HUT75677A - Granular product or tablet containing an effer vescent system and an active pharmaceutical substance, as well as a method for its preparation - Google Patents

Description

The present invention relates to a pharmaceutical composition in granular or, more preferably, tablet form, comprising a effervescent system and, preferably, an acid-sensitive, therapeutic agent such as cisapride, beta-carotene, a H2 blocking agent such as cimetidine or ranitidine and / or it should be administered in a effervescent pharmaceutical composition containing a small amount of effervescent component or having a relatively low acid-neutralizing capacity.

Until now, it has only been difficult to incorporate acid-sensitive active ingredients into effervescent tablets or effervescent instant granular products in a stable form, since this material is hydrolyzed or degraded when in contact with the acid component of the effervescent system in such a composition. Furthermore, when a substance also affects the surface tension of the water, foaming occurs which is undesirable for the consumption of the effervescent solution or the hydrophobic portions of the active ingredient tend to creep up on the glass wall. On the other hand, in some cases, the antitussive side effect of the effervescent tablet is undesirable for many drugs. Accordingly, it is an object of the present invention to provide a effervescent system that avoids the aforementioned drawbacks and enables the patient to administer therapeutic agents, including acid-sensitive substances having hydrophobic or water surface tension properties, as a pleasant effervescent solution. A further object of the present invention is to provide a effervescent tablet or instant effervescent granulated product having an acid binding capacity of 5 meq. (measured by The United States Pharmacopoeia 23, National Formulary 18, Test 301) in order to avoid undesired antacid activity. This is particularly advantageous for any H2 blocker. Finally, it is desirable that the tablet or granu84265-4505-Ga / ms

The product was rapidly dissolved in water at about 15-20 ° C in less than about 2 minutes.

The following is a summary of the invention.

This solution to the problems described above is surprisingly simple, cost-effective and efficient in accordance with the present invention, for example, by first coating the acid particles with a composition comprising at least one inert material that reduces the melting point of the acid particles surface. and thereafter affixing at least a second coating comprising an alkali metal and / or alkaline earth metal carbonate and / or bicarbonate and optionally a partial reaction product of the carbonate or bicarbonate with the same or different organic acid.

The invention will now be described in more detail with reference to the detailed description and some preferred embodiments.

Within the scope of the invention, inert materials include water and / or alcohol soluble polymers such as polyvinylpyrrolidone, carbohydrates such as sucrose, pentaerythritol, glucose, and fructose (although the latter two are only slightly alkaline effervescent granules of bicarbonate). under the influence of Maillard, which makes them prone to yellowing and therefore not particularly advantageous for use in the invention), hydrocolloids such as maltodextrin, dextrin and the like; higher alcohols such as xylitol, mannitol and sorbitol are particularly preferred.

Various embodiments of the invention are described in the claims.

PCT Patent Publication No. WO 93/00886 discloses the incorporation of a foreign acid, preferably gluconic acid delta-lactone acid, which hydrolyses to a gluconic acid, on the surface of the carrier crystals, resulting in a decrease in the melting point due to disruption of the crystal lattice. However, this measure does not, of course, provide adequate protection for acid-sensitive active substances. Therefore, it has not yet been possible to apply the solution described above in the case of acid-sensitive active substances.

British Patent No. 1,270,781 discloses a solution in which acid carrier crystals are coated with a thin polymer layer, for example polyvinylpyrrolidone, carboxymethylcellulose or the like, for use in effervescent tablets. However, this results in an undesirable prolongation of the dissolution time and causes foaming problems when used in the examples of 1-5% by weight of polyvinylpyrrolidone; furthermore, when the coating is applied in the form of an ethanol or aqueous solution, some acid will always pass from the carrier crystals to the layer in solution, thereby providing insufficient protection for the acid-sensitive active substances. Furthermore, over the past 20 years, those skilled in the art have been unsatisfactory in solving the problem of introducing acid-sensitive active ingredients into effervescent systems, not only the storage problem, but also the preparation of tablets of relatively low weight, very low acid neutralizing capacity and short dissolution time. A effervescent tablet is generally defined as being particularly rapid when the dissolution (or complete suspension) of the tablet components occurs within 120 seconds, preferably 90 seconds or less.

However, according to the invention, after the inert material, preferably only a small amount, has been applied to the acid particles, alkali metal and / or alkaline earth carbonate and / or bicarbonate particles are attached to the surface of the particles to prevent the active substance and acid interaction.

Furthermore, EP-A1-415 326 proposes a process wherein a few times the amount of sugar coating is carried on an acid carrier crystal in order to achieve a slight tingling effect on the chewable tablet or the suckable tablet in combination with the bicarbonate. capable of solving a combination of problems and tasks, such a system is not reactive enough to dissolve a effervescent tablet in water within a reasonable time. The purpose of this solution was to slow down the reaction between the acid and the carbonate so as not to cause too much effervescent effect in the mouth.

If a tablet with an acid, bicarbonate, and calcium core were coated with an inert substance, such as an aqueous, alcoholic, or aqueous alcoholic solution of sorbitol, as described in US-A-4 127 645, such a tablet would not provide reliable protection against acid-sensitive active substances in the core. However, if the mixture were compressed into tablets with an inert substance (e.g. maltodextrin, optionally sugar, US-A-4 650 669; mixed with sorbitol and vitamins, US-A-5 223 264 suitable only for chewable tablets), then either reagent would be co-coated or unwanted agglomerated granules would be formed. In both cases, the tablet's reaction to dissolution is too slow and the dissolution time would be too long or the solution would contain more sugar than desired. Furthermore, it is very likely that unprotected acid particles would also be present on the surface of the agglomerated granules, resulting in greater instability of the acid-sensitive active substances.

U.S. Pat. No. 4,867,942 discloses a process wherein solid edible organic acid carrier crystals are coated on their surface with a pre-reacted buffer solution, in particular with an acidic alkali metal and / or alkaline earth metal salt of a solid edible organic acid. Subsequently, most of the acid crystals and an amount of carbonate or bicarbonate bind to this coating side by side. The water which is liberated in various neutralization partial reactions is removed by final treatment with alcohol and vacuum drying. Such processes are not advantageous because, in the case of acid-sensitive active substances, an additional acid on the surface of the acid crystal reacts simultaneously with the alkali metal carbonate and thus the reaction takes place too quickly and consequently is not sufficiently uniform. Therefore, such a • ·

- The 5-slot product does not completely prevent the reaction of the mixed acid-sensitive active ingredient because acid crystals are present on the surface of the granules.

In contrast to the foregoing, the structure of the effervescent systems of the present invention not only prevents direct contact between the acid-sensitive active ingredient and the acid crystal, resulting in a substantially better-preserved effervescent tablet or granular product, but also allows substantially smaller amounts of effervescent tablets to be prepared. which results in a buffer system when dissolved. Thus, in contrast to the buffering system for anticorrosive effervescent tablets, the tablets of the present invention are well below 5 meq. may be below the acid neutralizing capacity. In addition, a sustained reaction in the preparation of the product and compression into a better tablet is achieved. Using the invention, a effervescent tablet may be prepared which first contains an acid-sensitive active ingredient such as cisapride or an H2 blocking agent such as cimetidine and is 5 meq per tablet (or per granular product). has an acid neutralizing capacity at a weight of only 1.6-2.3 g.

Further, in a particularly preferred embodiment of the invention, after coating the acid crystals with an inert material, at least a portion of the carbonate and / or bicarbonate particles intended for the total dose are applied to this coating to form a first neutral material coating of the acid crystals and forming a second sparkling granule, in some cases partially coated with an acid, with a carbonate and / or bicarbonate coating.

The invention is particularly useful in the preparation of products and processes such as those disclosed in EP-B1-76 340, US-A-4 867 942 and WO 93/00886, the disclosure and claims of which are incorporated herein by reference in their entirety. they are incorporated herein by reference in their entirety.

The use of an inert material, particularly sorbitol solution, reduces the melting point of the citric acid crystals. Thus, on the one hand, the adhesion force to the coating containing the following alkali metal or alkaline earth metal carbonates and / or bicarbonates increases, while at the same time this results in a slower and therefore more uniform reaction and better passivation of the citric acid crystal surface, the sparkling grains attack less. On the other hand, decreasing the melting point prolongs the recrystallization time of the citric acid or the citrates formed, which determines the better compressibility of the effervescent granules over a longer period.

The amount of inert material applied to the acid carrier crystals will depend on the amount of solvent used to moisten the acid, since it is soluble in aqueous solution up to 50-70% by weight. Therefore, it is preferred to use from 0.05 to 1.0% by weight of the acid, more preferably from 0.07 to 0.8% by weight. The use of less than 0.07% w / w provides only a weak effect, less than 0.05% w / w is not relevant to the invention: the shelf life of the acid-sensitive active ingredients is reduced. When dosed above 0.8% by weight, the material generally becomes influential and above 1.0% by weight the reactivity of the citric acid and effervescent system is significantly reduced.

However, in the case of granules, this is less of a problem, since a longer dissolution time seems desirable in order to allow time for the granules to be first immersed in water before being involved in the dissolution reaction. On the other hand, however, the amount of inert material that can be applied to the surface of citric acid, for example, is determined by the amount of solution that can be moistened with citric acid, since neutral materials are practically in solution and 50% to 70%. Citric acid crystals cannot be wetted with unlimited amounts of water and thus solvent.

In some cases, the neutral coating, particularly when attached to carbonate and / or bicarbonate particles, may contain small amounts of a solid edible organic acid and, in some cases, an acid other than the carrier crystalline acid described elsewhere in this specification. repe is also involved in increasing the melting point decrease and / or controlling the effervescent reaction and dissolution rate.

Each sparkling grain in itself is practically a small effervescent tablet and is itself sparkling. Therefore, if desired, a short dissolution time, a small amount and a low acid neutralization capacity can be achieved.

Previous attempts to produce fast-acting, small effervescent tablets using monosodium citrate instead of citric acid have been unsuccessful as this change greatly slows down the effervescent reaction, since monosodium citrate reacts much slower than sodium bicarbonate and the acid-consuming capacity of tablets usually exceeds 5 meq. value.

On the other hand, a very thin monosodium citrate coating according to the invention preferably acts as a third or fourth layer, which may optionally contain an additional inert material since 1 mol of monosodium citrate binds 1 mol of crystal water and thus contributes to drying or to keep it dry. Further, uncoated citric acid surfaces may be coated again or more fully with bicarbonate.

In addition, since many substances produce a taste sensation, many of which may be unpleasant, especially those which give a bitter taste, it is desirable to maintain the final effervescent solution, especially since it is in the form of a beverage, in a pH range of 3.8 to 4.6. Experience has shown that in this range, in particular, bitter materials can be masked much more effectively.

Although not mandatory, it is preferable to remove the remaining water from the granules by a final alcohol treatment. Alcohol can disrupt the binding of crystal water, since the remaining moisture is removed by evaporation with the alcohol during drying. Small amounts of antifoaming agent may be added to the alcohol to accelerate dissolution in the finished tablet.

Many of the above-mentioned active ingredients, especially cimetidine and cisapride, often cause foaming of the effervescent tablet. However, this is not so

-8 foaming, all triggered by surfactants. That is, the active ingredients themselves do not foam when mixed with water. They are caused by the formation of carbon bubbles when the effervescent particles in the tablet dissolve.

These bubbles burst, leaving carbon dioxide on the surface. When a less soluble or more hydrophobic material is present, the insoluble particles encapsulate the carbon dioxide bubbles and successfully form a film on them to form a bubble burst, forming a foam-covered bubble on their surface. However, such foam formed between the effervescent granules prevents the reaction from continuing and thus dissolving the tablet or granules rapidly. According to the invention, this phenomenon is prevented by the addition of a very small amount of at least one antifoam agent, which results in any foam being formed immediately upon initiation of the effervescent reaction.

Preferably, the antifoaming agent comprises all fillers, dyes, and the like. in an amount of 0.005-0.5% w / v or 0.05-2.0% w / w of the active ingredient. Administration of less than 0.005% w / w does not have a satisfactory effect and administration of more than 0.5% w / w may lead to problematic or unacceptable side effects.

For soluble, though not soluble, active ingredients such as cimetidine, 0.1-0.3 '% by weight of simethicone is used, equivalent to 0.016-0.028% (about 0.03%) of the total tablet weight. . The situation is somewhat different for insoluble hydrophobic active ingredients, such as cisapride (monohydrate thereof), wherein 1% simethicone is used per active ingredient, but this amount is 0.006% based on the total weight of the 1.6 g tablet. Obviously, cisapride, a poorly soluble hydrophobic drug, requires a greater amount of antifoaming agent to suppress foaming, but results in substantially smaller amounts of simethicone being used per tablet, so the proportions are reversed.

In the case of soluble active substances, such as cimetidine and ranitidine, the amount of simethicone is used in order to suppress the lower tendency to foam during the topical reaction during dissolution of the effervescent tablet, whereas for cisapride, as mentioned above, it is significantly higher, and the principle is therefore somewhat different.

When used in larger amounts, simethicone forms a film on the surface after dissolution of the effervescent tablet due to the fact that, especially in the case of insoluble active ingredients, particles of the active substance accumulate and remain dependent, resulting in an unattractive dissolving behavior. to form a ring on the glass wall.

However, in some cases, very small amounts of a surfactant such as docusate sodium are added. Due to their wettable nature, such drug particles dissolve faster and no longer adhere to foam bubbles. The proportion of such materials must be determined very precisely in advance in order to achieve the desired dissolution characteristics.

Although in some cases the antifoaming agent may be used in the foaming systems and / or active ingredient, it is not preferred according to the invention. In the former case, this may result in an undesired retardation of dissolution and reaction of the effervescent components unless a very small amount of an antifoaming agent is used to achieve the desired effect. In the second case, only those active substances which do not lose their solubility or stability are affected when the antifoaming agent is applied at 40 ° C in a solution in a solvent (e.g., methyl ethyl ketone and acetone). Furthermore, in the manufacturing process using finely powdered active ingredients, the addition of an antifoaming agent leads to poor distribution, since the active ingredient particles adhere to the droplets of the antifoaming agent.

• ·

It is therefore advantageous for the present invention to first form a typical granular product of the antifoam agent and inert material, which product is then blended with the effervescent system and the active ingredient, and optionally further excipients (e.g., perfumes, sweeteners, and the like), and compressed into tablet form.

The humidity released during the preparation of the effervescent system by the neutralization reaction and not completely removed by heating and / or vacuum treatment, and the humidity taken up from the air during storage, is particularly suitable for this amount of anhydrous sodium carbonate Absorbs 10 moles of water) or sodium sulfate. The agent may be combined with one or more coatings applied to the carrier crystal, or may be added to the total mixture. Its use improves shelf-life by further reducing or completely preventing the acid-sensitive drug from reacting with the acid by reducing moisture. However, an excess of such a humectant such as sodium carbonate is undesirable as it may delay the effervescent reaction.

Therefore, when using sodium carbonate as a desiccant, it cannot be used to completely coat the effervescent granules, since it is advantageous to use only small amounts which have the effect of drying the remainder of the moisture or delaying the reaction during manufacture and advantageous to avoid undesirable prolongation . Therefore, the final addition of sodium carbonate cannot be used as a complete coating (or as a tablet coating), both in terms of volume and particle size (about 0.1-0.05 mm), and it is not desirable to create a continuous coating of the already present coating. hydrogen carbonate. However, it can be partially fixed to the sodium carbonate sparkling granules. However, it is also possible that the sodium carbonate is not added until after the drying operation.

• * · Γ · »·» · «« · · · · · · · · · · · · · ·

The percentage of sodium carbonate per tablet is essentially determined by some 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 forth.

Preferably, the wetting agent, particularly sodium carbonate, is present in the total weight, including any fillers, flavorings, and the like. It is added in an amount of from 1 to 10%, especially from 4 to 6% by weight. At doses below 4%, only a weak effect is achieved, while below 1% the drying effect and the stability increase are too low and have no relevance to the invention. When administered above 6%, a troublesome effect occurs as sodium carbonate dissolves too slowly and reacts too poorly; Above 10%, the dissolution time is already significantly prolonged, since sodium carbonate first absorbs water (10 moles of crystal water per mole) before the effervescent tablet is dissolved, i.e. calcined, and then reacts with citric acid.

It should be emphasized here that 1 mol of sodium citrate binds 1 mol of crystalline water, forming a layer in sorbitol or sorbitol alone, and against any residual moisture, the sorbitol layer prevents or prevents any acid from damaging the active ingredient.

If all the steps described above are followed in accordance with the invention, effervescent tablets may be prepared with substances for which this is known to be difficult, for example, with a weight of 1.6 g and a dissolution time of less than 100 s. It is noted that, in particular, the hydrophobic nature of cimetidine further prolongs the dissolution time with respect to other drugs, provided otherwise the conditions are the same.

Granulation with sorbitol solution allows rapid dissolution without incorporation of an otherwise necessary external acid, such as that described in WO 93/00886.

Furthermore, the steps of the invention allow the preparation of the effervescent systems of the invention, and in any case the tablets themselves, to allow the preparation of the effervescent system. · »

12 control of the reactions occurring on the surface of individual crystals or granules, thus constituting a local mechanism and additionally providing the advantages described above during dissolution.

The system is extremely capable of processing materials that are both acid-sensitive and poorly water soluble. Such materials, such as cisapride, exhibit a very unpleasant behavior in suspension because, as mentioned above, they tend to foam together with the effervescent system, to form an unpleasant ring on it, and tend to agglomerate on the surface of the beverage.

Each of the above-mentioned problems can be effectively overcome by preparing separate granules. For this purpose, in a further embodiment of the invention, there is provided a carrier comprising Aerosil and / or an inert material, to which the active ingredient is preferably applied by partially dissolving the surface of its particles and / or binders and / or, if desired, surfactants. and dried or bonded to the surface of the carrier with binders.

The amount of suspended material, such as cisapride, is up to 8% by weight, preferably up to 4.5% by weight, based on the total weight of the mixture, since the use of a larger amount would result in the granule particles settling after dissolution of the tablet. On the other hand, the amount of binder is likewise limited to 1% by weight, since otherwise the active ingredient, the suspended material and the binder would form undesirable agglomerated granules which dissolve only by difficulty and sink to the bottom of the liquid, i.e. a larger amount of binder is prevented.

The invention will now be described in more detail with reference to the exemplary embodiments thereof. However, these examples are provided for purposes of illustration only and are not intended to be limiting, and many other embodiments and variations will be apparent to those skilled in the art.

· · · · · · · · · · · · · · · · ·

Alternatively, the active ingredient may be dissolved in methyl ethyl ketone or acetone and applied as a coating on mannitol, Aerosil®, and sodium bicarbonate.

Example 1

Preparation of effervescent tablets containing 200 mg cimetidine:

(a) Preparation of a sparkling system

102 parts by weight of coarse citric acid and 25 parts by weight of finely powdered citric acid or tartaric acid are sucked into a preheated vacuum vessel and heated to about 60 ° C with stirring (finely powdered citric acid is on which up to 30% hydrogen carbonate can be attached). Then 0.85 parts by weight of solution 1, consisting of 36 parts of water, 36 parts of sorbitol, 21 parts of citric acid and 7 parts of sodium bicarbonate, are aspirated and distributed over citric acid with stirring. Subsequently, 52.5 parts by weight of sodium bicarbonate and 4.4 parts by weight of aspartame are added, followed by drying under a vacuum of less than 200 mbar, 1.9 parts by weight of sodium carbonate are added and the mixture is stirred. and the mixture was dried under vacuum under 15 mbar.

An additional 0.6 parts by weight of the above solution is then aspirated into the vessel and distributed under stirring. The resulting effervescent granules are dried under vacuum under stirring. If desired, 0.25 parts by weight of 96% ethanol are added to the dry mixture. Then, 9.3 parts by weight of sodium carbonate is again bound to the surface of the sparkling grain. After a further final drying, the product is sieved.

b) Preparation of granular antifoam agent 7.7 parts by weight of sorbitol powder are added to a vacuum vessel with a jacket temperature of ° C and heated to 50 ° C. Then 0.2 parts by weight of simethicone were aspirated into a 5: 3 butanone / acetone mixture.

- in the form of a 30% solution of 14 giblets, the mixture is stirred with a vibratory stirrer and dried at a temperature of at least 45 ° C to 15 mbar under a full vacuum.

c) Preparation of complete mixture

In a mixer, 20 parts by weight of cimetidine, optionally 21.1 parts by weight of sorbitol powder and 178.4 parts by weight of the effervescent system of step a) are stirred for 10 minutes at 6 rpm. Subsequently, 7 parts by weight of the antifoam granule prepared in step b) were added and sieved through a 0.6 mm sieve, followed by addition of 4.5 parts by weight of lemon flavor and stirring for another 5 minutes at 6 rpm. The final mixture was compressed into 2.3 g tablets, each containing 200 mg cimetidine and a hardness of 6-8 kp.

Example 2

Preparation of effervescent tablets containing 200 mg cimetidine, effervescent granules containing citric acid and malic acid

102 parts by weight of coarse citric acid, 25 parts by weight of powdered citric acid and 1.1 parts by weight of malic acid are mixed in a preheated vacuum vessel at 60 ° C. A solution 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 sucked in and mixed with citric acid with stirring. Then, 52.5 parts by weight of sodium bicarbonate and 4.4 parts by weight of aspartame are added and the mixture is dried under vacuum under 200 mbar. 1.9 parts by weight of sodium carbonate are then sucked into the vessel and distributed with stirring and then dried under a vacuum of 15 mbar. Finally, a final drying with ethanol was carried out and 9.3 parts by weight of sodium carbonate were added. In the following, the procedure of Example 1 is followed.

Example 3

Preparation of effervescent tablets containing 400 mg cimetidine and mannitol as neutral substance

49 parts by weight of citric acid were aspirated into a preheated vacuum vessel and heated to 60 ° C with stirring. Then 0.45 parts by volume of solution 1 are drawn into the container - the solution is made up of 0.25 parts by weight of water and 0.20 parts by weight. • · · · «·

15 mannitol, and the solution is partitioned between citric acid and 14.7 parts by weight of sodium bicarbonate and 3.2 parts by weight of aspartame are added. After stirring, the reaction was started and dried under vacuum at 200 mbar. 0.5 parts by weight of sodium carbonate are then drawn into the vessel and uniformly distributed with stirring and then dried under vacuum at 15 mbar. Then, 0.5 parts by weight of solution 2 is added, the components of the solution are given for solution 1, plus 0.16 parts by weight of monosodium citrate, and the solution is distributed by stirring. The effervescent granules thus obtained are dried under stirring under a vacuum of less than 20 mbar and 2.8 parts by weight of sodium carbonate are added. To this mixture were then 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 flavoring agent and 4 parts by weight of the antifoam granule prepared according to Example 1b).

Example 4

Effervescent tablets containing 300 mg cimetidine and maltodextrin as inert substance

The procedure described in Example 3 was followed, except that a effervescent tablet containing 300 mg of cimetidine was prepared using 50% maltodextrin solution in the same amount as in the 400 mg form.

For each example where a tablet containing 100 to 400 mg of cimetidine is prepared, the tablet weight may be 2.3 g. The tablets preferably have a dissolution time of 60-150 seconds and a buffering capacity of 5 meq. below USP XXII as measured by back titration of the effervescent tablet dissolved in 70 ml of water with 0.5 N NaOH after addition of 30 ml of 1.0 N HCl.

Table 1 below shows the percentages of the individual ingredients in a given complete mixture according to the preferred embodiments shown, which therefore represent the preferred range:

· • • «« * * * * * *

- Table 161

cimetidine 2-30% (Equivalent to effervescent tablet containing 50-600 mg cimetidine) Citric acid 30-60% sorbitol 5-20% Sodium hydrogen carbonate 10-30% mannitol 2-10% Sodium carbonate 2-10% simethicone 0.005-0.5% aspartame 1-4% flavoring 0.1-3%

One hundred and fifty tablets of cimetidine containing 100, 200, 300 and 400 mg of cimetidine, each with a total weight of 2.31 g,

its composition is given in Table 2. Table 2 300 mg 400 mg 100 mg 200 mg cimetidine 4.30 8.70 13 17.3 Citric acid 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 Sodium hydrogen carbonate 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 flavoring 2.0 2.0 0.9 0.9 simethicone 0.02 0.02 0.02 0.02

Example 5

Cisapride effervescent tablets

(a) Preparation of sparkling grains

655 parts by weight of crystalline citric acid, 70 parts by weight of citric acid powder and 8 parts by weight of sodium saccharin were heated to 60 ° C with stirring. 2.8 parts by weight of the solution are then drawn with 0.6 parts by weight of the solution.

17 parts 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 and distributing the solution by stirring. 340 parts by weight of sodium bicarbonate and 2 parts by weight of aspartame are then added and reacted. To the mixture was added 77 parts by weight of sodium carbonate and dried under vacuum at 15 mbar with slow stirring.

b) Preparation of the granulated active ingredient

Insoluble and hydrophobic cisapride was coupled to a suspending agent using a binder and a small amount of surfactant as follows: 10 parts by weight of cisapride, 2 parts by weight of polyvinylpyrrolidone and 0.8 parts by weight of docusate in 1 part by weight ethanol and 40 parts by weight acetone. 10 parts by weight of Aerosil® solution, uniformly distributed and then dried with stirring. The granules are sieved to a range of 0.1-0.3 mm.

c) Preparation of the final mixture

To 1152 parts by weight of sparkling granules 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 agent, 50.2 parts by weight of antifoam granules (50 parts by weight of mannitol) the mixture was stirred for 15 minutes until uniform distribution and then compressed into 1.6 g tablets with an acid neutralizing capacity of only 2 meq. Such low acid neutralizing capacity cisapride effervescent tablets have not been known to date.

Example 6 effervescent tablet β-carotene

In this highly acid and oxidation sensitive material, particular care must be taken to cover the acid. The surface and the contact zone of β-carotene should be kept alkaline. Therefore, the sparkling granules should be at least partially coated with calcium carbonate to provide an alkaline surface. However, this results in a slightly longer dissolution time, which is desirable in this case, since β-carotene needs time to resuspend as the tablet dissolves.

- 18h. Large amounts of sorbitol, as disclosed in U.S. Pat. No. 5,223,264, are by no means suitable for the preparation of effervescent tablets of β-carotene to be dissolved or suspended in water.

(a) Production of sparkling granules

1315 parts by weight of citric acid, 7 parts by weight of sodium saccharin and 45 parts by weight of sodium cyclamate are heated under vacuum to 50 ° C. Then, 16.8 parts by weight of a solution of 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 with the citric acid and distributed by stirring. Then 400 parts by weight of calcium carbonate and 190 parts by weight of citric acid are added and the mixture is heated to 60 ° C with stirring. This is followed by a second granulation using 44 parts by weight of the above solution, after distribution and mixing, 403 parts by weight of sodium bicarbonate and 52 parts by weight of sodium carbonate before drying. The mixture was then dried under vacuum at 15 mbar with slow stirring.

b) Preparation of the final mixture

2415 parts by weight of the effervescent granules prepared in step a) 130 parts sorbitol, 540 parts mannitol and 50 parts flavoring, 2-15 parts 100% β-carotene, water-suspensible encapsulated β-carotene and optionally 50-250 parts C vitamin and / or 10-75 parts by weight of water-suspended solid tocopheryl acetate corresponding to 100% tocopheryl acetate, and other vitamins, if desired. The product weighs 3.3 g and has a dissolution time of 60-90 s.

Example 7

Ranitidine effervescent tablet

(a) Production of sparkling grains

840 parts by weight of crystalline citric acid, 210 parts by weight of citric acid powder, 45 parts by weight of sodium cyclamate and 4 parts by weight of sodium saccharin are heated in a vacuum vessel to 60 ° C. Then, a solution containing 6 parts by weight of water, 1 part by weight of sodium citrate and 3 parts by weight of sorbitol is aspirated and distributed with stirring. 500 parts by weight of sodium bicarbonate are then added and reacted, followed by addition of 370 parts by weight of monosodium citrate, which is also reacted. Finally, 100 parts by weight of sodium carbonate are added and the granules are dried under slow stirring under a vacuum of less than 15 mbar.

b) Preparation of the final mixture

To the effervescent granules prepared above, 167 parts by weight of ranitidine hydrochloride, 125 parts by weight of mannitol, 100.4 parts by weight of granulated antifoam (containing 100 parts by weight of mannitol and 0.4 parts by weight of simethicone) and flavoring agent are added. This mixture was stirred for 15 minutes for uniform distribution and then compressed into 2.5 g tablets. The tablets have a dissolution time of 60-80 s, an acid neutralizing capacity of about 2 meq, and tablets having 6.8% by weight ranitidine hydrochloride, 42.0% citric acid, 14.8% monosodium citrate, 20.0% by weight. sodium bicarbonate, 4.0 wt% sodium carbonate, 2.0 wt% sweetener, 5.0 wt% mannitol, 0.1 wt% sorbitol, 4.0 wt% granular antifoam (0.016 wt% dimethyl containing polysiloxane) and containing 1.2% by weight of flavoring.

Example 8

545 parts by weight of crystalline citric acid and 133 parts by weight of powdered citric acid or tartaric acid are stirred at 60 ° C. A first coating of 6 parts by weight of water and 4 parts by weight of sorbitol is then applied to the surface by stirring. Subsequently, 222 parts by weight of sodium bicarbonate are reacted on the surface of the citric acid and finally 80 parts by weight of sodium bicarbonate are added. The product was dried with slow stirring. The granules were sieved to 1.5 mm and then stirred at 10 rpm for 10 minutes with 167 parts by weight of ranitidine hydrochloride, 100 parts by weight of antifoam granules (containing 0.4 parts by weight of simethicone and 100 parts by weight of lactose) and 54 parts by weight of sweetener. and 40 parts by weight of flavoring agent until an even distribution of 20 is obtained. The mixture is then compressed into tablets of 1.43 g, having a dissolution time of 65-70 s, a hardness of 8 and an acid neutralizing capacity of about 1.5 meq. The product does not contain monosodium citrate. Ranitidine effervescent tablets have a low acid neutralizing capacity that has not yet been described.

Example 9

38.2% citric acid was heated to 060% with 0.26% sodium saccharin and then a solution of 0.6% water, 0.18% sorbitol and 0.12% sodium citrate based on the weight of the final mixture. two thirds. The solution was distributed for 5 minutes with stirring at 10 rpm. Subsequently, 16.2% by weight of sodium bicarbonate and 2.9% by weight of aspartame are added and fixed on the surface of the citric acid by reaction with a neutral material coating. A second moistening is then performed on the remaining one third of the above solution; 12.9% by weight of monosodium citrate and finally 5.2% by weight of sodium carbonate are added. The sparkling granules are dried under slow stirring at a temperature of at least 50 ° C under a vacuum of 15 mbar. The underlying effervescent product is sieved to 1.5 mm and mixed with 11.0 wt% ranitidine hydrochloride, 6.5 wt% mannitol, 6.5 wt% antifoam granules and 0.2 wt% flavoring. Is compressed into tablets weighing 55 g, having a dissolution time of 50 s, a hardness of 7.3 and an acid neutralizing capacity of less than 2 meq.

Example 10

Only carrier crystalline particles coated with inert material

Because cisapride, for example, is not very acid-sensitive compared to ranitidine, it is also possible to provide acid protection as described below, since it is embedded in granules.

(a) Preparation of acid crystals coated with a neutral substance

593 parts by weight of crystalline citric acid and 70 parts by weight of citric acid powder were heated to 60 ° C and then 4 parts by weight of sorbitol in 4 parts by weight of water.

-21 solution and spread over the citric acid surface with stirring. Finally, the citric acid so coated is dried under vacuum at 50-60 ° C.

In both the effervescent product form disclosed herein and the sparkling granules comprising the second alkali metal or alkaline earth metal carbonate coating, it is possible to protect cisapride against, for example, the addition of sodium bicarbonate to the citric acid in the drug particles.

b) Preparation of the active ingredient granules

160 parts of mannitol, 10 parts of cisapride, 5 parts of aerosil and 10 parts of sodium bicarbonate were heated to 60 ° C with stirring, followed by 27 parts of methyl ethyl ketone (or 45 parts of acetone), 2 parts of alcohol, 2 parts of poly Half of a solution of (vinylpyrrolidone) K30, 1 part propylene glycol, and 0.8 part docusate sodium was added and distributed evenly for 5 minutes for uniform wetting. The mixture was then dried in vacuo (0.8 bar), the second half of the above solution was aspirated into the vessel and redistributed with stirring for 5 to 10 minutes and then dried under vacuum.

The active ingredient granules are then sieved to 0.3 mm, and these granules already have enhanced protection against acid attack simply by the presence of sodium bicarbonate. These can then be mixed with the inert acid coated crystals, residual carbonates and bicarbonates, and other tablet ingredients and compressed into tablets.

c) Preparation of the final mixture

The active ingredient granules dried in step a) and coated with citric acid in step a) contain 50 parts by weight of sweetener, 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. with an antifoam granulate and 20 parts by weight of a flavoring agent and then compressed into tablets weighing about 1.6 g, having a dissolution time of 60-70 seconds and a hardness of 7.

Example 11

Cisapride effervescent tablets

(a) Preparation of sparkling granules

Citric acid consisting of 300 parts by weight of granules, 80 parts by weight of fine granules and 40 parts by weight of powder and 5 parts by weight of sodium saccharin are uniformly moistened with 60 parts by weight of solution containing 0.4 parts by weight of sorbitol, 0.15 parts by weight of sodium bicarbonate 0.45 parts by weight of citric acid and 1.2 parts by weight of water. 12 parts by weight of malic acid are then aspirated and evenly fixed 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 redistributed evenly. Finally, the material is covered with 46 parts by weight of sodium carbonate, dried in vacuo and sieved through a 1.2 mm sieve to remove it from the container.

b) Preparation of the active ingredient granules: One part by weight of polyvinylpyrrolidone is dissolved in 12 parts by weight of ethanol, 6 parts by weight of propylene glycol and 6 parts by weight of docusate are added, followed by dilution with 165 parts by weight of methyl ethyl ketone. Half of this solution was distributed in a mixture of 960 parts of mannitol, 30 parts of Aerosil®, 60 parts of sodium bicarbonate and 61 parts of cisapride heated to 60 ° C. The mixture was partially dried under vacuum, then further moistened with the second half of the solution, then dried completely and sieved through a 0.3 mm sieve to remove it from the container.

The final mixture was prepared in an analogous manner to Example 5.

Claims (27)

Claims Claims 1. A granular effervescent product for oral administration of one or more pharmaceutically active substances in aqueous solution or suspension, which can be compressed into tablets and / or in tablet form, characterized in that it contains carrier crystals of at least one solid edible organic acid having at least one first coating. substantially coated, the first coating comprising at least one water and / or alcohol soluble inert material, applied in a relatively small amount relative to the acid particles, and suitable for reducing the melting point of the acid crystals, and having at least one second coating comprising a coating of an alkali metal salt of at least one solid edible organic acid and at least one solid edible organic acid of an alkali metal carbonate, an alkali metal bicarbonate, an alkaline earth metal bicarbonate, contains at least one compound from the earth metal salt thereof. Granular product or tablet according to claim 1, characterized in that the inert material is a water-soluble polymer, a higher alcohol, a carbohydrate and a hydrocolloid or a mixture thereof, and the inert material is about 0.05 to 1.0% by weight. , preferably from about 0.07% to about 0.8% by weight. Granular product or tablet according to claim 1 or 2, characterized in that a humectant is fixed on the effervescent granules, the humectant being preferably anhydrous sodium carbonate and / or sodium sulfate, preferably in an amount of about 4 to 10% by weight. % by weight of the total mixture. 4. A granular product or tablet according to any one of claims 1 to 4, characterized in that the effervescent granules have at least one additional coating comprising at least one solid edible organic acid as an alkaline and / or alkaline earth metal salt and optionally containing an additional neutral 24 and, if preferred, at least one of the coatings also comprises an antifoaming agent. 5. Granular sparkling product according to any one of claims 1 to 3, characterized in that the granulated product or the granulated product pressed into a tablet form further comprises at least one antifoaming agent which is present in the granular product as an ingredient thereof. Granular product or tablet according to claim 4 or 5, characterized in that the anti-foaming agent is dimethicone and / or simethicone in an amount of about 0.005-0.5% by weight of the total mixture or about 0.05-2. 0% by weight of the pharmaceutically active agent. 7. A granular product or tablet according to any one of claims 1 to 3, characterized in that it has an acid binding capacity of less than 5 meq, preferably less than 3 meq, as measured by USP XXIII Test 103. 8. Granular product or tablet according to any one of claims 1 to 3, characterized in that its total weight does not exceed 2.5 g, preferably 2.0 g, in water at room temperature with a dissolution time of less than 180 s, preferably less than 120 s. 9. A granular product according to any one of claims 1 to 3, characterized in that the hydrophobic substance is present in the form of granules separated from the effervescent component, wherein the hydrophobic material is coated with at least one suspending agent and / or inert material, preferably mannitol and / or sorbitol. or fixed to it. Granular product or tablet according to claim 9, characterized in that the granulate further comprises at least one binder, preferably polyvinylpyrrolidone and / or a small amount of a surfactant, preferably dioctyl sodium sulfosuccinate and / or sodium. lauryl sulfate and / or alkali metal and / or alkaline earth metal carbonate and / or bicarbonate. -25 11. A granular product according to any one of claims 1 to 4, characterized in that from about 2% to about 30% by weight of cimetidine, about 30% to about 60% by weight of solid edible organic acid, about 12% to about 40% by weight of at least one alkali metal or alkaline earth metal carbonate. or bicarbonate (of which about 2-10% by weight of sodium carbonate as a wetting agent) about 1-4% by weight of a sweetener, about 0.01-30% by weight of a neutral substance (of which about 0.01-0.05% by weight of a neutral material coating), preferably about 3-20% by weight of sorbitol and about 2-10% by weight of mannitol, about 0.005-0.5% by weight of antifoaming agent and about 0.1-3% by weight of flavoring agent. 12. A granular product or tablet according to any one of claims 1 to 4, characterized in that about 0.4 to 4.5% by weight of cisapride, about 0.4 to 4.5% by weight of suspending agent, about 0.1 to 1% by weight of binder, based on the total weight of the mixture. , preferably polyvinylpyrrolidone, about 0.03-0.35% by weight surfactant, preferably dioctyl sodium sulfosuccinate, about 30-55% by weight solid, edible organic acid, preferably citric acid, about 12-40% by weight at least one alkali metal or alkaline earth metal carbonate or bicarbonate (of which about 2-10% by weight of sodium carbonate as a wetting agent), about 0.3-2.5% by weight of a sweetener, about 0.02-55% by weight an inert material (of which about 0.02-0.1% by weight of inert coating) is preferably in the form of maltodextrin, lactose and / or mannitol, about 0.005-0.05% by weight of an antifoaming agent, preferably dimethicone and / or simethicone, and about 0.2-5% by weight of flavoring contains material. 13. A granular product or tablet according to any one of claims 1 to 3, characterized in that its ingredients, based on the total weight of the mixture, are as follows: - about 0.1 to 0.5% by weight of β-carotene (100%), - about 0 to 2% by weight of tocopheryl acetate (100%), Granular product or tablet according to any one of claims 1 to 10, characterized in that it contains the following ingredients, based on the total weight of the mixture: about 3-14% by weight of ranitidine hydrochloride (75-300 mg / dose), about 30% by weight. -50% citric acid, about 0-20% monosodium citrate, about 10-30% sodium bicarbonate, about 2-10% sodium carbonate, about 1-3% sweetener, about 0.05% -0.2% by weight of neutral material for the first coating, and about 0-15% by weight of additional inert material, about 0-8% by weight of antifoam granules and about 0.1-4% by weight of flavoring agent. An effervescent tablet comprising at least one pharmaceutically active substance and an effervescent system comprising: at least one solid edible organic acid, at least one alkali metal carbonate or bicarbonate as a gasifying component, and at least one alkali metal salt of the acid; and the carrier crystals of the at least one acid have at least two coating layers, the first layer comprising at least one solid edible organic acid or an alkali metal salt thereof or a mixture thereof, and the second layer containing at least one alkali metal salt of the at least one acid; and the first layer -27 another inert material which may be a water soluble polymer, a higher alcohol, a carbohydrate and / or a hydrocolloid. A granular product or tablet comprising the effervescent system of claim 1 and cisapride as a pharmaceutically active substance, wherein the total weight of the product or tablet is less than 2 g, preferably less than 1.6 g, having an acid binding capacity of less than 5 meq. below meq. A granular product or tablet comprising the effervescent system of claim 1 and the pharmaceutically active substance cimetidine, wherein the total weight of the product or tablet is less than 2.5 g, preferably less than about 2.0 g, and has an acid binding capacity of less than 5 meq. Below 3 meq. 18. A granular product or tablet comprising the effervescent system of claim 1 and ranitidine as a pharmaceutically active substance and having a total weight of less than 2.6 g, preferably less than 2.0 g, and an acid binding capacity of less than 3 meq, preferably 2 meq. below. 19. Procedure 1-18. For the preparation of a granular product or tablet according to any one of claims 1 to 3, characterized in that the crystals of the at least one solid edible organic acid are moistened with an aqueous solution of an inert material followed by an alkali metal and / or alkaline earth carbonate and / or the powdered form is uniformly dispersed and adhered to the wet surface layer by stirring, then the effervescent granules so prepared are dried, and a pharmaceutically active substance, preferably an acid-sensitive substance, in particular one of H2 blockers, cimetidine, ranitidine, cisapride and β-carotene. mixed with excipients and optionally compressed into tablets. 20. The method of claim 19, wherein the effervescent granules are coated with at least one additional coating moistened with a solution of a buffering agent, the buffering agent preferably being at least one of an alkali metal carbonate, an alkali metal bicarbonate, alkaline earth metal carbonate, alkaline earth metal bicarbonate, at least -28 is an alkali metal salt of a solid edible organic acid, and an alkaline earth metal salt of at least one solid edible organic acid. 21. The method of claim 19 or 20, wherein the solution further comprises an inert material which is a water soluble polymer, a higher alcohol, a carbohydrate, a hydrocolloid or a mixture thereof. 22. A 19-21. A process according to any one of claims 1 to 4, characterized in that the sparkling granules are mixed with the active ingredient together with a granular product which is prepared by applying an antifoaming agent in a suitable solvent to the surface of a neutral material particle and removing the solvent by drying. 23. A 19-22. A process according to any one of claims 1 to 4, characterized in that the dried effervescent granules are moistened with ethanol, preferably containing a dissolved antifoam agent, and then dried again by evaporation of the ethanol to remove any residual moisture. 24. A 19-23. A process according to any one of claims 1 to 4, wherein the pharmaceutically active substance is applied to the suspending agent particles in solution as a solution, together with a binder and / or a surfactant, uniformly distributed and then dried. 25. A 19-24. A process according to any one of claims 1 to 3, wherein the pharmaceutically active substance is mixed with at least one inert substance, at least one suspending agent and at least one of the following substances: alkali metal carbonate, alkali metal bicarbonate, alkaline earth metal carbonate, - bicarbonate, an alkali metal salt of at least one solid edible organic acid, an alkaline earth metal salt of at least one solid edible organic acid; then applying to the particles of the mixture at least once a solution of at least one binder and / or surfactant, distributing thereon and drying. • · -2 926. A process for preparing sparkling granules from a powdered or granulated mixture comprising a solid, edible organic acid and an alkali metal and / or alkaline earth metal carbonate and / or bicarbonate, under vacuum, wherein at least one of the components is highly reactive to the reaction. passivate in stage a measured amount of polar solvent is added in addition to treatment with the heated mixture in vacuo, the maximum specified value of the pressure difference caused by the developing means is dosed during the reaction solvent for carbon dioxide of 10 ⁵ Pa (1000 mbar), the released carbon dioxide, the volume and mass of this is determined from the differential pressure, and the heat treatment is repeated after drying the mixture as many times as necessary to passivate the surface; RIS solvent dissolved a neutral substance which can be a water soluble polymer, a higher alcohol, a carbohydrate and / or a hydrocolloid. -26- about 35-70% by weight of a solid edible organic acid, preferably about 0-10% by weight ascorbic acid, about 35-55% by weight citric acid and about 0-5% by weight malic acid, - about 11-38% by weight of at least one an alkali metal or alkaline earth metal carbonate or bicarbonate, preferably about 5-15% by weight of calcium carbonate and about 5-20% by weight of sodium bicarbonate, - about 1-4% by weight of a sweetener, - about 0.1- 35% by weight of neutral material (of which about 0.1 to 0.5% by weight of the neutral material coating), preferably about 1 to 10% by weight of sorbitol and about 5 to 25% by weight of mannitol, and - about 0.3 to 3% by weight flavoring agent. 27. A process for the preparation of a effervescent granular material comprising at least one solid, crystalline edible organic acid and at least one alkali metal or alkaline earth metal carbonate which, by reaction with said organic acid in aqueous solution, produces carbon dioxide: reacting a portion of the organic acid and carbonate in solution with water and / or alcohol to form a pre-reaction product, the resulting pre-reaction product being added to a further amount of the organic acid in crystalline form with careful mixing to form a first coating reaction of the organic acid crystals followed by the release of crystal water - forming at least one additional coating, including some carbonate on the organic acid crystals, which adheres to the first coating, - upon application of the last coating, terminating the reaction by drying, wherein z an inert substance is added which is neutral • * The substance is a water and / or alcohol soluble polymer, a higher alcohol, a carbohydrate and / or a hydrocolloid.