Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-09-06
2002-08-13
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S466000, C424S490000, C424S497000, C514S951000, C514S770000, C514S784000
Reexamination Certificate
active
06432450
ABSTRACT:
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 ° C., 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-
Gergely Gerhard
Gergely Irmgard
Gergely Thomas
Gergely Gerhard
Oliff & Berridg,e PLC
Spear James M.
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