Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Effervescent preparations
The invention relates to a process for producing medicament-containing
effervescent
preparations with at least partial melting of a preparation component and to
effervescent preparations obtainable by this process.
Effervescent preparations such as, for example, effervescent powders or
effervescent
tablets are a formulation form, for example for active substances with a long
absorption time or with a tendency to irritate the gastric mucosa, which is
able to
mitigate the disadvantageous properties meritioned for the active substances.
Medicament-containing effervescent preparations therefore enjoy increasing
popularity. They are normally produced in 3 to 4 stages, namely by
a) granulating the effervescent composition consisting of COZ donor and C02-
releasing acidic component,
b) mixing the other components (active substances and other ancillary
substances),
c) combining the components obtained frorn process steps a) and b) and, where
appropriate,
d) tabletting the mixture obtained in step c).
Since both the CO2 donor and the acidic component are relatively unsuitable
for
direct tabletting, the components of the effervescent composition have in the
past
been subjected, where appropriate in combination with the active substance, to
a
granulation process before the tabletting; compare, for example, German
Offenlegungsschrift 22 16 072. The stability of the effervescent tablets
produced in
this way is, however, still unsatisfactory. The additional use of buffer
substances and
flavourings (which, after all, usually consist of many individual different
compounds) in particular results in a sensitivity to water which leads, on
storage, to
discoloration, distension and degradation reactions. To avoid these unwanted
reactions, effervescent preparations are often sealed in metal foils. Although
this
measure extends the shelf life, it is not possible reliably to prevent
distension of the
metal foil sachets on prolonged storage.
It has now been found, surprisingly, that the stability of medicament-
containing
effervescent preparations can be increased by a process in which a preparation
component is melted.
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The invention thus relates to a process fo:r producing medicament-containing
effervescent preparations consisting of
A. effervescent composition containing
(i) CO2 donor and
(ii) acidic component,
B. pharmaceutical active substance and
C. ancillary substance,
characterized in that
at least one of the two components A(i), A(ii) and, where appropriate, other
effervescent preparation components are dispersed in molten C) sugar and/or
sugar
alcohol andlor sugar substitute, and the resulting mixture is tabletted where
appropriate.
The invention entails dispersing where appropriate one, a plurality or all of
the
remaining effervescent preparation components in the melt.
A preferred process is characterized in that
- a melt of component A(i) and/or A(ii) and C) fusible sugar and/or sugar
alcohol
and/or sugar substitute is comminuted during or after the cooling,
- the comminuted product is mixed with active substance B, with component (i)
or
(ii), which is still missing where appropriate, of the effervescent
composition A
and, where appropriate, with further ancillary substances C and, where
appropriate,
- the resulting mixture is tabletted.
Preferred CO2 donors A(i) comprise alkali metal and alkaline earth metal
carbonates
and bicarbonates, especially sodium and potassium carbonates and bicarbonates,
and
magnesium and calcium carbonates.
Suitable as acidic component A(ii), which liberates carbon dioxide from the
COZ
donor A(i), are all physiologically acceptable acids (so-called "acidulants"),
which
are strong enough to liberate carbon dioxide from component A(i); such acids
have a
first equilibrium exponent pKa of from 1 to 7, preferably 2 to 6 (at 25 C).
Preferred
acidic components A(i) comprise ascorbic acid and polybasic carboxylic acids
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having 3 to 8, preferably 4 to 6, C atoms and 2 to 4 carboxyl groups per
molecule,
such as, for example, vitamin C, malic acid, citric acid, tartaric acid and
mixtures
thereof.
Suitable pharmaceutical active substances C cornprise
analgesics such as ibuprofen, ketoprofen, paracetamol, acetylsalicylic acid,
COX2
inhibitors such as nimesulide, meloxicam, naproxen, propyphenazone,
metamizole,
antacids such as hydrotalcite, magaldrate, calciu.m carbonate,
antiasthmatics/bronchospasmolytics such as salbutamol, tulobuterol,
terbutaline,
cromoglicic acid, ketotifen, theophylline,
antibiotics such as quinolones, tetracyclines, cephalosporins, penicillins,
macrolides,
sulphonamides, polypeptides,
phychopharmaceuticals such as benzodiazepines, haloperidol, amitryptyline,
carbamazepine,
antirheumatics such as phenylbutazone, indometacin, diclofenac, piroxicam,
antidiabetics such as metformin, glibenclamide, acarbose, glisoxepide,
antiallergics/antihistamines such as astemizole, terfenadine, loratadine,
clemastine,
bamipine, cetirizine,
antihypotensives such as etilefrine, norfenefrine, dihydroergotamine mesilate,
antitussives such as codeine, dextromethorphan, clobutinol, dropropizine,
antihypertensives such as beta blockers such as propranolol, atenolol,
metoprolol,
prazosin,
antihypertensives such as calcium channel blockers such as nifedipine,
nitrendipine,
diltiazem, verapamil, felodipine, nimodipine,
laxatives such as sodium picosulphate, lactulose, lactitol,
mucolytics/expectorants such as ambroxol, bromhexine, guaifenesin,
acetylcysteine,
carbocisteine,
H2 blockers such as ranitidine, famotidine, pirenzepine,
local anaesthetics such as benzocaine, lidocaine, procaine,
antiemetics/prokinetics such as metoclopramide, domperidone, meclozine,
dimenhydrinate,
lipid lowering agents such as fenofibrate, bezafibrate, pravastatin,
fluvastatin,
agents effective for migraine, such as caffeine, dihydroergotamine,
ergotamine,
sumatriptan, pizotifen,
sympathomimetics such as pseudoephedrine, pl:ioledrine,
vitamins and minerals.
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The ancillary substances C, which should melt at least partially in the
process
according to the invention, have, as single substance and/or in mixtures,
preferably
melting points of from 30 to 200, preferably from 40 to 160 C. Preferred
ancillary
substances of this type are soluble in water, that is to say they generally
have a
solubility in water of at least 10, preferably at least 30, and, in
particular, at least
40 g/100 ml of water at 20 C.
Fusible sugars C comprise, for example, monosaccharides such as glucose,
mannose,
galactose, arabinose, xylose, ribose and disaccharides such as sucrose,
lactose,
maltose. Sugar alcohols C preferred for the iiivention comprise xylitol,
mannitol,
sorbitol, isomalt, lactitol, erythritol, threitol, ribitol, arabitol and
dulcitol. Preferred
sugar-alcohols of this type are described, for example, in EP-B 435 450. The
term
"sugar substitutes" for the purpose of the invention does not include sugar
alcohols.
Preferred sugar substitutes C comprise acesulfame, aspartame, saccharin,
sodium
cyclamate.
Further ancillary substances C comprise flavourings, sweeteners, lubricants,
flow
regulators, disintegrants and bulking agents such as, for example, starch and
starch
derivatives, cellulose and cellulose derivatives, polyethylenes.
The effervescent preparations obtainable accorcling to the invention may
contain the
components in a wide variety of ratios of amounts; preferred effervescent
preparations contain (in each case in parts by weight)
A: 5 to 95, preferably 10 to 80,
B: 5 to 95, preferably 40 to 60,
C: 1 to 60, preferably 15 to 30 (sugar, sugar alcohol, or sugar substitute)
and,
where appropriate,
I to 50, preferably 5 to 15 (other ancillaiy substances).
The effervescent composition A preferably contains
30 to 70% by weight of CO2 donor and
70 to 30% by weight of acidic component,
in each case based on A.
The melt of effervescent composition A (component) and fusible sugar and/or
sugar
alcohol and/or sugar substitute C can be prepared, for example, by adding
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effervescent composition A (components) to a melt of sugar and/or sugar
alcohol
and/or sugar substitute C or by melting a mixture of effervescent composition
A
(components) and sugar and/or sugar alcohol and/or sugar substitute C.
However, the process according to the invention can also be carried out by
contacting all components of the effervescent preparation with the molten
sugar
and/or sugar alcohol and/or sugar substitute for the purpose of dispersion,
whether by
premixing all components and heating together, or whether by melting sugar
and/or
sugar alcohol and/or sugar substitute and dispersing the remaining components
(simultaneously or successively) in the melt. It is, of course, possible to
use mixed
forms of the process variants described.
The melt can be produced in virtually any suitable manner;
Thus, it is possible straightforwardly to use heatable stirred vessels. It is
also possible
to use a melt-granulation process as described, for example, in WO 92/6679. A
preferred process is melt extrusion as describeci, for example, in EP-A 686
392. It is
possible to employ for the extrusion commerci.ally available single screw and
twin-
screw extruders. It is moreover possible to feed the starting materials to the
extrusion
via a weigh feeder. The melt temperature cai7 be 30 to 200 C. The pressure can
preferably be 2 to 200 bar, depending on the die orifice (preferably 0.5 to 5
mm) and
the speed of rotation (preferably 5 to 400 revolutions/minute). The output can
vary
within wide limits, but is preferably 1 to 100 kg/hour. The extrudates are
cooled
where appropriate. After the comminution, they can be mixed with active
substance
B and, where appropriate, further ancillary substances C, and tabletted where
appropriate.
Preferably neither water nor an organic solvent which is volatile under the
processing
conditions is employed in the process according to the invention, that is to
say
preferably water and solvent are absent from the process. In other words,: the
process
is precisely not that described in German Offenlegungsschrift 22 16 072 or in
Acta Pharm. Suec., 24, (2), 84, 1987
Drug Dev. Ind. Pharm. 13, (9-11), 1891-1913, 1987
Drug Dev. Ind. Pharm. 14, (13), 1791-98, 1988.
The process according to the invention can be carried out continuously or
batchwise.
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In the process according to the invention, component A(i) and/or A(ii) and,
where
appropriate, further effervescent preparation components are dispersed in the
fusible
sugar, sugar alcohol or sugar substitute C, that is to say the fusible
component C
forms a matrix in which A(i) and/or A(ii) and, where appropriate, further
effervescent preparation components are embedded.
Thus the invention also relates to effervescent preparations consisting of
A. effervescent composition containing
(i) CO2 donor and
(ii) acidic component,
B. pharmaceutical active substance and
C. - ancillary substance,
characterized in that ancillary substance C contains fusible sugar and/or
sugar
alcohol and/or sugar substitute, and component A(i) and/or A(ii) is dispersed
in a
matrix of fusible sugar and/or sugar alcohol and/or sugar substitute.
The percentage data in the following examples are based on weight in each
case.
Examples
Example 1
Effervescent preparation consisting of separately extruded components A(i) and
A(ii)
Extrudate I
Mannitol and sodium bicarbonate are mixed in the ratios indicated in the
table. The
mixture is processed in a twin-screw extruder (Leistriz Micro 27/40D) at a
speed of
rotation of 30 rpm and with a die diameter of 1 nim. The dies are arranged
around the
outer diameter of the screws. Mixing zones and die temperature are at 80 C.
The
extrudate is cooled on a cooling belt and then coinminuted with an oscillating
sieve.
Extrudate II
Mannitol, citric acid and sodium citrate are mixed and extruded and further
processed as above.
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Extrudate I: Extrudate II:
Mannitol 60% 60%
Sodium bicarbonate 40%
Citric acid 6.7%
Sodium citrate 33.3%
Based on a single dose, 125 g of extrudate I and 150 mg of extrudate II are
mixed
with 500 mg of acetylsalicylic acid, 5 mg of aspartame and 30 mg of orange
flavour
and packed in a sachet.
Example 2
In analogy to Example 1, extrudate I and extrudate II are extruded at a
temperature of
70 C, with a die diameter of 0.8 mm and a speeci of rotation of 26 rpm.
Extrudate I: Extrudate II:
Xylitol 60% 60%
Sodium bicarbonate 40%
Citric acid 40%
Based on a single dose, 125 mg of extrudate I and 150 mg of extrudate II are
mixed
with 500 mg of acetylsalicylic acid, 4 mg of' saccharin and 30 mg of mandarin
flavour and packed in a sachet.
Example 3
In analogy to Example 2, extrudate I and Extrudate II are extruded at a
temperature
of 60 C, with a die diameter of 1 mm and a speed of rotation of 35 rpm.
Extrudate I: Extrudate II:
Xylitol 30% 30%
Sodium bicarbonate 70%
Citric acid 70%
Based on a single dose, 125 mg of each of extn.idate I and II are mixed with
150 mg
of ascorbic acid and 2.5 mg of chlorpheniramine maleate and packed in a
sachet.
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Example 4
In analogy to Example 2, extrudate I and extrudate II are extruded at a
temperature of
60 C, with a die diameter of 2 mm and a speed of rotation of 35 rpm
Extrudate I: Extrudate II:
Isomalt 60%
Xylitol 60%
Potassium bicarbonate 40%
Ascorbic acid 40%
Based-on a single dose, 125 mg of extrudate I and 250 mg of extrudate II are
mixed
with 500 mg of acetylsalicylic acid, 5 mg of saccharin, 2 mg of aspartame and
30 mg
of orange flavour and packed in a sachet.
Example 5
In analogy to Example 1, extrudate I and extrudate II are extruded at a
temperature of
60 C, with a die diameter of 1 mm and a speed of rotation of 35 rpm.
Extrudate I: Extrudate II:
Mannitol 60% 60%
Sodium bicarbonate 20%
Calcium carbonate 20%
Ascorbic acid 40%
Based on a single dose, in each case 1500 mg of extrudate I and 750 mg of
extrudate
II are mixed with 5 mg of aspartame and 10 mg of redcunant flavour and packed
in a
sachet.
Example 6
A formulation with only one extruded componerit, namely A(ii)
Extrudate II from Example 2 1200 mg
Famotidine 10 mg
Sodium bicarbonate 400 mg
Sodium carbonate 100 mg
Magnesium stearate 20 m
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In analogy to Example 1, only the acid component is extruded, and the alkaline
effervescent component and the active substance are mixed therewith.
Subsequently,
magnesium stearate is mixed in. This mixture is compressed to an effervescent
tablet.
Example 7
Joint extrusion of A(i) and A(ii)
Xylitol 60%
Na citrate 14%
Sodium bicarbonate 23%
Citric acid 3%
Production process: -
A) Extrusion in analogy to'Example 1, or
B) Melt xylitol at about 120 C and rrteter and stir in the components
successively. After cooling, the melt cake is comminuted.
Based on a single dose, in each case 600 mg of the resulting extrudate, 200 mg
of
acetylcysteine and 10 mg of lemon flavour are inixed. The resulting powder
mixture
is packed in a sachet.
Example 8
A mixture of 54% xylitol, 6% pseudoephedrine, 14% sodium citrate, 23% sodium
bicarbonate and 3% citric acid is extruded in analogy to Example 1. The
extrudate is
t 25 comminuted and packaged.
Stability comparison of ASA-containing effervescent formulations
Determination of the degradation product salicylic acid (SA) after storage in
packaging impermeable to water vapour at 25 C for 3 months
Initial SA SA content after
content 3 months
ASA effervescent granules, flavoured* 0.02% 1.61%
ASA effervescent granules (extruded), flavouredXX 0.04% 0.18%
ASA effervescent tablet, flavoured* 0.3% 1.83%
ASA effervescent tablet, unflavoured* 0.17% 0.8%
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* Granules are produced by conventional technology (comparative test)
xx According to the invention
