DE202016005032U1 - Fast disintegrating Ivy drinking tablets without decay accelerator - Google Patents

Abstract

Solid pharmaceutical composition in the form of directly compressed, fast-dissolving tablets for the preparation of a drink solution and / or for oral use, comprising: (a) at least 60% by weight of one or more water-soluble excipients selected from the group of spray-agglomerated, directly compressible sugars and / or sugar alcohols; (b) 0.2 to 10% by weight of ivy leaf extract (c) 1 to 10% by weight of crystalline ascorbic acid; (d) optionally, up to 5% by weight of a water-soluble zinc compound; (e) further optionally one or more other water-soluble additives selected from the group of natural and / or synthetic sweeteners, flavoring agents, flavors, plant extracts, plant concentrates, plant powders and acidulants; (f) optionally magnesium dicitrate; and (g) at most 0.01% by weight of one or more disintegrants selected from the group consisting of cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl starch, starches, microcrystalline cellulose, cross-linked alginic acid, ion exchange resins, gellan, xanthan and soy polysaccharides; and (h) at most 0.01% by weight of effervescent additives such as sodium bicarbonate and citric acid.

Description

The present invention relates to novel compositions, in particular fast disintegrating tablets free of disintegrants or effervescent additives containing the slightly water-soluble active ingredient vitamin C (ascorbic acid), ivy leaves extract and optionally water-soluble zinc compounds. The compositions are used primarily for the treatment of colds, in particular associated cough; In addition, they also act, among other things, as dietary supplements and / or in the therapy or prevention of vitamin C deficiency states and can, for. B. dissolved in water and administered in the form of a hot or cold drink.

Background of the invention

The Common Ivy (Hedera helix L.) is a native of Europe, perennial and evergreen root climbing plant from the family Araliaceae, which is used as a drug drug. For this purpose, mainly used are the dried, whole or cut ivy leaves (Hederae folium) harvested in spring or summer, from which liquid and dry extracts are obtained by means of ethanol or ethanolic-aqueous solutions. Ivy extracts, and in particular the contained in the ivy extract alpha-hederin, have an outflow-promoting, cough-soothing, bronchial dilating, expectorant effect, which can be used to beneficial for colds with cough, as fixed mucus liquefies and can be coughed off better. In addition, ivy extracts also have an antimicrobial and anti-inflammatory effect.

As for many active ingredients with good solubility in water (eg soluble, slightly soluble and very slightly soluble according to the definition of the European Pharmacopoeia), it is also possible for vitamin C and ivy leaf extract to dispense the active ingredient in the form of tablets dissolving rapidly in the mouth or orodispersible and / or in the form of drinking solutions or tablets for the preparation of drinking solutions (eg as hot or cold drinks). The latter are also referred to in the literature as drinking tablets.

These fast-dissolving dosage forms are particularly advantageous for children and the elderly, as these user groups have more frequent problems swallowing solid dosage forms. Drinking solutions are also particularly advantageous for the administration of ivy leaf extracts as well as for supplementing vitamin C supply during typical viral infections such as colds, since they also provide sufficient liquid in addition to the required ivy leaf extract and vitamin C and thus, for example, help to moisturize the mucous membranes and possibly stuck mucus even easier to liquefy than z. As with solid ivy extract extract formulations, and thus to facilitate its removal from the bronchi and nasal passages.

In the literature as well as on the market fast-dissolving vitamin C or ivy leaf extract preparations with disintegrants such as effervescent additives or disintegrants are known; for example in the form of effervescent tablets. Here, an effervescent additive of a salt of carbonic acid in combination with an acid - often sodium bicarbonate in combination with citric acid - for a relatively rapid disintegration and dissolution in water in about 60-120 seconds, depending u. a. the size of the tablet to be dissolved, the amount of water and the optional stirring. Often, however, remain after dissolving unsightly edges in the vessel used; z. B. often on the upper edge of the glass. In addition, effervescent extract-containing effervescent formulations in particular often have an unsightly foaming effect owing to the saponin content of the ivy. In addition, effervescent tablets often contain a certain amount of sodium, which may be of concern for sodium-sensitive patients with hypertension or kidney diseases (especially if in parallel to the vitamin C substitution even drugs are given as effervescent formulations), but also in healthy patients hypertension - and can increase stroke risk.

Another option known to those skilled in the art for rapid disintegration of tablets is the use of common disintegrants; z. Example from the group of crosslinked sodium carboxymethylcellulose (croscarmellose, z. B. Ac-Di-Sol ^®, Vivasol ^®, Solutab ^®), cross-linked polyvinylpyrrolidone (crospovidone, z. B. Kollidon ^® CL, Polyplasdone ^® XL), cross-linked sodium carboxymethyl starch (eg. B. Explotab ^®), starches (eg. as corn starch), microcrystalline cellulose (MCC, z. B. Elcema ^®, Vivapur ^®), cross-linked alginic acid, ion exchange resins (e.g., Amberlite ^® IRP 88 ), soy polysaccharides (eg. B. Emcosoy ^®), and gums such as gellan, xanthan, karaya and tragacanth.

These disintegrants cause accelerated decay by swelling pressure and / or their "wicking", but are often insoluble in water and would therefore also become edges and / or sediments in vessels Most of them leave behind and therefore are less suitable for drinking tablets. On the one hand, this can be an aesthetic problem and, on the other hand, it can also cause the user of a tablet to wait unnecessarily long for complete dissolution, since he can not know whether the remaining small residue is an active substance or excipient.

For vitamin C are also known in the literature also fast dissolving or orodispersible vitamin C tablets without effervescent additive or without disintegrant additive. Often these are based on a sugar or sugar alcohol, or combinations thereof, to give the preparations a pleasant sweetness and to moderate or mask the strong acidic taste of the vitamin C. In addition, sugar or sugar alcohols provide a majority of a pleasant mouthfeel when disintegrating or dissolving in the oral cavity.

US 3,873,694 A describes fast dissolving vitamin C tablets with a maximum content of 30 wt .-% based on a directly compressible granules of 65-85 wt .-% of a crystalline sugar (preferably dextrose monohydrate) and 15-35 wt .-% maltodextrin. The granules were recovered by mixing dextrose monohydrate and maltodextrin followed by wet granulation using a maltodextrin solution. The tablets have a hardness of approx. 7.5 SC (Strong Cobb), ie approx. 52.5 N. They are therefore only just above the 50 N level, which according to the experience of the inventors, is required by a to ensure sufficient fillability or removability from tablet tubes, blisters or sealing strips. In addition, the tablets in question have a disintegration time of at least 10-11 minutes and are therefore anything but fast dissolving from the inventors' point of view. Disintegration times of less than 1 minute would be desirable; ideally also a complete resolution under 1 minute.

US 5,869,098 A and WO 00/09171 A1 describe fast-dissolving or chewable vitamin C tablets based on a type of cotton candy, which is spun from a carbohydrate such as sucrose with the addition of sugar alcohols such as xylitol and sorbitol and Tween 80. The cotton candy cut to 1-1000 μm particles is then directly pressed with vitamin C, or optionally coated vitamin C particles; depending on the pressing force, fast-dissolving orodispersible tablets, so-called ODTs (2 to 4 pounds, 8.9 to 17.8 N), or chewable vitamin C tablets (10 to 12 pounds, 44.5 to 53.4 N). Although extremely short disintegration times of less than 30 seconds, sometimes less than 10 seconds, are described for the ODTs (but not for the harder chewable tablets). However, this is ensured for the ODTs only by the extremely low tablet hardness, which is too low for normal handling of the ODT tablets during manufacture and / or by the consumer, if they are to be filled, for example, in tablet tubes.

US 6,187,336 B1 describes on the one hand porous, fast-dissolving vitamin C-containing moldings predominantly based on erythritol, which are first moistened, shaped as a "dough" and then dried under reduced pressure and 40 ° C. These i. A. Disintegration times of less than 30 seconds. Parallel to this describes US 6,187,336 B1 for comparison also a directly compressed formulation consisting of 71.4 wt .-% erythritol, 7.2 wt .-% sucrose and 21.4 wt .-% vitamin C, which after pressing for 18 h at 30 ° C and 89 % relative humidity (RH) was annealed and finally dried for 3 h at 60 ° C and atmospheric pressure. Although this is still acceptable with a disintegration time of 108 seconds, it is significantly slower than the porous formulations dried under reduced pressure. In addition, the direct compression formulation concerned is loud US 6,187,336 B1 also an insufficient hardness.

In addition, describes US 6,187,336 B1 in that the addition of sucrose or lactose to the erythritol has a negative effect, ie a slowing down, on the disintegration times; Thus, for example, the disintegration time of a formulation containing 90% by weight of erythritol and 10% by weight of vitamin C is ~ 14 seconds, while the formulation contains 60% by weight of erythritol, 30% by weight of sucrose and 10% by weight. % Vitamin C is ~ 146 seconds.

US 2012/034302 A1 also describes sugar-based granulated vehicles suitable for direct tableting of rapid-dissolving dosage forms and containing at least 70-100% of at least two low-formability sugars. A preferred example is a mixture of dextrose monohydrate and sucrose in the ratio 70:30 to 60:40, which is granulated with an aqueous solution of dextrose monohydrate and maltodextrin; For example, in the top-spray process in a fluidized bed apparatus. For the exemplary directly compressed vitamin C tablets, containing 20% by weight, weighing 800 mg and having a diameter of about 12.7 mm, a granulated vehicle of 66.8% by weight dextrose monohydrate, 30, 6% by weight of "6X" powdered sugar (containing 3% by weight of corn starch) and 1.4% by weight of microcrystalline cellulose (MCC). The tablets can be compressed sufficiently hard, but specified US 2012/034302 A1 no specific disintegration or dissolution times, but merely mentions that the tablets dissolve pleasantly in the mouth with minimal chewing.

WO 2009/058798 A2 also describes sugary, fast-dissolving vitamin C formulations that dissolve in the mouth in less than 60 seconds. However, in addition to at least 40% by weight of a carbohydrate (eg dextrose monohydrate, sucrose, sorbitol, mannitol), 5 to 40% by weight of a salt hydrate are also used, and optionally disintegrants (eg croscarmellose sodium, sodium Carboxymethyl starch, crospovidone).

In general, it is known in all the documents mentioned that a balance between tablet hardness and dissolution time is necessary for high-dissolution dosage forms, since higher hardnesses in all documents were equivalent to slower disintegration (if times and hardness were specified). Therefore, the tablet hardnesses for fast-dissolving oral tablets in the literature often found in the low to very low range, below about 25-30 N. Harder tablets dissolve much slower in the majority and are then often used as chewable tablets or as mixed forms between chewable tablets and fast dissolving tablets; such as In "Rite Aid Vitamin C 250mg, Fast Dissolving, Chewable Tablets".

In addition, the documents primarily describe smaller rapid dissolving tablets with diameters of less than 13 mm, usually around 10 mm, and comparatively low weights of less than 1000 mg, since the tablets described are intended to melt in the mouth. For larger tablets with diameters greater than 13 mm, sometimes greater than 20 mm, and weights often well above 1000 mg up to 5000 mg, which are very commonly used for drinkable tablets, the balance between tablet hardness and disintegration or dissolution time is against even more difficult to achieve.

On the one hand, larger tablets generally have to be slightly harder to ensure adequate fillability or removability from tablet tubes, blisters or sealing strips. For the inventors, a guide value of at least 50 N has been found to be necessary, better still at least 65 N; So in some cases significantly above most previously mentioned in the literature directly pressed, fast-dissolving vitamin C tablets.

Second, larger tablets such as drinking tablets have a less favorable surface to volume ratio and longer diffusion paths for the penetrating dissolution medium. Due to their size they are compared to the smaller oral tablets at a disadvantage in terms of the "wicking" of some excipients.

The present invention is therefore based on the object to provide a directly compressed composition for the slightly water-soluble active ingredients ivy extract and vitamin C and optionally water-soluble zinc compounds available, which is also suitable for larger dimensions, such. B. diameters from 15 mm and / or weights of 1500 mg or more and curing of at least 50 N still dissolves quickly and without residue, preferably in less than 60 seconds. In addition, the composition should not foam appreciably on dissolution and moreover ensure the stability of the active ingredients ivy extract and vitamin C, and moreover should be simple and economical to produce.

• (a) mindestens 60 Gew.-% eines oder mehrerer wasserlöslicher Hilfsstoffe ausgewählt aus der Gruppe sprüh-agglomerierter, direkt verpressbarer Zucker und/oder Zuckeralkohole;
• (b) 0,2 bis 10 Gew.-% Efeublätterextrakt
• (c) 1 bis 10 Gew.-% kristalline Ascorbinsäure;
• (d) optional bis zu 5 Gew.-% einer wasserlöslichen Zinkverbindung;
• (e) weiterhin optional einen oder mehrere weitere wasserlösliche Zusätze ausgewählt aus der Gruppe natürlicher und/oder synthetischer Süßstoffe, Geschmackskorrigenzien, Aromen, Pflanzenextrakte, Pflanzenkonzentrate, Pflanzenpulver und Säurungsmitteln;
• (f) weiterhin optional Magnesiumdicitrat; sowie
• (g) maximal 0,01 Gew.-% eines oder mehrerer Sprengmittel ausgewählt aus der Gruppe von quervernetzter Natriumcarboxymethylcellulose, quervernetztem Polyvinylpyrrolidon, quervernetzter Natriumcarboxymethylstärke, Stärken, mikrokristalliner Cellulose, quervernetzter Alginsäure, Ionenaustauscherharzen, Gellan, Xanthan und Soja-Polysacchariden; und
• (h) maximal 0,01 Gew.-% an Brausezusätzen wie Natriumhydrogencarbonat und Zitronensäure.

This object is achieved by the solid pharmaceutical composition according to the invention in the form of directly compressed, rapidly dissolving tablets for the preparation of a drink solution and / or for oral use, comprising:

• (A) at least 60 wt .-% of one or more water-soluble excipients selected from the group of spray-agglomerated, directly compressible sugars and / or sugar alcohols;
• (b) 0.2 to 10% by weight of ivy leaf extract
• (c) 1 to 10% by weight of crystalline ascorbic acid;
• (d) optionally, up to 5% by weight of a water-soluble zinc compound;
• (e) further optionally one or more other water-soluble additives selected from the group of natural and / or synthetic sweeteners, flavoring agents, flavors, plant extracts, plant concentrates, plant powders and acidulants;
• (f) optionally magnesium dicitrate; such as
• (g) at most 0.01% by weight of one or more disintegrants selected from the group consisting of cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl starch, starches, microcrystalline cellulose, cross-linked alginic acid, ion exchange resins, gellan, xanthan and soy polysaccharides; and
• (H) maximum 0.01 wt .-% of effervescent additives such as sodium bicarbonate and citric acid.

This means that the tablets according to the invention are essentially free of known effervescent additives and / or disintegrants as well as free from difficult and very water-soluble as well as practically water-insoluble active or auxiliary substances (solubilities according to European Pharmacopoeia).

In a specific embodiment, the tablets according to the invention contain 10 mg to 200 mg ivy leaf extract, preferably 20 mg to 120 mg, more preferably 30 mg to 110 mg. The tablets according to the invention may contain, for example, a single dose of 35 mg ivy leaf extract, which according to current knowledge corresponds to a usual daily dose for children under 6 years. The usual daily dose for children of about 6-12 years is about 70 mg, the daily dose for children over 12 years and adults about 105 mg. Such amounts may be administered by taking, for example, tablets containing 35 mg of ivy leaf extract per day, or alternatively by the single administration of tablets which already contain 70 mg or 105 mg of ivy leaf extract as a single dose. In further embodiments, the tablets according to the invention accordingly contain a single dose of 70 mg or of 105 mg of ivy leaf extract.

In a specific embodiment, the tablets according to the invention contain at least 70% by weight of one or more water-soluble auxiliaries selected from the group of spray-agglomerated, directly compressible sugars and / or sugar alcohols.

In a particular embodiment, the tablets according to the invention have a diameter between 15 mm and 30 mm and a web height between 5 mm and 15 mm.

In a further embodiment, the tablets according to the invention have a weight of ≥ 1500 mg (ie 1500 mg or more); or a weight of ≥ 2500 mg or even ≥ 3500 mg. For example, the tablets may have a weight of about 4000 mg to about 4500 mg.

This means that the tablets according to the invention can be larger and heavier than common peroral tablets or intraoral tablets such as ODTs. Such larger, heavier tablets (with, for example, diameters between 15 mm and 30 mm and weights of 1500 mg and higher) are frequently, but not exclusively, used as so-called drinking tablets. In the context of the invention, the term "drinking tablet" refers to those tablets which are intended for preparing a drink solution, e.g. B. in the form of a hot or cold drink after dissolving in about 150-300 mL of water.

At the same time, in a preferred embodiment, the tablets according to the invention have a hardness of at least 50 N, preferably of at least 65 N, e.g. About 70 N, about 80 N or about 100 N. In a further embodiment, the tablets according to the invention have a hardness between 65 N and 115 N, preferably between 70 N and 100 N. The hardness is chosen according to the invention that the fillability in or removability from tablet tubes, blisters or sealing strips is sufficiently ensured (ie without breaking or even crumbling), while at the same time decay and dissolution proceeds quickly and without residue.

The advantage of these tablets according to the invention lies in the fact that, despite the sometimes considerably larger dimensions and the higher weight (in comparison to, for example, common ODTs), they usually completely disintegrate within 60 seconds in 200 ml of hot water at 60 ° C. or higher and dissolve without residue with little stirring; often within 20 to 30 seconds even though they have a hardness of at least 50N. By using water-soluble, spray-agglomerated, directly compressible sugars and / or sugar alcohols such as sucrose, sufficiently hard, yet fast-dissolving tablets can be directly compressed which dissolve even faster than those in which an explosive such as corn starch, croscarmellose or crospovidone was additionally added.

Surprisingly, this advantageous dissolution behavior is especially for drinking tablets with ivy leaf extract. In the form of effervescent tablets, as known on the market (in combination with effervescent additives), unfortunately, the saponin-containing ivy leaf extract often tends to foam and prolongs the dissolution time of said effervescent tablets to over 120 seconds. To avoid or at least reduce this foaming of effervescent tablets, the extract may be pregranulated with lipophilic or amphiphilic substances before being mixed with the effervescent components; eg. by addition of medium-chain triglycerides (eg., Miglyol ^®), simethicone and / or emulsifiers. However, this measure also shortens the dissolution time only to a limited extent; an exemplary effervescent tablet of z. B. 22 mm diameter, about 5 mm ridge height and about 1.7 wt .-% ivy leaf extract (pre-granulated) still needed around the 110 seconds. In addition, there is still slight foaming, even if it is not so resistant.

In contrast, the drinking tablets with ivy leaf extract according to the invention usually dissolve without residue and without foam formation in 200 ml of hot water at 60 ° C. or higher, with little stirring and within 60 seconds; often already within 20 to 30 seconds. And even after one year storage at room temperature, no changes could be made in terms of appearance, odor and Due to their sensitivity to moisture, effervescent tablets are often only available in sealed seal strips, but less often in tablet tubes.

In addition, direct processing (direct compression) without intermediate steps is possible with the tablets or drinking tablets according to the invention; pre-granulation of the ivy leaf extract as in effervescent tablets is no longer necessary. This saves both time and costs. In addition, despite the very bitter ivy leaf extract, the tablets of the invention are palatable and do not foam on dissolution.

Since the tablets according to the invention are frequently too large for decay testers according to the invention, the disintegration time in vitro is determined as it would occur in the usual use of the user:
The tablets are placed in a glass with about 200 mL of hot water at 60 ° C or higher - for tests in cold water alternatively water of about 19 ° C - and the decay waiting; ie until no significant larger tablet fragments are more visible, but rather a granule or powder-like residue. Then stir briefly (about 3-10 turns) to ensure complete, residue-free dissolution.

In the case of the tablets according to the invention, this stirring must thereafter be repeated at most once and the disintegration times are less than 120 seconds in hot water at 60 ° C. or higher.

In a preferred embodiment, the tablets of the invention disintegrate in 200 mL of hot water at 60 ° C or higher within 60 seconds, preferably within 30 seconds, more preferably within 20 seconds; and then dissolve without residue, optionally with brief stirring as described above.

According to the invention, the water-soluble auxiliaries according to (a) are selected from the group of spray-agglomerated, directly compressible sugars and / or sugar alcohols; For example, sucrose, mannitol, lactose, sorbitol, xylitol, and / or mixtures thereof. Spray-agglomerated, directly compressible sucrose is in Germany z. B. distributed by Südzucker AG under the name Compri. Compri O is the pure sucrose, without further additions of binders such as starch (Compri S), maltodextrin (Compri M3) or gelatin (Compri Tailor-made).

In a preferred embodiment, the water-soluble excipient according to (a) is spray-agglomerated, directly compressible sucrose; For example in the form of Compri O. The spray-agglomerated, directly compressible sucrose can be present as a single substance, d. H. without the addition of further sugars and / or sugar alcohols; z. Alternatively, the sucrose may be in admixture with other sugars such as lactose and / or sugar alcohols such as mannitol; for example, with a sucrose content of the mixture of about 99 wt .-% to about 65 wt .-%; In other words, when sucrose mixtures are used, they should contain no more than about 1% to about 35% by weight of other sugars and / or sugar alcohols. It has been found that with Compri O, even at hardnesses of 110 N, rapid dissolution of the tablets according to the invention takes place.

In further alternative embodiments, for example. For the use by diabetics, the water-soluble excipient according to (a) spray-agglomerated, directly compressible mannitol (z. B. Pearlitol ^® 200SD), sorbitol or xylitol or spray-agglomerated, directly compressible lactose ( z. B. FlowLac ^® 100). Here too, the embodiments may optionally be mannitol, sorbitol, xylitol or lactose as individual substances or in the form of mixtures with other sugars and / or sugar alcohols.

In a large number of cases, however, sucrose is the preferred sugar according to (a), since the relatively large amounts of sugar alcohols usually present in drinking tablets can potentially have a laxative effect, or larger amounts of lactose can lead to gastrointestinal problems with appropriately sensitive persons (lactose intolerance). ,

As described above, the tablets according to the invention according to (c) contain 1 to 10% by weight of crystalline ascorbic acid, preferably 3 to 6% by weight. The exact amount per tablet depends on the generally recommended values for the daily dose and / or the maximum daily dose in the intended user group (eg children or adults), as well as the intended administration frequency (for example, one tablet, once, twice or three times daily dissolved and drunk). Usually, the amount of vitamin C per tablet is in the range 50-250 mg depending on the user group, eg. B. about 180 mg for adults.

In a further preferred embodiment, the water-soluble zinc compound according to (d) is zinc gluconate. Zinc gluconate is preferred because it has a better bioavailability than, for example, inorganic zinc compounds such as zinc sulfate, zinc carbonate or zinc oxide. Zinc is often given in combination with vitamin C, especially in cold remedies, as the combination in deficient patients relieves cold symptoms and / or shortens the disease.

The tablets according to the invention are usually admixed with at least one further water-soluble additive according to (e) selected from the group of natural and / or synthetic sweeteners, flavoring agents, flavors, plant extracts, plant concentrates, plant powders and acidulants in order to adapt the organoleptic properties of the tablets and thus the compliance to increase the user.

For example, sweeteners such as acesulfame K (E 950), aspartame (E 951), aspartame-acesulfame salt (E 962), sodium cyclamate (E 952), neohesperidin (E 959), neotame (E 961), saccharin (E. 954), sucralose (E 955), stevioside (E 960), and / or thaumatin (E 957). In a preferred embodiment, the tablets of the invention contain about 0.4 to 0.6 wt .-%. a combination of acesulfame K, aspartame, for example, in the ratio of about 1: 1; or 0.4 to 0.6% by weight. a combination of acesulfame K, aspartame and Stevia (e.g., Truvia ^®.), for example in a ratio of about 1:. 1: 0.01 to one another. The choice and / or combination of sweeteners and their content with respect to the total mixture depends primarily on the selected flavor and / or the intended user group; so like it z. For example, children are generally a little sweeter than adults.

Acidifiers which can be used are acidic auxiliaries, such as citric acid, tartaric acid, malic acid, succinic acid, and acid salts thereof, for example monosodium citrate and / or disodium citrate; especially citric acid in combination with monosodium citrate.

Independently of the acidifying agents, the tablets according to the invention optionally contain magnesium dicitrate (also known as trimagnesium dicitrate), a non-acidic salt of citric acid; preferably 1 to 5 wt .-% based on the total powder mixture to be compressed, for. B. 2 to 3 wt .-%.

Furthermore, various flavors, plant extracts, plant concentrates and plant powders may be added to the tablets of the present invention to create any flavor. Thus, for example, aromas of peach, passion fruit, orange, berry fruits such as raspberries, strawberries, blackberries, blueberries, blackcurrant (cassis) or lemon, as well as lemon powder, sage extract, sage aroma, honey powder, elderflower powder, elderflower powder, elderflower Flavor or blueberry flavor can be used in combination with the above-mentioned sweeteners and acidulants and are hereby selected and / or combined with each other so that the flavors peach, passion fruit, orange, raspberry, strawberry, blackberry, blueberry, cassis, lemon, sage , Honey, elderberries or mixtures of these flavors such. Peach passion fruit, red fruits (includes cassis), honey sage or lemon honey can be produced. Other possible flavors are melon, grapefruit, tropical fruits (such as mango, passion fruit), cranberry, but also herbaceous directions such as peppermint or ginger.

In principle, flavors such as coffee, cocoa or chocolate are not excluded, but they tend to harmonize less well with the sour taste of vitamin C and the very thin consistency of the tablets dissolved in water.

In a further embodiment, the tablets according to the invention comprise a maximum of 0.01% by weight of sparingly water-soluble to practically water-insoluble flow-regulating lubricants and / or mold release agents, such as, for example, Fumed silica, magnesium stearate and / or stearic acid; So they are essentially free of these tabletting excipients. The inventors have found that the tablets according to the invention can be pressed directly without incorporation of these tableting excipients into the powder mixture in a hardness range of between 65 and 115 N, thereby resulting in a completely water-soluble, rapidly dissolving formulation. Optionally, if necessary, an external pollination of the stamp with magnesium stearate.

In a further embodiment, the tablets according to the invention contain 75 to 80% by weight of spray-agglomerated, directly compressible sucrose, 0.4 to 3% by weight of ivy leaf extract, 3 to 6% by weight of crystalline ascorbic acid, 0.7 to 1% by weight .-% zinc gluconate and 2 to 3 wt .-% magnesium dicitrate. In a specific embodiment, these tablets have a diameter of 20-30 mm, a ridge height of 5 to 10 mm, a weight of at least 3000 mg and a hardness of 65 N to 115 N. In a more specific embodiment, these tablets have a diameter of 25 mm, a ridge height of 6 to 8 mm, a weight of at least 4000 mg and a hardness of 65 N to 115 N; So z. B. a weight of about 4200 mg and a hardness of about 70 to 100 N.

• (a) 75 bis 80 Gew.-% sprüh-agglomerierte, direkt verpressbare Saccharose,
• (b) 35 mg bis 105 mg Efeublätterextrakt
• (c) 3 bis 6 Gew.-% kristalline Ascorbinsäure,
• (d) 0,7 bis 1 Gew.-% Zinkgluconat,
• (e) wasserlösliche natürliche und/oder synthetische Süßstoffe, Geschmackskorrigenzien, Aromen, Pflanzenextrakte, Pflanzenkonzentrate, Pflanzenpulver und/oder Säurungsmitteln, die optional so ausgewählt und/oder kombiniert sind, dass die Geschmacksrichtungen Pfirsich, Maracuja, Orange, Himbeere, Erdbeere, Brombeere, Blaubeere, Cassis oder Mischungen hiervon erzeugt werden; sowie
• (f) 2 bis 3 Gew.-% Magnesiumdicitrat; und weisen einen Durchmesser von 20 bis 30 mm, bevorzugt 25 mm, auf sowie eine Steghöhe von 5 bis 10 mm, bevorzugt 6 bis 8 mm, ein Gewicht von mindestens 3000 mg, bevorzugt mindestens 4000 mg, und eine Härte von ca. 65 N bis 115 N; also z. B. ein Gewicht von ca. 4200 mg und eine Härte von ca. 70 bis 80 N.

In a preferred embodiment, the tablets according to the invention contain

• (a) 75 to 80% by weight of spray-agglomerated, directly compressible sucrose,
• (b) 35 mg to 105 mg of ivy leaf extract
• (c) 3 to 6% by weight of crystalline ascorbic acid,
• (d) 0.7 to 1% by weight of zinc gluconate,
• (e) water-soluble natural and / or synthetic sweeteners, flavoring agents, flavors, plant extracts, plant concentrates, plant powders and / or acidifiers, which are optionally selected and / or combined such that the flavors peach, passion fruit, orange, raspberry, strawberry, blackberry, Blueberry, Cassis or mixtures thereof are produced; such as
• (f) 2 to 3% by weight of magnesium dicitrate; and have a diameter of 20 to 30 mm, preferably 25 mm, and a ridge height of 5 to 10 mm, preferably 6 to 8 mm, a weight of at least 3000 mg, preferably at least 4000 mg, and a hardness of about 65 N. up to 115 N; So z. B. a weight of about 4200 mg and a hardness of about 70 to 80 N.

• (a) 75 bis 80 Gew.-% sprüh-agglomerierte, direkt verpressbare Saccharose,
• (b) 35 mg, 70 mg oder 105 mg Efeublätterextrakt
• (c) 3 bis 6 Gew.-% kristalline Ascorbinsäure,
• (d) 0,7 bis 1 Gew.-% Zinkgluconat,
• (e) Pfirsich-Maracuja-Aroma oder rote Früchte-Aroma (beinhaltet Cassis) in Kombination mit Acesulfam K und Aspartam, sowie
• (f) 2 bis 3 Gew.-% Magnesiumdicitrat.

In one embodiment, the tablets of the invention have a diameter of 25 mm, a ridge height of 6-8 mm, a weight of at least 4000 mg, and a hardness of about 70 to 80 N; and included

• (a) 75 to 80% by weight of spray-agglomerated, directly compressible sucrose,
• (b) 35 mg, 70 mg or 105 mg ivy leaf extract
• (c) 3 to 6% by weight of crystalline ascorbic acid,
• (d) 0.7 to 1% by weight of zinc gluconate,
• (e) peach-passion fruit aroma or red fruit flavor (includes cassis) in combination with acesulfame K and aspartame, as well
• (f) 2 to 3% by weight of magnesium dicitrate.

• (a) Bereitstellen von mindestens 60 Gew.-% eines oder mehrerer wasserlöslicher Hilfsstoffe ausgewählt aus der Gruppe sprüh-agglomerierter, direkt verpressbarer Zucker und/oder Zuckeralkohole;
• (b) Bereitstellen von 0,2 bis 10 Gew.-% Efeublätterextrakt
• (c) Bereitstellen von 1 bis 10 Gew.-% kristalliner Ascorbinsäure;
• (d) optional, Bereitstellen von
• – bis zu 5 Gew.-% einer wasserlöslichen Zinkverbindung; und/oder
• – einem oder mehreren weiteren wasserlöslichen Zusätzen ausgewählt aus der Gruppe natürlicher und/oder synthetischer Süßstoffe, Geschmackskorrigenzien, Aromen, Pflanzenextrakte, Pflanzenkonzentrate, Pflanzenpulver und Säurungsmitteln; und/oder
• – Magnesiumdicitrat
• (e) Mischen aller bereitgestellten Pulverkomponenten bis zur Homogenität;
• (f) Direktes Verpressen der in Schritt (e) erhaltenen homogenen Pulvermischung.

In a further aspect of the invention, there is provided a process for the preparation of the solid pharmaceutical composition of the invention in the form of directly compressed, high-speed tablets for the preparation of a drink solution and / or for oral use, comprising the following steps:

• (A) providing at least 60% by weight of one or more water-soluble auxiliaries selected from the group of spray-agglomerated, directly compressible sugars and / or sugar alcohols;
• (b) providing from 0.2% to 10% by weight of ivy leaf extract
• (c) providing from 1 to 10% by weight of crystalline ascorbic acid;
• (d) optionally, providing
• Up to 5% by weight of a water-soluble zinc compound; and or
• - one or more further water-soluble additives selected from the group of natural and / or synthetic sweeteners, flavoring agents, flavors, plant extracts, plant concentrates, plant powders and acidulants; and or
• - Magnesium dicitrate
• (e) mixing all provided powder components to homogeneity;
• (f) Direct compression of the homogeneous powder mixture obtained in step (e).

EXAMPLES

Example 1: Disintegration times of pure, disintegrant-free sucrose formulations with ivy leaf extract

To evaluate the disintegration times of various disintegrant-free sucrose tablet formulations in cold (about 19 ° C) and in hot (about 60 ° C) water, the ingredients listed in Table 1 are weighed, mixed homogeneously and then to tablets with 25 mm diameter and a weight of about 4100 mg pressed. Table 1: Composition of the direct tabletting mixtures (in% by weight) ingredients Ivy Trinktabs 1 Ivy Trinktabs 2 Sucrose (Compri O) 78,95 78.86 Ascorbic acid (crystalline) 4.37 4.37 zinc gluconate 0.89 0.89 Acesulfame K 0.26 0.26 aspartame 0.26 0.26 Monosodium citrate wfr. 7.57 7.57 citric acid 4.13 4.13 Ivy Leaf Extract (Extr. Hedarae helic., Fol. Spir) 0.85 0.85 Peach and passion fruit flavor 0.29 0.38 Magnesium dicitrate wfr. 2.43 2.43 anh. = anhydrous

The resulting tablets have a height of about 6.9 to 7.1 mm and, with the desired hardness of about 70-80 N, are sufficiently hard for good fillability in tablet tubes, blisters or sealing strips (this is generally a Hardness of at least 50 N required). All tablets disintegrate in a glass with about 200 mL of water within 20 seconds (hot) or 30 seconds (cold) completely and then dissolve without residue with short stirring.

Example 2: Disintegration times of pure sucrose formulations versus formulations with different disintegrants

In order to evaluate the disintegration times of various sucrose tablet formulations with or without the addition of disintegrants in cold (about 19 ° C) or in hot (about 60 ° C) water, the ingredients listed in Table 2 are weighed, mixed homogeneously and then compressed into tablets of 25 mm diameter and a weight of about 4200 to 4700 mg. For this purpose, the explosive-free powder mixture additionally contains corn starch, croscarmellose sodium or Kollidon ^® CL may be added as disintegrant. The disintegrating agent content in the total amounts to be tableted or in the directly compressed tablet is 10 wt .-% for corn starch and 5 wt .-% each of croscarmellose sodium and Kollidon ^® CL. Table 2: Composition of the direct tabletting mixtures (in% by weight) ingredients sucrose Sucrose + 5% Kollidon ^® CL Sucrose + 5% croscarmellose sodium Sucrose + 10% cornstarch Sucrose (Compri O) 77.71 73.83 73.83 69.94 Kollidon ^® CL - 5.00 - - Croscarmellose sodium - - 5.00 - corn starch - - - 10.00 Ascorbic acid (crystalline) 4.30 4.08 4.08 3.87 zinc gluconate 0.88 0.83 0.83 0.79 Acesulfame K 0.26 0.24 0.24 0.23 aspartame 0.26 0.24 0.24 0.23 Monosodium citrate wfr. 7.45 7.07 7.07 6.70 citric acid 4.58 4.35 4.35 4.12 Ivy leaves extract 1.19 1.13 1.13 1.07 Peach and passion fruit flavor 0.52 0.49 0.49 0.46 Magnesium dicitrate wfr. 2.86 2.72 2.72 2.58 anh. = anhydrous

All the tablets thus obtained have the desired hardness of about 70-80 N and are therefore sufficiently hard for good fillability in tablet tubes, blisters or sealing strips.

Surprisingly, only the disintegrant-free sucrose tablets disintegrate completely in a glass with about 200 ml of water within 20 seconds (hot) or 30 seconds (cold) and then dissolve without residue with brief stirring, while all formulations containing explosives have more than 60 seconds ( hot) or more than 100 or 120 seconds (cold) for complete decay and subsequent nearly residue-free dissolution, regardless of the choice of disintegrant. The investigation thus shows that the spray-agglomerated sucrose (Compri O) is most suitable without the addition of disintegrants.

Example 3: Disintegration times of pure sucrose formulations versus sucrose, mannitol or lactose plus 5% by weight of croscarmellose additive

To the disintegration times of various tablet formulations (sucrose without disintegrant additive or sucrose, mannitol or lactose with the addition of 5 wt .-% croscarmellose sodium) in cold (about 19 ° C) or in hot (about 60 ° C) water To evaluate, the ingredients listed in Table 3 are weighed, mixed homogeneously and then compressed into tablets of 25 mm diameter, and a weight of about 4200 to 4400 mg. For this purpose, mannitol or lactose instead of sucrose is used in the croscarmellose sodium-containing powder mixture already described in Example 2 for sucrose. Table 3: Composition of the direct tabletting mixtures (in% by weight) ingredients sucrose Sucrose + 5% croscarmellose sodium Mannitol + 5% Croscarmellose-Na Lactose + 5% croscarmellose-Na Sucrose (Compri O) 77.71 73.83 - - Mannitol (Pearlitol ^® SD 200) - - 73.83 - Lactose (F1owLac ^® 100) - - - 73.83 Croscarmellose sodium - 5.00 5.00 5.00 Ascorbic acid (crystalline) 4.30 4.08 4.08 4.08 zinc gluconate 0.88 0.83 0.83 0.83 Acesulfame K 0.26 0.24 0.24 0.24 aspartame 0.26 0.24 0.24 0.24 Monosodium citrate wfr. 7.45 7.07 7.07 7.07 citric acid 4.58 4.35 4.35 4.35 Ivy leaves extract 1.19 1.13 1.13 1.13 Peach and passion fruit flavor 0.52 0.49 0.49 0.49 Magnesium dicitrate wfr. 2.86 2.72 2.72 2.72 anh. = anhydrous

All the tablets thus obtained have the desired hardness of about 70-80 N and are therefore sufficiently hard for good fillability in tablet tubes, blisters or sealing strips.

Surprisingly, only the disintegrant-free sucrose tablets disintegrate completely in a glass of about 200 ml of water within 20 seconds (hot) or 30 seconds (cold) and then dissolve without residue with brief stirring, while all formulations containing explosives at least 50 seconds (hot ) or more than 100 seconds (cold) for complete disintegration and subsequent almost residue-free dissolution, regardless of the choice of sugar or sugar alcohol. In addition, the lactose or mannitol-containing formulations require repeated stirring for almost complete dissolution, while a short stirring is sufficient for the disintegrant-free sucrose tablets.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 3873694 A [0009]
• US 5869098 A [0010]
• WO 00/09171 A1 [0010]
• US 6187336 B1 [0011, 0011, 0011, 0012]
• US 2012/034302 A1 [0013, 0013]
• WO 2009/058798 A2 [0014]

Claims (16)

Solid pharmaceutical composition in the form of directly compressed, fast-dissolving tablets for the preparation of a drink solution and / or for oral use, containing: (A) at least 60 wt .-% of one or more water-soluble excipients selected from the group of spray-agglomerated, directly compressible sugars and / or sugar alcohols; (b) 0.2 to 10% by weight of ivy leaf extract (c) 1 to 10% by weight of crystalline ascorbic acid; (d) optionally, up to 5% by weight of a water-soluble zinc compound; (e) further optionally one or more other water-soluble additives selected from the group of natural and / or synthetic sweeteners, flavoring agents, flavors, plant extracts, plant concentrates, plant powders and acidulants; (f) optionally magnesium dicitrate; such as (g) at most 0.01% by weight of one or more disintegrants selected from the group consisting of cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl starch, starches, microcrystalline cellulose, cross-linked alginic acid, ion exchange resins, gellan, xanthan and soy polysaccharides; and (H) maximum 0.01 wt .-% of effervescent additives such as sodium bicarbonate and citric acid. The pharmaceutical composition according to claim 1, wherein the tablets contain 10 mg to 200 mg of ivy leaf extract, preferably 20 mg to 120 mg, more preferably 30 mg to 110 mg. A pharmaceutical composition according to claim 1, wherein the tablets contain at least 70% by weight of one or more water-soluble excipients selected from the group of spray-agglomerated, directly compressible sugars and / or sugar alcohols. A pharmaceutical composition according to claims 1 to 3, wherein the tablets have a diameter between 15 mm and 30 mm and a web height between 5 mm and 15 mm. A pharmaceutical composition according to claims 1 to 4, wherein the tablets have a weight of ≥ 1500 mg, or ≥ 2500 mg ≥ 3500 mg. Pharmaceutical composition according to claims 1 to 5, wherein the tablets have a hardness of at least 50 N, preferably at least 65 N. A pharmaceutical composition according to claims 1 to 6, wherein the tablets have a hardness between 65 N and 115 N, preferably between 70 N and 100 N. A pharmaceutical composition according to claims 1 to 7, wherein the water-soluble excipient according to (a) is spray-agglomerated, directly compressible sucrose; optionally in mixtures with 1% to 35% by weight of other sugars and / or sugar alcohols. The pharmaceutical composition according to claims 1 to 8, wherein the water-soluble zinc compound according to (d) is zinc gluconate. Pharmaceutical composition according to claims 1 to 9, wherein the water-soluble additives according to (e) are selected and / or combined such that the flavors peach, passion fruit, orange, raspberry, strawberry, blackberry, blueberry, cassis, lemon, sage, honey, Elderberries or mixtures thereof are produced. A pharmaceutical composition according to claims 1 to 10, wherein the tablets disintegrate in 200 mL of hot water of 60 ° C or higher within 60 seconds, preferably within 30 seconds, more preferably within 20 seconds; and then dissolve without leaving residue. A pharmaceutical composition according to claims 1 to 11, wherein the tablets comprise at most 0.01% by weight of sparingly water-soluble to substantially water-insoluble flow control lubricants and / or mold release agents, e.g. As fumed silica, magnesium stearate and / or stearic acid Pharmaceutical composition according to claims 1 to 12, wherein the tablets comprise 75 to 80% by weight of spray-agglomerated, directly compressible sucrose, 0.4 to 3% by weight of ivy leaf extract, 3 to 6% by weight of crystalline ascorbic acid, 0, 7 to 1 wt .-% zinc gluconate and 2 to 3 wt .-% magnesium dicitrate. A pharmaceutical composition according to claim 13, wherein the tablets have a diameter of 20-30 mm, a ridge height of 5 to 10 mm, a weight of at least 3000 mg and a hardness of 65 N to 115 N. A pharmaceutical composition according to claim 14, wherein the tablets have a diameter of 25 mm, a ridge height of 6 to 8 mm, a weight of at least 4000 mg and a hardness of 65 N to 115 N. A pharmaceutical composition according to claim 13 or 14, wherein the tablets contain 35 mg to 105 mg ivy leaf extract, and wherein the water-soluble additives according to (e) in the tablets are optionally selected and / or combined such that the flavors peach, passion fruit, orange, raspberry , Strawberry, blackberry, blueberry, cassis, or mixtures thereof.