Link:  Pharm/Biotech Resources

Title:  Soluble, gum-containing, coated chewable tablet

United States Patent:  6,932,979

Issued:  August 23, 2005

Inventors:  Gergely; Gerhard (Vienna, AT); Gergely; Irmgard (Vienna, AT); Gergely; Thomas (Vienna, AT)

Assignee:  Dr. Gergely & Co. (Vienna, AT)

Appl. No.:  407134

Filed:  April 7, 2003

The soluble, rubber-containing, coated chewable tablet contains chewable components, syrup components and fat or wax components and optionally fillers. It can be prepared by a process in which pulverulent chewable components are mixed with the molten fat or wax components. The mixture, with the addition of at least one syrup component, then becomes a crumbly material, which is then cooled to below 0° C., then milled to a particle size of not more than 5 mm and, after cooling to below 10° C., compressed to give tablets which are coated in a known manner. The finished product-due to compression of the cooled granules-presumably has a partially granular structure in which the moisture has been initially immobilized by the low temperature. After compression, this moisture becomes mobile as a result of heating (in particular during the coating process) and migrates or diffuses-initially at the surface-into the water-soluble ingredients present. These are partially dissolved and give a highly viscous, thixotropic, chewable material.

Chewing gum formulations based on natural rubber have been widely used in the pharmaceutical industry. Their advantages are the pleasant and popular dosage form and rapid, sublingual absorption of an active ingredient. However, the serious disadvantage of such formulations is a rubber material which remains after chewing and which has resulted in, for example, antiemetics based on this material being undesired in aircraft and, for example, simply the possession of chewing gum being punishable in Singapore.

On the other hand, it is also known from the confectionery industry that gum arabic and sugar-containing solutions can be boiled and can be cast in suitable shapes which are then optionally coated. For example, the two U.S. Pat. Nos. 4,698,232 and 5,476,678 describe fiber-containing chewable materials having a foamed matrix of gum arabic and gelatin and an unfoamed matrix of sugar syrup.

DE-A1-4444051 describes a chewable tablet which rapidly disintegrates in the mouth and in which hydrophilic active ingredient particles are coated with or embedded in a hydrophobic material, optionally with or in gum arabic. GB-B-1142377 describes a chewable tablet for cleaning the teeth, in which one part each of gum arabic and gelatin are mixed with two parts of glycerol and various small amounts of additives.

For the preparation of a pharmaceutical formulation, all these products and their production processes are unsuitable or only of limited suitability. On the one hand, it is desired to achieve slow release to the body distributed over several minutes in the case of various active ingredients, e.g. antiemetics or disinfectants; the formulation ideal to date for this purpose, in a chewing gum, is increasingly meeting resistance, as already mentioned. On the other hand, the production process known from the confectionery industry often cannot be used for the high requirements of good manufacturing practice in the pharmaceutical industry and is much too expensive for relatively small batches, also in terms of the cost of the apparatus.

It is therefore the object of the invention to provide a composition and a process in which active ingredients, such as expectorants (clobutinol, salbutamol), throat disinfectants, vitamins and/or trace elements, even in low dosage, can be incorporated into a soluble chewing gum material in an appropriately exact dose, which can be compressed, by technology meeting the pharmaceutical requirements, to give tablets which result in a soluble, chewable material.

This object is achieved for the first time in a surprising manner by the combination of the features or measures stated in claim 1, by virtue of the fact that a granular material is formed owing to the composition and the process. Further preferred embodiments of the invention are described in the features of the dependent claims. The invention proposes this novel product and preparation process, which avoids the abovementioned disadvantages and meets the desired requirements. This is achieved by the fact that the composition and the process provide a granular material, good processibility-in particular during comminution and admixing of further additives and with regard to the compressibility-being possible by cooling.

In the context of the invention, "chewable components" are to be understood as meaning all those substances which, alone or mixed with one another, behave like chewing gum for at least 1, preferably at least 2, in particular at least 3, min when chewed, but begin to dissolve during this time and are then completely dissolved and swallowed with the saliva. This range of substances includes, inter alia, but not exclusively: gum arabic, tragacanth, guar gum, xanthan gum, pectins; but also dry syrups, such as, for example, dry glucose syrup and/or fructose syrup; soluble cellulose derivatives, such as, for example, sodium carboxymethylcellulose. Dry glucose syrup likewise exhibits partly rubber-like behavior on chewing.

In comparison, in the context of the invention, "syrup components" are understood as meaning exclusively those which are used either as syrup or in highly concentrated solution, such as, for example, 80% glucose syrup, 70% maltodextrin solution, swollen gelatin, but also other syrups, such as corn, sugar or invert sugar syrup (Invertin® Merck). Glucose syrup can be completely or partly replaced by other concentrated carbohydrate, sugar alcohol, gelatin or similar solutions. It is important to maintain as small an amount of water as possible, since the mixture otherwise becomes a slurry, as in the prior art. On the other hand, a certain amount of moisture, from about 4 to about 7%, must remain in the coated tablet since, on drying out and at a moisture content of less than 2%, the tablet would no longer give a malleable, chewable material and would become too hard to bite.

Fat components used may be all edible, animal and vegetable fats. These are triglycerides which essentially consist of mixtures of glyceryl esters of higher fatty acids, in particular of vegetable or animal origin, for example of the order of magnitude of C₁₀ to C₂₂, whose melting point is not below 60° C.

The addition of waxes, such as, for example, beeswax, solid paraffin, ozocerite or similar substances, which ensure a longer chewing time, have proven particularly advantageous with regard to the chewability. The addition of beeswax, in particular, improves the chewability and reduces the adhesion to the teeth. The addition of relatively small amounts of glycerol or propylene glycol makes the tablet core softer to bite.

The process is carried out in principle according to the following scheme: all powder components are introduced into a surface mixer and mixed at slow speed. Thereafter, glycerol and a melt comprising fats and waxes are introduced and carefully mixed with the powder. Finally, a-for example carbohydrate-containing-syrup is added and if required-for example for reducing the viscosity to facilitate processing-can be heated to about 40° C., but unheated glucose syrup may also be used. Mixing is continued until a crumbly mass forms. The addition of the pharmaceutical active ingredient depends on its type, i.e. on its taste and/or on its stability criteria; if it is stable and has a neutral taste, it is added simply by mixing as a powder into the starting mixture; in another case, it is added, for example, by dissolving in the fat melt, surrounded by the hydrocolloid, or in a matrix whose taste has been masked by suitable measures, for example, in the case of dimenhydrinate, in polymethacrylic esters, HPMCP (hydroxypropylmethylcellulose phthalate), alginic acid and the like.

The crumbly material can be cooled either batchwise in bags of plastics sheet, for example in a refrigerator or freezer, or during passage on a cooling conveyor belt. For example, the bags are placed in a bed of dry ice and covered with dry ice. Thereafter, the material can be comminuted to the desired particle size of from about 2 to about 5 mm-for example by milling and sieving. The additives, such as, for example, additional artificial sweeteners, flavors and the like, and active ingredients or active ingredient mixtures, active ingredient matrix, etc., are then mixed with this comminuted material. The final mixture is then fed-expediently via a cooling zone, for example through a double jacket which is cooled on the outside with brine coolant-to a tablet press, preferably a rotary tablet press, and is compressed to give tablets of the desired size.

The temperature to which freezing or cooling is effected should be tailored to the respective mixture. The individual components of the mixture form a complex system with one another and mutually influence one another with respect to the behavior during the milling process and the compressibility. If the moisture content is at the upper limit, freezing must be effected to lower temperatures. Furthermore, it should be ensured that processing takes place as far as possible in a closed system and/or in a room with low atmospheric humidity and/or during short periods, in order to keep the condensation of atmospheric humidity on the material as small as possible or to take this moisture into account during formulation.

The tablets in the form of tablet cores can then be coated in a manner known per se. During coating, the cores are as a rule warmed to about 40 to about 50° C. At this temperature, the moisture which was added with concentrated syrup solution and/or gelatin solution penetrates the chewable components, and a very readily chewable material is formed, the dry syrup promoting or improving the chewability.

The product defined in claim 1 presumably has-owing to compression of the cooled granules-a particulate structure in which the moisture is initially immobilized by the low temperature. After compression, this moisture becomes mobile owing to heating (in particular during the coating process) and migrates or diffuses-initially at the surface-into the water-soluble ingredients present. These are partially dissolved and give a highly viscous, thixotropic, chewable material.
 

Claim 1 of 31 Claims

1. A soluble chewable tablet comprising

a pharmaceutically active ingredient, whereby said pharmaceutically active ingredient is slowly released when said tablet is chewed, said tablet becoming thixotropic when chewed but not fully dissolving for at least one minute when chewed, and said tablet slowly dissolves when said tablet is chewed after said at least one minute, so as to completely dissolve thereafter in saliva during chewing;

10 to 60 percent by weight of at least one chewable component selected from the group consisting of gum arabic, tragacanth, guar gum, dry glucose syrup, dry fructose syrup and carboxymethyl cellulose:

20 to 50 percent by weight of at least one syrup component selected from the group consisting of carbohydrate syrup, concentrated maltodextrin solution and sugar alcohol syrup;

2 to 12 percent by weight of at least one fat or wax component selected from the group consisting of fat components having a melting point not above 60° C. and wax components having a melting point of less than 70° C.; wherein the chewable component is partially dissolved by the syrup component.

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