DE20102817U1 - Lozenges and chewing pills with cyclodextrin - Google Patents

Description

SUCKING AND CHEWING PASTILLES WITH CYCLODEXTRIN

The invention relates to molded lozenges and chewing pastilles based on hydrocolloids containing a cyclodextrin and one or more chemically defined pharmaceutical active ingredients or plant extracts.

Pastilles - see also W. Rahn, Pharmazeutische Zeitung, pp. 2214-2218 (1982) - are generally understood to be preparations that are sucked or chewed in the mouth. A distinction is made between tablets, hard candies and gum pastilles (also called gummy candies).

The processes for producing these dosage forms differ fundamentally from one another.

Tablets are pressed on tablet machines. The tablet mass must be prepared by mixing and granulating. Various authors have already dealt with granulation methods for active ingredients that are difficult to process.

Candies are made by mixing sucrose and glucose syrup, boiling at around 130 ^° C and removing the water from the mass in a vacuum to 0.5 to 2% by weight. The active ingredients and flavourings are added to the viscous candy mass, which has been cooled to around 85 ^° C, and mixed in by kneading. In cone rollers and other candy machines, the candy mass is pulled into strands, shaped and cut while constantly cooling. It is well known that the distribution of the active ingredients is quite inaccurate due to the viscous nature of the candy mass.

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Gum pastilles or lozenges and chewing pastilles in the sense of the present invention are produced by first dissolving hydrocolloids such as gum arabic together with sucrose, glucose syrup, sorbitol, xylitol and/or maltitol solution in water in a stirred vessel and then dissolving, emulsifying or suspending the active ingredients in this base mass. The casting mass obtained in this way is poured into so-called powder trays. These are, for example, flat wooden boxes measuring approx. 80 x 40 cm, which are filled with starch, in particular corn starch. The desired shapes are pressed into the smoothed powder using a stamp board and the warm casting mass is pumped into the resulting depressions in precise doses, whereby the poured mass does not combine with the powder. Horde after horde, 500 to 1000 pastilles each, are cast in this way, stacked and the water is removed from the pastilles in drying chambers over the course of 3 to 4 days, leaving only 5 to 15% by weight, and in particular 10% by weight, of residual moisture. The pastilles produced in this way are "powdered" and then given a final treatment, for example with beeswax.

WO 92/0214, WO 93/10797, WO 94/25002 and WO 95/30407 describe lozenges and chewing pastilles based on hydrocolloids, each containing different active ingredients.

Unfortunately, the galenic form of the gum pastille is not equally suitable for all active ingredients. Due to the fact that a lozenge or chewing pastille is kept in the mouth for a long time, the taste of the pastille is of paramount importance. In the case of bitter active ingredients, sweetening and flavoring the pastilles are often not enough to mask the bitter taste. Such active ingredients have therefore not been available in a lozenge until now.

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The object of the present invention, in comparison with the prior art, was to find a way to make bitter medicinal substances, whether chemically defined or herbal, available in the galenic form of the cast lozenge and chewing pastille.

The above object is achieved by lozenges and chewing pastilles based on hydrocolloids which are soluble in water or gel-forming in aqueous systems, in particular selected from gum arabic, gelatin, xanthan gum, agar, tragacanth, aliginates, carrageenan, starch and pectin, preferably 10 to 60% by weight of gum arabic and/or 5 to 30% by weight of gelatin, in each case based on the total mass of the pastilles, which contain a cyclodextrin and optionally further auxiliary substances and additives.

Beta-cyclodextrin, l-alpha-cyclodextrin, l-hydroxypropyl-beta-cyclodextrin and/or dimethylbeta-cyclodextrin are preferably used as cyclodextrin. It has been found that beta-cyclodextrin, for example, which is only about 2% water-soluble, can be incorporated in an extremely simple manner in a finely dispersed form into pastilles based on the natural and/or synthetic polymers mentioned above and is suitable for masking bitter plant extracts and bitter chemical active ingredients.

The term "pastilles" and in particular the term "pastilles for sucking and chewing" in the sense of the present invention includes those that are produced by casting. Such pastilles are also referred to in science as "solid solutions" that are converted back into liquid solutions when sucked. Accordingly, the pastilles according to the present invention consist of various shaped elastic moldings that

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contains a finely distributed cyclodextrin in a mixture of hydrocolloid and other auxiliary substances and additives.

With the help of the present invention, it is possible to achieve a precise individual dosage of the pastille with a relatively gentle processing of the components, for example the plant extracts.

With the above-mentioned, at least partially or completely water-soluble, natural and/or synthetic polymers, which are selected according to the invention from tragacanth, alginates, carrageenan, starch and pectin, which can be used in addition to gelatin and/or gum arabic, a particularly good incorporation of the cyclodextrin is possible, since it is possible to work at relatively low temperatures. A particularly homogeneous distribution of the active ingredient, for example a plant extract, is created in the total mass, which means that the active ingredient content in the individual pastilles only fluctuates with a very small standard deviation. In addition, the process according to the invention makes it possible to produce relatively highly concentrated active ingredient pastilles, which was previously impossible due to the bitterness of these active ingredients.

If, in accordance with the present invention, active pharmaceutical ingredients are used in lozenges and chewing tablets, this includes chemically defined active ingredients as well as plant extracts. Particularly preferred chemically defined active pharmaceutical ingredients include, for example, dextromethorphan, sodium dibunate, ambroxol, clobutanol, dimenhydrinate, tramadol hydrochloride, caffeine, codeine, paracetamol and/or theophylline.

Plant extracts which can be used in a special way in the sense of the present invention include, for example,

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Thyme extract, ginger extract, green tea extract, primrose extract, St. John's wort extract, devil's claw extract, artichoke extract, horse chestnut extract, marigold extract, essential oils such as peppermint oil, eucalyptus oil, myrtol, anisole, fennel oil, black cumin oil and/or sage oil.

With the help of the present invention, it is possible to embed pharmaceutical active ingredients containing bitter substances as well as sharp-tasting ingredients such as those in ginger in a simple process in a dosage form that is pleasant for the patient. The cyclodextrin, preferably beta-cyclodextrin, contained in the lozenges and chewing pastilles according to the invention masks the bitter substances, in particular by adsorption. With the help of the present invention, sensitive flavorings, such as those found in plant extracts in particular, are also protected.

Particularly preferred natural and/or synthetic polymers which can be used in addition to gum arabic and/or gelatine in the sense of the present invention are also known under the term "hydrocolloids". The auxiliary substances and additives are preferably selected from sucrose, glucose syrup, sugar alcohols, isomalt, starch, sweeteners, fats, waxes, paraffin oil.

Corresponding basic recipes for pastilles are known in the state of the art under the term "gum pastilles". These derive their name from the raw material used in them, Arabic gum, and the elasticity of the pastilles. In the context of the present invention, this hydrocolloid is also preferably used as a basic material because it gives the pastille good sucking properties.

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As already mentioned, it is necessary that the pastilles according to the invention taste so good that they are not refused or swallowed. To improve the taste, other appropriate excipients known in the art, such as taste correctors and essences, as well as essential oils, can be used, thus combining therapeutic effect and taste improvement.

The base mass of the pastille preferably contains 10 to 60% by weight of gum arabic and/or 5 to 30% by weight of gelatin, each based on the total mass of the pastilles.

The amount of cyclodextrin in the pastilles according to the invention can be varied within a wide range. Preferably, the amount of cyclodextrin, preferably --cyclodextrin, should be as low as possible in relation to the total formulation. Accordingly, in the sense of the present invention, the amount of cyclodextrin is 1 to 50% by weight, in particular 5 to 40% by weight, in relation to the total mass of the pastille.

The pastilles according to the invention can be produced, for example, by dissolving the polymers defined above with other auxiliary substances and additives in water to form a viscous solution. Beta-cyclodextrin is suspended or dissolved in this base mass together with the bitter active ingredients and/or extracts and then this liquid mass is poured into molds in a mogul system. The still liquid pastilles thus obtained are dried in drying chambers at 40 to 70 ^° C, preferably 40 to 50 ^° C, then separated from the powder and subjected to a final treatment, for example with beeswax.

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The particular advantages of the pastilles according to the invention and of the process for their production are a low temperature stress on the excipients and active ingredients and their complete homogeneity in the casting mass, which allows a high accuracy of the active ingredient dosage.

Examples of implementation:
Example 1:

This object was achieved according to the invention by a multi-stage manufacturing process, namely

1. Prepare the base mass from Arabic gum, maltitol solution
and water

2, Add a mixture of beta-cyclodextrin and dextro
methorphan

3. Addition of usual sweeteners and flavourings
4. Pouring the mass into a mogul system

5. Drying the pastilles

6. Separating the pastilles from the molding powder and final treatment

2558 kg of solution containing 21.5% by weight of water, 34% by weight of gum arabic and 44.5% by weight of maltitol solution was prepared in a stirred vessel at 50 to 75 ^° C with stirring. This base mass was filtered through a sieve with a mesh size of 200 pm.

In this base mass, 180 kg of a mixture of 94.17 wt.% beta-cyclodextrin and 5.83 wt.% dextromethorphan.HBr were incorporated.^ By adding flavors and sweeteners, the

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The mass was ready and poured into powder trays in a mogul plant. After the pastilles had dried at 40 to 60 ⁰ C to the required final weight, they were separated from the mold powder, i.e. dusted and polished with an oil-wax mixture.
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Example 2:

Production of ginger lozenges

This object was achieved according to the invention analogously to Example 1 by a multi-stage production process, namely

1. Preparation of the base mass from gum arabic, xanthan gum, water, sorbitol and maltitol solution

2. Add a mixture of beta-cyclodextrin, water and ginger extract

3. Adding sweeteners and flavourings

4. Pouring the mass of a Mughal plant

5. Drying the pastilles

6. Separating the pastilles from the molding powder and final treatment

In a stirred vessel I, 2091 kg of solution were prepared at 50 to 75 ^° C with stirring, which contained 30.8% by weight of gum arabic, 0.07% by weight of xanthan gum, 4.78% by weight of sorbitol, 19.1% by weight of water and 45.25% by weight of maltitol solution. This base mass was filtered through a sieve with a mesh size of 200 pm.

In parallel, 355.5 kg of a mixture of 5.62 wt.% ginger spissum extract from ginger rootstock (15 to 35:1) - extraction agent ethanol 96% - and 94.38 wt.% beta-cyclodextrin were prepared by suspending beta-cyclodextrin in the required amount of process water at 55 to 60 ⁰ C and dissolving the ginger

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Extract was stirred in homogeneously. This mixture was added to the basic batch in the stirred vessel.

The other ingredients, such as sweeteners and flavors, were then added one after the other and the mixture was stirred until it was completely homogeneous. The mixture was then poured into powder trays in a mogul system. After the pastilles had dried at 40 to 60 ^° C to the required final weight, they were separated from the molding powder, i.e. dusted and polished with an oil-wax mixture.

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Claims (7)

1. Lozenges and chewing pastilles based on water-soluble hydrocolloids or hydrocolloids which form gels in aqueous systems, with an active pharmaceutical ingredient and a cyclodextrin, together with other excipients and additives if necessary. 2. Lozenges and chewing pastilles according to claim 1, characterized in that they contain 10 to 60% by weight of gum arabic and/or 5 to 30% by weight of gelatin, 20 to 75% by weight of active pharmaceutical ingredient and in particular 5 to 40% by weight of cyclodextrin, in each case based on the total mass of the pastilles. 3. Lozenges and chewing pastilles according to claim 1 or 2, characterized in that the bitter medicinal active ingredient is chemically defined. 4. Lozenges and chewing pastilles according to claim 3, characterized in that the active pharmaceutical ingredient comprises dextromethorphan, sodium dibunate, ambroxol, clobutanol, dimenhydrinate, tramadol hydrochloride, caffeine, codeine, paracetamol and/or theophylline. 5. Lozenges and chewing pastilles according to claim 3, characterized in that the active pharmaceutical ingredient is selected from plant extracts with bitter ingredients, in particular thyme extract, ginger extract, green tea extract, primrose extract, St. John's wort extract, devil's claw extract, artichoke extract, horse chestnut extract, marigold extract, essential oils, such as peppermint oil, eucalyptus oil, myrtol, anise oil, fennel oil, black cumin oil and/or sage oil. 6. Lozenges and chewing pastilles according to claim 1, characterized in that the excipients and additives are selected from sucrose, glucose syrup, sugar alcohols, isomalt, starch, sweeteners, waxes and/or paraffin oil. 7. Lozenges and chewing pastilles according to one of claims 1 to 6, characterized in that the cyclodextrin is selected from beta-cyclodextrin, I-alpha-cyclodextrin, I-hydroxypropyl-betacyclodextrin and/or dimethyl-betacyclodextrin.