Note: Descriptions are shown in the official language in which they were submitted.
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4-17295 +
Liquid oral formulation
The invention relates to an aqueous oral pharmaceutical preparation of
diclofenac, and to
its use and preparation. .
Diclofenac, chemical nameo-(2,6-dichloroanilino)phenylacetic acid, is known as
a potent
analgesic and antirheumatic and is described, for example, in US Patent No.
3,58,690.
Much effort has been directed tovciard developing for this active ingredient
an aqueous,
individually dosable oral form of administration which has a neutral or
pleasant taste and,
in addition, has a satisfactory shelf life so as to make available to doctors
and patients an
appropriate alternative to other oral preparations.
It is known that diclofenac has a bitter taste and causes a scratching
sensation in the throat.
In addition; it has proven disadvantageous that;when customary aqueous oral
solutions are
used, water-insoluble hydrates are formed which result in precipitations. It
is furthermoze
known that diclofenac cyclizes; in particular in acid solwation, to form 1-
(2,6-dichloro-
phenyl)indolin-2-one. Thus, corresponding aqueous pharmaceutical formulations
of diclo-
'fenac do not.have an adequate shelf life and, as a consequence; would ztot
meet the criteria
for registration as a medicament.
The present invention had'the object of developing an aqueous oral
pharmaceutical prepa-
ration'of diclofenac which does not have the disadvantages mentioned:
This object is' achieved by the preparation according to the invention. This
has the'features
that a pH range is selected in which the active ingredient has the lowest
water solubility
and'that diclofenac is in suspended form.
Surprisingly, when aqueous formulations of this type are used; absolutely no
prohibiaive
formation of indolinone; in particular, is observed. In addition, preparations
of this type
have a pleasant taste and do not cause a scratching sensation in the throat.
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The preferred active ingredient concentration of the preparation according to
the invention
is about 0.5 to about 10°lo by weight, in particular about 1 to about
5% by weight,
primarily about 1% by weight.
The pH range according to the invention is, in particular, between about 2 and
about 3.5,
preferably between about 2.5 and about 3.5, and is established by means of
pharmaceu-
tically acceptable acids or buffer systems which are known per se. Suitable
pharmaceuti-
cally acceptable acids are preferably carboxylic acids, such as acetic acid,
malonic acid,
fumaric acid, malefic acid, succinic acid, lactic acid, tartaric acid or
primarily citric acid.
Examples of buffer systems of this type are sodium citrate/HCl or citric
acid/phosphate
buffer.
Appropriate forms of administration of the suspension according to the
invention are
drops, mixtures, juices or syrups, which may also be used in dose-unit forms.
The composition according to the invention may contain further
pharmaceutically
acceptable adjuncts and additives, far example preservatives, antioxidants,
fragrances,
dyes, sweeterners, suspension stabilizers and/or wetting agents.
Suitable preservatives, which protect against infestation by microorganisms,
are benzoic
acid or salts thereof, such as sodium, potassium or calcium salts; 4-
hydroxybenzoic acid
esters, such as methyl, ethyl or propyl 4-hydroxybenzoate (PHB esters),
phenols, such as
tert-butyl-4-methoxy- or 2,6-ditert-butyl-4-methylphenol; phenyl (lower
alkanols), benzyl
alcohol, ~-chloro- or 2,4-dichlorobenzyl alcohol, 2-phenylethanol or 3-
phenylpropanol,
chlorohexidine diacetate or digluconate, thiabendazole, furthermore
nitrofural; quarternary
ammonium halides, such as alkonium bromide, benzalkonium chloride, cetrimonium
bromide; phenododecinium bromide or cetylpyridinium chloride; or primarily
sorbic acid,
for example in a proportion of about 0.01 to about 0.1% by weight.
Suitable antioxidants, which are intended to inhibit oxidative processes, are,
for example;
sulfites, such as alkali metal sulfites, alkali metal bisulfites or alkali
metal pyrosulfites, for
example the corresponding sodium or potassium salts, thiodipropionic acid;
thioglycol;
thiolactic acid, glutathione, but preferably cystein, ascorbic acid and esters
thereof, for
example ascorbic acid myristate, palmitate or stearate, or esters of gallic
acid, such as
propyl; octyl or dodecyl esters, for example in a propartion of about 0.01 to
about 0.1 % by
weight. Synergists, such as citric acid, citraconic acid, phosphoric acid or
tartaric acid,
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may be admixed.
To improve the flavour, suitable fragrances are, for example, etherial oils,
in particular
those derived from fruits, such as oranges, and oils from Seville oranges,
mandarines or
lemons, and furthermore caramel.
Examples of suitable dyes are Indigo Tin I(blue), Amaranth (red), Yellow
orange S
(orange), Tartrazine XX (yellow.) or chlorophyll (green).
Examples of suitable sweeteners, which are present in high concentration, in
for example,
syrups, are sugar such as monosaccharides or disaccharides, far example D-
glucose,
D-fructose, D-xylose, maltose or sucrose, polyols, such as glycerol, dulcitol,
mannitol,
sorbitol or xylitol, or artificial sweeteners, such as saccharine or the
corresponding
sodium, potassium or calcium salt; cyclamate or the corresponding sodium or
calcium salt,
aspartam or acesulfam or the potassium salt thereof, furthermore Dulcin or
ammonium
glycyrrhizinate.
The suspension stabilizers are intended to ensure that the individual doses
removed have a
constant active ingredient content. Examples of appropriate stabilizers are
inorganic
suspension stabilizers, for example colloidal silicates having a high
aluminium and
magnesium content, such as bentonite, Veegum or Gel White, colloidal silica,
for example
Aerosil~ (Degussa); Cabosil~ (Cabot), organic stabilizers, for example
swelling agents;
such as alginates; for sadiuna alginate; calcium alginate or propylene glycol
alginate; gum
arabic; tragasanth, karaya gum, sterculia gum, carrageen; guar gum or agar;
synthetic or
semisynthetic swelling agents; for example 1,2-epoxide polymers, in,particular
ethylene
oxide homopolymers having a degree of polymerization of about 2;000-100,000,
which
are known, for example, under the trade name Polyox~ (Union Carbide),
preferably
swellable cellulose ethers; for example methyl- or ethyl cellulose, hydroxy
ethyl cellulose;
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, m~th~l- or
ethylhydroxyethyl
cellulose, carboxymethyl cellulose or an alkali metal salt thereof, or
microcrystalline
cellulose, or water-soluble' polyvinyl compounds; such as polyvinyl acetate,
polyvinyl
alcohol or polyvinylpyrrolidane:
Wetting agents may advantageously be added to the stabilizers. Examples of
suitable
wetting agents are sulfosuccinates; such as dihexyl sulfosuceinate; dibctyl
sulfosuccinate
or diamyl sulfosuccinate, sulfonates or sulfates, for example Na
alkylnaphthalene-
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sulfonates, fatty alcohol sulfonates or fatty alcohol polyglycol ether
sulfates, fatty acid
polyglycol esters, for example polyethylene glycol stearates, polyglycol
esters of Cg-Ct8
fatty acids, fatty alcohol polyglycol ethers, for example lauryl, cetyl,
stearyl or oleyl
alcohol polyglycol ether or cetylstearyl alcohol polyglycol ether, poly(fatty
acid) ester
polyglycol ethers, for example polyethylene glycol sorbitan monolaurate,
monopalmitate,
monostearate or monooleate, glycerol fatty acid ester polyglycol ether or
pentaerythritol
fatty acid polyglycol ether, sucrose esters, for example sucrose monostearate
or distearate
or sucrose rnonopalmitate, ethoxylated vegetable oils, for example ethoxylated
castor oil
or hydrogenated and ethoxylated castor oil, or block polymers, such as
polyoxyethylene-
polyoxypropylene polymers.
The aqueous oral pharmaceutical preparations of diclofenac according to the
invention axe
prepared, for example, as follows depending on the nature of the form of
administration.
Thus, for example, the adjuncts and additives are incorporated into the water
with or
without warming, for example in a temperature range of from about 20°
to about 100°C.
The active ingredient is then suspended in this base. However, the sequence of
mixing the
companents of the preparation according to the inventiorr is not important.
To prepare syrups, for example, the suspension agent and the appropriate
suspension
stabilizer are added to the water. A sweetener and, if desired, preservatives,
antioxidants,
fragrances and/or dyes are incorporated with or without warming, for example
in a
temperature range of from about 50° to about 100°C. The active
ingredient is then
suspended in the medium.
The aqueous oral pharmaceutical preparation according to the invention can be
used; for
example, for treating pain and inflammatory processes.
The invention also relates, in particular, to the preparations and preparation
processes
described in the Examples.
The Examples below serve merely to illustrate the above-described invention;
however,
they are not intended to represent a limitation.
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Example 1: Syrup containing 1% by weight of diclofenac.
Composition:
Diclofenac (free acid) 1.00
g
Hydroxyethyl cellulose (Natrosol 250 G) 0.50
g
Cellulose and sodium carboxymethyl cellulose1.20
(Avicel RC 591) g
Sorbitol solution 25.00
g
Sorbic acid 0.05
g
Vitamin C 0.10
g
Citric acid 0.20
g
Saccharine sodium 0.06
g
Demineralized water '71.89
g
100.00 g
pH: 2.9
Preparation: Avicel is suspended in the water using a high-speed mixer,
Natrosol is ad-
mixed, arid the mixture is left to swell for about 1 hour. Sorbitol solution
and sorbic acid
are added, and the mixture is heated to about 85° with stirring. After
the mixture has been
cooled to room temperature, Vitamin C, citric acid and saccharine are
dissolved consecu-
tively therein with stirring. The active ingredient is suspended in the
mixture with the aid
of the mixer, and the mixture is subsequently deaerated.
Example 2: Syrup containing 1% of diciofenac:
Diclofenac (free acid) 1.0 g
Sucrose 40.0 g
Agar powder 0:3 g
Sorbic acid 0.1 g
Vitamin C 0:1 g
Citric acid 1 AQ 0.2 g
Disodium phosphate 2 AQ 0.08 g
Lemon aroma 0.1 g
Demineralized water 58.12 g
100.00 8
pH; 3.2
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Preparation: The water is waned to about 90°C and sorbic acid is
dissolved therein. Agar
powder is subsequently scattered into the mixture and dispersed using a high-
speed mixer.
The mixture is then left to swell at 90°C for about 30 minutes. The
sucrose is added and
dissolved with stirring. After the mixture has cooled to about 40°C,
citric acid, disodium
phosphate and Vitamin C are added consecutively and dissolved. After the
fragrance has
been added, the active ingredient is ground with a small amount of the base
and then
distributed in the remainder of the base.
Example 3: Mixture containing 1% of diclofenac.
Diclofenac (free acid) 1.0 g
Hydoxyethylcellulose (Natrosol 250 G) 0.5 g
Cellulose and sodium carboxymethylcellulose
(Avicel RC 591) 1.2 g
Sorbic acid 0.1 g
Vitamin C 0.1 g
Citric acid 1 AQ 0.2 g
Saccharine sodium 0.06 g
Disodium phosphate 2 AQ O.OIi g
Lemon aroma O.l g
Demineralized water 97.16 g
100.00 g
P~~ 3.2
preparation: Avicel is dispersed in 50 g of water using a high-speed mixer,
Natrosol is
admixed; and the mixture is left to swell for about 1 hour: Tha remainder of
the water
(4'7.16 g) is heated to about 60°C and sorbic acid is dissolved
therein. After the latter
mixture has cooled to 40°C, saccharin, citric acid; disodium phosphate
and i~itamin C are
added consecutively and dissolved. This solution is nnixed with the Avicel
dispersican.
After the fragrance has been added, the active ingredient is ground with a
small amount of
the base and then distributed in the remainder of the base:
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Example 4: Drops containing 1% of diclofenac:
Diclofenac (free acid) 1.0 g
Meyprogat 150 (guar gum) 0.5 g
Sorbitol solution 50.0 g
Sorbic acid 0.1 g
Vitamin C 0.1 g
Citric acid 1 AQ 0.2 g
Disodium phosphate 1 AQ 0.0$ g
Lemon aroma 0.1 g
Demineralized water 47.92 g
100.00 g
pH: 3:1
Preparation: The water is warmed to about 90°C and sorbic acid is
dissolved therein.
Meyprogat is scattered into the mixtuxe and dispersed using a high-speed
mixer. The
mixture is then left to swell at 90°C for about 30 minutes. Soxbitol
solution is then added.
After the mixture has cooled to about 40°C, citric acid, disodium
phosphate and Vitamin
C are addedconsecutively and dissolved with stirring. After the fragrance has
been added,
the active ingredient is ground with a small amount of the base and then
distributed in the
remainder of the base.
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Example 5: Syrup containing 1% by weight
of diclofenac.
Diclofenac (free acid) 1.00 g
I-Iydroxyethyl cellulose (Natrosol 250 0.50 g
G)
Cellulose and sodium carboxymethylcellulose
(Avicel RC 591 ) 1.20 g
Sorbitol solution 25.00 g
Sorbic acid 0.05 g
Vitamin C 0.60 g
Citric acid 1.00 g
Saccharine sodium 0.06 g
Dernineralized water 70.59 g
100.00 g
pH: 2.3
Preparation: Avicel is suspended in the -speed mixer; Natrosol is
water using a high
admixed and the mixture is left to swell
for about 1 hour: Sorbitol solution and
sorbic acid
are added; and the mixture is heated to
about 85 with stirring. After the mixture
has
cooled to room temperature, Vitamin C;
citric acid and saccharine are dissolved
consecutively therein with stirring. The
active ingredient is then suspended therein
using
the mixer, and the mixture is subsequently
deaerated.
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Example 6: Syrup containing 1°Jo by weight of diclofenac.
Diclofenac (free acid) 1.00 g
Hydroxyethylcellulose (Natrosol 250 G) 0.50 g
Cellulose and sodium carboxymethylcellulose (Avicel FC 591) 1.20 g
Sorbitol solution 25.00 g
Vitamin C 0.60 g
Citric acid 1.00 g
Methylparaben 0.12 g
Propylparaben 0.05 g
Saccharine sodium 0.06 g
Demineralized water 70.49 g
100.00 g
pH: 3.0
Preparation: Avicel is suspended in the water using a high-speed mixer,
Natrosol is
admixed, and the mixture is left to swell for about 1 hour. Sorbitol solution
and sorbic acid
are added, and the mixture is heated to about 85° with stirring. After
the mixture has
cooled to room temperature, Vitamin C, citric acid and saccharine are
dissolved
consecutively therein with stirring. The active ingredient is suspended
therein using the
mixer, and the mixture is subsequently deaerated.
