenised. The mixture of active sub-
stance and silicon dioxide is then added in vacuo, with stir-
ring and homogenisation and the mixture is homogenised for a
further 10 minutes in vacuo. The high shear forces described
are characterised, for example, in that the mixture of active
substance and silicon dioxide in a 1000 kg batch is sucked into
the circulation in a mixer of the Becomix RW 1000 type at a ro-
tor speed of about 3500 rpm (corresponding to a circumferential
speed of about 26 m/s) and then homogenised for 10 minutes.
Finally, the flavouring is added in vacuo, with stirring and
homogenisation. This method makes use of the foam-breaking
properties of the flavouring, which shortens the subsequent
process of de-aerating the suspension (vacuum). The suspension
can be transferred from the mixer into bulk containers under
pressure.
