CZ251996A3 - Granular product or tablet containing effervescent system and an active pharmaceutical substance as well as process for preparing thereof - Google Patents

Abstract

In accordance with this invention, there is provided a granular product with an effervescent system which comprises acid-sensitive pharmaceutically active substances, such as, for example, beta-carotene, cimetidine, ranitidine or cisapride, which is specially useful to prevent antacid action, having an acid-binding capacity below about 5meq, at a weight of about 1.6 to about 2.3 grams. The effervescent grains are made from carrier crystals of at least one solid, edible organic acid, preferably citric acid, and are present as a granular product, separate from the pharmaceutically active substance, and are coated with at least one layer of a neutral substance which is soluble in water and/or alcohol and which is able to bring about a melting point depression of the acid grains at their surface, such as, for example, a water-soluble polymer, a higher alcohol, a carbohydrate and/or a hydrocolloid. A second coating contains at least a part of the alkali and/or alkaline earth carbonate or bicarbonate provided for the total dosage.

Description

Technical field

9 Ί o A '

The invention relates to a granular pharmaceutical composition or, in particular, to tablets containing an effervescent system and preferably an acid-sensitive pharmaceutical substance such as cisapride, beta-carotene,

An H2 blocker such as cimetidine or ranitidine, and / or a substance to be administered in an effervescent pharmaceutical composition with relatively small amounts of effervescent components or a relatively low acid-neutralizing (acid-binding) capacity.

BACKGROUND OF THE INVENTION

Until now, it has been difficult to incorporate acid-sensitive drugs in a stable form into effervescent tablets or effervescent instant granular products because, upon contact with the effervescent system, such compositions have hydrolysed or decomposed, i.e., not stable enough to be stored.

In addition, whenever such a substance also affects the surface tension of the water, foaming occurs which is highly undesirable when consuming the effervescent solution, or in any case the hydrophobic portion of the drug tends to adhere to the glass.

On the other hand, in certain cases, the antacid side effect of effervescent tablets is undesirable for many drugs.

Accordingly, it is an object of the present invention to provide an effective system that avoids the above disadvantages and offers the possibility of administering pharmaceutical agents to a patient, including acid-sensitive substances having hydrophobic properties or properties affecting the surface tension of water in pleasantly drinkable effervescent solutions.

It is a further object of the present invention to provide effervescent tablets or instant effervescent products with an acid-binding capacity of less than 5 meq (as measured by Test No. 31 of The United States Pharmacopoeia 23, National Formulary 18) to prevent undesirable antacid effects. This is particularly advantageous for all H2 blockers. Finally, it is desired that the tablets or granular product be rapidly soluble in water at a temperature of about 15 to 20 ° C in less than about 2 minutes.

SUMMARY OF THE INVENTION

A solution to the above problems can be obtained by a surprisingly simple cost-effective and efficient method according to the invention, for example by first substantially coating the acid particles with a mixture containing at least one neutral substance which causes a decrease in the melting point of the acid grains on them. one second coating comprising an alkali and / or alkaline earth carbonate and / or bicarbonate, and optionally a partial reaction product of the carbonate or bicarbonate with it or with another organic acid.

The invention is discussed in more detail below in detailed discussion and illustrating several preferred embodiments.

Detailed description

Neutral substances according to the invention include water-soluble polymers and / or alcohol such as polyvinylpyrrolidone, carbohydrates such as sucrose, pentaerythritol, glucose and fructose (although the last two under the influence of only a weakly alkaline grain surface due to bicarbonate coating are subjected to Maillard reaction) for yellowing and hence not particularly preferred) hydrocolloids such as maltodextrin, dextrin and the like; higher alcohols such as xylitol, mannitol and sorbitol are particularly preferred.

Various embodiments of the present invention are described in the delimitation of the dependent claims.

It is true that WO93 / 00886 discloses that a foreign acid, possibly a gluconic acid delta-lactone that hydrolyzes to gluconic acid, can be incorporated into the surface of acidic carrier crystals, with the result that the crystal lattice breaks down and a melting point is achieved. However, such a measure cannot provide adequate protection for acid-sensitive active substances. Thus, it has hitherto been impossible to use the invention WO93 / 00886 for acid-sensitive active substances in practice.

It has also been proposed (British Patent 1,270,781) to coat acidic carrier crystals for effervescent tablets with a thin polymeric layer such as polyvinylpyrrolidone, carboxymethylcellulose and the like. However, this results in undesirable retardation of the dissolution time and, in the case of one to 5 percent by weight of the pyrrolidone described therein, leads to foam formation. In addition, some acid is always transferred from the carrier crystal to the solution layer when coating with an ethanolic or aqueous solution, whereby the acid-sensitive active ingredients would not be sufficiently protected.

Moreover, those skilled in the art for over 20 years have not been able to successfully solve this problem of accommodating acid-sensitive active substances in effervescent systems, not only in storage, but also in relatively small weight small tablets with very low acid-neutralizing capacity and short dissolution time.

An effervescent tablet is defined to be reasonably fast when dissolution (or complete suspension) of the tablet components takes less than 120 seconds, preferably 90 seconds or less.

According to the invention, however, after (preferably only a small amount) of the neutral substance which has been deposited on the acid grains, an alkali carbonate and / or alkaline earth carbonate and / or bicarbonate particles are anchored on the grain surface to avoid interaction between the acid and the active substance.

Furthermore, the method proposed in EP-Al-415 326 for coating acidic carrier crystals several times with a certain amount of sugar in order to achieve a slightly prickly effect for chewable tablets or caramels in combination with bicarbonate would not solve a combination of problems or problems: such a system would not be sufficiently reactive for dissolving the effervescent tablet in water in a reasonable time. The aim of EP-A1 was to slow down the reaction between the acid and the carbonate in order not to produce an undesirable high effervescence in the mouth.

If, as disclosed in the prior art (US-A-4 127 645), a tablet having a bicarbonate and calcium core was coated with a neutral substance such as sorbitol in an aqueous, alcoholic or aqueous alcoholic solution, such a tablet would not provide reliable protection for the acid-sensitive active substances contained in the core. However, if the mixture has been compressed with a neutral substance (e.g., maltodextrin when required as a mixture with sugar, US-A-4 560-669; sorbitol with vitamins, US-Ak-5 223 264, only suitable as a prickly chewable tablet) to obtain tablets, then either reactants would be coated simultaneously or unwanted agglomerated granules would be formed.

In both cases, the dissolution reaction of the tablet would be too slow and the dissolution time would thus be undesirably increased or the solution would contain undesirably high amounts of sugar. In addition, it is very likely that in agglomerated granules the acid particles would be present unprotected on the surface of the granules, resulting in greater instability for the acid-sensitive active ingredients.

U.S. Pat. No. 4,867,942 discloses a process in which the solid edible organic acid carrier crystals are coated on their surface with a pre-reacted buffering solution, in particular an alkaline salt and / or alkaline earth salt of the solid edible organic acid. Then more acid crystals and an amount of carbonate or bicarbonate are anchored side-by-side on the coating. The water that is released in the various neutralization partial reactions is removed by final treatment with alcohol and vacuum drying.

However, such a process is disadvantageous in that for acid-sensitive drugs on the surface of the acid crystals, the additional acid simultaneously enters the reaction with the alkali carbonate and the reaction thus proceeds too quickly and consequently insufficiently uniformly. Thus, the product thus formed in this way cannot completely prevent the reaction of the acid-sensitive drug mixed with it due to the acid crystals lying on the grain surface.

In contrast, the structure of the effervescent system of the present invention not only prevents direct contact of the acid-sensitive drug with the acid crystals, thereby forming effervescent tablets or granular product with substantially greater storage stability, but also allows for substantially smaller tablets, i.e. tablets with small amounts of effervescent components. when dissolved, leads to a buffer system. Thus, the present tablets of the invention in contrast to buffer systems of antacid effervescent formulations may have far less than 5 meq acid-neutralizing capacities.

Also, under the conditions of preparation of the product, a delayed reaction and better compression in tablets are obtained. With the aid of the present invention, effervescent tablets may be prepared comprising, first, an acid-sensitive drug such as cisapride or an H2 blocker such as cimetidine and having an acid-neutralizing capacity of less than 5 meq / tablet (or granular product) weighing only 1.6 to 2.3 g.

Further, according to a particularly preferred embodiment of the present invention, after covering the acid crystals with a neutral substance coating, at least a portion of the carbonate and / or bicarbonate particles intended for the full dose may be applied to the coating such that effervescent grains are formed from the acid crystals upon and a second coating of carbonate and / or bicarbonate, which has partially reacted with acid in some cases.

The invention may be particularly useful for products or processes as described, for example, in EP-B1-76340, US-A-4,867,942 and WO93 / 00886, the disclosure of which claims are deemed to be disclosed herein.

Application of a neutral substance, in particular a sorbitol solution, for example, causes a decrease in the melting point on the surface of the citric acid crystals. Thus, on the one hand, the adhesion force for another coating containing alkali or alkaline earth carbonates and / or bicarbonates increases, and at the same time it means a slower and therefore more uniform reaction of the citric acid crystal surface and better passivation, so that the acid-sensitive drugs are less attacked by effervescent grains. On the other hand, lowering the melting point prolongs the recrystallization time of the citric acid or citrates that have formed, which means better compressibility of the sparkling grains over a longer period of time

The amount of neutral substance deposited on the acid carrier crystals depends on the amount of solvent with which the acid can be wetted, since a maximum of 50 to 70% by weight can be dissolved in aqueous solution. It is therefore preferable to add an amount of 0.05 to 1.0, in particular 0.07 to 0.8% by weight, based on the acid. Additions of less than 0.07% have only a weak effect and smaller additions of less than 0.05% have no effect according to the invention: the shelf life of the acid-sensitive active substances is reduced. Additions of over 0.8% generally begin to have a detrimental effect, and additions above 1.0% greatly retard the reactivity of citric acid and the effervescent system.

However, this may be less disturbing in the case of grains, as a longer dissolution time may be desirable here to allow the grains to be immersed initially in water and only then to conduct the dissolution reaction. Otherwise, however, the amount of neutral substance that can be applied to, for example, citric acid is determined by the amount of solution with which the citric acid can be wetted, since neutral substances are in fact applied in solution and a 50 to max. 70% solution can be prepared. . The citric acid crystals cannot be wetted with an unlimited amount of water and therefore solvent.

Under certain circumstances, a neutral coating, especially when carbonate and / or bicarbonate particles are anchored thereon, may also contain small amounts of solid edible organic acid and in some cases acid different from the acid from which the carrier crystals are - as noted in the other context - but also here to enhance the lowering of the melting point and / or to control the effervescent reaction and dissolution rate.

As such, each such effervescent grain is in fact a small effervescent tablet and effervesces as such. Thus, when a short dissolution time is required, a small amount and a low acid neutralizing capacity can be achieved.

Attempts to achieve rapid action of small effervescent tablets using monosodium citrate instead of citric acid have failed because this citrate slows the effervescent reaction considerably, since it reacts slowly with sodium bicarbonate, and thus the tablets typically have an acid capacity exceeding 5 meq.

On the other hand, the very thin monosodium citrate coating according to the invention, in particular as a third or fourth layer, which may contain another neutral substance, if desired, has an advantageous effect since even a mole monosodium citrate ligand 1 mol crystallization water and thus contributes to drying or maintaining dryness. Moreover, in any case, the uncovered surfaces of citric acid may be covered again or more fully with bicarbonate.

In addition, since many substances exhibit some form of taste sensation that is often unpleasant, especially for those that exhibit bitterness, it is desirable to maintain the final effervescent solution, especially since it is in the beverage form in the range of pH 3.8 to 4.6. Experience has shown that in this range in particular, bitter substances can be effectively masked.

Although not necessary, it is preferred to remove residual water from the reaction grains during their preparation by final treatment with alcohol. Alcohol can disrupt the binding of the crystallization water, since during drying the residual moisture is removed along with the evaporation of the alcohol.

Small amounts of antifoam agent can also be added to the alcohol to speed up the dissolution of the finished tablet.

Many of the above drugs, especially cimetidine and cisapride, often cause foaming of effervescent tablets. However, this is not due to the foaming effect of the surfactants. It should be noted that the active agents themselves do not foam when mixed into water. Instead, when the effervescent particles dissolve in the tablet, bubbles of carbon dioxide are formed.

These bubbles burst and detect CC ^ on the surface. Now, if a less soluble or more hydrophobic substance is present, the undissolved particles envelop the CO 2 bubbles and the formation of such a film gradually prevents rapid bursting of the bubbles, so that these bubbles are concentrated on the surface and so are concentrated. creates foam. However, the foam already formed between the effervescent grains interferes with the already ongoing reaction and thus with the rapid dissolution of the tablet or grains. With this circumstance, the invention is overcome by the addition of very small amounts of at least one antifoam, with the result that any foam formed during the effervescent reaction collapses immediately.

The antifoam is preferably added in an amount of 0.05 to 0.5% by weight based on the total amount including fillers, flavorings etc. or 0.05 to 2.0% by weight based on the active ingredient. Additions of less than 0.005% have no effect in relation to the invention, additions of greater than 0.5% lead to increased difficulties or unacceptable side effects.

For active substances which are soluble, although not too freely soluble, as in the case of cimitidine, an amount of 0.1 to 0.3% by weight, based on the active substance equivalent, of 0.016 to 0.028% (about 0, 03%) based on the total weight of the tablet.

The situation is somewhat different in the case of an insoluble hydrophobic active substance such as cisapride (monohydrate used) where 1% simethicone based on the active substance is used, but an amount of 0.006% is the result when referring to a tablet weighing 1.6 g .

It is evident that cisapride, as a poorly soluble hydrophobic active ingredient, requires a larger amount of antifoam to suppress the foam, but the desired fillers and effervescent base results in a substantially smaller amount of simethicone used per tablet, so that the ratios are reversed.

In the case of soluble active substances such as cimetidine or ranitidine, simethicone is required in small amounts to suppress a low tendency of foaming in the local reaction of dissolving the effervescent tablet, whereas in the case of cisapride, the foaming tendency is substantially greater and the principle it is therefore also slightly different.

If larger amounts are used, the formation of the simethicone film occurs on the surface after dissolution of the effervescent tablet due to the fact that - especially in the case of insoluble active substances - particles of active substance accumulate and remain suspended, resulting in unattractive dissolution behavior. moreover, it tends to form a circle on the glass wall.

In some cases, very small amounts of surfactants such as sodium docusate are also added. Due to their wettable nature, such drug particles dissolve more rapidly and no longer adhere to foam bubbles. The proportion of such substances must be determined very precisely in order to achieve the desired dissolution properties.

Although in some cases the antifoam may be applied to the effervescent system or drug, this is not preferred according to the invention. In the first case, it could cause undesirable retardation of dissolution and effervescence reaction unless very small amounts of antifoam are used to achieve the desired effect. In the latter case, only those drugs which, when the antifoam comes out of solution in a solvent (for example, methyl ethyl ketone and acetone) at 40 ° C, do not lose either their solubility or stability.

In addition, during manufacture using finely powdered medicaments, the addition of antifoams may lead to poor dispersion, since the drug particles themselves bind to the antifoam droplets.

It is therefore advantageous according to the invention to first form a typical granular product from antifoams and a neutral substance, which product is then mixed with the effervescent system and the drug plus other adjuvants when needed (e.g. perfumes, sweeteners, etc.) and the mixture is then compressed into tablets.

The moisture released in the preparation of the effervescent system by the neutralization reaction and not completely removed by heating and / or vacuum treatment, as well as the moisture extracted from the air during storage, can best be bound by adding a moisture-binding agent, especially anhydrous sodium carbonate. mol) or sodium sulfate.

The composition may be bound by either applying it to one or more coatings deposited on the carrier crystals, or by adding the composition to the total composition. This improves the shelf life, since the reaction of the acid-sensitive active ingredient with the acid is further suppressed or prevented completely by reducing moisture. However, excessive amounts of such a moisture-binding agent, such as sodium carbonate, are not desirable as they may retard the effervescent reaction.

Sodium carbonate as a desiccant should therefore not be used to completely cover the effervescent grains since it is advantageous to work with only small amounts effective to merely dry residual moisture or to delay the reaction during manufacture and to prevent undesirable prolongation of the dissolution time of the tablet.

Thus, the final addition of sodium carbonate should not be used to completely cover (or coat the tablet) both the amount and the size of the grains (about 0.1 to 0.05mm) and thus is not suitable for forming a continuous coating on an already present bicarbonate. However, it may be partially trapped on sparkling grains. However, it is also possible not to add sodium carbonate until drying is complete.

Essentially, the percentage of sodium carbonate per tablet depends on several factors such as the amount of effervescent base used, the amount and type of fillers used, the presence of other carbonates such as calcium carbonate, and so on.

The moisture-binding agent, in particular sodium carbonate, is preferably added in an amount between 1 to 10%, in particular 4 to 6% by weight (based on the total amount including any fillers, aromas, etc.). Additions of less than 4% have only a weak effect and, for additions of less than 1%, the drying effect and the increase in stability are too small to have no effect in accordance with the present invention.

Additions of over 63 generally begin to have an adverse effect, since sodium carbonate dissolves more slowly and reacts worse, above 10% the dissolution time is already considerably prolonged because sodium carbonate first absorbs water (up to 10 molecules of crystallization water) when dissolving the effervescent tablet. means it is calcined and only then reacts with citric acid.

It should be emphasized here that 1 mole of crystallization water can be bound to a mole of sodium citrate itself developing in or on the sorbitol layer and despite any residual moisture present, the sorbitol layer prevents or delays any harmful effect of the acid on the drug.

If all the prescribed steps of the invention are carried out, effervescent tablets may be formed even with the above mentioned difficult substances, which, for example, with a tablet weight of 1.6 g, have a dissolution time of less than 100 seconds. It should also be noted that cimetidine, in particular due to its hydrophobic properties, further prolongs the dissolution time compared to other drugs under otherwise identical conditions

Granulation with a sorbitol solution allows rapid dissolution without incorporating the additional acid that is otherwise required, for example, according to WO93 / 00886.

In addition, during the preparation of the effervescent systems of the present invention and in any case of the tablets themselves, the steps of the present invention will allow the control of reactions taking place on the surface of individual crystals or grains, thus forming a low mechanism.

This system is also particularly well suited for processing substances which are both acid-sensitive and poorly water-soluble.

Such substances, such as cisapride, exhibit very poor suspension behavior because, as mentioned above, they lead to foaming together with the effervescent system, adhering to the glass wall, forming an unpleasant circle and tend to agglomerate on the surface of the beverage.

All of the above problems can be effectively overcome by preparing separate grains. For this purpose, sir still gave an execution of this t n <7 n

It consists of an aerosol and / or a neutral substance, in which the medicament is preferably administered with the surface of its grains partially dissolved, and / or with binder and / or surfactants, if necessary. , and is dried or bound to the support surface by means of binders.

The amount of suspended substance is limited mostly to 8%, preferably mostly 4.5% by weight (based on the total mixture), for example for cisapride, since larger amounts would lead to an increased immersion of the granular particles upon dissolution of the tablet. On the other hand, the amount of binder used is similarly limited to 1% by weight, since this otherwise results in undesirable agglomerated grains of the active substance, the suspended substance and the binder, which dissolve with difficulty and then sink to the bottom, i.e. prevent the desired suspension.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be fully described and explained with reference to the following examples of preferred embodiments. However, these examples are given for illustrative purposes only, and many other embodiments and variations will be readily apparent to those skilled in the art, and the examples are not intended to limit the scope of the present invention or claims or the nature thereof.

Alternatively, the drug may also be dissolved in methyl ethyl ketone or acetone and coated on mannitol,

Aerosil and sodium bicarbonate.

Example 1

Preparation of effervescent tablets containing 200 mg cimetidine

a) Preparation of sparkling system

102 parts by weight of coarse citric acid and 25 parts by weight of finely powdered citric acid (this latter part is advantageous for improving the construction of sparkling grains on the carrier crystal, since the powder particles form a rough surface on which up to about 30% bicarbonate can be anchored) is sucked into a preheated vacuum tank and heated to about 60 ° C with stirring. 0.85 parts by weight of solution 1, which was made up of 36 parts by weight of both water and sorbitol, part by weight of citric acid and 7 parts by weight of sodium bicarbonate, were then aspirated and dispersed on the citric acid by stirring.

Then 52.5 parts by weight of sodium bicarbonate and 4.4 parts by weight of aspartame are added to the mixture, and the mixture is stirred and dried under vacuum to 2. After that, 1.9 parts by weight of sodium carbonate are sucked up and dispersed in 3 mixtures with stirring, and the mixture is then dried under vacuum to 1.5 bar.

0.6 parts by weight of this solution are then aspirated and dispersed in the mixture with stirring. The resulting effervescent grains were dried under vacuum to about 10 mm Hg with stirring. If necessary, 0.25 parts by weight of 96% by weight alcohol is also used to dry the mixture and aspirate. Then 9.3 parts by weight of sodium carbonate are re-bound to the surface of the effervescent grains. After further final drying, the product was removed through a sieve.

b) Preparation of a granular defoamer

In a vacuum mixing tank with a jacket temperature of 80 ° C, 7.7 parts by weight of sorbitol powder are stored and heated to 50 ° C. Then, 0.2 parts by weight of cimethicone in 30% butanone / acetone (5: 3) is aspirated, agitated by vibration stirring and dried under a full vacuum of up to 1500 Pa.

Μ V 0 at a temperature of at least 45 C.

c) Preparation of the total mixture

In the mixer, 20 parts by weight of cimetidine are mixed with 21.1 parts by weight of sorbitol powder, if necessary, and stirring is continued for 10 minutes at 6 rpm with 178.4 parts by weight of the effervescent system prepared in a).

Then 7 parts by weight of the antifoam granules prepared in b) and sized through a 0.6 mm sieve and 4.5 parts by weight of lemon flavor are added and mixed for a further 5 minutes at 6 rpm. The final blend was compressed into 2.3 g tablets containing 200 mg of cimetidine and having a hardness of 6-8 kp.

Example 2

Preparation of effervescent tablets containing 200 mg cimetidine and citric acid and malic acid in effervescent grains

102 pbw of crude citric acid, 25 pbw of powdered citric acid and 1.1 pbw of malic acid are heated to 60 ° C with stirring in a preheated vacuum tank. A solution consisting of 0.4 parts by weight of water, 0.22 parts by weight of sorbitol and 0.22 parts by weight of malic acid is then sucked in and dispersed into citric acid with stirring.

Then 52.5 parts by weight of sodium bicarbonate and 4.4 parts by weight of aspartame are added to the mixture and dried. While stirring under vacuum to 2.10 Pa. Then 1.9 parts by weight of sodium carbonate are sucked in and dispersed in mixture 3 with stirring, and then vacuum drying up to 1.5 x 10 Pa is performed. Finally, final drying with ethanol can be carried out and then 9.3 parts by weight of sodium carbonate are added to the mixture. The remainder of the procedure is similar to Example 1.

Example 3

Effervescent tablets containing 400 mg of cimetidine and mannitol as a neutral substance by weight of citric acid are aspirated into a preheated vacuum tank and heated to 60 ° C with stirring.

Then 0.45 parts by weight of solution 1, prepared from 0.25 parts by weight of water and 0.20 parts by weight of mannitol, are sucked in and dispersed into citric acid with stirring, then 14.7 parts by weight of sodium bicarbonate and 3.2 parts by weight are added. by weight of aspartame.

The reaction is started with stirring and then dried at a pressure of 2 bar.

0.5 parts by weight of sodium carbonate are then aspirated and dispersed in the mixture with stirring, and then dried under 3 vacuum to 1.5 bar. Then 0.5 parts by weight of solution 2, prepared from solution 1 by adding 0.16 parts by weight of monosodium citrate, are sucked into the mixture and the mixing is dispersed. The effervescent grains obtained are then dried under vacuum and agitated up to 2.10 Pa and finally 2.8 parts by weight of sodium carbonate are added. 17.3 parts by weight of cimetidine, 4.3 parts by weight of mannitol, 8 parts by weight of sorbitol, 0.9 parts by weight of arcma and 4 parts by weight of the antifoam granules prepared according to Example 1b) are then added to this mixture until uniform distribution.

Example 4 effervescent tablets containing 300 mg of cimetidine as well as maltodextrin as neutral substance

Similar to Example 3, for a 300 mg cimetidine effervescent tablet, a 50% maltodextrin solution was selected, which was then used in the same amount as the 400 mg form

In all these examples, in which the tablets contain 100-400 mg cimetidine, the tablet weight may be 2.3 g. The tablets have a dissolution time of preferably 60-150 seconds, buffering capacity below 5 meq, measured according to USP XXII, by back titration (with 0 1.5 N NaOH) of the effervescent tablet dissolved in 70 mL of water and 30 mL of 1.0 N HCl was added.

The values given in Table 1 below are% of individual components in the respective total mixture of the preferred embodiments shown, and are therefore within the following preferred ranges.

Table 1 cimetidine

- 30% (corresponds to an effervescent tablet containing 50 to 600 mg of cimetidine) citric acid 30 - 60% sodium bicarbonate

- 30% sodium carbonate

- 10% aspartame sorbitol mannitol

- 20%

- 10% simethicone

0,005 - 0,5% aroma

0.1 - 3%

The preferred percent composition of cimetidine effervescent tablets or grain bags containing 100, 200, 300 and 400 mg cimetidine with a total weight of 2.31 g is summarized in Table 2 below.

Table 2

100 mg 200 mg 300 mg 400 mg and m + i i-i i ri / 1 Til o η n Ί Λ Ί P -> 3 w w »V (j _f f ie JL i X /; □ acid lemon 50 50 48.2 48.2 sodium citrate 0.04 0.04 0.04 0.04 aspartame 1.74 1.64 2.54 3.24 sorbitol 12.5 12.5 12.8 8.00 hydrogen carbonate sodium 20.7 20.7 14.7 14.7 sodium carbonate 4.4 4.4 3.5 3.3 mannitol 4.3 4.3 4.3 HMA lemon aroma 2,0 2,0 0.9 0.9 simethicon 0.02 0.02 0.02 0.02

Example 5

Cisapride effervescent tablets

a) Preparation of sparkling grains

655 pbw of crystalline citric acid, pbw of powdered citric acid and 8 pbw of sodium saccharin are heated to 60 ° C with stirring.

2.8 parts by weight of a solution containing 0.6 parts by weight of sorbitol, 0.3 parts by weight of trisodium citrate, 0.5 parts by weight of citric acid and 1.6 parts by weight of water are then aspirated into this mixture and dispersed with stirring. Then 340 parts by weight of sodium bicarbonate as well as 2 parts by weight of aspartame are added and reacted. Prior to drying, 77 parts by weight of sodium carbonate are added, and the mixture is dried under vacuum, with slight stirring, to 1.5 bar.

b) Preparation of a granular drug

Insoluble and hydrophobic cisapride is attached to the sus- p. A solution of 10 parts by weight of cisapride, 2 parts by weight of polyvinylpyrrolidone and 0.8 parts by weight of sodium docusate in 1 part by weight of ethanol and 40 parts by weight of acetone is applied to 10 parts by weight of the aerosol, uniformly dispersed and then is dried with stirring. The grains are sieved to 0.1-0.3 mm.

c) Preparation of the final mixture

To 1,152 parts by weight of the effervescent grains are added 50 parts by weight of maltodextrin, 100 parts by weight of lactose, 184 parts by weight of mannitol, 40 parts by weight of flavoring, 50.2 parts by weight of defoaming granules (0.2 parts by weight of simethicone coated on 50 parts by weight of mannitol) as well as the granular drug prepared in b), stirring is carried out for 15 minutes for uniform distribution, and the mixture is then compressed into 1.6 g tablets having an acid neutralizing capacity of 2 meq.

Cisapride effervescent tablets having such a low acid neutralizing capacity are still unknown.

Example 6

Beta-carotene effervescent tablets

With this extremely acid- and oxidatively-sensitive substance, particular attention must be paid to the acid coating. The surface and contact zone of the bata-carotene must be kept alkaline. Therefore, the effervescent grains are coated at least in part with calcium carbonate, thereby providing an alkaline surface. However, this leads to a slightly longer dissolution time, which is desirable in this case, since beta-carotene takes time to suspend while the tablet dissolves. The large amounts of sorbitol as in US-A-5 223 264 mentioned at the outset are in no case suitable for beta-carotene effervescent tablets to be dissolved or suspended in water.

a) Preparation of sparkling grains

315 parts by weight of citric acid, 7 parts by weight of sodium saccharin and 45 parts by weight of sodium cyclamate are heated in a vacuum tank to 50 ° C.

Then 16.8 parts by weight of the solution prepared from

3.6 parts by weight of calcium carbonate, 19 parts by weight of citric acid, 12 parts by weight of sorbitol and 45 parts by weight of water are mixed and dispersed into citric acid with stirring.

Then 400 parts by weight of calcium carbonate and 190 parts by weight of citric acid are added and the mixture is mixed. while warming to 60 ° C with stirring. This is followed by a second granulation with 44 parts by weight of the above solution, and after dispersion and mixing, 403 parts by weight of sodium bicarbonate are added, and also before drying 52 parts by weight of sodium carbonate. The mixture is then vacuum dried to 1.5 bar with slow stirring.

b) Preparation of the final mixture

130 parts by weight of sorbitol and 540 parts by weight of mannitol and 50 parts by weight of aromatic, encapsulated water-suspended beta-carotene and corresponding to 2 to 15 parts by weight of 100% beta-carotene plus up to 250 parts by weight of vitamin C and / or solid tocopheryl acetate water-suspendable (corresponding to 10 to 75 parts by weight of 100% tocopheryl acetate), plus other vitamins, if desired, are mixed with 2415 parts by weight of the effervescent grains prepared according to a).

The product has a tablet weight of 3.3 g and has a dissolution time of 60 to 90 seconds.

Example 7

Ranitidine effervescent tablets

a) Preparation of sparkling grains

840 pbw of crystalline citric acid, 210 pbw of powdered citric acid, 45 pbw of sodium cyclamate and 4 pbw of sodium saccharin are heated in a vacuum mixing tank at 60 ° C. Then a solution consisting of 6 pbw of water, 1 pbw of citrate is aspirated. sodium and 3 parts by weight of sorbitol and dispersed with stirring.

500 parts by weight of sodium bicarbonate are then added and allowed to react, followed by 370 parts by weight of monosodium citrate, which is also allowed to react. Finally, 100 parts by weight of sodium carbonate are added, and the granules are dried with slow stirring up to 1500 Pa.

b) Preparation of the final mixture

To the effervescent grains thus prepared are added 125 parts by weight of mannitol plus 100.4 parts by weight of the granulated defoamer (consisting of 100 parts by weight of mannitol and 0.4 parts by weight of simethicone) and a flavoring agent. The mixture is stirred for 15 minutes to distribute evenly and then compressed into tablets of 2.5 g

These tablets have a dissolution time of 60 to 80 seconds and an acid neutralizing capacity of about 2 meq and contain (in% by weight) 6.8 ranitidine hydrochloride, 42.0 citric acid, 14.8 monosodium citrate, 20.0 sodium bicarbonate, 4.0 sodium carbonate 2.0 sweeteners, 5.0 mannitol, 0.1 sorbitol, 4.0 granulated antifoam (containing 0.016 dimethylpolysiloxane) and 1.2 flavor.

Example 8

545 parts by weight of crystalline citric acid and 133 parts by weight of powdered citric or tartaric acid are mixed with heating to 60 ° C. Then, as a first coating, a solution consisting of 6 parts by weight of water and 4 parts by weight of sorbitol is dispersed with stirring.

Then 222 pbw of sodium bicarbonate are prepared to react on the citric acid surface and finally 80 pbw of sodium bicarbonate are added.

The product is dried with slow stirring.

The grains are sized to 1.5 mm and then mixed for 10 minutes at 10 rpm with 167 parts by weight of ranitidine hydrochloride, 100 parts by weight of defoamer granules (containing 0.4 parts by weight of simethicone and 100 parts by weight of lactose), plus 54 parts by weight. parts by weight of sweetener and 40 parts by weight of aroma until a uniform distribution is obtained. The mixture is then compressed into tablets weighing 1.43 g and having a dissolution time of 65 to 70 seconds, a hardness of 8 and an acid neutralizing capacity of about 1.5 meq. The product contains no monosodium citrate. Ranitidine effervescent tablets having such a low acid neutralizing capacity have not been known.

Example 9

38.2% citric acid is heated with 0.26% sodium saccharin to 60 ° C and then 2/3 of a solution consisting of 0.6% water, 0.18% sorbitol and 0% is applied. , 12% sodium citrate. This solution was dispersed for 5 minutes with stirring at 10 rpm. Then 16.2% sodium bicarbonate and 2.9% aspartame are added and anchored to the surface of the citric acid by reaction and coating of the neutral substance. This is followed by a second wetting with a third 1/3 of the solution, followed by the addition of 12.9% monosodium citrate and finally 5.2% sodium carbonate. The effervescent grains are dried under agitation which is slow and under vacuum application at a temperature of 1500C.

The basic effervescent granular product is sized to 1.5 mm and mixed with 11.0% ranitidine hydrochloride, 6.5% mannitol, 6.5% antifoam granules plus 0.2% flavor, and compressed into 1.55 tablets. g having a dissolution time of 50 seconds at a hardness of 7.3 and an acid-neutralizing capacity of less than 2 meq.

Example 10

Carrying crystal grains coated with neutral material only

Although cisapride, for example as compared to ranitidine, is not as highly sensitive to acid, it is nevertheless also possible to achieve acid protection by the procedure described below, especially since the drug is embedded in granules.

a) Preparation of neutral-coated acid crystals

593 parts by weight of crystalline citric acid plus 70 parts by weight of powdered citric acid are heated to 60 ° C. A solution of 4 parts by weight of sorbitol in 4 parts by weight of water is then applied and dispersed on the surface of the citric acid by stirring. Finally, the citric acid coated in this way is vacuum dried at 50 to 60 ° C.

In both the effervescent product form and the effervescent grains containing a second alkali or alkaline earth carbonate coating, it is possible to protect cisapride, for example against attack by citric acid in medicinal grains, by the addition of sodium bicarbonate.

b) Preparation of drug grains

160 parts by weight of mannitol, 10 parts by weight of cisapride, 5 parts by weight of aerosol and 10 parts by weight of sodium bicarbonate are heated to ° C with stirring. Then, half of the solution is added 27 parts by weight of methyl ethyl ketone (or 45 parts by weight of acetone), parts by weight of alcohol, 2 parts by weight of polyvinylpyrrolidone K30, part by weight of propylene glycol and 0.8 parts by weight of sodium docatate and dispersed for 5 minutes. The mixture is dried at 8.10 Pa, the second part of this solution is sucked and redistributed with stirring for 5 to 10 minutes and finally vacuum dried.

The active agent grains are then sieved to 0.3 mm and already have increased protection against acid attack simply because they contain sodium bicarbonate. They can then be mixed with neutral-coated acid crystals, remaining carbonates and bicarbonates, as well as other tablet components, and compressed into tablets.

c) Preparation of the final mixture

The dried citric acid is coated according to a) and then mixed with the drug grains prepared according to b), then 80 parts by weight of sodium carbonate, 430 parts by weight of sodium bicarbonate and 50 parts by weight of maltodextrin, 100 parts by weight of lactose, 150 parts by weight of mannitol are added. 50 parts by weight of an antifoam granulate and 20 parts by weight of flavoring, and then compressed into tablets weighing about 1.6 g having a dissolution time of 60 to 70 seconds at a hardness of 7.

Example 11

Cisapride effervescent tablets

a) Preparation of sparkling grains

Citric acid consisting of 300 parts by weight of grains, 80 parts by weight of fine grains and 40 parts by weight of powder, together with 5 parts by weight of sodium saccharin, is uniformly wetted at 60 DEG C. by 2.2 parts by weight of a solution containing 0.4 parts by weight sorbitol, 0.15 part by weight of sodium bicarbonate, 0.45 part by weight of citric acid and 1.2 parts by weight of water.

12 parts by weight of malic acid are then aspirated and an evenly anchored on the sorbitol layer formed on the citric acid crystals. Finally, 205 parts by weight of sodium bicarbonate and 1.2 parts by weight of aspartame are aspirated and dispersed evenly. Finally, the material is coated with 46 parts by weight of sodium carbonate, vacuum dried and screened through a 1.2 mm sieve.

b) Preparation of grains with active ingredient by weight parts of polyvinylpyrrolidone is dissolved in 12 parts by weight of ethanol, 6 parts by weight of propylene glycol and 6 parts by weight of sodium docatate are added and the mixture is diluted with 165 parts by weight of ethyl methyl ketone.

Half of this solution is dispersed in a mixture of 960 parts by weight of mannitol, 30 parts by weight of aerosol, 60 parts by weight of sodium bicarbonate and 61 parts by weight of cisapride, which is heated to 60 ° C.

Partial drying is then carried out under vacuum and further wetting is carried out with the other half of the solution, followed by complete drying and screening through a 0.3 mm sieve.

The final mixture was prepared analogously to Example 5.

Claims (26)

PATENT Claims □ i 5 oo 0 q o 6 9 i A granular effervescent product suitable for the preparation of an aqueous solution or suspension of at least one pharmaceutically active substance for oral administration, capable of being compressed into tablets and / or the product in tablet form, characterized in that it comprises effervescent grains obtained from carrier crystals at least one solid edible organic acid substantially coated with at least one coating comprising at least one water-soluble and / or alcohol-soluble neutral substance, said neutral substance being effective to lower the melting point of the acid crystals on their surface, and at least one selected from the group consisting of an alkali carbonate, an alkali bicarbonate, an alkaline earth carbonate, an alkaline earth bicarbonate, an alkali salt of at least one solid organic edible acid, an alkaline earth salt of at least one solid edible organic acid is deposited on the coating. 2. The granular product or tablet of claim 1 wherein the neutral is selected from the group consisting of a water-soluble polymer, a higher alcohol, a carbohydrate, and a hydrocolloid, and the neutral is present in an amount of from about 0.05 to about 1.0. % by weight, preferably from about 0.07 to about 0.8% by weight. A granular product or tablet according to claim 1 or 2, wherein the moisture binding agent is anchored on the effervescent grains, wherein the moisture binding agent is preferably selected from the group consisting of anhydrous sodium carbonate and sodium sulfate and preferably is applied in an amount of about 4 to about 10% by weight of the total mixture. A granular product or tablet according to any one of the preceding claims 1 to 3, characterized in that at least one further coating comprising a substance selected from the group consisting of alkali salts and / or alkaline earth salts of at least one solid edible organic acid as a buffer is applied to the effervescent grains. and optionally containing a further neutral substance, and preferably at least one of these coatings comprises an antifoam. The granular effervescent product or tablet according to any one of claims 1 to 4, wherein the granular product or the granular product compressed into a tablet form further comprises at least one antifoam agent present in the granular product itself. 6. The granular product or tablet of claim 4 or 5, wherein the defoamer is selected from the group consisting of dimethicone and simethicone and is applied in an amount of from about 0.005 to about 0.5% by weight of the total composition or from about 0, % To about 2.0% by weight of the pharmaceutically active ingredient. A granular product or tablet according to any one of the preceding claims, characterized in that it has an acid-binding capacity of less than 5, preferably less than 3 meq, measured according to USP XXII. A granular product or tablet according to any one of claims 1 to 7, characterized in that it has a dissolution time of less than 180 seconds in water at room temperature at a total weight of not more than 2.5 g, preferably not more than 2.0 g. , preferably less than 120 seconds. A granular product or tablet according to any one of the preceding claims, characterized in that it comprises a pharmaceutically active substance which is hydrophobic and the hydrophobic substance is present in the grains separately from the effervescent components, in which grains the hydrophobic substance is coated or grounded. at least one substance selected from the group consisting of suspending agents - preferably selected from the group comprising Aerosil 'and Avicel' - and neutral substances - preferably selected from the group consisting of mannitol and sorbitol. A granular product or tablet according to claim 9, characterized in that the grains also comprise at least one component selected from the group consisting of binders, preferably polyvinylpyrrolidone (PVP), small amounts of surfactant, preferably selected from sodium dioctyl sulfoccinate and sodium lauryl sulfate, alkaline carbonate and / or alkaline earth and / or bicarbonate. A granular product or tablet according to any one of claims 1 to 10 comprising, based on the total mixture, about 2 to about 30% by weight of cimetidine, about 30 to about 60% by weight of a solid edible organic acid, about 12 to about 3%. 40 wt% of at least one alkali or alkaline earth carbonate or bicarbonate (of which about 2 to about 10 wt% is sodium carbonate as a moisture binding agent), about 1 to about 4 wt% sweetener, about 0.01 to about 30 wt% neutral substances (of which about 0.01 to about 0.05% by weight is neutral for the coating), preferably about 3 to about 20% by weight sorbitol and about 2 to about 10% by weight mannitol, about 0.005 to about 0.5% and about 0.1 to about 3% by weight of a flavoring agent. A granular product or tablet according to any one of the claims 1 to 10 comprising, based on the total composition, the following components: about 0.4 to about 4.5% by weight of cisapride, about 0.4 to about 4.5% by weight of a suspending agent, about 0.1 to about 1% by weight of a binder, preferably polyvinylpyrrolidone (PVP), about 0.03 to about 0.35% by weight of a surfactant, preferably sodium dioctyl sulfinate, about 30 to about 55% by weight of a solid edible organic acid, preferably citric acid, about 12 to about 40% by weight of at least one alkali or alkaline earth carbonate or bicarbonate (of which about 2 to about 10% by weight is sodium carbonate as a moisture binding agent), about 0.3 to about 2% by weight sweetener, about 0.02 to about 55% % by weight of a neutral substance (of which about 0.02 to about 0.1% by weight is a neutral substance coating), preferably selected from the group consisting of maltodextrin, lactose and mannitol, about 0.005 to about 0.05% by weight % of an antifoam agent, preferably selected from dimethicone and simethicone, and about 0.2 to about 5% by weight of the aromatizate. A granular product or tablet according to any one of the claims 1 to 10, characterized in that it contains, based on the total mixture, the following components: - about 0.1 to about 0.5% by weight of beta-carotene (100%), - about 0 to about 2% by weight of tocopheryl acetate (100% by weight), about 35 to about 70% by weight solid edible organic acid, preferably about 0 to about 10% by weight ascorbic acid, about 35 to about 55% by weight citric acid, about 0 to about 5% by weight malic acid, about 11 to about 38% by weight of at least one alkaline or alkaline earth carbonate or bicarbonate, preferably about 5 to about 15% by weight calcium carbonate, and about 5 to about 20% by weight sodium bicarbonate, about 1 to about 4% by weight sweetener, about 0.1 to about 35.0% by weight of a neutral substance, of which about 0.1 to about 0.5% by weight is neutral for the coating, preferably about 1 to about 10% by weight sorbitol and about 5 to 25% by weight mannitol, and about 0.3 to about 3% by weight of flavoring. A granular product or tablet according to any one of claims 1 to 10 comprising, based on the total mixture, the following components: about 3 to about 14 wt% ranitidine hydrochloride (75 to 300 mg per dose), about 30 to about 50 wt% citric acid, about 0 to about 20 wt% monosodium citrate, about 10 to about 30 wt% sodium bicarbonate, about 2 up to about 10% by weight of sodium carbonate, about 1 to about 3% by weight of a sweetener, about 0.05 to about 0.2% by weight of a neutral coating for the first coating, as well as about 0 to 15% by weight of other neutral substances, about 0 to about 8%. and about 0.1 to about 4% by weight of an aromatizate. 15. An effervescent tablet comprising at least one pharmaceutically active ingredient and an effervescent system comprising at least one solid edible organic acid and at least one alkali metal carbonate or hydrogen carbonate gas-forming component and at least one alkali metal salt in at least two layers deposited on the carrier crystals comprising at least one acid, wherein the first layer comprises at least one other solid edible organic acid or an alkali metal salt of the other acid or both, while the second layer comprises at least one alkali metal salt of the at least one acid, the first layer additionally containing a neutral substance selected from a group consisting of a water-soluble polymer, a higher alcohol, a carbohydrate, and a hydrocolloid. A granular product or tablet with an effervescent system and cisapride as a pharmaceutically active ingredient, characterized in that it has an acid-binding capacity of less than 5 meq, preferably less than 3 g, with a total weight of less than 2 g, preferably less than about 1.6 g. mekv. A granular product or tablet with an effervescent system and cimetidine as a pharmaceutically active substance, characterized in that, with a total weight of less than 2.5 g, preferably less than 2.0 g, it has an acid-binding capacity of less than 5 meq, preferably less than 3 meq. A granular product as an effervescent tablet and ranitidine as a pharmaceutically active substance, characterized in that, with a total weight of less than 2.6 g, preferably less than 2.0 g has an acid-binding capacity of less than 3 meq, preferably less than 2 meq. Process for preparing a granular product or tablet according to any one of the preceding claims 1 to 18, characterized in that the crystals of at least one solid edible organic acid are wetted with an aqueous solution of a neutral substance and then alkaline carbonate and / or alkaline earth carbonate and / or the bicarbonate in powder form evenly disperses and anchors on the wet surface layer with stirring, after which the effervescent grains thus prepared are dried and mixed with a pharmaceutically active substance, preferably an acid-sensitive substance, in particular a substance selected from the group consisting of H2-blockers, cimetidine, ranitidine, cisapride and beta-carotene, and pharmaceutically acceptable adjuvants, and optionally compressed into tablets. Method according to claim 19, characterized in that at least one additional coating is applied to the effervescent grains by wetting the grains with a buffer substance solution, preferably one selected from the group consisting of alkali carbonate, alkaline bicarbonate, alkaline earth carbonate, alkaline earth bicarbonate, alkaline salts of at least one solid edible organic acid; and alkaline earth salts of at least one solid edible organic acid. The method of claim 19 or 20, wherein the solution further comprises a neutral substance selected from the group consisting of a water-soluble polymer, a higher alcohol, a carbohydrate, and a hydrocolloid. A method according to any one of claims 19 to 21, characterized in that, in addition to the medicament, the effervescent grains are also mixed with the granular product which is formed by applying an antifoaming agent in a suitable solvent to the surface of the neutral particles and drying the solvent. A method according to any one of claims 19 to 22, characterized in that the dried effervescent grains are wetted with ethanol, preferably containing dissolved antifoam, and dried again by evaporating ethanol to remove residual moisture. Method according to any one of claims 19 to 23, characterized in that, before admixing with the effervescent system, the pharmaceutically active substance is applied together with the binder and / or surfactant in solution and uniformly distributed on the grains of the suspending agent and dried. Method according to any one of claims 19 to 24, characterized in that the pharmaceutically active substance is mixed with at least one neutral substance, at least one suspending agent and at least one dose selected from the group of alkali carbonate, alkali bicarbonate, alkali carbonate prior to admixing with the effervescent system. soil, alkaline earth bicarbonate, alkali salts of at least one solid edible organic acid, alkaline earth salts of at least one solid edible organic acid, after which the solution of at least one binder and / or surfactant is applied and dispersed on the grains of the mixture at least once and dried. 26. A process for producing effervescent grains from a powdery granular mixture of a solid edible organic acid and an alkali metal and / or alkaline earth metal carbonate and / or bicarbonate under vacuum, characterized in that for passivating the surface of at least one of the components add a measured amount of polar solvent to the heated mixture during the vacuum treatment, the difference in pressure induced by the evolution of carbon dioxide when the solvent is added during the reaction - shall be determined up to a maximum of 1. 10 Pa, the volume and mass of carbon dioxide released is determined from this pressure difference and this heat treatment is repeated after rapid drying of the mixture as many times as necessary to obtain surface passivation as shown by evident slowing of reaction and reduced gas evolution and wherein said neutral solvent dissolves a neutral substance selected from the group consisting of a water-soluble polymer, a higher alcohol, a carbohydrate, and a hydrocolide. 27. A process for preparing an effervescent granular material comprising at least one solid crystalline edible organic acid and at least one alkali metal or alkaline earth metal carbonate which cleaves CC > 2 after reaction with the organic acid in an aqueous solution, characterized in that part of the organic acid is pre-reacted. an acid and this carbonate in solution in water and / or an alcohol to form a pre-reaction product, - the pre-reaction product is added to another portion of the organic acid in crystalline form with vigorous stirring to form a first coating by reacting with the crystals of the organic acid and liberating the remaining crystallization water, - depositing at least one further coating comprising the carbonate on the crystals of the organic acid adhering to it, and the reaction is terminated after the last coating has been dried by drying, and to this pre-reaction product a neutral substance selected from the group consisting of a water-soluble or alcohol-soluble polymer, a higher alcohol, a saccharide and a hydrocolloid is added.