Note: Descriptions are shown in the official language in which they were submitted.
'`' `,' ; `' ! '; ,/t:r;,
:L 3 ~ 7 ~ 9 ~
Azelastine embonate, processes for i-ts preparation and
pharmaceutical ~ormulations which contain azelastine embonate as
active substance
Azelastine is an active substance having an anti-allergic and
asthma-prophylactic effect. The chemical designation is:
4-(p-chlorobenzyl)-2-hexahydro-1-methyl-azepine-4-yl-
1-(2H)-phthalazinone (German Patent No. 21 64 058).
An important use of azelastine as an anti-allergic agent is oral
application, in particular in the form of tablets, capsules,
solutions or suspensions, as well as also applica-tion in the
form of aerosols.
The use of azelastine in the form of solutions or suspensions
has, however, hitherto not been possible since azelastine has
such a penetrating, bitter taste that patients would refuse to
take such azelastine solutions or azelastine suspensions orally.
It has also proved impossible to overcome this bitter taste
through conversion into the most varied salts.
It has now been found that azelastine, on conversion into the
salt with embonic acid can be converted into a product which no
longer possesses the penetrating bitter taste and which is
therefore suitable for use in, for example, orally taken
formulations. Azelastine embonate is a salt of azelastine with
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-- 2
embonic acid whereby this salt is composed of 2 Mol of
azelastine and 1 Mol of embonic acid (see Example 1).
The azelastine embonate of the invention is particularly
suitable for the preparation of orally taken pharmaceutical
formulations of azelastine in the form of stable suspensions,
for example in the form of a juice. The embonate of the,
invention can naturally also be used for the preparation of
other pharmaceutical formulations of azelastine such as, for
example, tablets, capsules or sprays.
Should the azelastine embonate of the invention be used for the
preparation of aqueous suspensions these are suspensions which
contain as active substance 3 to 3000 mg, preferably 15 to 240
mg, in particular 60 to 120 mg parts by weight of azelastine
embonate related to 100 ml of suspension. Use is preferably made
here of an azelastine embonate having a particle size under 100
~m. The pH value of such a suspension lies in the range of 3 to
9, preferably 5 to 8, in particular 6 to 7.
An azelastine embonate suspension is particularly favourable
consisting of a thixotropic system which has high viscosity in
the rest state, the skeleton of which collapses, however, on
slight mechanical loading (for example on pouring) so that the
suspension (for example the juice) becomes free-flowing.
~3:~7~
-- 3
Swel]ing agents are for example used in the preparation of such
a thixotropic suspension in water. Such swelling agents are, for
example: natural macromolecules (for example alginates, pectins,
tragacanth, hydrocolloidal polysaccharides such as xanthane
rubber), semi-synthetic macromolecules (such as cellulose
ether), synthetic macrornolecules (for example polyacrylates,
polyvinylpyrrolidone) as well as inorganic hydrogen sources (for
example colloidal silicic acid, bentonite)~ These swelling
agents may be used individually or in mixtures. On the basis of
their pronounced thixotropic properties formulations with
xanthane rubber have been found particularly suitable for the
preparation of stable, free-flowing suspensions.
These swelling agents may be used individually or in a mixture.
The total amount of swelling material related to 100 ml of
suspension is, for example 0.1 to 10, preferably 0.5 to 5 g~
When xanthane rubber is used, the amount of xanthane rubber is,
for example, 0.1 to 3, preferably 0.3 to 1.5, in particular 0.5
to 1 g, in polyacrylates 0.1 to 1 g, in alginates and tragacanth
0.1 to 0.2 g, in pectins and cellulose ethers 0.5 to 5 g, in
polyvinylpyrrolidone and inorganic hydrogen formers 1 to 10 g
(in each case related to 100 ml of suspension).
~3~7~
Furthermore the azelastine embonate suspensions of the invention
optionally contain preservatives, sweeteners, flavourings and
colouring agents conventionally used in pharmacy and
pharmaceutical formulations~
Preservatives that may, for example, be used are organic acids
(for example sorbic acid, benzoic acid), phenols (for example
lower alkyl p-hydroxybenzoates), organic mercury compounds (for
example thiom~r sal), ~uaternary ammonium compounds (for example
benzethonium chloride), aromatic and aliphatic alcohols (for
example 1,2-propylene glycol, benzyl alcohol), chlorohexidine.
The preservatives can also be used in the form of their salts
~for example alkali salts such as sodium henzoate) and naturally
also as mixtures.
The amount of preservative in 100 ml of suspension may, for
example, lie in the case of sorbic acid between 0.05 g and
1.0 g, benzoic acid 0.1 g and 0.2 g, thiomer sal 0.001 g and
0.091 g, benzethonium chloride 0.005 g to 0.02 g, 1,2-propylene
glycol 10 g nnd 30 g, benzylalcohol 1.0 g and 2.0 g,
chlorohexidine 0.001 to 0.01 g.
A mixture o~ p-hydroxybenzoic acid lower alkyl esters i5
preferahly used. The sum of p-hydroxybenzoic acid lower alkyl
esters related to 100 ml of suspension lies, for example,
between 0.1 and 0.3 g, preferably between 0.15 g and 0.25 g, in
particular between 0.15 g and 0.20 g.
:
~3175~
-- 5
Sweeteners that may, for example, be used are: saccharine,
cyclamate, aspartam, fructose, saccharose, sorbitol, mannitol as
well as, preferably, xylitol. The amount o sweetener naturally
depends on the sweetening value. Generally the amount, related
to 100 ml of suspension i5 0.005 to 0.1 for saccharine, 0.5 to
2.0 for cyclamate, 0.005 to 0.3 for aspartam, l.0 to 60 g for
fructose, saccharose, sorbitol and mannitol. In the case of
xylitol, thisj~mount is, for example, 1 to 60, preferably 15 to
60, in particular 30 to 40 g.
Flavourings that may be used are: essential oils (for example
peppermint oil, balm mint oil, lemon oil), fruit extracts (for
example lemon, grapefruit, pineapple~, aromatic drug extracts
(liquorice root, aniseed, fennel), nature-identical and
synthetic flavourings. ~aspberry flavouring has, for example,
been found to be particularly suitable.
The amount of flavouring is, for example, related to 100 ml of
suspension, between 0.001 to 5 or also 10, preferably 0.01 to 1,
in particular 0.01 to 0.1 g~ In the case of raspberry flavouring
0.01 to 0.1, preferably 0.01 to 0.05, in particular 0.02 to 0.04
g per 100 ml of suspension are, or example, possible.
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-- 6
Possible colouring agents are, for example: t~e conventionally
permitted food colouring agents, colouring agents of natural
foodstuffs tfor example curcumin riboflavin, chlorophyll,
xanthophylls), synthetic organie colouring agents (azo dyes, azo
colouring lacquers), inorganic synthetic colouring agents (for
example titanium dioxide, iron oxide). Synthetie azo dyes sueh
as, for example, amaranth have proved to be particularly
suitable.
The amount of colouring agents may, for example, lie between
0.001 and 1.0, preferably 0~001 and 0.1, in particular 0.001 and
0.01 g, related to 100 ml of suspension. For amaranth 1 to 10,
preferably 1 to 5, in partieular 2 to 4 mg are, for example,
possible related to 100 ml of suspension.
Adjustment of the required pH value is appropriately effeeted
using inorganie aeids (hy~roehlorie acid, sulphurie aeid,
phosphorie aeid), organie aeids (for example eitrie aeid, maleie
aeid), inorganie bases (Eor example sodium hydroxide solution,
pota.ssium hydroxide solution) or by means of the salts
conventionally used herefor, for example ammonium cloride,
sodium eitrate, sodium dihydrogenphosphate).
For the prep~ration oE suspensions of the azelastine embonate of
the in~ention it is possible to use water as wel] as other
physiologically acceptable liquids. Such liquids may, for
_ 7 - ~ 3 ~ ~ 5 ~ ~
example, be: monovalent and multivalent lower alcohols, such as
ethanol, propylene glycol, glycerine and polyglycols with
molecular weights of 200 to 600. It is also possible to use
mixtures of these liquids with each other as well as with water.
Possihle liquid carrier substances may also, for example, be:
natural oils (for example olive oil), synthetic and
semi-synthetic oily pharmaceutical liquid carriers such as
triglycerides of saturated plant acids with ~ to 12 carbon atoms
and their mix~ures.
For preference these are purely aqueous suspensivns.
Should mixtures of water and other liquids be used, these are,
for example, mixtures wherein the content of the non aqueous
proportion is 1 to 60, prefarably 10 to 40, in particular 20 to
30 percent by weight, related to 100 grams of suspension.
Wetting agents may optionally also be added to the suspensions
of the invention. Wetting agents that may be used are, for
example; anionic tensides, for example soaps, fatty alcohol
sulfates, nonionogenic tensides, for example polyethylene glycol
A!~ti~ r~1
fatty acid esters (Myrj1), polyethylene glycol fatty alcohol
ethers (Bri~), sorbitane fatty acid esters ~Span1), polyethylene
glycol sorbitane fatty acid esters (Tween/), polyethylene
glycol-polypropylene glycol derivatives (Pluronics~).
7 ~ ~ ~
Sorbitan fatty acid esters (with saturated or unsaturated
aliphatic carboxylic acids of C10 to C20, polyoxyethylene
fatty alcohol ethers (alcohols of C10 to C20) and
polyethylene glycol-sorbitan carboxylic acid esters (saturated
or unsaturated aliphatic carboxylic acids f C10 to C20) are
preferably used.
The amount of wetting agent, related to 100 ml of suspension
may, for example, be: 1 to 10-5, preferably 0 5 to 0.001 in
particular 0.1 to 0.01 g. The wetting agent has the function of
ensuring optimum dispersion o the non-dissolved active
substance. Optionally the required amount of the appropriate
wetting agent should be ascertained during preliminary trials.
The a~elastine embonate suspensions o the invention have, for
example, viscosities in a range of 0.05 to 0.72, preferably 0.09
to 0.18, in p~rticular 0.1~ to 0.15 Pascal seconds (Pa.s.) at a
shearing speed of 110 per second in the rotation viscosimeter.
It is, moreover, possible to add addition~l embonic acid to the
azelastine embonate suspensions of the invention. Per 100 ml of
suspension it is, for example, possible to add 1 to 2000 mg,
preferably 20 to 1000 mg, in particular 50 to 150 mg of
additional embonic acid to the azelastine embonate already
present. The surplus embonic acid surprisingly effects an
improvement in taste.
~ 3 ~
g
For the preparation of suspensionSwith propellants (aerosols)
the conventional propellants (propane, butane, fluorochlorohydro-
carbons) are used in addition to or in place of the auxiliary
substances mentioned. For such suspensions the azelastine
embonate should, for example, have a particle size with
diameters between 5 - 10~um -~
The preparation of such aerosols is for example effected by
dispersing 3 ~b 3000 mg of azelastine embonate in 100 ml of a
mixture of chlorinated fluorinated hydrocarbons and/or
hydrocarbons with addition of 0.25 to 3 g of sorbitane trioleate
as well as optionally with other auxiliary substances at a
temperature between -55C and -~55C and fills the suspension
obtained into tins which are or will be closed with dosage
valves which release 0.025 to 0.1 ml of the suspension per
actuation. The preparation of azelastine embonate of this
particle size is effected through grinding in a conventional
micronizing apparatus.
For the preparation of other oral formulations of azelastine
embonat~ the conventional pharmaceutical and galenically used
auxiliary or carrier agents are used. For tablets, for example,
the following auxiliary and carrier agents are used (amounts in
percent by weight per tablet).
- 10 - ~ ~ ~ 75 9~
illing agents (5-95~): for example starch, cellulose, lactose,
saccharose, fructose, sorbitol,
mannitol, calcium phosphate.
inding agents (1-80~): gelatine, cellulose ether, pectins,
alginates, polyvinylpyrrolidone,
lactose, microcrystalline cellulose.
lasting agen~s (1-10~): alginates, starch, pectins,
carboxymethyl cellulose, polyvinyl
polypyrrolidone, ultramylopectin,
bentonite.
ubricants (0.2-10~): stearic acid, stearate, polyglycols,
talcum, highly d.isperse silicon
dioxide.
Tablets may also COntAin: anti-adhesion agents, absorption
accelerators, hydrophilization ~gents, wetting agents and
equivalent agent5.
Coated tablets are often manufactured which, for example, also
contain corresponding film formers and coating materials as well
as dyestuffs, softeners, polishing agants.
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The filling agents, binding agents and lubricating agents
mentioned may also be used in the other oral medicinal forms
(capsules, granulates and the like)
Tablets as well as other oral formulations (capsules,
granulates) contain, for example, between 0.5 and 30 mg,
preferably 1 and 20 mg, in particular 1.5 and 12 mg of
azelastine embonate.
The preparatioln of the embonate of the invention is effected
through conversion of azelastine or an acid addition salt of
azelastine with embonic acid or a salt of embonic acid in an
appropriate solvent with optional heating. The conversion is
efiected at temperatures of 18 to 150C, in particular 20 to
100C, preferably between 20 to 50C.
Solvents that may be used are, for example: lower aliphatic
C1-C6-alcohols (methanol, ethanol, propanol, isopropanol,
butanol~, lower aliphatic ketones with 3 to 8 carbon atoms
(acetone, methylethylketone), glycolether, cyclic ethers
(dioxan, tetrahydrofuran), esters of lower aliphatic carboxylic
acids with lower aliphatic alcohols, amides and N-alkyl-substi-
tuted amides of aliphatic C1-C4-carboxylic acids
(dimethylformamide, dimethylacetamide), C1-C6-dialkyl-
sulfones (dimethylsulone, tetramethylene sulfone),C~-C6-dialkylsulfoxides (dimethylsulfoxide) as well as other
- 12 - ~ 317 ~ ~ ~
aprotic agents such as N-methylpyrrolidone, tetramethylurea,
hexamethylphosphoric ac;.d triamide, acetonitrile, mixtures of
these agents amongst themselves as well as mixtures with water.
In the case of aqueous mixtures the proportion of water is
generally not highar than 30 percent by volume. The conversion
can moreover also occur in alcohol-ether mixtures, whereby for
example aliphatic C2-C6-ethers and cyclic ethers can be
used~ Conversi.on is also possible into mixtures of lower
aliphatic alcohols wi-th halogenated aliphatic or aromatic
hydrocarbons.
Azelastine and embonic acid are used in a ratio of 2 : 1.
Preference is thereby given to the use of an excess of
azelastine of 1 - 20, in particular 1 - 5~ related to the amount
of embonic acid which is necessary for the above mentioned
ratio.
Should the azelastine be used in tha form of its salt, salts
with the following acids are, for example, possible: strong and
medium-strong inorganic acids (halohydric acids such as HCl,
HBr, nitric acid, phosphoric acids, sulphuric acid), strong to
weakly organic acids such as aliphatic and aromatic sulphonic
acids (methane sulphonic acid, toluene sulphonic acid),
aliphatically saturated and unsaturated single and multibasic
carboxylic acids, aromatic carboxylic acids (benzoic acid,
toluenecarboxylic acid).
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- 13 -
The embonic acid may also be used in the form of a salt. Salts
of embonic acid which can, for example, be used are: alkali
metal salts (Na, K, Li), alkaline earth metal salts, magnesium
salts, ammonium salts, alkylammonium salts.
The preparation of the pharmaceutical azelastine embonate
formulations is effected through mixture or homogenization of
the azelastinq,embonate with the remaining auxiliary and carrier
substances at temperatures between 15 and 80, preferably 18 to
40, in particular 20 to 30C. In order to reduce the pathogens
(sterilization) it is optionally possible to heat for 15 to 60
minutes to 80 to 140, preferably 110 to 125C.
For the preparation of suspensions it is, for example, possible
to proceed as follows: the swelling agent (0.1 to 10, preferably
0.3 to 1.5 g per 100 ml of suspension and optionally one part of
the other auxiliary substance) are dissolved in water or in the
other liquids or mixtures of liquids mentioned at 20 to 30C
whereby tha amount of water or the amount of liquid is so
measured that the finished suspension contains 0.03 to 30,
preferably 0.4 to 6, in particular 0.8 to 1.2 l of water or
liquid related to 1 g of azelastine embonate. The aqueous
solution so obtained mAy then be heated for 10 to 120,
preferably 15 to 60 minutes to 80 to 134C, preferably 20 to
30 minutes to 110 to 121C.
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- 14 -
Following cooling to 25 to 35C a wetting agent is optionally
added to this solution followed by the mixture of the azelastine
embonate and optionally the preservatives, sweeteners, dyestuffs
and optionally flavourings and o-ther auxiliary and/or carrier
substances prepared at temperatures of 20 to 30C and the
result homogenized (temperature 15 to 35C, preferably 20 to
30C). ]'
This process is optionally followed by the addition of
1avourings as well,as adjustment of the pH value to 3 to 9.
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- 15 -
The preparation of the above-mentioned azelastine embonate
suspension uses, for example, for 1 gram oE azelastine embonate:
0.005 to 600 g, preferably 300 g to 400 g of sweetener
0.01 to 10 g, preferably 0.2 to 0.4 g of flavouring
Part of the a~ount of flavouring,mentioned here can optionally
also be added t~ the suspension later on.
Example 1:
Azelastine embonate
HD ~ ~ooa~
O
Azelastine Embonic acid
(2 Mol) (1 Mol)
177.5 g (1.01 x 2 x 0.21 mol) of azelastine hydrochloride are
dissolved by stirring in 4500 ml of ethanol 80~ in a beaker.
After addition of 90 6 g (0.21 mol) of embonic acid disodium
salt the procedure is continued only until this has dissolved,
ca. 4 minutes.
:~3~7~a~
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The result is then immediately filtered through a fluted filter
and the filtrate allowed to stand quietly overnight. The
embonate precipitates out rapidly. This is suction filtered,
washed with 80~ ethanol and then with pure ethanol and dried in
a vacuum for 20 hours at 60C. Yield 195 g (80~ of theory).
The product t~ereby obtainad is stirred in ice water for 5 hours
for further purification, suction filtered, washed first with
ice water, then with ethanol and dried in a vacuum at 60c for
20 hours. Yield 195 g (80~ of theory). The azelas-tine embonate
is obtained in the form of a crystalline, weakly
yellowish-coloured powder.
Melting point: 197 to 201C.
The IR spectrum is shown in Fig. 1. For the nuclear magnetic
resonance spectrum, see Fig 2.
1 3 ~L 7 ~ 9 ~
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Example 2:
Azelastine embonate suspension
3000 ml of suspension corresponding to 3300 g contain:
Azelastine embonate 3,600 g
Xanthane rubber ' 21,000 g
Xylitol 1 200,000 g
Sodium propyl-4-hydroxybenzoate1,200 g
(Na-salt of 4-hydroxybenzoic acid
propyl ester)
Sodium methyl-4-hydroxybenzoate4,200 g
(Na-salt of 4-hydroxybenzoic acid
methyl ester)
Hydrochlorid acid 1 N 21,000 g (a)
Raspberry flavouring O.9OO g
Amaranth (permitted red dyestuff)0.150 g
Purified water 2 047,950 g
3 300,000 g
a~ The hydrochloric acid is required for adjustment of the pH
value to 6.5. Use of hydrochloric acid deviating from the
value given is compensated by corresponding reduction in the
purified water used.
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Preparation:
800.0 g of xylitol and 21.0 xanthane rubber are dissolved in
2000 g of water with stirring in a 3000 ml beaker. The solution
is then heated for 30 minutes at 115 degrees Celsius in an
autoclave. Following cooling to circa 40 degrees, the solution
is suction filtered under vacuum with recirculation into the
working container of a homogenizing apparatus.
400.0 g of xylitol, 1.2 g of sodium propyl-4-hydroxybenzoate,
4.2 y of sodium methyl-4-hydroxyben2Oate, 0.15 g of amaranth and -
3.6 g of azelastine embonate are mixed in a porcelain dish and
suction filtered into the previously prepared solution in the
working container of the homogenizing apparatus.
0.9 g of raspberry flavouring and 21.0 g of hydrochloric acid
are suction filtered under vacuum and recirculation into the
working container of the homogenizing apparatus. The suspension
is homogenized for 15 minutes.
The p~ value of the suspension so obtained is adjusted to 6.5
through addition of hydrochloric acid. The hydrochloric acid
used is compensated by a reduced use of purified water. The
formula for the calculation of the amount of water used is:
47~9~ g - hydrochloric acid used in g = amount of water in g.
~ 3 ~ 7 ~
- 19 -
The suspension obtained is a viscous, red coloured juice (pH
value 6.3 to 6.7).
Effective component per 100 ml: 0.1200 g of azelastine embonate
Smell: of raspberries
Taste: raspberry flavour
Viscosity: 0.1 - 0.15 Pascal seconds (Pa.s.)
The juice (bu~k goods) is, for example, filled into screw-top
brown glass bottles. The filling of the bulk goods should be
effected in such a manner that no air is entrapped through
excessively ast pouring.
The juice is, for example, stored at room tempe~ature.
~3~75~;~
- 20 -
Example 3:
Azelastina embonate suspension
5000 ml of suspension corresponding to 5500 g contain:
Azelastine embonate 6,000 g (1)
Xanthane rubber 32,500 g
Xylitol 1 500,000 g
Sodium propyl-4-hydroxybenzoate2,000 g
Sodium methyl-4-hydroxybenzoate7,000 g
Embonic acid 5,000 g
Raspberry flavouring 1,500 g
Amaranth (red dyestuf) 0.250 g
Citric acid 64,000 g
Sodium hydroxide 32,500 g
Purified water 3 849,250 g (2
5 500,000 g
1) The azelastine embonate was passed through a sieve of pore
size 100 ~m before processing
2) The pH value of the suspension is optionally adjusted with 1
N sodium hydroxide solution to 6.5. The consumption of
sodium hydroxide solution is deducted from the water.
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I - 21 -
Method of preparation
I. 400 g of xylitol and 32.5 g of xanthane rubber are rubbed
together and this mixture dissolved in 3000 g of water with
stirring. The solution is heated for 30 minutes at 115C
in an autoclave. The water evaporating during autoclaving is
replaced. After cooling to ca. 30C the solution is then
transferred under vacuum and recirculation into the working
container of a homogenizing apparatus.
II. In the order ]isted, 64 g of citric acid, 5 g of embonic
acid, 2 g of sodium propyl-~-hydroxybenzoate, 7 g of sodium
methyl-4-hydroxybenzoate, 0.25 g of amaranth, 6 g of
azelastine embonate, 1.5 g of raspberry flavouring and
1100 g of xylitol are suction filtered under vacuum with
recirculation into the working container oE a homogenizing
apparatus. The pH value is optionally adjusted to 6.5 using
1 N sodium hydroxide solution.
The result is flushed through with water and filled up to
the final volume of 5000 ml. The suspension is homogenized
for 15 minutes under vacuum and recirculation.
The resultant suspension is a viscous red juice.
Viscosity ~ 0.1 - 0.15 Pascal seconds (Pa.s.)
pH value = 6.3 - 6.7
- 22 -
Density = 1.09 - 1.11 g/ml
Smell: of raspberries
Taste: raspherry flavour
