DE102013004263A1 - Fast-dissolving oral dosage form and method of making the same - Google Patents

Abstract

The invention relates to an orally soluble dosage form with an active ingredient, characterized in that the active ingredient is embedded in a matrix of at least one lipid that melts or softens close to 37 degrees Celsius and a food-safe syrup.

Description

The production of orally slightly soluble dosage forms is becoming more and more important, as ingestion without water is valued by customers and is also possible when swallowing is difficult. The preparation of such dosage forms is costly. For example, it has been proposed to freeze-dry or sublimate drugs in solution in a mold to produce readily soluble but highly hygroscopic and fragile preparations. Alternatively, the injection of wet starting material with contents was suggested, followed by a drying step. The use of sugars in direct compression or spray drying and direct compression has also been proposed. However, the resulting dosages generally have a slightly attractive mouthfeel, tend to be more adherent and sticky. Finally, the use of Super Disintegrants such as Crosscarmelose or PVP allows fast-dissolving tablets, but produce an unpleasant chalky mouthfeel in the mouth.

US 6733781 describes a preparation using a lipid and a sugar in an undissolved form wherein the lipid is restricted to about 20% by weight of the dosage form prepared by tableting. The administration according to this application limits the use of the lipid to 20% in order to ensure tableting. However, it has been found that higher lipid contents lead to a far better mouthfeel and unproblematic processing is possible by the addition of a food-grade syrup which manages without high pressures as in the case of tableting. In this way, the mouthfeel can be improved without the tabletting as in US 6733781 limits the mass fraction of lipid. The use of sugar after US 6733781 is limited to the solid, tabletable form of the sugar. This is used to create a better possibility in the mouth. In comparison, in the present invention, the food-safe syrup is used to improve the mouthfeel by its water content, but at the same time as a process aid for shaping, through which much higher levels of lipid can be used.

US 2004/0241208 A1 on the other hand describes a dosage form which is near free of fatty acids, has a moisture content of 10-13% and a relatively fine particle structure, which is based on fondant. Although sets US 2004/0241208 A1 As in the present invention, a food-grade syrup is used, but this is used to bind the crystallized particles or added fondant sugar particles to obtain, at least in part, sugar crystals of size 2-35 microns. The production after US 2004/0241208 A1 thus requires higher temperatures to reach the so-called soff ball stage (112-116 ° C), which makes particular heat-sensitive active ingredients such as enzymes and microorganisms in contrast to the present invention with generally 42 ° C not processable. Furthermore, the presentation is after US 2004/0241208 A1 sensitive to drying and requires a complex coating, since the administration is dependent on a moisture content of 10-13%, to produce the claimed pleasant mouthfeel. Otherwise the fondant mixture would dry out, become hard and brittle. By contrast, the present invention does not rely on a particular moisture content in the dosage form and is substantially more stable to moisture or drying due to the lipid content.

It is an object of the present invention to describe a dosage form which, in contrast to the prior art (lyophilization / sublimation / tablet molding) is moisture-stable and dissolves rapidly in the oral cavity, without chalking or sticking to larger agglomerates due to disintegration (direct compression / Superdisintegrants), wherein the handling of the presentation compared to the prior art is better possible because the dosage form is less fragile.

In particular, it is an object of the present invention to describe a dosage form which is suitable for temperature-sensitive and / or pressure-sensitive active substances such as enzymes and microorganisms. In one embodiment, the object of the present invention is to describe a dosage form of an enzyme and a probiotic which is based on the present invention.

It is a further object of the present invention to describe a method for producing such a dosage form.

It has been found that the use of a lipid that melts or softens to near 37 degrees Celsius and a food grade syrup results in a dosage form that is rapidly soluble in the mouth through the combination of body temperature and saliva, without particles being perceived or a stronger adhesion to the teeth, wherein the durability and processability (packaging, filling, etc) is optimized over the prior art.

At the same time, by the use of the lipid, it is possible to prepare a preparation which is substantially more moisture-stable than known in the art, since it constitutes a natural moisture barrier. The use of a food-grade syrup additionally improves the mouthfeel, gives the presentation a certain plasticity, which prevents breakage during processing (packaging, filling, transport) and allows the production of high lipid content preparations.

Furthermore, it was found that the use of the food-grade syrup raises the temperature susceptibility of the cocoa butter without disturbing the melting, whereby the administration can withstand temperatures above 37 degrees for a period of at least 30 minutes.

Suitable lipids of the present invention are those that substantially melt or soften between 34-42 degrees Celsius, preferably between 36-40 degrees Celsius, and most preferably at 37 degrees Celsius. It is also possible according to the invention to use a lipid mixture of at least two lipids, in so far as at least one of these exhibits the properties mentioned.

A lipid or a suitable lipid mixture is understood in particular to be fatty acids, waxes and triacylglycerides. A mixture of these preferred lipids, for example the triacylglycerides and the waxes for a better barrier to moisture, is possible according to the invention. Suitable lipids are, in particular, natural lipids, such as beeswax, canauba wax, coconut oil, cocoa butter, or synthetic lipids, in particular hardened fats, such as hardened palm oil or hardened coconut oil. The lipids may also be in micronized form, such as micronized waxes. In particular, lipids or mixtures with lipid content are suitable, which are used for the preparation of suppositories. The suitable lipids of the present invention must be edible.

Suitable food-grade syrups according to the present invention consist of a solution of at least one saccharide in a solvent. Suitable solvents are, in particular, water or glycerol. Suitable saccharides are in particular monosaccharides, di-, tri- and / or oligosaccharides, preferably glucose, fructose, sucrose, lactose maltose, maltotriosen, hydrolyzed starches of different degrees of hydrolysis, oligofructoses, oligolactoses and maltodextrins, most preferably a high proportion of one or more higher molecular weight Saccharides is chosen to reduce the hygroscopicity. A saccharide mixture is possible according to the invention. Also additives, in particular additives such as polymers, in particular natural rubber, are possible according to the invention. It is also possible according to the invention to use sugar alcohols which can be prepared from saccharides, in particular xylitol, maltitol, isomalt, or other sugar alcohols.

Suitable food-safe syrups are, in particular, natural syrups such as cane syrup, sugar beet syrup, maple syrup, honey, syrups such as algavendil juice and syrup from hydrolysed starch raw materials such as rice syrup or corn syrup, but also industrial syrups such as, in particular, glucose syrup, glucose-fructose syrup or syrups based on starches or maltodextrins. Modified saccharides such as sugar alcohols, in particular xyllitol or isomalt, can also be used.

The content of the saccharide (s) of the syrup is preferably in the range of so-called supersaturation, and lower contents, in particular 60% saccharide content, which are industrially more manageable, are also possible.

Active substances according to the present invention include all intentionally ingested substances. Preferably, the present invention can be used in substances, be taken orally or should be effective in the stomach, but also the use of gastric stable or coated / encapsulated mageninstabiler agents is useful possible. Preferably, the present invention is used to make enzymes, more preferably galactosidases, glutaminases or isomerases, most preferably beta-galactosidases ingestible. Among the beta-galactosidases acid-stable beta-galactosidases are preferably used, including Aspergillus, Bacillus or Lactobacillus species. Likewise, microorganisms, so-called probiotics, can be used with the present invention insofar as they themselves are gastric juice-stable, such as Bacillus coagulans or certain yeasts or have been rendered enteric-stable by coating. However, the ingestion of nichtmagensaftstabiler species according to the invention is possible, insofar as no vital cells are needed or the effect should occur orally. The gift of lysates is also possible.

It is possible according to the invention for the active substances, in particular enzymes and / or microorganisms, to be in dried form or to be in liquid form, in particular in a glycerol solution. Suitable drying methods include freeze drying and spray drying with, among others, maltodextrin or calcium phosphate.

The addition of surfactants such as lecithin or substances for absorption of excess fat such as maltodextrins, phosphates or silicates may be necessary to ensure processing.

According to the invention, the administration can be coated in order to further optimize the stability, by, inter alia, hard panning, soft panning, Envelope with fats or waxes, spray coating, whereby polymers can be used in these processes.

Accordingly, the administration according to the invention consists at least of at least one active substance, at least one lipid and at least one food-grade syrup. The dosage form according to the invention in this minimal form contains at least 20%, preferably 30%, most preferably 33% of lipid. It is preferred that the dosage contain at least 9% of food grade syrup, preferably between 20-50%, most preferably 25%.

The inventive method is characterized according to the preparation of a mixture of at least one active ingredient, at least one lipid and at least one food-grade syrup, wherein at least 20% of lipid are contained and at least 9% of food-safe syrup.

The further processing of the mixture according to the invention is possible by the method known in the art for shaping soft high-viscosity compositions, such as hand forms, shapes with food-grade forms, injection methods, extrusion, compression, granulation, cutting, rolling and tableting.

Example 1:

Fifty grams of cocoa butter were melted to 42 degrees and cooled to 33 degrees, then mixed by hand in a bowl with 50 grams of a beta-galactosidase containing 100,000 FCC / g (pure from Amano Enzymes) until a uniform mixture was obtained. 40 g honey was mixed in after the mass reached room temperature. The recovered mass was kneaded intensively after cooling and partial crystallization of the cocoa butter until a homogeneous mixture was erzeut. The mass proved to be malleable and could be turned into pills with a rolling mill.

Example 2:

Fifty grams of cocoa butter were melted to 42 degrees and cooled to 33 degrees, then mixed with 50 grams of a beta-galactosidase at 100,000 FCC / g (spray dried with maltodextrin) by hand in a bowl until a uniform mixture was achieved. 40 g of corn syrup were mixed in after the mass reached room temperature. The recovered mass was kneaded intensively after cooling and partial crystallization of the cocoa butter until a homogeneous mixture was erzeut. The recovered mass was pressed with silicone molds in spherical form and cured at room temperature.

Example 3

Fifty grams of cocoa butter were melted to 42 degrees and cooled to 33 degrees, then mixed by hand with 50 grams of a beta-galactosidase at 50,000 FCC / g (spray-dried with calcium phosphate) in a bowl until a uniform mixture was achieved. 35 g of glucose syrup were mixed in after the mass reached room temperature. The recovered mass was kneaded intensively after cooling and partial crystallization of the cocoa butter until a homogeneous mixture was erzeut. The recovered mass was extruded and cut into appropriate units.

Example 4

50 g of cocoa butter were melted to 42 degrees and cooled to 33 degrees, then mixed with 50 g of a lyophilizate from Bacillus coagulans spores (25 × 10 ^ 9 units, filler maltodextrin) by hand in a bowl until a uniform mixture was achieved. 40 g of corn syrup were mixed in after the mass reached room temperature. The recovered mass was kneaded intensively after cooling and partial crystallization of the cocoa butter until a homogeneous mixture was erzeut. The recovered mass was pressed with silicone molds in spherical form and cured at room temperature.

Example 5

The mixture of Example 1 was turned into balls and heated to 47 degrees for 30 minutes. It remained dimensionally stable and could continue to be handled without breaking.

Example 6

The mixture from example 2 was turned into balls and exposed to high humidity for 24 h in a water-filled expeller. Water condensation in the form of beads on the surface was not apparent, which would represent a visible reduction in quality due to the hygroscopicity.

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 6733781 [0002, 0002, 0002]
• US 2004/0241208 A1 [0003, 0003, 0003, 0003]

Claims (2)

An orally rapidly dissolving dosage form, characterized by at least one active ingredient, at least one lipid and at least one food-grade syrup, wherein at least 20% of lipid and at least 9% of food-safe syrup are included. A process for producing a fast-dissolving dosage form, characterized by the preparation of a mixture of at least one active ingredient, at least one lipid and at least one food-grade syrup, wherein at least 20% of lipid are contained and at least 9% of food-safe syrup.