Title:  Effervescent granules with delayed effervescent effect

United States Patent:  6,432,450

Issued:  August 13, 2002

Inventors:  Gergely; Gerhard (Gartengasse 8, A-1053, Vienna, AT); Gergely; Irmgard (Vienna, AT); Gergely; Thomas (Vienna, AT)

Assignee:  Gergely; Gerhard (Vienna, AU)

Appl. No.:  656118

Filed:  September 6, 2000

The effervescent granules with delayed effervescent effect consist of at least one acid component and one component evolving gas under the action of acid, as well as of active substances, fragrances, plant extracts, vitamins, minerals etc. admixed as needed, the particles of the acid component being coated with--preferably 1 to 30% by weight of--at least one carbonate compound--possibly including a partial reaction--and/or a hydrocolloid. The gas-evolving component consists of alkali hydrogen carbonate, alkali carbonate, and/or alkaline-earth carbonate particles which are coated with at least one further substance, particularly with a melt of polyethylene glycol 6000. The particles preferably have a grain size above 0.2 mm.

Description of the Invention

The invention concerns effervescent granules with delayed effervescent effect according to the preamble of claim 1, particularly for a presentation in sachets.

Unlike known effervescent tablets, the effervescent granules packed in sachets very often are difficult to handle; when hitting the surface of the liquid, the components of the effervescent system such as citric acid and sodium hydrogen carbonate which--in order to attain rapid dissolution--most often are relatively fine-grained immediately start to react while producing effervescence. Depending on their specific weight, further components, be it adjuvants or active substances, either are retained on the surface for some time or drop to the bottom, and poorly dissolve there. This effect is further amplified when the granules are poured from a commercial type of sachet, which in most cases is close to square-shaped and for this reason has a relatively wide tear opening (occasionally in the size range of the liquid surface). The components of the effervescent mix then hit a correspondingly large part of the liquid surface as a relatively thin layer.

It has been the aim of the invention, therefore, to develop effervescent granules with delayed effervescent effect that are readily and freely flowing. Due to their specific packaging, these granules offer consumer-friendly handling and may contain vitamins, minerals, trace elements or pharmaceutically active substances as well as sweeteners and flavors. The aim was a simple preparation which would allow the product to be manufactured at a favorable price, and granules to be obtained which drop to the bottom without reacting when introduced into (water, and produce their effervescent effect, only after several seconds at the bottom, thus producing turbulence in the liquid which achieves dissolution of active substances or vitamins, minerals and other ingredients with very small quantities of these delayed-action effervescent mixes.

From EP-A1-642,784 a coating of the carbonate particles is known which serves for a better fixation of the pharmaceutically active substance, exactly on these carbonate particles. This effervescent mix would yield an insufficient delay relative to the aim of the present invention.

In EP-A1-233,839, an effervescent mix is described in which both components imperatively are coated with xanthan, which is not readily soluble and hence leads to dissolution times of up to 35 min, a time entirely useless for the present aims.

In GB-A1-1,270,781, it is described in a few examples that for the purposes of improved stability, not only the acid component but also the carbonate component of the effervescent mix be coated with very slight amounts of polyethylene glycol and HPMC (hydroxypropylmethylcellulose). This again would lead to a delay that is highly insufficient for the purposes of the present invention.

The object of the present invention is surprisingly well achieved according to the invention by the actions listed in claim 1. Advantageous further embodiments of the invention are described in the characteristics of the dependent claims.

It was seen that the passivation and the coarse-grained structure of the organic acids such as citric and tartaric acid yield some effect, but this is far from adequate for the purposes of attaining a sufficient delay in the effervescent effect.

It is necessary, therefore, to delay or process the gas-evolving components of the carbonate phase in the effervescent system, that is, the alkali and/or alkaline-earth carbonates and/or alkali hydrogen carbonates, in such a way that one can achieve the desired effect, viz., a distinctly delayed effervescent action upon introduction into the water and an effervescent effect evolving from the bottom.

In general, the retarding substances can be sugars, sugar alcohols or colloids which are applied to the particles of the alkaline, gas-evolving: mixture of carbonates and bicarbonates and yield a delay effect after drying.

An effect particularly suitable for this system is achieved by polyethylene glycols, which produce satisfactory delay effects in effervescence because of the time during which they themselves take up water, and also because of their interference with the reaction. In preference, polyethylene glycol 6000 is employed; mixtures of polyethylene glycol 4000 with polyethylene glycol 10,000 can also be employed. A satisfactory quantity to be employed in order to achieve the desired effect proved to be 5 to 15 percent by weight referred to the gas-evolving components. To the fused polyethylene glycol one can add further substances such as colloids, for instance very fine gum guar powder or xanthan, as well as a micronized acid component. A micronized, poorly soluble acid component such as fumaric or adipic acid that has been introduced into the melt leads to the advantage that overly agglomerated granules of the alkali hydrogen carbonates and alkali carbonates or alkaline-earth carbonates can readily dissolve. Here a charge of 1 to 3 percent by weight relative to the gas-evolving components or 10 to 30 percent relative to the polyethylene glycol charge will suffice.

The gas-evolving substances can now be granulated with alcoholic solutions of polyethylene glycols, and then dried. This approach produces an appropriate delay of the effervescent effect, already in a mixture with a citric acid treated with alkaline-earth carbonate.

It is a particularly preferred preparative approach for the purposes of attaining a delay to mix and homogenize these gas-evolving carbonates and/or bicarbonates and then slowly add fused polyethylene glycols to the mixture at a high temperature, preferably drop by drop. At high temperatures of about 120 to 160^oC., polyethylene glycols need more time to solidify, hence sufficient time is available during the mixing for coating of the individual particles with a film of polyethylene glycol. It is advisable then, of course, to select coarse-grained alkaline components and for instance use a coarse-crystalline form of the granular sodium carbonate or sodium hydrogen carbonate, since such particles sink more rapidly, which produces a delayed effervescent effect from the bottom. Sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate as well as magnesium carbonate are suitable here.

It has been found to be advantageous in the case of sodium hydrogen carbonate to select a grain size distribution where the major sieve fraction is in the range between 0.1 and 0.4 mm, preferably to the extent of 50 to 85% and particularly preferably to the extent of 70 to 85%. For potassium hydrogen carbonate, a grain size of <0.5 mm is recommended, although the main portion of the particles should be above 0.1 mm. In view of the poorer solubility of sodium carbonate, this can be employed in a finer quality, for instance with the main portion of the grains between 0.07 and 0.2 mm. Calcium carbonate is preferably used in an amount of up to 30% by weight of the gas-evolving components.

A further improvement of the system can be achieved, as indicated earlier, by the appropriate superficial passivation of the acids, preferably with calcium or magnesium salts, which leads to an additional delay of the reaction start.

For active substances such as paracetamol, lactulose, N-Acetylcysteine, ranitidine, plant extracts, multivitamins and/or trace elements, for instance, an organic acid treated with 1 to 10% by weight of calcium carbonate can serve as the acid component to which the alkali hydrogen carbonates, alkali carbonates, and/or alkaline-earth carbonates that have been delayed in their effervescent effect are then added as described above. This yields, on one hand the desired, delayed effervescent effect and on the other hand the intended stability.

For products intended to contain trace elements, the same basic approach can be conceived, since the composition according to the invention does not need any additional action to incorporate the trace elements.

In the case of calcium and/or magnesium products, the corresponding alkaline-earth carbonate or oxide can be used to treat the organic acid. The amount of calcium and/or magnesium that must additionally be introduced, largely depends on the desired doses of calcium and magnesium ions; in the instance of calcium, for instance, granulated or precipitated calcium carbonates having corresponding flow properties can be incorporated in addition into the alkaline carbonate phase. In the case of magnesium products, one can either apply up to 30% by weight of magnesium carbonate to the organic acid particles or add trimagnesium dicitrate to the final mix, in order to reach the desired amount of magnesium ions.

The preferred acid component is citric acid having a main sieve fraction of 50 to 95% by weight within grain sizes of 0.3 to 0.7 mm. It is particularly preferred to use citric acid grit with a relatively coarse grain, the grain sizes of the main sieve fraction (about 80%) being between 0.3 and 0.6 mm. Coarser grain sizes may retard the reaction too much. With an appropriate passivation of the grains, one can also use a somewhat finer citric acid, for instance one having the main sieve fraction of 50 to 95% by weight within grain sizes of 0.2 to 0.4 mm, in order to obtain the desired product. The preferred grain size will lastly depend, not only on the rate of dissolution of the acid and gas-evolving components selected, but also on the final formulation and on other active substances incorporated into the granules. For instance, the citric acid can be mixed with 1 to 10% by weight of calcium carbonate and then brought in contact with a solution producing superficial passivation and thus, on one hand the delayed effervescent effect and on the other hand an enhanced stability of the granules is attained. The solution used to treat the mixture of citric acid and calcium carbonate (which has for instance a particle size of <5 .mu.m, the preferred size being 0.1 to 0.2 .mu.m) can be an aqueous or alcoholic or aqueous-alcoholic solution of citric acid containing between 40 and 80% by weight of citric acid in. the solution.

It is possible, too, to employ an aqueous buffer-granulating solution according to European Patent No. 0,272,312. For an even stronger delay of the effervescent effect, hydrocolloids can be employed. These can either be applied after moistening of the mixture of organic acid with carbonate, where an amount of 1 to 5% by weight is preferable. Or one can introduce the hydrocolloids into the granulating solution, in which case smaller amounts of 0.1 to 1% by weight are required. Maltodextrins, polyvinylpyrrolidone, gum guar, gum arabic and all hydrocolloids soluble in water, ethanol or their mixtures can be employed as hydrocolloids.

Treatment of the organic acids can be performed with all current, technically known methods such as fluidized-bed driers, vacuum granulators as well as continuous reaction systems. If necessary, the organic acid after the treatment can be dried to secure optimum stability.

After the treatment the dried organic acid is screened to a grain size of 1 to 2 mm. Acid thus treated is mixed in a final mixing step with the carbonate phase and with the active substances, vitamins and/or minerals and/or trace elements. With an additional amount of alkali carbonates or alkali hydrogen carbonates one can also set a desired pH value.

This basic mixture can be provided with all current, permitted sweeteners such as aspartame, sodium cyclamate, saccharin sodium salt, acesulfame as well as the corresponding fragrances and flavors. When needed, fillers which in their grain size distribution match the basic granules can be introduced, for instance sugars or sugar alcohols such as mannitol, sorbitol, xylitol etc.; granulated maltodextrins can also be used as fillers.

In this system, relatively large amounts of soluble active substances can be dissolved on account of the vortex action initiated at the bottom. It is for instance possible to dissolve 10 g of lactulose with about 3 to 4 g of the granulated mixture of citric acid coated with calcium carbonate in combination with the carbonate phase.

This system also yields satisfactory dissolution behavior for granulated plant extracts usually having a very strong lump and slime-forming tendency. Depending on their properties, the plant extracts may merely be admixed to the system, for instance Echinacea, Agnus castus, ivy and Cimicifuga. It is recommendable, however, to perform an additional step by treating the extract with an antifoaming or wetting agent, which improves the vortex formation and the effect of the granules dissolving with a delay from the bottom.

The active substances can be integrated into the system in the most diverse manners. In the case of water-soluble active substances, admixing to the effervescent mix components usually will suffice. Depending on their sensitivity to acids or alkaline components, small amounts of the active substances can bei introduced, either into the citric acid component or into the carbonate phase, in order to be uniformly distributed in the granules.

Through its special effervescent effect, the system reveals an extremely good dispersing action even for insoluble active substances such as paracetamol. In the case of an active substance that is very poorly wettable or present in large amounts, it may become necessary to apply a special treatment to it and then introduce it as an individual phase.

For vitamin products such as vitamin C or multivitamin products, a dry mix of the treated citric acid with the carbonate phase and the vitamin C or, for the multivitamin products, with the multivitamins can be prepared which is then packed, preferably into special elongated sachets.

A further advantage of the effervescent system according to the invention is brought out by a special packaging in tubular long sachets. The sachets are preferably made in a width of 10 to 30 mm and a length of 7 to 20 cm. The amount of effervescent granules that is required depends on the active substances that should be incorporated. The weight of a sachet may for instance be 1 g if only small amounts of active substances are to be dissolved. In the case of effervescent mineral mix sachets which should contain a given amount, for instance, of calcium or magnesium, it will be necessary to use the appropriate amount of citric acid in order to set the desired pH value, so that the effervescent mineral mix sachets may weigh as much as 4-5 g. These elongated sachets have the advantages of a more consumer-friendly handling and more rapid penetration of the granules into the water, juice or mixed drinks, since the granules hit the liquid surface as a thin, concentrated jet which, because of the delayed effervescent effect, does not react at once producing effervescence but swiftly passes through the surface, drops to the bottom of the cup and only there starts to effervesce. This is an additional device for preventing effervescence of the effervescent granules upon first contact with the water surface and floating of the granules on the surface prior to their sinking and generating the effervescent effect.

It was found as a surprise that with a citric acid thus treated, and with the carbonate phase, one can achieve, both the desired retardation of the effervescent effect and a stability meeting the requirements of the ICH guidelines. On the other hand, the elongated sachet contributes substantially to the applications of the pharmaceutical form, since the granules are not spread flat on the water surface but fall to the bottom of the cup as if through a pipe, and develop their effervescent action only from there.

Claim 1 of 18 Claims

What is claimed is:

1. Effervescent granules with delayed effervescent effect, consisting of at least one acid component and one gas-evolving component of alkali hydrogen carbonate, alkali carbonate, and/or alkaline-earth carbonate particles evolving gas under the action of acid, as well as of active substances, fragrances, plant extracts, vitamins, minerals admixed as needed, the at least one acid component comprising particles coated with at least one of the following compounds: alkali carbonate, alkali hydrogen carbonate, alkaline-earth carbonate, alkaline-earth oxide, hydrocolloid, wherein the particles of the gas-evolving component are coated with a melt of polyethylene glycol or mixtures of polyethylene glycols.
 

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