Effervescent mixture with alkali metal salts or lysinates of acidic, insoluble or slightly soluble active ingredients

The effervescent mixture contains at least one acidic, insoluble or slightly soluble pharmaceutical active ingredient in the form of its soluble alkali metal salt or lysinate, which is present as an intimate mixture with the alkaline component and preferably coats the particles of the alkaline component of the effervescent system, for example sodium bicarbonate and/or sodium carbonate. Both components in very finely powdered form may also be present as granules, with the aid of a binder. In particular, the effervescent mixture contains, per 100 parts of active ingredient, at least 0.5 part, preferably 1 to 3 parts, of a surfactant, in particular dioctyl sulfosuccinate, and/or at least 1 part, preferably 3 to 5 parts, of a binder or suspending agent, in particular polyvinylpyrrolidone. The acidic component of the effervescent system is passivated on the surface.

BACKGROUND OF THE INVENTION 
The invention relates to effervescent mixtures containing at least one 
acidic, insoluble or slightly soluble pharmaceutical active ingredient in 
the form of its soluble alkali metal salt or lysinate. Such pharmaceutical 
active ingredients are, for example, organic derivatives of acetic acid or 
propionic acid, for example ibuprofen, naproxen, diclofenac, butabarbital, 
phenobarbital, cefazolin, diatrizoate, ethacrynate, flurbiprofen, 
sulfacetamide or hetacillin. 
The acidic active ingredients cannot, as a rule, be obtained in finely 
disperse or colloidal form and are therefore preferably administered as 
their potassium salts (for example hetacillin) or lysinates (for example 
ibuprofen) or as their sodium salts (including ibuprofen and most of the 
other active ingredients mentioned above) in solution. 
In contrast to the pure acids, the alkali metal salts of such active 
ingredients are generally freely water-soluble but often have a bitter 
taste and are precipitated from acidic solutions frequently in lumpy form 
and/or with foam formation; the same occurs in the case of solid dosage 
forms as a result of the gastric acid. These active ingredients therefore 
easily lead to irritation of the stomach walls. 
To avoid these disadvantages, EP-A1-369 228 has already proposed 
granulating 100 parts by weight of a water-soluble ibuprofen salt with 200 
to 1000 parts by weight of vehicle, 30 to 80 parts by weight of stabilizer 
(for example polyvinylpyrrolidone, "PVP") and 10 to 100 parts by weight of 
an alkali metal carbonate, and mixing the resulting granules with 100 to 
400 parts by weight of the acid component. The aim here is to obtain the 
sodium salt in solution after dissolution of the effervescent tablet. This 
is achieved, inter alia, by virtue of the fact that the pH is in any case 
always above 6 in the case of the chosen composition. However, such a 
solution has an unpleasant taste, for example diclofenac sodium even has a 
bitter taste. In addition, very large amounts of PVP are required to 
prevent precipitation of the active ingredient as acid during 
effervescence. 
DESCRIPTION OF THE INVENTION 
It is therefore the object of the invention to provide effervescent 
mixtures of the type stated at the outset which ensure delayed 
precipitation of the active ingredients, but always in finely disperse or 
even colloidal form, under the action of acidic solutions or of the 
gastric acid. Furthermore, the resulting pH should be 4 to 5.5, at which 
effervescent solutions or suspensions are substantially more pleasant to 
drink. 
According to the invention, this object is achieved for the first time, 
surprisingly, if both the soluble active ingredient salt and the acidic 
component of the effervescent system are passivated on the surface. 
Preferably, the alkali metal salt or lysinate coats the particles of the 
alkaline component of the effervescent system, for example sodium 
bicarbonate and/or sodium carbonate, and is covered in particular with 
further alkali metal carbonate. The active ingredient layers expediently 
also contain (per 100 parts by weight of active ingredient) at least 0.5 
part by weight, preferably 1 to 3 parts by weight, of a surfactant, in 
particular docusate sodium or sodium laurylsulfate. Selecting the 
combination of very small amounts of stabilizer (or even no stabilizer at 
all) with surface-passivated components from the many possible 
formulations in the attempt to achieve the object was not obvious even to 
a person skilled in the art and required a large number of considerations. 
In theory, individual acids can be obtained in micronized form. However, 
the precipitate according to the present invention is substantially finer 
than the form in which it would be possible to obtain a finely pulverulent 
active ingredient. The alkali metal salt or lysinate of the active 
ingredient acid first dissolves during the dissolution of the effervescent 
tablet or effervescent mixture, owing to the close contact with a sodium 
bicarbonate or a sodium carbonate particle; said active ingredient acid is 
precipitated only subsequently, in the solution prepared for drinking, by 
the acid component of the effervescent system, for example within 5 
seconds, optionally even in colloidal form, but in any case in finely 
disperse form. However, the finely disperse particles remain suspended for 
a relatively long time and therefore give a liquid which is pleasant to 
drink. 
In the stated finely disperse or even colloidal form, the acid no longer 
irritates the stomach walls, which are moreover protected by the buffer 
action of the effervescent system. 
The active ingredients according to the invention are generally those which 
are intended to be absorbed not in the acidic medium of the stomach but in 
the alkaline medium of the intestine. The finely disperse form of the 
active ingredient in the solution also limits the passage through the 
stomach to about 15 to 20 minutes, so that immediate absorption can take 
place on entry into the pylorus and the intestine, owing to the very large 
surface area of finely disperse or almost colloidal acid particles of the 
active ingredient. 
However, in order to achieve this effect, whereby the alkali metal salt or 
lysinate of the active ingredient goes into solution briefly on 
dissolution of the effervescent tablet and whereby only thereafter (after 
a delay) the active ingredient is precipitated in acid form by the 
remaining acidic solution, which may have a pH of 4 to 5.5, it is 
necessary to bind the alkali metal salt or lysinate of the active 
ingredient very intimately with the alkali metal carbonate, for example 
sodium bicarbonate or sodium carbonate, so that, at the instant of 
dissolution, alkaline protection is achieved around the particles, which 
delays the precipitation. This does not function if the active ingredient 
salt is merely mixed with an effervescent base, since in this case there 
is immediately contact with the acid, for example citric acid, at the 
instant of dissolution. 
It is therefore expedient if pharmaceutically or toxicologically acceptable 
surfactants, such as, for example, docusate sodium or sodium laurylsulfate 
(dark-colored or pasty surfactants which are difficult to process are 
unsuitable), preferably in combination with binders, such as, for example, 
dextrin, polyvinylpyrrolidone or hydrocolloids, such as, for example, 
maltodextrin, are also added to the mixture. The suspension properties of 
the active ingredient acid in the liquid are greatly improved as a result. 
However, excessively large amounts of binder may cause undesirable foam 
formation and delay the dissolution of the effervescent tablet. The effect 
is also dependent on whether an aqueous or alcoholic solution is used. 
It is therefore expedient if the mixture contains at least 1 part by 
weight, preferably 3 to 5, in particular not more than 20, parts by weight 
of binder or suspending agent, in particular polyvinylpyrrolidone. In 
contrast to the EP-A1 mentioned at the outset, only small amounts of 
binder are required here since the active ingredient acid is to be formed 
from its alkali metal salt or lysinate as early as during the dissolution 
of the effervescent tablet and is to be distributed in finely disperse 
form in the solution. A surfactant is therefore also preferably used in 
order to achieve better wetting of the acid particles during dissolution. 
The binding of the active ingredient can be achieved in various ways: 
1. The alkali metal salt or lysinate is dissolved and the solution is 
applied to sodium bicarbonate; drying is then carried out; the active 
ingredient salt crystallizes out on the surface of the sodium bicarbonate 
crystal. 
2. The very finely powdered active ingredient is mixed with the sodium 
bicarbonate; both are agglomerated with a binder, for example dextrin. In 
this way, too, it is possible to achieve binding of the active ingredient 
salt to the sodium bicarbonate or sodium carbonate, since the binders do 
in fact slowly go into solution. Thus, the active ingredient first goes 
into solution as a salt and precipitated as the acid in finely disperse or 
colloidal form only after a delay, following the action and the reaction 
with the acid component of the effervescent system.

EXAMPLE 1 
25 parts of diclofenac sodium are dissolved, with 10 parts of propylene 
glycol, 40 parts of sorbitol, 1 part of polyvinylpyrrolidone K30 and 0.5 
part of a surfactant substance, in particular docusate sodium, in 40 parts 
of ethanol and 15 parts of water. The addition of a surfactant is 
advantageous because in particular the particles are immediately wet at 
the stage of the acid precipitation and agglomeration is therefore even 
more readily prevented. This solution is applied to 350 parts of sodium 
bicarbonate and thoroughly distributed; this is followed by the addition 
of 100 parts of sodium carbonate, which first absorbs water and only then 
goes into solution, in order to improve the alkaline protection. The 
material is then dried in vacuo and sieved to the desired particle size 
of, for example, 0.1 to 0.5 mm. The granules are then mixed with an acidic 
effervescent base consisting of a solid, edible, organic, 
surface-passivated acid and, if required, pressed to give tablets. 
The surface passivation can be carried out in a manner known per se, for 
example as described in EP-B1-272 312 or WO93/00886. However, it is also 
possible to avoid the reaction between acid and carbonate in the 
passivation by coating or covering the surface of the acid crystals, for 
example of the citric acid, with a solution of sodium citrate and then 
applying to this coat sodium bicarbonate and/or sodium carbonate from a 
solution in the form of a coat. This application is particularly 
expediently effected in a vacuum mixing vessel and provides the best 
possible protection. 
EXAMPLE 2 
25 parts of diclofenac sodium are mixed with 350 parts of sodium 
bicarbonate and granulated together with the following solution: 15 parts 
of dextrin, 1 part of PVP and 0.5 part of a surfactant substance are 
dissolved in 20 parts of ethanol and 20 parts of water. The product is 
then dried, sieved to 0.1-0.5 mm, depending on requirements, and finally 
further treated as in Example 1. 
EXAMPLE 3 
1 part by weight of docusate sodium, 2 parts by weight of PVP and 100 parts 
by weight of naproxen sodium are dissolved in 400 parts by weight of 73% 
alcohol. 700 parts by weight of sodium bicarbonate are heated to 
50.degree. C. in a vacuum mixer while stirring; the solution is aspirated 
by means of a vacuum and homogeneously distributed while stirring, after 
which 150 parts by weight of sodium carbonate are applied to the wet 
granules. The granules are finally dried in vacuo while stirring, and 
sieved to 0.25 mm. Preparation of the acid granules surface-passivated 
with sodium bicarbonate: 
1400 parts by weight of crystalline citric acid and 200 parts by weight of 
powdered citric acid are heated to 60.degree. C. in a vacuum mixer while 
stirring and are wet with 6 parts by weight of water. Thereafter, 200 
parts by weight of sodium bicarbonate are added and allowed to react at 
the surface of the citric acid, after which 50 parts by weight of sodium 
carbonate are added. The product is dried in vacuo while stirring. 
The naproxen granules and the acid granules are mixed with one another, and 
sweetener, flavor and fillers are added. Mixing is then carried out for 
homogenization, and the granules are pressed to give tablets weighing 3.2 
g. 
When the effervescent tablet is introduced into water, the tablet dissolves 
in about 80 seconds, the naproxen being distributed in the solution in the 
form of a fine suspension, at a pH of 4-4.5.