AT500101A1 - encapsulation - Google Patents

Description

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The invention relates to a method for encapsulating sensitive substances. Sensitive substances, that is, volatile and / or hydrolysis-sensitive and / or oxidation-sensitive substances.

Numerous substances are volatile or show high sensitivity to external influences (moisture, atmospheric oxygen). Examples of these would be essential oils, herbal extracts, such as grape extracts, pharmaceutical active substances, in particular hydrolysis-sensitive active substances or even food dyes.

The associated poor durability can be significantly improved by encapsulation. Numerous methods have thus been developed to achieve this goal, the preferred matrix being hydrogenated sugars and combinations with polysaccharides or also modified starches.

A commonly used method would be spray drying. Here, in the simplest case, aqueous solutions of the matrix materials are mixed with an essential oil or an active substance, and the dispersion is forced through nozzles in a wide vertical shaft and the fine droplets are dried by a stream of hot air. The drying process results in a highly porous matrix.

Another possible method is freeze-drying, which once again requires a porous product and loss of low-boiling components.

For some time, methods for microencapsulation via melting are known (EP 1 013 176 Al). Described is a method in which a mixture of mannitol and sorbitol is first melted at 190 ° C and added during cooling, a crystallization-suppressing substance, so that one comes to a temperature of the melt of 150 ° C. Thereafter, the liquids, such as essential oils, introduced under pressure in the temperature range between 150 and 146 ° C, the mixture kept at this temperature and placed on a conveyor belt, where it solidifies after some time. The main part of this process is the long and high temperature load on the substance to be encapsulated. Especially essential oils are usually complex mixtures of numerous components that can undergo numerous reactions when exposed to temperature. Furthermore, decomposition products of the matrix constituents can form at such high temperatures.

In DE 198 22 036 A an effervescent preparation is disclosed. By embedding at least one CO2 donor or an acidic component and, if appropriate, further effervescent preparation components in a sugar alcohol, the stability is improved. Reactions that are catalyzed by the presence of the acid or the C02 donor can thus be prevented. Protection against external influences, such as oxygen or moisture, is not disclosed.

According to EP 0 62 9 393 A2, preparations based on crystalline polyols are described. In this process, ewin sugar alcohol is melted, a phosphopeptide is dispersed in the molten sugar alcohol, and the mixture is cooled with stirring. Finally, it is cooled slowly until the sugar alcohol crystallizes completely. A melt extrusion with a much shorter temperature load was not mentioned in the document described.

In GB 972 459 a process for the preparation of confectionery based on starch (derivatives) and sugar alcohols is described. However, neither the use of a recrystallizing sugar alcohol, such as mannitol or xylitol, nor a dry and solvent-free (plasticizer-free extrusion described), on the contrary: the presence of water is mandatory. Also, no encapsulation of pharmaceutical or sensitive substances is described.

WO 98/12932 describes sweets containing xylitol. Extrusion or encapsulation is not disclosed. * • · * * · ♦ * • ♦ • • • • • • • • • • • · · · · · · · · · · · · ·

Accordingly, it is the object of the present invention to develop a process with which preparations of volatile and / or hydrolysis-sensitive and / or oxidation-sensitive and / or temperature-sensitive substances can be prepared which are stable and in which no or only slight losses are to be processed Substances arise. Furthermore, the process should be simple to perform and easy to implement and implement on an industrial scale. Finally, the process of the invention should be carried out as possible without the addition of moisture. By the method described it should also be possible to significantly reduce the temperature load on melt extrusion us thus to protect the entrapped substances significantly.

Accordingly, the present invention provides a process for encapsulating substances in a matrix containing sugars, sugar alcohols, sugar substitutes and mixtures thereof, by extrusion through an extruder having one or more temperature zones, characterized in that the matrix is characterized by to be encapsulated substances at a temperature at which the sugar, sugar substitutes or mixtures thereof in a partially molten state (at least 20%, preferably 60%) leave the extruder.

This is achieved by extruding the individual heating zones at a temperature below the melting point of the matrix mixture.

Accordingly, the present invention provides a process for encapsulating substances in a matrix containing sugars and / or sugar alcohols and or sugar substitutes and mixtures thereof by extrusion through an extruder having one or more temperature zones, characterized in that the matrix is extruded with the substances to be encapsulated at a temperature at which the matrix leaves the extruder in a partially molten state. (Under temperature profile according to the invention, the sequence of temperature settings of the successive heating zones (cylinder understood).

The invention also provides a method for

Encapsulation of substances in a matrix consisting of A) sugar alcohol (s) and / or sugar (s) and / or sugar substitute (s) B) additives capable of forming a eutectic with A. C) excipients (additives, if acids, then only weak acids, in particular malic acid and only in a small amount between 1-3%), wherein the matrix is mixed with the substances to be encapsulated and the mixture is extruded dry and solvent-free at a temperature (temperature profile in which the component A is partially melted ,

Partially melted means that the component A is the

Extruder leaves in partially molten state.

The invention also provides a method for

Encapsulation of substances in a matrix consisting of A) a sugar alcohol or a sugar alcohol mixture B) additives which can form a eutectic with A), and C) auxiliaries, wherein the matrix is mixed with the substances to be encapsulated and the mixture is dry and extruded solvent-free at a temperature at which component A) is partially melted.

The object according to the invention is also achieved by a method for encapsulating substances, wherein the substances are mixed with a matrix which contains at least 30% of a recrystallizing sugar alcohol and the mixture is melt-extruded dry and solvent-free.

With the present invention, all possible substances can be encapsulated, in particular pharmaceutical or cosmetic substances. However, the present invention is particularly suitable for providing volatile and / or hydrolysis-sensitive and / or difficult-to-disperse substances in encapsulated form, in particular pharmaceutical active ingredients, vitamins and oils, fat waxes.

However, the present invention is particularly suitable for the provision of volatile and / or hydrolysis-sensitive and / or difficult to disperse substances in encapsulated form, in particular pharmaceutical agents, vitamins and oils, fats, waxes, especially if they are also temperature-sensitive (heat-sensitive), as by the process according to the invention described the

Processing temperatures can be significantly reduced.

Accordingly, the present invention also provides a process for encapsulating temperature-sensitive (heat-sensitive) substances in a matrix containing sugars and / or sugar alcohols and or sugar substitutes and mixtures thereof by extrusion through an extruder having one or more temperature zones characterized in that the matrix is extruded with the substances to be encapsulated at a temperature at which the matrix leaves the extruder in a partially molten state. (Under temperature profile according to the invention, the sequence of temperature settings of the successive heating zones (cylinder) understood.

The invention also provides a process for the encapsulation of temperature-sensitive (heat-sensitive) substances in a matrix consisting of A) sugar alcohol (s) and / or sugar (s) and / or sugar substitute (s) B) additives which form a eutectic with A. C) auxiliaries (additives, if acids, then only weak acids, especially malic acid and only in a small amount between 1-3%), wherein the matrix is mixed with the substances to be encapsulated and the mixture dry and solvent-free at a temperature ( Extruded temperature profile, in which the component A is partially melted.

Partially melted means that component A leaves the extruder in a partially molten state.

The invention also provides a method for

Encapsulation of heat-sensitive substances in one

Matrix consisting of A) a sugar alcohol or a sugar alcohol mixture B) additives which can form a eutectic with A), and C) auxiliaries, wherein the matrix is mixed with the substances to be encapsulated and the mixture dry and solvent-free at a temperature is extruded, in which the component A) is partially melted.

The object of the invention is also achieved by a method for encapsulating temperature-sensitive (heat-sensitive) substances, wherein the substances are mixed with a matrix containing at least 30% of a recrystallizing sugar alcohol and the mixture is melt-extruded dry and solvent-free.

By heat-sensitive it is meant that the substances decompose at a temperature above 100 ° C, ie form decomposition products, or react with atmospheric oxygen.

With the present invention, all possible substances can be encapsulated, in particular pharmaceutical or cosmetic substances. However, the present invention is particularly suitable for providing volatile and / or hydrolysis-sensitive and / or difficult-to-disperse substances in encapsulated form, in particular pharmaceutical active ingredients, vitamins and oils, fat waxes. Surprisingly, it has been found in the course of the research on the present invention that sugar alcohols, which actually do not appear suitable as monomeric substances for extrudates, in the context of the process of the invention are outstandingly suitable as a basis for melt extrudates of the mentioned, mostly unstable substances.

With the melt extrudate according to the invention storable preparations of such volatile and / or oxidation-sensitive and / or hydrolysis-sensitive substances in a simple manner, namely with only a single extrusion step, dry, ie without the addition of moisture (without the addition of water) sugar alcohols are hygroscopic different degrees and accordingly contain different amounts of residual moisture), and without previous melting of the matrix material can be produced. Furthermore, the addition of solvents which are undesirable in the preparations obtained are not required, which is why in the present process, without the addition of moisture and other solvents in particular without the addition of alcohols, alcohol / water mixtures, polyhydric alcohols, such as glycerol, or propylene glycol worked can be.

In addition, sugar alcohols have a lower calorific value and are not cariogenic.

According to the invention, sugars, sugar alcohols, sugar substitutes and mixtures thereof can also be processed with a glass transition below 30 ° C to give a room temperature hard and stable matrix in which the substance to be encapsulated is enclosed.

The inventive method u. a. the following advantages over the prior art.

Matrix materials of lower cost can be processed by melt extrusion. - Ers pharmaceutical active ingredients and vitamins can be homogeneously distributed and protected against external influences. - The extrusion temperature and thus the heat load for the sensitive substances can be significantly reduced.

It is possible to process sugar alcohols with anti-cariogenic activity, in particular xylitol. - Optimization of process parameters: achieving higher pressures; - In the case of volatile substance encapsulation, even for low boiling point substances, the process shows little sign of foam after leaving the nozzle.

Although it is known that extrusion is particularly suitable for processing thermally sensitive substances (J. Breitenbach, Schmelzextrusion an integrated

Manufacturing concept, pharmacy in our time, 2000), this being due to the short residence time and thus short heat load of the substances to be processed, however, this method has only been using thermoplastic polymers for various

Used active ingredients.

Sugar alcohols are monomeric substances. Consequently, their melts show too low viscosity to be suitably entrained by the screw in the extruder, the dispersibility and thus an extrudate more homogeneous

To ensure composition or to produce high material pressure and thus to encapsulate volatile substances without loss. Alcohols are sugar alcohols by the inventive processing excellent as a matrix material for processing by melt extrusion.

Preferably, the matrix consists of A) main constituent: sugar (s) and / or sugar alcohol (s) and / or sugar substitute (s) B) additives (all data in% by weight) 0-50% preferably 20-30% substance or substance mixture that with A

C) 0-10% auxiliaries, preferably 0-5%, and is melt extruded at a temperature at which component A is partially melted (partially crystalline) (at least 20%, preferably at least 60% solid (crystalline)).

According to the invention, sugar alcohols with a glass transition below room temperature can also be processed as component A) according to this process to give a hard and stable matrix in which the substance to be encapsulated is enclosed. Preferably, a sugar and / or sugar alcohol and / or sugar substitute having a melting point between 60 and 200 ° C and a molecular weight between 90 and 500 g / mol is used as component A.

Preferably, but not limiting, a recrystallizing sugar alcohol, in particular mannitol or xylitol, is used as component A. Under recrystallizing sugar alcohol is understood to be a sugar alcohol, which can be brought to crystallization via extrusion by convection and in which the crystallized fraction causes complete crystallization after exiting the extruder, or recrystallized from the melt without convection. If no such sugar alcohol is used, according to the process of the invention, the extrudate obtained would be partly amorphous and partly crystalline.

IQ

Molecular transport processes could lead to changes in the

Composition of the matrix, with the following exclusion of the sensitive substances and thus would not be useful.

Germische of sugar (s) and / or are preferred

Used sugar alcohol (s) and / or sugar substitute (s) and / or component B, by which a

Broadening of the melting range results. This will be the

Process better controllable (narrow melt range would not allow a constant flow rate to be set (increased

Risk of clogging of the extruder and consequent no constant product quality). Preference is given to a mixture of a crystallizing sugar alcohol having a

Sugar substitute used in particular glucono-delta-lactone.

The processing conditions are preferably chosen so that the matrix forms a solid solution, that is, the process parameters are chosen so that despite extrusion of a predominantly solid matrix these (especially components A and B in the form of a solid after extrusion, which would mean that the matrix material was completely melted at least once, and this is possible will be shown in the later examples.

The screw speed is according to the invention in this case between 30 to 1000, preferably between 100 to 300 U / min

The material pressure according to the invention is between 0 and 200, preferably between 3 and 13 bar.

The torque is according to the invention between 0-90, preferably between 15 to 45 Nm.

Under sugar substitutes according to the invention are all substances to understand that show at least a low degree of sweetness, show a melting point between 60 ° C and 200 ° C and have a molecular weight between 90-500 g / mol. •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• ••••••••••

Specifically, examples thereof are glucono-delta-lactone, aspartame, acesulfame, saccharin, sodium cyclamate.

Preferred sugar alcohols are xylitol and / or mannitol. However, other sugar alcohols, such as erythritol, threit, ribitol, arabitol and dulcitol, may also be used.

Suitable sugars are mojinosaccharides, di- and trisaccharides, in particular glucose and fructose.

According to the invention, however, other sugar alcohols and mixtures thereof may serve as a matrix. Examples, but not limiting, would be isomalt, sorbitol, maltitol, or lactitol. According to the preferred embodiment of the method, the matrix material contains (50-80)% of component A.

As component B substances are used, which result in an expansion of the melting range with component A, as a result of which the process becomes more controllable and / or which increase the viscosity, which leads to stronger temperature gradients of the extrusion mass. It is essential that component B is a substance which can form a eutectic with component A, ie that the two melts are soluble in one another.

Examples of these are mono-, di-, trisaccharides, in particular glucose, fructose, or inner esters of acids such as, for example, glucono-delta-lactone, and / or also polysaccharides, such as maltodextrins and / or modified starches. Exceptions are acids. Because these would cause a strong change in taste, if you then only in small amounts (0-5%, preferably 0-3%) are added (component C). Preferably, as component B, additives having a molecular weight greater than 500, preferably greater than 900, g / mol are used.

The processing conditions are preferably chosen so that in the extrudate component A and B form a solid solution. 12? • · · · · · 12? • • • • • • • • • ♦♦ > · * · · · Μ

By solid solution it is meant that the components (A) and Bs show a uniform melting peak in DSC analyzes.

The temperature settings of the individual heating zones are preferably below the peak onset (melting point).

Of course, the preparation may contain low molecular weight constituents in the additives, in particular in the case of starch degradation products.

Furthermore, as component B, taste-neutral or at least slightly sweet-tasting substances are used.

According to the preferred embodiment of the method, the matrix material contains 0-70%, preferably 20-50%, in particular 20-30% component B.

The matrix should therefore be homogeneous in the molten state, i. essentially (<10%, especially <2%) is not in two liquid phases.

As excipients C all pharmaceutically and food law accepted substances can serve. For example, it is possible to add substances which facilitate the subsequent processing, grinding (Aerosil), granulation, etc., or improve the dispersibility (emulsifiers), or else the stability, of antioxidants. But it can also be added to food dyes, etc. According to the invention, component C can also be dispensed with. If, in addition, organic acids are used as component C, these are especially weak acids, such as malic acid, preferably in an amount of 0-3%. For example, weak organic acids such as malic acid or citric acid provide an optimum pH of the matrix in the slightly acidic range, which particularly improves the shelf life of essential oils, which usually exhibit high sensitivity to alkaline hydrolysis. According to the invention, component C can also be dispensed with.

Sensitive substances which are encapsulated according to the invention are oxidation-sensitive and / or hydrolysis-sensitive and / or volatile and / or temperature-sensitive substances. Examples of this but not limiting odors and flavors, essential oils such as orange oil, orange peel oil, lemon oil, eucalyptus oil and mixtures thereof and / or vitamins, especially vitamin C, D3, A, K, E, plant extracts such as extracts of grapes, St. John's Wort , Thyme or resveratrol and / or pharmaceutical active substances, in particular hydrolysis-sensitive active substances.

Preferably, the substances to be entrapped is hydrophobic.

Preferably, the substances form a solid dispersion with the matrix.

The substances can be present in the matrix dispersed in the form of a solid solution.

However, oily solutions or dispersions of active substances, in particular lipophilic active substances or vitamins such as vitamin K or vitamin D in oils, in particular medium-long chain and long-chain triglycerides, may also be considered to be sensitive according to the invention.

According to another aspect, solutions and / or

Dispersions of sensitive substances in oils, fats or waxes are encapsulated according to the invention.

According to the invention, it is extruded at a temperature at which component A is partially melted. Usually, both component A) and component B) are partially melted, or the homogeneous mixture of A) and B) is partially molten. However, it may also be extruded shortly above the melting point of component A), provided that this does not affect the homogeneity of the composition of the invention. ···················································

Composition negatively affected. It is important, above all, that component A leaves the extruder in the partially molten state.

The outlet nozzle is usually heated with heating cartridges in order to prevent clogging.

According to the invention, the process steps of mixing and extruding can be carried out in one or more apparatuses.

In the context of the method according to the invention, the substances can be mixed with the matrix material without previous melting, or the sensitive substances can be introduced into the extruder in zones of different material pressures via suitable pumping systems.

According to the invention can be used as extruder single-screw machines, multi-screw machines combing and non-meshing, the same direction and in opposite directions. According to the preferred embodiment of the method, a co-rotating twin-screw extruder is used.

Most sugars, sugar alcohols, sugar substitutes and mixtures thereof show no recrystallization and remain in the amorphous state. Surprisingly, it has been shown according to the invention that sugar, sugar alcohols, sugar substitutes and mixtures thereof are virtually shear-induced to crystallize via extrusion, and the crystallized fraction effects the complete crystallization of the sugar, the sugar alcohols, the sugar substitutes and mixtures thereof after leaving the extruder, or also as partially crystalline mass of a mixture of sugar alcohols, or mixtures of sugar alcohols with acids such as citric acid, malic acid, inner esters of acids such as glucono-delta-lactone, or sugars such as glucose or fructose can be extruded and are thereby as a successful method of encapsulation. 15 ♦ · · · · · · · · · · · ♦ ···················································································································· ♦ · ♦ ♦ · V ', »· ♦♦ ··

The crystallization-suppressing substance mentioned in EP 1013176, in particular glucono-delta-lactone, is amorphous, while in the preparation according to the invention it can be largely crystalline in melt extrusion.

Preferably, the matrix material used in the process according to the invention contains mannitol, xylitol, maltitol, sorbitol, isomalt, lactitol, mono-. Di- and trisaccharides, such as glucose, fructose, glucono-delta-lactone, or mixtures thereof.

According to a preferred embodiment, the matrix material independently contains a polysaccharide, in particular maltodextrin, modified starch or mixtures thereof, an organic acid, in particular malic acid in small amounts &lt; preferably 0-3%, 0-10 component C), the cyclic ester of an organic acid, emulsifiers, in particular sugar esters, lecithin or mixtures thereof.

Preferably, the matrix material independently contains 30-90%, preferably 50-75%, sugar alcohol, preferably recrystallizing sugar alcohol, especially mannitol or xylitol, 1-10% preferably 3-5% of an organic acid, 0-55%, preferably 20-30 % a polysaccharide, in particular a hydrolysis product of starch or a modified starch, and 0-10%, in particular 0-5% emulsifiers.

Preferably, the matrix material according to the invention consists of (A) 50-100%, in particular 70-80%, sugars, sugar alcohols, sugar additives or mixtures thereof, (B) 0-50%, preferably 20-30%, of a substance which is combined with (A ) can form a eutectic and has a molecular weight greater than 900 g / mol and (C), 0-10%, in particular 1-5%, auxiliaries.

In the context of the method according to the invention, the substances can be missed without prior melting with the matrix material, or the substances are introduced continuously via suitable pump systems into the extruder in zones of different material pressures.

In the context of the present invention, the melting point of the matrix is understood as meaning the peak onset in DSC analyzes of component A or of the solid solution of components A and / or components (B), to which the matrix (also as a mixture) in DSC analyzes shows the peak onset.

The matrix material, in particular mannitol-containing matrix materials, is preferably mixed with the substances at a material pressure of 2 to 10 bar

According to a further preferred embodiment, the corresponding sugar alcohols are brought to crystallization by convection.

Preferably, the extrusion is carried out at at least 5 ° C, preferably at least 15 ° C below the melting point of the sugar alcohol corresponding to the extrudate [(A), or (A) and (B)].

As already mentioned, preferred substances to be extruded or encapsulated according to the invention are polyunsaturated fatty acids, omega fatty acids, fish oils, vitamins, especially fat-soluble vitamins such as vitamins A, D, E, K, plant extracts such as grape extract, odorants, essential oils , as well as solutions or dispersions of drugs or vitamins, especially vitamin D and vitamin K in oils, greases or waxes, oily solutions of lipophilic drugs, or mixtures thereof.

The melt extrudates according to the invention are also distinguished by the fact that the substances are completely enclosed and therefore no contact of the substance with the outer surface of the capsule is present.

Preferred substances are vitamins, for example vitamin C, in particular fat-soluble vitamins, such as vitamins A, D, E, K; furthermore unsaturated fatty acids, such as omega fatty acids, essential oils and extracts (anethole nat. chines, angelica root oil belg., aniseed oil, pine oil, valerian oil, basil oil Comoros, bay oil, mugwort oil, bergamot oil, blood orange oil, cade oil rect., cajeput oil, cananga oil , Cardamom oil, cassia oil, cedar leaf oil,

Cedar wood oil, citronella oil, citron juice flavor oil, oriander oil,

Curry leaves oil, Davana oil, dill herb oil, d-limonene, elemi oil, \

Tarragon oil, eucalyptus citriodora, eucalyptus oil radiata, fennel oil, pine oil, galangal oil, galangal root oil, geranium oil, grapefruit oil, guaiac wood oil, helichrysum oil, rosehip oil, hops oil, ginger oil, jasmine absolue, jatamansi (naarden oil), chamomile oil, camphor oil, canoe oil, carrot seed oil, pine needle oil, Spearmint oil, caraway oil, mountain pine oil, lavandin oil, lavender oil, lemongrass oil, lovage root oil, lime oil, litsea oil, cubeba oil, bay leaf oil, macis flower oil, marjoram oil, tangerine oil, manuka oil, lemon balm oil, menthol brasil, mint oil, sage oil, nutmeg oil, myrrh oil, myrtle oil, clove leaf oil, clove flower oil, neroli oil , Orange oil, Orange terpene, Origanum oil, Palmarosa oil, Patchouli oil,

Parsley leaf oil, petitgrain oil, pepper mint oil, rose oil, sage oil, sandalwood oil, celery seed oil, thuja oil, thyme oil, grape extract verbena oil, juniper berry oil, frankincense oil, wine yeast oil, ylang ylang I Comorne, cinnamon leaf oil, pine oil (pine oil), lemon oil, citron oil, onion oil, cypress oil). Further preferred substances are pharmaceutical active substances, in particular oxidation-sensitive (for example unsaturated compounds, in particular steroids, beta-carotene, etc.). Finally, hydrolysis-sensitive active substances, for example acetylsalicylic acid, are also preferred.

In accordance with the invention encapsulated essential oils and herbal extracts may be. Anethole nat. chines, angelica root oil belg., aniseed oil, pine oil, valerian oil, basil oil Comoren, bay oil, mugwort oil, bergamot oil, blood orange oil, cade oil rect., cajeput oil, cananga oil, cardamom oil, cassia oil, cedar leaf oil, cedar wood oil, citronella oil, citron juice aroma oil, coriander oil, curry leaf oil, Davana oil, dill herb oil, d-limonene, elemi oil, tarragon oil,

Eucalyptus Citriodora, eucalyptus oil radiata, fennel oil, pine oil, galangal oil, galangal root oil, geranium oil, grapefruit oil, guaiac wood oil, helichrysum oil, rosehip oil, hop oil, ginger oil, jasmine absolue, jatamansi (naarden oil), chamomile oil, camphor oil, canoe oil, carrot seed oil, pine oil, spearmint oil, caraway oil, Mountain pine oil, lavandin oil, lavender oil, lemongrass oil, lovage root oil, lime oil, citrus oil, bay leaf oil, mace oil, marjoram oil, tangerine oil, manuka oil, lemon balm oil, menthol brasil, mint oil, sage oil, nutmeg oil, myrrh oil, myrtle oil, clove leaf oil, clove flower oil, neroli oil, orange oil, orange terpene, Origanum oil, Palmarosa oil, Patchouli oil, Parsley leaf oil, Petitgrain oil, Peppermint oil, Rose oil, Sage oil, Sandalwood oil, Celery seed oil, Thuja oil, Thyme oil, Grape extract Verbena oil, Juniper berry oil, Frankincense oil, Wine yeast oil, Ylang Ylang I Comoros, Cinnamon leaf oil, Zirbelkiefern l (Arvenöl), lemon oil, lemon oil, onion oil, Cypress oil.

In a further aspect, the present invention relates to a melt extrudate consisting of encapsulated (entrapped) substances in a matrix containing sugars, sugar alcohols, sugar substitutes or mixtures thereof. The substances are preferably volatile and / or hydrolysis-sensitive and / or oxidation-sensitive and / or difficult-to-disperse substances, in particular pharmaceutical active ingredients and / or vitamins as well as solutions or dispersions pharmaceutically active substances and / or vitamins in oils, fats or waxes; The matrix preferably contains at least 30% of a recrystallizing sugar alcohol.

Preference is given to melt extrudates which are obtainable by the process according to the invention.

The Schmelextrudate invention are characterized in that the sensitive substances are completely encapsulated in the matrix. By crushing the Schmelzextrudates can remain in one or the other case a little material on the surface. However, it should be at least 90% preferably, preferably 99%, especially 99.9%, in... * be included in the matrix, ie that by solid / liquid (solvent in which the matrix does not dissolve or in the case of volatile substances extraction in air) extraction not more than 90%, preferably 99%, especially 99.9%, can be removed.

If pharmaceutical active ingredients are used, they may be melted at the processing conditions and thus finely dispersed in the sugar alcohol matrix. However, active substances can also be introduced in micronized form. In addition, oils, fats or waxes as carriers of pharmaceutical agents and / or vitamins can be encapsulated by the method according to the invention in order to improve their bioavailability, stability or compatibility, as well as to protect the taste.

According to a further aspect, the invention relates to a process for the preparation of solid solutions of pharmaceutical active substances in sugars, sugar alcohol (s) and / or sugar substitutes and, if appropriate, excipients.

According to a further aspect, the present invention has for its object to develop a method with which preparations of solid solutions of poorly water-soluble (difficult to disperse) pharmaceutical active ingredients can be prepared and this without the addition of moisture or solvent.

Accordingly, the present invention also provides a process for preparing solid solutions of substances in a matrix containing sugars, sugar alcohols, sugar substitutes and mixtures thereof, by extrusion through an extruder having one or more temperature zones, characterized in that the matrix is extruded with the pharmaceutically active substances at a temperature at which the sugars, sugar substitutes or mixtures thereof are partially dispersed in. \ ········ Z · J ································································ * ·· · molten state (at least 20%, preferably 60%) leave the extruder.

This is achieved in that the individual heating zones at a temperature below the melting point of the solid solution of matrix material with the poorly dispersible substance (poorly water-soluble pharmaceutical agent). Accordingly, the present invention provides a process for preparing solid solutions of pharmaceutical agents in a matrix containing sugar and or sugar alcohols and or sugar substitutes and mixtures thereof, by extrusion through an extruder with one or more temperature zones, characterized in that the matrix with the poorly dispersible substances (poorly water-soluble pharmaceutical active substances are extruded at a temperature at which the mixture leaves the extruder in a partially molten state. (Temperature profile is taken to mean according to the invention the sequence of temperature settings of the heating zones following one another (cylinder)).

The invention also provides a method for

Preparation of solid solutions of pharmaceutical active substances in a matrix consisting of A) sugar alcohol (s) and / or sugar (s) and / or sugar substitute (s) B) additives which can form a eutectic with A. C) auxiliaries (additives, if acids, then only weak acids, especially malic acid and only in a small amount between 1-3%), wherein the matrix is mixed with the pharmaceutical agent and the mixture is extruded dry and solvent-free at a temperature (temperature profile in which the component A partially melted is present.

Partially melted means that component A or the resulting solid solution of component A and the pharmaceutically active agent leaves the extruder in a partially molten state.

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The invention also provides a process for the encapsulation of substances in a matrix, consisting of A) a sugar alcohol or a sugar alcohol mixture B) additives which can form a eutectic with A), and C) auxiliaries, wherein the matrix with the pharmaceutical Active ingredient is mixed and the mixture is extruded dry and solvent-free at a temperature at which the component A) or the solid solution of component (A) and the difficultly dispersible substance (poorly water-soluble pharmaceutical agent) is partially melted.

The object according to the invention is also achieved by a process for the preparation of solid solutions of pharmaceutical active substances, the poorly dispersible substances (poorly water-soluble pharmaceutical active substances) having a matrix which is at least 30% of a recrystallizing

Sugar alcohol contains mixed and the mixture is melt extruded dry and solvent-free.

With the present invention, all possible solid solutions of pharmaceutical agents can be prepared. However, the present invention is particularly suitable for providing substances which are difficult to disperse (poorly water-soluble substances), in particular pharmaceutical active substances. Surprisingly, it has been found in the course of research on the present invention that sugar alcohols, which actually do not appear suitable as monomeric substances for extrudates, in the context of the inventive method are excellent as a basis for melt extrudates of the mentioned, usually difficult to disperse substances.

With the melt extrudate according to the invention, solid solutions of pharmaceutical active ingredients can be dried in a simple manner, namely with only a single extrusion step, ie without the addition of moisture (without addition of water, sugar alcohols are of varying degrees hygroscopic and thus contain different amounts of residual moisture), and without prior Melting of the matrix material can be produced. Furthermore, the addition of solvents which are undesirable in the preparations obtained are not required, which is why in the present process, without the addition of moisture and other solvents in particular without the addition of alcohols, alcohol / water mixtures, polyhydric alcohols, such as glycerol, or propylene glycol worked can be.

In addition, sugar alcohols have a lower calorific value and are not cariogenic.

According to the invention, sugars, sugar alcohols, sugar substitutes and mixtures thereof with a glass transition below 30 ° C can also be processed to give a matrix which is hard and stable at room temperature, into which poorly dispersible substance usually a poorly water-soluble pharmaceutical agent is molecularly dispersed and enclosed.

The inventive method u. a. the following advantages over the prior art.

Solid solutions of poorly water-soluble pharmaceutical agents can be formed in rapidly soluble matrices. Solid solutions of difficultly dispersible substances (active pharmaceutical ingredients) in matrices of natural or natural materials without solvent and moisture can be produced continuously by melt extrusion. - Fast soluble sugar alcohols with simultaneous anti-cariogenic effect, in particular xylitol, can be processed.

Although it has been known that extrusion is particularly suitable for processing thermally sensitive substances (J. Breitenbach, Schmelzextrusion an integrated

Manufacturing concept, pharmacy in our time, 2000), this being due to the short residence time and thus short heat load of the substances to be processed, however, this method has been used only by using thermoplastically processable polymers and for various active ingredients.

As already mentioned, the commonly used sugar alcohols are monomeric substances. Consequently, their melts show too low viscosity to be suitably entrained by the screw in the extruder, the dispersibility and thus an extrudate more homogeneous

To ensure composition or to produce high material pressure.

However, sugar alcohols are very suitable as a matrix material for processing by melt extrusion due to the processing method according to the invention.

Preferably, the matrix consists of A) main constituent: sugar (s) and / or sugar alcohol (s) and / or sugar substitute (s) B) additives (all data in% by weight) 0-50% preferably 20-30% substance or substance mixture that with A

C) 0-10% auxiliaries preferably 0-5% and is melt extruded at a temperature at which the component A or the mixture of Komponete A and the poorly dispersible substance (poorly water-soluble pharmaceutical agent) partially melted (partially crystalline present ) (at least 20%, preferably at least 60% solid (crystalline) is present.

According to the invention can be prepared by this method as component A) and sugar alcohols with a glass transition below 24

Room temperature are processed, thereby forming a hard and stable matrix, in which the substance to be encapsulated is present. Preferably, a sugar and / or sugar alcohol and / or sugar substitute having a melting point between 60 and 200 ° C and a molecular weight between 90 and 500 g / mol is used as component A.

Preferably, but not limiting, a recrystallizing sugar alcohol, in particular mannitol or xylitol, is used as component A. Under recrystallizing sugar alcohol is understood to be a sugar alcohol, which can be brought to crystallization via extrusion by convection and in which the crystallized fraction causes complete crystallization after exiting the extruder, or recrystallized from the melt without convection. This means that the sugar alcohol is at least 95% crystalline in DSC analyzes. If no such sugar alcohol is used, the extruded product obtained would be partly amorphous and partly crystalline in accordance with the process of the invention. Molecular transport processes could lead to changes in the composition of the matrix, with subsequent exclusion of the difficult-to-disperse substances, which would thus not be expedient.

Preferably, mixtures of sugar (s) and / or sugar alcohol (s) and / or sugar substitute (s) are used and / or component B is used, which results in a broadening of the melting range. This makes the process easier to control (a narrow melting range would not allow a constant throughput to be set (increased risk of clogging of the extruder and consequently no constant product quality.) Preferably, a mixture of a recrystallizing sugar alcohol with a sugar substitute, in particular glucono-delta-lactone, is used.

The processing conditions are preferably chosen so that the matrix with the difficult-to-disperse substance forms a solid solution, that is to say that the process parameters are selected such that, despite extrusion, the predominantly 25

Part of solid mass (especially component A and optionally B and / or C after extrusion with the active ingredient in the form of a solid solution, which would mean that the matrix material was at least once completely melted with active ingredient.) Amazingly, this is possible despite extrusion of a For the most part solid mass possible.

Only by a sufficiently high viscosity is a mass of the screw entrained in the extruder and the dispersibility guaranteed with the following homogeneous composition of the extrudate. Sugar alcohols, sugars, and also sugar substitutes are monomeric and with decreasing sweetness oligomeric substances. A corresponding promotion is achieved in which is extruded at a temperature at which the matrix substances or the mixture of matrix substances with the pharmaceutical active ingredient is partially melted. Due to the temperature gradients which occur especially in twin-screw extruders, a dynamic melting and crystallization process is established. As a result, sensitive substances are simultaneously distributed homogeneously and enclosed or forms solid solutions of pharmaceutical agents in the described matrix.

Under sugar substitutes according to the invention are all substances to understand that show at least a low degree of sweetness, show a melting point between 60 ° C and 200 ° C and have a molecular weight between 90-500 g / mol. Specifically, examples thereof are glucono-delta-lactone, aspartame, acesulfame, saccharin, sodium cyclamate.

Preferred sugar alcohols are xylitol and / or mannitol. However, other sugar alcohols, such as erythritol, threit, ribitol, arabitol and dulcitol, may also be used.

Suitable sugars are myoinosaccharides, di- and trisaccharides, in particular glucose and fructose.

According to the invention, however, other sugar alcohols and mixtures thereof may serve as a matrix. Examples, but not limiting, would be isomalt, sorbitol, maltitol, or lactitol. According to the preferred embodiment of the method, the matrix material contains (50-80)% of component A.

As component B, substances are used which give an enlargement of the melting range with the component A, whereby the process becomes more controllable, and / or which increase the viscosity, thereby making it stronger

Temperature gradient of the extrusion mass comes. It is essential that component B is a substance which can form a eutectic with component A, ie that the two melts are soluble in one another.

Examples of these are mono-, di-, trisaccharides, in particular glucose, fructose, or inner esters of acids such as, for example, glucono-delta-lactone, and / or also polysaccharides, such as maltodextrins and / or modified starches. Exceptions are acids. Because these would cause a strong change in taste, if you then only in small amounts (0-5%, preferably 0-3%) are added (component C). Preferably, as component B, additives having a molecular weight greater than 500, preferably greater than 900, g / mol are used.

But it can also be completely dispensed with component B.

For example, a pharmaceutically active agent itself could be melt extruded with a sugar alcohol, such as mannitol or xylitol, yielding a wide melting range and forming a solid solution via extrusion.

The processing conditions are preferably chosen so that in the resulting extrudate component A and optionally component B with the difficult to disperse substance forms a solid solution.

By solid solution it is meant that the component (s) A and, and otherwise, B 'with the poorly dispersible 27

Substance (poorly water-soluble pharmaceutical agent in DSC analyzes show a uniform melting peak.

The temperature settings of the individual heating zones are preferably below the peak onset (melting point) of the solid solution formed by extrusion of component A and optionally B and with the poorly dispersible substance (poorly water-soluble pharmaceutical active ingredient.

Of course, the preparation may contain low molecular weight constituents in the additives, in particular in the case of starch degradation products.

Furthermore, as component B, taste-neutral or at least slightly sweet-tasting substances are used.

According to the preferred embodiment of the method, the matrix material contains 0-70%, preferably 20-50%, in particular 20-30% component B.

The matrix should therefore be homogeneous in the molten state, i. essentially (<10%, especially <2%) is not in two liquid phases.

As excipients C all pharmaceutically and food law accepted substances can serve. For example, it is possible to add substances which facilitate the subsequent processing, grinding (Aerosil), granulation, etc., or improve the dispersibility (emulsifiers), or else the stability, of antioxidants. But it can also be added to food dyes, etc. According to the invention, component C can also be dispensed with. If, in addition, organic acids are used as component C, these are especially weak acids, such as malic acid, preferably in an amount of 0-3%. For example, weak organic acids such as malic acid or citric acid provide an optimum pH of the matrix in the slightly acidic range which results in the shelf life of difficult to disperse substances, which are usually high

Sensitivity to alkaline hydrolysis show improved. According to the invention, component C can also be dispensed with.

Hardly dispersible substances are, in particular, poorly water-soluble active substances (see list of preferred substances below).

In a further aspect, the present invention relates to a melt extrudate consisting of encapsulated (entrapped) substances in a matrix containing sugars, sugar alcohols, sugar substitutes or mixtures thereof. The substances are preferably volatile and / or hydrolysis-sensitive and / or oxidation-sensitive and / or difficult-to-disperse substances, in particular pharmaceutical active ingredients and / or vitamins as well as solutions or dispersions pharmaceutically active substances and / or vitamins in oils, fats or waxes; The matrix preferably contains at least 30% of a recrystallizing sugar alcohol.

Preference is given to melt extrudates which are obtainable by the process according to the invention.

The Schmelextrudate invention are characterized in that the sensitive substances are completely encapsulated in the matrix. By crushing the Schmelzextrudates can remain in one or the other case a little material on the surface. However, at least 90% preferably, preferably 99%, especially 99.9%, should be included in the matrix, i. that by solid / liquid (solvent in which the matrix does not dissolve or in the case of volatile substances extraction in air) extraction not more than 90%, preferably 99%, especially 99.9%, can be removed.

According to the invention, it is extruded at a temperature at which component A is partially melted. Usually both component A) and component B) are partially melted, or the homogenous mixture 29 ···································· ······································.

Mixture of A) and B) is partially molten. However, it can also be extruded shortly above the melting point of component A), provided this does not adversely affect the homogeneity of the composition. It is important, above all, that component A leaves the extruder in the partially molten state.

The outlet nozzle is usually heated with heating cartridges in order to prevent clogging.

According to the invention, the process steps of mixing and extruding can be carried out in one apparatus or in a plurality of apparatuses.

In the context of the method according to the invention, the substances can be mixed with the matrix material without previous melting, or the sensitive substances can be introduced into the extruder in zones of different material pressures via suitable pumping systems.

According to the invention can be used as extruder single-screw machines, multi-screw machines combing and non-meshing, the same direction and in opposite directions. According to the preferred embodiment of the method, a co-rotating twin-screw extruder is used.

Most sugars, sugar alcohols, sugar substitutes and mixtures thereof show no recrystallization and remain in the amorphous state. Surprisingly, it has been possible according to the invention to demonstrate that sugar, sugar alcohols, sugar substitutes and mixtures thereof are virtually shear-induced by extrusion, and the crystallized fraction effects the complete crystallization of the sugar, the sugar alcohols, the sugar substitutes and mixtures thereof after leaving the extruder, or also as semicrystalline mass of a mixture of sugar alcohols, or mixtures of sugar alcohols with acids such as citric acid, malic acid, internal esters of acids such as glucono-delta-lactone, or sugars such as glucose or sugars or glucose * * Μ · · · · · · · · · · · · · · · · · # * · · # · ····· • · · · · · · · ·

Fructose can be extruded and are thereby as a successful method for the preparation of the mentioned solid solutions.

The crystallization-suppressing substance mentioned in EP 1013176, in particular glucono-delta-lactone, is amorphous, while in the preparation according to the invention it can be largely crystalline in melt extrusion.

Preferably, the matrix material used in the process according to the invention contains mannitol, xylitol, maltitol, sorbitol, isomalt, lactitol, mono-. Di- and trisaccharides, such as glucose, fructose, glucono-delta-lactone, or mixtures thereof.

According to a preferred embodiment, the matrix material independently contains a polysaccharide, in particular maltodextrin, modified starch or mixtures thereof, an organic acid, in particular malic acid in small amounts &lt; preferably 0-3%, 0-10%, component C), the cyclic ester of an organic acid, emulsifiers, especially sugar esters, lecithin or mixtures thereof.

Preferably, the matrix material independently contains 30-90%, preferably 50-75%, sugar alcohol, preferably recrystallizing sugar alcohol, especially mannitol or xylitol, 1-10% preferably 3-5% of an organic acid, 0-55%, preferably 20-30 % a polysaccharide, in particular a hydrolysis product of starch or a modified starch, and 0-10%, in particular 0-5% emulsifiers.

Preferably, the matrix material according to the invention consists of (A) 50-100%, in particular 70-80%, sugars, sugar alcohols, sugar additives or mixtures thereof, (B) 0-50%, preferably 20-30%, of a substance which is combined with (A ) can form a eutectic and has a molecular weight greater than 900 g / mol and (C), 0-10%, in particular 1-5%, auxiliaries. 31 • · · · · · «·« • · · · · · · · · · · · · · · · · · · · ·

In the context of the process according to the invention, the substances which are difficult to disperse can be missed without prior melting with the matrix material, or the substances are introduced continuously via suitable pump systems into the extruder in zones of different material pressures.

In the context of the present invention, the melting point of the matrix is understood as meaning the peak onset in DSC analyzes of component A or of the solid solution of components A and / or components (B), to which the matrix (also as a mixture) in DSC analyzes shows the peak onset.

The matrix material, in particular mannitol-containing matrix materials, is preferably mixed with the difficult-to-disperse substances (pharmaceutical active substances) at a material pressure of 2 to 10 bar.

According to a further preferred embodiment, the corresponding sugar alcohols are brought to crystallization by convection.

Preferably, the extrusion is carried out at at least 5 ° C, preferably at least 15 ° C below the melting point of the extrudate [solid solution of (A), optionally also (B), with the hardly dispersible substance] (adjusted temperature profile, does not correspond the actual). The temperature ranges during the extrusion are therefore preferably 5 to 15 ° C. below the melting point of component A or of the mixture of A and B. The temperature zones of the extruder are preferably adjusted to temperatures below the melting point.

In particular, the following substances can be provided as active compounds according to the invention:

Acarbose, Acebutolol, Acecarbromal, Aceclidine, Acedapsone, Acedisulfone Sodium, Acefylline, Piperazine, Aceglatone, 32 ··· * ♦ · · · ♦ • 9 9 φ 9 9 9 9 * 9 9 · · · · · 9 9 9 · · ··· ·· 9 9 ·

Aceglutamide, acepromazine, acetohexamide, acetohydroxamic

Acemannan, acemetacin, acenocoumarol,

Acetarsol, Acetazolamide, Acetiromat,

Acesulfame, Acetiromte, Acetohexamide, Acid, Acetophenazine,

Acetylaminonitropropoxybenzene, acetylcholine chloride, acetylcysteine, acetyldigitoxin, acetyldigoxin, acetylleucine, acetylsalicylic acid, acexamic acid, acyclovir, acifran, acipimox, acitretin, aclarubicin, aclatonium napadisilate, aconiazide, acriflavinium chloride, acrivastine, actaplanine, adamexin, adapalene, ademetionine, adenine (USP), Adenosine, Adenosine Phosphate, Adinazolam, Adiphenine, Adipiodone, Adrafinil, Adrenalone, Afloqualone, Ajmaline, Alacepril, β-Alanine, Albendazole, Alclofenac, Alclometasone, Alcuronium Chloride, Aldioxa, Aldosterone, Alendronate, Alexitol Sodium, Alfacalcidol, Alfadolone , Alfapostol, Alfaxalone, Alfentanil, Alfuzosin, Algedrate, Algestone Acetophenide, Alglucerase, Alibendol, Alimemazine, Alizapride, Alkavervir, Allantoin, Alloclamide, Allylestrenol, Alminoprofen, Almitrine, Alpidem, Alpiroride, Alprazolam, Alprenolol, Alprostadil, Alsactide, Alseroxylon, Alteplase, Altrenogest, Aluminum Acetate, Aluminum Phosphate, Ambazone, Ambenoinium Chlorine ide, Ambroxol, Ambuphylline, Amcinonide, Amezinium Metilsulfat, Amfebutamone, Amfenac, Amfepramone, Amicarbalide, Amidefrine Mesilate, Amifostine, Amikacin, Amikhelline, Aminaphtone, Aminitrozole, Aminoglutethimide, Aminohippuric Acid, y- Aminohydroxybutyric Acid, Aminopropylon, Amiodarone, Amisulpride, Amitraz, Amlodipine, Amogastrin, Amosulalol, Amoxicillin, Amperozide, Amphotericin B, Ampicillin, Amrinone, Amsacrine, Anagrelide, Anazolene Sodium, Ancitabine, Ancrod, Androisoxazole, Androstenediol, Anethole Trithione, Angiotensinamide, Anileridines, Anistreplase, Antithrombin III, Apalcillin, Apomorphine, Apramycin, Aprobarbital, Aprotinin, Arbekacin, Argotroban, Argipressin, Arginine, Arotinolol, Articaine, Ascorbic Acid, Aspartame, Aspoxicillin, Astemizole, Astromicin, Atenolol, Atovaquone, Atracurium Besilate, Atropine, Atropine Methonitrate, Atropine Oxides, Auranofin, Aurothioglucose, Aurotioprol, Azaperone, Azapropazone, Azelastine, Azidamfenicol, Azidocillin, Azintamide, Azithrom ycin, 33 • · · · ♦ ··· · • ······································

Azlocillin, aztreonam bacampicillin, bambuterol, bamethane, bamifylline, barbexaclone, barbital, barnidipine, batroxobin, beclamide, beclobrate, beclometasone, befunolol, bekanamycin, bemegride, benactyzine, benazepril, bencyclane, bendazac, bendroflumethiazide, benexate, benflourex, benfotiamine benfurodil hemisuccinate, benidipine, Benmoxin, Benorilate, Benperidol, Benproperine, Benserazide, Bensuldazic Acid, Bentazepam, Bentiacide, Bentiromide, ß-Benzalbutyramide, Benzalkonium Chloride, Benzarone, Benzathine Benzylpenicillin, Benzatropine, Benzbromarone, Benzetimide, Benzilonium Bromide, Benziodarone, Benznidazole, Benzocaine, Benzonatate, Benzoxonium Chloride , Benzoyl Peroxides, Benzpiperylones, Benzquinamides, Benzothiazides, Benzydamines, Benzyl Benzoates, Benzyl Hydrochlorothiazides, Benzyl Hydrobenzoates, Benzylpenicillin, Bnzylthiouracil, Bephenium Hydroxynaphthoates, Bepridil, Beractant, Beraprost, Bergapten, Betacarotene, Betaine, Betamethasone, Betanidine, Betaxolol, Bethanechol Chlorine ide, betoxycaine, bevantolol, bevonium metylsulfates, bezafibrates, bezitramides, bibenzonium bromides, bibrocathol, bietamiverines, bietaserpines, bifemelans, bibifibrates, biotin, biperiden, bisantrene, bisaramil, bisbentiamines, bisdequalinium diacetate, bismuthates, bismuth subgallates, bismuth subsalicylates, bisoprolol, bisoxatin Bispyrrithion Magsulfex, Bitolterol, Bolandiol, Boldenone, Bopindolol, Bornaprine, Bretylium Tosilate, Brinase, Brivudine, Bromazepam, Bromazine, Bromochlorenone, Bomberric Acid, Bromindione, Bromoisoval, Bromocyclo, Bromocriptine, Bromopride, Bromosalicylchloranilide, Bromoperidol, Bronopol, Brotizolam, Brovanexine Brovincamine, broxuridine, bucillamine, bucladesine, bucolome, bucumolol, budesonide, buformine, bumadizone, bumetanide, bunaftine, bunamidine, bunamiodyl, bunazosin, bunitrolol, buphenine, bupivacaine, bupranolol, buprenorphine, buquinolate, buramate, buserelin, buspirone, busulfan, butacaine, Butacetin, Butafosfan, Butalamin, Butalbital, Butamben, Butamirat e, butanilicains, butperazines, butaverines, butethamines, buthiopurines, buticides, butobarbitones, buticides, butobarbitones, butopiprines, butorphanol, butronium bromides, butylparaben, butylphenamides, 34 ························· · «· · · · · · · · · * *« · · · · · · · · · · · · · * * ♦ &amp;«#

Cabergoline, Cadexomer, Cadralazine, Cafaminol, Cafedrine, Caffeine, Calcifediol, Calcipotriol, Calcitonin, Calcitriol, Calcium Dobesilate, Calcium Folinate, Calcium Glubionate, Calcium Glucoheptonate, Calcium Gluconate, Calcium Levulinate, Calcium Mesoxalate, Calcium Pantothenate, Calcium Pidolate, Calcium Trisodium Pentetate , Camazepam, Cambendazole, Camostat, Camylofin, Canrenone, Capobenic, Capreomycin, Capsaicin, Captodiame, Captopril, Carazolol, Carbachol, Carbaethopendecine Bromide, Carbaldrate, Carbamazepine, Carbamoylphenoxyacetic Acid, Carbaril, Carbasalate Calcium, Carbazochrome, Carbenicillin, Carbenoxolome, Carbectocin, Carbimazole, Carbinoxamines, Carbocrometh, Carbomethoxythiazolidines, Carboplatin, Carboprost, Carboquone, Carbromal, Carbutamide, Carbuterol, Carfecillin, Cargutocin, Cardindacillin, Carisoprodol, Carmofur, Carmustine, Carnidazole, Caroverine, Carpipramine, Carpronium Chloride, Carteolol, Carumonam, Carvedilol, Casanthranol, Cathine, Cefacetrile , Cefaclor, Ce fadroxil, cefalexin, cefaloglycine, cefaloridine, cefalotine, cefamandole, cefapirin, cefatrizine, cefazedone, cefazolin, cefbuperazone, cefdinir, cefipime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizine, cefonicidin, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, Cefoxitin, Cefpimizole, Cefpiramide, Cefpirome ,. Cefpodoxime, Cefprozil, Cefradine, Cefroxadine, Cefsulodine, Cefazidime, Cefteram, Ceftezole, Ceftibuten, Ceftiofur, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzonam, Celiprolol, Cellulase, Celucloral, Centchromane, Ceruletide, Cetiedil, Cetirizine, Cetotiamine, Cetraxate, Chenodeoxycholic Acid, Chloral Hydrates, chloralodol, chloralose, chloramphenicol, chlorobenzoxamine, chlorhexidine, chlormadinone, chlormerodrin, chlormezanone, chloroacetic acid, chlorobutanol, chloroprocaine, chlorothiazide, chlorotrianisene, chlorphenesin, chloroxine, chloroxylenol, chloropyraminr, chloroquine, chlorophenamine, chlorphenesin, chlorphenesin carbamate, chlorphenethazine, chlorphenoxamine, Chlorphentermine, Chlorproethazine, Chlorpromazine, Chlorpropamide, Chlorprothixene, Chlorquinaldol, Chlortalidone, Chlortetracycline, Chlorthenoxazine, Chlorzoxazone, Choline Alfoscerate, Choline Chloride, Choline 35 «» «♦ ··« · · · t · · ····· · · · · T «·· ·

Salicylates, choline theophyllinates, chorionic gonadotrophin, chromocarb, chymopapain, chymotrypsin, cianidanol, cibenzolines, ciclacillin, cicletanines, cicloheximides, ciclomethasone, ciclonicates, ciclopirox, ciclosporin, cycloalic acid, cilastatin, cilazapril, cilostazol, cimetidine, cimetropium bromides, cinametic acid, cinchocaine , Cinepazet, Cinepazide, Cinitapride, Cinmetacin, Cinolazepam, Cinoxacin, Cinoxate, Ciprofibrate, Ciprofloxacin, Ciramadol, Cisapride, Cisplatin, Citicoline, Citiolone, Cladribine, Clanobutin, Clarithromycin, Clavulanic Acid, Clebopride, Clefamide, Clemastine, Clemizole, Clemizole Penicillin, Clenbuterol , Clidinum Bromide, Clindamycin, Clinofibrate, Clobazam, Clobenzepam, Clobetasol, Clobetasone, Clobutinol, Clocanfamide, Clocapramine, Clocortolone, Clodronic Acid, Clofedanol, Clofenamide, Clofenotane, Clofenvinfos, Clofezone, Clofibrate, Clofibric Acid, Clofibride, Cloforex, Clomethiazole, Clometocillin Clomifene, clomocycline, clonazepam, clonidine, clopamide e, Clophenthixol, Cloperastine, Cloprednol, Cloprostenol, Cloquinate, Cloacetadol, Cloranolol, Clorazepate, Clorexolone, Cloricromen, Cloridarol, Clorindione, Clorprenaline, Closantel, Clostebol, Clotiazepam, Cloxacillin, Cloxazolam, Cobamamide, Cocaine, Cocarboxylase, Codeine, Cogalactoisomerase, Colchicine, Colecalciferol, Colestipol, Colfosceril palmitate, Colistin, Corbadrine, Corticorelin, Cortisone, Cortivazole, Coumafos, Coumarin, Creatinolfosfate, Cresyl Acetate, Croconazole, Cromoglicic Acid, Cropropamide, Crotamiton, Crotetamide, Cryofluorane, Cyacetacide, Cyanocobalamin, Cyclamate Calcium, Cyclandelate, Cyclobarbital, Cyclobutyrol, Cyclodrine, Cyclofenil, Cycloguanil Embonate, Cyclomethycaine, Cyclopenthiazide, Cyclopentolate, Cyclophosphamide, Cycloserine, Cyclothiazide, Cyclovalone, Cycotiamine, Cynarine, Cypermethrin, Cyprodenate, Cyproterone, Cytarabine, Cytidine, Dacarbazine, Dacisteine, Dactinomycin, Danazol, Dantrolene, Dantron, Dapsone , daunorubicin, Deanol, Debrisoqui ne, decimemide, decoquinate, deferoxamine, deflazacort, dehydrocholic acid, dehydroemetine, delapril, delmadione, delorazepam, deltamethrin, demanyl phosphate, dembrexine, demecarium bromide, demeclocycline, demegestone, demexiptiline, demoxytocin, denatonium benzoate, 36 · · · · · · · ······························································· #

Denaverine, Denopamine, Deoxyribonuclein Acid, Deptropine, Dequalinum Chloride, Deserpidines, Desflurane, Desglugastrin, Deslanoside, Desloreline, Desmopressin, Desogestrel, Desonide, Desoxmetasone, Desoxycortone, Detajmium Bitartrate, Dexamethasone, Dexetimide, Dexfenfluramine, Dexibuprofen, Dexpanthenol, Dexrazoxane, Dextran Iron Complex , Dextranomer, Dextromethorphan, Dextromoramide, Dextropropoxyphene, Dextrose, Dextrothyroxine Sodium, Dezocine, Diacerein, Diamfenetide, Diamorphine, Diazepam, Dizoxide, Dibekacin, Dibenzepine, Dibrompropamidine, Dibosomalan, Dichlorphenazone, Dichlorisone, Dichloroacetic Acid, Dichlorophene, Dichlorovos, diclofenac, Diclofenamide, Dicloxacillin , Dicoumarol, Dicycloverine, Didanosine, Dienestrol, Diethylamine Salicylate, Diethylcarbamazine, Diestylstilbestrol, Diethyltoluamide, Difebaramate, Difemerine, Difenidol, Difenpiramide, Difetarsone, Diflorasone, Diflucortorone, Diflunisal, Difluprednate, Digitoxin, Digoxin, Diheyverine, Dihydrocodeine, Dihydroerg ocristine, dihydroergocryptine, dihydroergotamine, dihydrostreptomycin, dihydrotachysterol, dihydroaluminum aminoacetate, dilazep, dilevalol, diloxanide, diltiazem, dimazole, dimecrotic acid, dimefline, dimenhydrinate, dimercaprol, dimethadione, dimethoxanate, dimethyl sulfoxide, dimethyltubocurarium chloride, dimetofrine, dimetotiazine, dimegamide, dimoxyline, Dimypylate, Dinitolmide, Dinoprost, Dinoprostone, Dinsed, Diodone, Diosmin, Dioxybenzone, Diperodone, Diphenhydramine, Diphenoxylate, Diphenylpyraline, Dipipanone, Dipiproverine, Dipivefrine, Diponium Bromide, Diprophylline, Diproquallone, Dipyridamole, Dipyrocetyl, Disopyramide, Distigmine Bromide, Disulfiram, Ditazole, Dixyrazine, Docusate Sodium, Dodicin, Dodecyltriphenylphosphonium Bromide, Domiodol, Domiphen Bromide, Domperidone, Dopexamine, Dornase Alfa, Doxacurium Chloride, Doxapram, Doxazosin, Doxefazepam, Doxifluridine, Doxofylline, Doxorubicin, Doxycycline, Dronabinol, Droperidol, Droproizine, Drostanolone, Drotaverine , Drotebanol, Droxicam, Dyclonine, Dydrogesterone, Dyflos, ebastine, Ecabet, Econazole, Ecothiopate Iodide, Edetol, Edoxudine, Edrophonium Chloride, Eflornithine, Efloxate, Elcatonine, Eledoison, Elliptinuim Acetate, Embramine, Emorfazone, Enelapril, 37 * ··· · · «· · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Enelaprilat, Enbucrilate, Encainide, endralazine, Endrisone, Enflurane, Enilconazole, Enocitabine, Enoxacin, Enoximone, Enoxolone, Enprostil, Enrfloxacin, Enviomycin, EBAP, Epalrestat, Epanolol, Eperisone, Ephedrine,

Epecillin, epimestrol, epinephrine, epirizole, epirubicin, epitropanol, epomediol, epoprostenol, eprozinol, eptazocine, ergocalciferol, ergometrine, ergotamine, eritrityl

Etomidolines, Etynodiol, Famatidine, Febarbamate,

Tetranitrates, Erythromycin, Erythromycin Acistrate,, Erythrosine Sodium, Escin, Eseridine, Esmolol, Estradiol, Estramustine, Estriol, Estrone, Estropipate, Etacrynic Acid, Etafenone, Etamiphylline, Etamvivan, Etamsylate, Eat Salad, Ethadione, Ethambutol, Ethaverine, Ethchlorvynol, Ethenzamide , Ethinamate, Ethinyl Estradiol, Ethiodized Oil (131I), Ethionmide, Ethisteone, Ethoheptazine, Ethosuximide, Ethotoine, Ethyl Biscoumacetate, Ethyl Chloride, Ethylene Strenol, Ethyl Loflazepate, Ethylmorphine, Etidocaine, Etidronic Acid, Etilefrine, Etiprostone, Etodroxizine, Etofenamate, Etofibrate, Etofylline , Etofylline clofibrate, etoglucide, etomidate, etoperidone, etoposide, etozolin, etretinate, eucalyptol, euprocin, exalamide, exiprobes,

Famprofazone, Fazadinium Bromide, Febantel, Febuprol, Fedrilate, Felbamate, Felodipine,

Felypressin, Fenalamide, Fenalcomine, Fenbendazole, Fenbufen, Fencamine, Fencarbamide, Fencibutirol, Fenclofenac, Fenclofos, Fenetylline, Fenfluthrin, Fenofibrate, Fenoprofen, Fenoverine, Fenoxazoline, Fenoxedil, Fenozolone, Fenprostalene,

Fenquizone, Fenspiride, Fentanyl, Fenticonazole, Fentonium Bromide, Feprazone, Ferrocholinate, Ferrous Fumarate, Ferrous Gluconate, Ferrous Sulfate, Fertirelin, Fezatione, Fibracillin, Fibrinolysin, Finasteride, Fipexide, Flamenol, Flavoxic Acid, Flavoxate, Flecainide, Fleroxacin, Floctafenine, Flomoxef , Florantyrone, Flosequinan,

Floxuridines, Fluanisone, Fluazacort, Flubendazole,

Fluclorolone acetonide, flucytosine, fludarabine, fludroxycortin, flufenamic

Flucloxacillin, Fluconazole, Fludiazepam, Fludrocortisone, Acid, Flugestone, Fluindione,

Flumazenil, flumecinol, flumequine, flumetasone, flumethrin, flunisolide, flunitrazepam, flunixin, flunoxaprofen, fluocinolone acetonide, floucinonide, fluocortin, 38 &lt; · · · Μ ···· φ φ • # · · Φ φ φ φ • • • • I • ΦΦ Φ φ • · · · · · · «· · · · · #

Fluorocortolone, fluorescein sodium, fluoresone,

Fluorometholones, fluorouracil, fluoxetine, fluoxymesterones, flupamesone, flupentixol, fluphenazine, flupirtine,

Fluprednidene, Fluprednisolone, Fluproquazone, Flurazepam,

Flurotyl, fluroxene, flubiprofen, fluspirilene, flutamide, flutazolam, fluticasone, flutoprazepam, fluvalinate, fluvastatin, fluvoxamine, foil acid, fominoben, formebolone, formestane, formocortal, formoterol, foscarnet sodium, fosfocreatinine, fosfomycin, fosfosal, fosinopril,

Fotemustine, Framycetin, Ftivazide, Fumagillin, Fumaric Acid, Fungichromin, Furaltadone, Furazidine, Furazolidone,

Gallopamil, gentamicin, gitoformates,

Furosemide, Fursultiamide, Fusidic Acid, Gabexate, Gadodiamide, Gadopentetic Acid, Gadoteric Acid, Galantamine, Ganciclovir, Gefarnate, Gemeprost, Gemfibrozil,

Gestonorone Caproate, Gestrinone, Gitloxin, Glafenine, Glaucine, Glaziovine, Glibenclamide, Glibornuride, Gliclazide, Glipizide, Gliquidone, Glisentide, Glisolamide, Glisoxepide, Glucagon, Glucametacin,

Glucofrangoline A, glucosamine, glucurolactone, glucuronamide, glutaral, glutathione, glutethimide, glycerol, glycobiarsol,

Glycol Salicylates, Glyoniazide, Glycopyrronium Bromide, Glycyclamide, Glymidine Sodium, Gonadorelin, Gonadotrophin, Goserelin, Gramicidin, Granisetron, griseofulvin, Guacetisal, Guaiapate, Guaietolin, Guaifenesin, Guaifylline, guaimesal,

Guemecycline, guanabenz, gunacline, guanadrel, guanethidine, guanfacine, guanoclor, guanoxan, gusperimus, halazepam,

Halcinonide, haletazone, halocarban, halofantrine,

Halofuginone, Halomethasone, Haloperidol, Halopredone,

Halothane, Haloxazolam, Haloxon, Haloquinols, Hematoporphyrin, Heparin Sodium, Hepronicate, Heptabarb, Heptaminol, Hetacillin, Hexachlorophene, Hexamidine, Hexapropymate,

Hexcarbocholines bromides, hexobarbital, hexobendines,

Hexoprenaline, Histamine, histidine, Histrelin, Homotropine Hydrobromide, Homotropine Methylbromide, Homosalate, Hopantenic Acid, Hyaluronic Acid, Hyaluronidase, Hydralazine,

Hydrargaphene, hydrocortamate, hydromorphone, hydroxycarbamide,

Hydrochlorothiazides, hydrocodone,

Hydrocortisone, Hydroflumethazide,

Hydroquinidine, hydroxocobalamin,

Hydroxydione Sodium Succinate, 39 · · · · ···· I »·« ···· ···· · · · · · · · · · · · · · · · · · · · · · · ·

Hydroxyestrone Diacetates, Hydroxymethylnicotinamides, Hydroxyprogesterones, Hymercromone, Hyoscine Butylbromide, Hyoscyamine, Hyprolose, Ibacitabine, Ibopamine, Ibudilast, Ibuprofen, Ibuproxam, Idanpramine, Idarubicin, Idoxuridine, Idrocilamide, Ifosfamide, Iloprost, Imipenem, Imolamine, Indapamide, Indeloxazine, indenolol, Indobufen, Indocyanine Green, Indomethacin, Indoprofen, Indoramine, Inosine, Inosine Pranobex, Inositol, Inositol Nicotinate, Insulin, Iobenguane, Iobenzamic Acid, Iocarmic Acid, Iocetamic Acid, Iodamide, Iodofenphos, Iodohippurate Sodium, Iodoxamic Acid, Iofendylate, Ioglicic Acid, Iohexol, Iopamidol , Iopentol, Iopodic Acid, Iopromide, Iopronic Acid, Iopydol, Iopydone, Ioseric Acid, Iotalamic Acid, Iotrolan, Iotroxic Acid, Ioversol, Ioxaglic Acid, Ioxitalamic Acid, Ipratropium Bromide, Iprazochrome, Iproniazid, Isepamicin, Isobromindione, Isocarboxazid, Isoconazole, Isoflupredone , Isoflurane, Isomethheptene, Isoniazid, Isonixin, Isoprenaline, Isopropamide Iodide, Isoso rbide, isosorbide dinitrate / mononitrate, isotretinoin, isoxicam, isoxsuprine, isradipine, itraconazole, itramine tosilate, ivermectin, josamycin, kanamycin, kawain, kebuzone, keracyanine, ketamine, ketanserin, ketazolam, ketobemidone, ketoconazole, ketoprofen, ketorolac, ketotifen, khellin, Khelloside, Kitasamycin, Labetalol, Lacidipine, Lactic Acid, Lactitol, Lamorigins, Lanatoside C, Lansoprazole, Lasalocid, Latamofex, Lenampicillin, Letosteine, Leuprorelin, Levallorphan, Levamisole, Levobunolol, Levocabastine, Levocarnitine, Levomepromazine, Levomethadone, Levomoprolol, Levonorgestrel, Levopropoxyphene, Levosulpiride, levothyroxine, lidocaine, lidoflazine, limaprost, lincomycin, lindane, linsidomine, liothyronine, lisinopril, lisuride, lithium salts, lobeline, lodoxamide, lofepramine, loflucarban, lomefloxacin, lomustine, loperamide, loprazolam, loracarbef, lorajmine, lorazepam, lorcainide, lormetazepam , Lovastatin, Loxapine, Loxoprofen, Luprostiol, Lymecycline, Lynestrenol, Lypressi n, Lysozyme, Mabuprofen, Mabuterol, Maduramicin, Magaldrate, Magnesium Pidolate, Malathion, Malotilates, Manidipine, Maridomycin, Mazaticol, Mazindol, Mazipredone, Mebendazole, Mebeverine, Mebrofenin, Mebutamate, Mebuticide, Mecillinam, Meclocycline, Meclofenoxate, Mecobalamin, 40 «· · · · · · · · · · ··································

Mecysteins, Medifoxamine, Medrogestone, Medroxyprogesterone, Medrylamine, Medrysone, Mefloquine, Mefruside, Megestrol, Melasoprol, Melinamide, Melitracene, Meloxicam, Melperone, Melphalan, Menadione, Menatetrenone, Menbutone, Menfegol, Mepenzolate Bromide, Mephenesin, Mephenoxalone, Mephenytoin, Mepitiostane, Mepivacaine , Mepixanox, mepramidil,

Meprednisone, meprobamate, meproscillarin, mepyramine,

Mequinol, merbromin, mercaptomerine, mercaptopurine,

Mercurobutol, Mercurophylline, Meropenem, Mesocarb,

Mesoridazine, Mestanolone, Mesterolone, Mesuximide, Metaclazepam, Metacycline, Metahexamide, Metamizole Sodium, Metampicillin, Metandienone, Metaxalone, Metenolone,

Metergolines, Metescufylline, Metformin, Methacholine Chlorides, Methadones, Methalesteril, Methandriol, Methaniazide, Methanthelinium Bromide, Methaqualone, Methazolamide, Methocarbamol, Methohexital, Methoprene, Methopromazine, Methoserpidine, Methotrexate, Methoxamine, Methoxsalen, Methoxyflurane, Methoxyphenamine, Methylbenzethonium Chloride, Methylchromone, Methylergometrine , Methylmethioninesulfonium bromides, methylpentynol, methylphenidates, methylphenobarbital, methylprednisolone, methylrosanilinium chloride,

Methyltestosterone, Methylthiouracil, Methyprylon,

Metipranolol, metofenazate, metoprolol, metronidazole, mezlocillin,

Methysergide, Meticillin, Metildigoxin,

Metisazone, metochalcone, metoclopramide,

Metolazone, metomidates, metopimacides,

Metoxibutropate, metrifonate, metrizamide,

Metyrapone, Mexazolam, Mexenone, Mexiletine,

Mianserin, Mibolerone, Miconazole, Micronomicin, Midazolam, Midecamycin, Midodrine, Mifepristone, Miloxacin, Milrinone, Miltefosine, Milverine, Minaprine, Minocycline, Minoxidil, Mirimostin, Miristalkonium Chloride, Mirtazapine, Misoprostol, Mitobronitol, Mitomycin, Mitotane, Mitoxantrone, Mivacurium Chloride, Mizoribine, Moclobemide, Mofebutazone, Molgramostine, Molindione, Molsidomine, Mometasone, Monalazone, Monensin, Monobenzone, Monoctanoin, Monoethanolamine Oleate, Moperone, Moracizine, Morantel, Morclofone, Morniflumate, Moroxydine, Morphine, Morpholine Salicylate, Morsuximide, Maspramine, Motretinide, Moxastine, Moxonidine; Mupyrocin, Muromonab-CD3, Muzolimine, Myrophine, Nabilone, Nabumetone, Nadolol, 41 • · · · · · · «· · · · · · · · · · · · · · · · · · · · ·

Nadoxolol, Nafcillin, Nalorphine, Naproxen, Nebacumab,

Nadroparin Calcium, Nafamostat, Nafarelin,

Naftolofos, Naftazone, Naftifine, Nalbuphine,

Naloxone, Naltrexone, Nandrolone, Naphazolines, Narasin, Naringin, Nasaruplase, Natamycin,

Nefopam, Nemomapride, Netilmicin, Niaprazine,

Nicardipine, nicergoline, niceritrol, niclosamide, nicopoxil, nicoclonate, nicocodine, nicofetamide, nicofibrate,

Nicofuranose, Nicofurate, Nicomol, Nicomorphine, Nicorandil, Nicotinamide, Nicotine, Nicotinic Acid, Nifetipine, Nifenalol, Nifenazone, Niflumic Acid, Nifuratel, Nifurapholine, Nifuroquine, Niforuxazide, Nifurzide, Nikethamide, Nilutamide, Nilvatipine, Nimesulide, Nimetazepam, Nimotipine, Nimorazole, Nimustine, Niperotidine, Nipradilol, Nomegestrol, Nomifensine, Nonoxinol, Nordazepam, Norfenefrine, Norgestrione, Nosantine, Noscapine, Novobiocin, Noxiptiline, Noxytiolin, Nystatin, Octabenzone, Octoxinol, Octapamine, Ofloxacin, Oleandomycin

Olsalacin, Ondansentron, Orazamide, Orgotein, Ornipressin, Orphenadrine, Oryzanol, Osalmid, Oubain, Oxaceprol, Oxacillin, Oxaflumazine, Oxametacin, Oxaflozane, Oxaproin, Oxandrolone, Oxatomide, Oxazepam, Oxalozam, Oxedrine, Oxeladine,

Oxendolone, Oxetacaine, Oxerutins, Oxetorone, Oxfendazole,

Oxibendazole, Oxilofrine, Oxirazepam, Oxitripan, Oxolamine, Oxprenolol, Oxybenzone, Oxybuprocaine, Oxybutynin,

Oxydibutanol, oxyfendrins, oxymetazolines, oxymesterones,

Oxymethurea, Oxymorohones, Oxypertine, Oxyphenbutazone, Oxyphenisatine, Oxyprothepine, Oxytocin, Ozagrel, Padimate 0, Palmidrol, Pamidronic Acid, Pancratin, Pangamic Acid, Panthetine, Papain, Papaverine, Paracetamol, Paraldyhyde, Paramethadione, Paramethasone, Parbendazole, Pargeverine, Pargyline, Parnaparin Sodium, Paroxetine, Paroxypropione, Paraquone, Pasiniazide, Pectin, Pefloxacin, Pegademase,

Pefloxacin, pemolines, penbutolol, pencillamine,

Pentaerithrityl tetranitrate, pentaerythrol, pentagastrin, pentapiperidine, pentazocine, pentetrazole, pentobarbital, pentorex, perazine, perfosfamide, perfexiline, perindopril, perisoxal, perlapine, permethrin, peruvodide, pethidine, phanquinone, phenacemide, phenazone, phencyclidine,

Phendimetrazine, phenelzine, pheneturide, phenindamine, pheninidione, pheniramine, phenobarbital, phenobutiondil, 42

Phentomamine, phenylphenol, phenytoin,

Phenolphthalein, phenolphthalol, phenodiazines, phenoperidines, phenotrine, phenoxybenzamine, phenoxyethanol, phenprobamates, phenprocoumon, phensuximides, phentermines,

Phenylaniline, phenylbutazone, phenylephrine,

Phenylpropanol, phenylpropanone amines,

Phloroglucinol, physostigmine, phthalylsulfathiazoles,

Phytomenadione, piperaline, picolamine, piketoprofen,

Pilocarpine, Pimeclone, Pimozide, Pinacidil, Pinazepam, Pinodolol, Pipamazine, Pipacetate, Piperacetazine, Piperzine, Piperidone, Pipethanate, Pipofezine, Pirazepam, Piprozoline, Pipotiazine, Pirenoxine, Pirenzepine, Piretanide, Piribedil, Pirifibrate, Piritramide, Pirindole, Piroheptin, Piromidic Acid , Piroxicam, Pirozadil, Pizotifen, Plaunotol, Ponalrestat, Potassium Glucaldrate, Potassium Iodide, Practolol, Pralidoxime Iodide, Pramiracetam, Pramiverine, Pramocaine, Pravastantin, Praziquantel, Prazosin, Prednisone, Pregnenolone, Prenalterol, Prenoxdiazine, Phenylamine, Pridinol, Prilocaine, Primidone, Pristinamycin, procainamide, procaine, procarbazine, procaterol, prochlorperazine, procodazole, procyclidine,

Profenamine, Progabide, Progesterone, Proglumide, Proguanil, Proligestone, Prolintane, Promazine, Promestriene,

Propamidine, Propendiazole, Propranolol, Protokylol,

Promethazine, Propafenone, Prapacetamol, Protallylonal, Propafenone, Propanocaine, Propatyl Nitrate, Propicillin, Propiomazime, Propizepine,

Propyliodone, Proylparaben, Prostalene,

Protriptolines, Proxibarbal, Proxymetacaine,

Proxyphylline, Prozapine, Pseudoephedrine, Psoralen, Pyrantel, Pyrocarbate, Pyridoxal Phosphate, Pyridoxine, Phyrimethamine, Pyritinol, Pyrolnitrin, Quazepam, Quinestradol, Quinethazone, Quinine, Quinupramine, Rafoxanide, Ramipril, Razoxane, Rebamipide, Remoxipride, Repirinast, Reproterol, Reserpiline, Reserpine , Retinol, Ribavirin, Rifaximine, Rilmenidine, Rimantadine, Rimiterol, Rimiprogin, Ritodrine, Ritiometan, Rociverine, Romurtedine, Ronidazole, Ronifibrate, Rosoxacin, Roxatidine, Roxithromycin, Rufloxacin, Ruscogeninm Rutoside, Salacetamide, Salbutamol, Salycilamide, Salicyloic Acid, Salinomycin, Salmeterol , Salsalates, sancyclines, saralasins, sarmazelin, scopolamine, secalciferol, secbutabarbital, scnidazoles, secobarbital, selegilines, sermorelin, setraline, 43 ····································· ♦ * · · · · · · · · · · · · · · · · ·.

Setastatin, Setiptiline, Siccanin, Simfibrate, Simvastatin, Sobrerol, Sodium Cyclamate, Sodium Dibumate, Sodium Feredetate, Sodium Picosulfate, Sodium Stibocaptate, Sodium Tetradecyl Sulfate, Sodium Tyroponoate, Sofalcone, Somastatin, Sorbinicate, Sotalol, Spaglumic Acid, Sparteine, Spiclomacine, Spiperone , Spirapril, Spizofurones, Stanozolol, Stenbolone, Stilophen, Stepronen, Strptozocin, Strophantine-K, Succimer, Succimide, Succinylsulfathiazole, Sucralfate, Sufentanil, Sulbactam, Sulbentine, Sulbutiamine, Sulconazole, Sulfacetamide, Sulfadiazine, Sulfadicramide, Sulfadimidine, Sulfadoxine, Sulfafurazole, Sulfaguanole , Sulfaenes, sulfaguanidines, sulfamazones, sulfamerazines, sulfamethizoles, sulfamethoxazoles, sulfametoxydiazines, sulfametrols, sulfamonomethoxines, sulfamoxones, sulfanilamides, sulfaperin, sulfaphenazoles, sulfapyrazoles, sulfasalazines, sulfathiazoles, sulfathiourea, sulfinpyrazone, sulfiram, sulfonylidines, sulfogaiacol, sulindac, sulisation, sulisobenzone, suloctidil , Sulodexide e, Sulprostone, Sultiame, Sultopride, Sumatripan, Suprofen, Suxibuzone, Tacrine, Telastine, Talbutal, Talinolol, Talniflumate, Tamoxifen, Tamsulosin, Taurolidine, Tacobactam, Teceleucine, Tegaflur, Teicoplanin, Telmesteine, Temafloxacin, Temazepam, Tenitramine, Tenoic Acid, Tenonitrozole , Tenoxicam, Terpenone, Terazosin, Terbinafine, Terbutaline, Terfenadine, Terconazole, Terguride, Teriparatide, Tericidone, Terlipressin, Terodiline, Tertatolol, Testolactone, Testosterone, Tetrabenazine, Tetracaine, Tetrachlorethylene, Tetracyclines, Tetramethyl ammonium iodide, Tetramisole, Tetrazepam, Tertramine, Tetoxoprine, Tetrylozin, Thebacon, Thenalidine, Theodrenaline, Theophylline, Theophylline Olamine, Thiamazole, Thiamine, Thiamphenicol, Thiamylal Sodium, Thiethylperazine, Thioacetazone, Thiobutabarbital, Thioctic Acid, Thiomersal, Thiophene, Thiopropazate, Thiopproperazine, Thioridazine, Thiosalicylic Acid, Thiotepa, Thiram, Thonzylamine, Thrombin, Tiabendazole, Tiadenol, Tiamenidine, Tianeptine, Tiapride, Tiaprost, Ticlatone, Ticlopidine, Tigemonam Tigloidine, Tilactase, TILBROQUINOL; Tilidine, Tilisolol, Timiperone, Timolane, Timonanic, Tinidazole, Tinoridine, Tiocarlide, Tioclomarol, Tioconazole, Tioguanine, Tiopronine, Tiotixene, ···· · · · · · · · · · · # * ·· *

Tiloxidazoles, Tioxolone, Tipepidine, Tiracizine, Tiratricol, Tiropramide, Tixocortol, Tizanidine, Tobramycin, Tocainide, Tocofibrate, Tocopherol tocopherylquinone, Tofenacin, Tofisopan, Tolozamide, Tolazoline, Tolbutamide, Tolciclate, Tolfenamic Acid, Tolindate, Tolmetin, Tolnaftate, Tolonidine, Toloxatone, Tolperisone , Tolpropamine, Tolrestat, Toltrazuril, Torasemide, Toremifene, Tosylchloramide Sodium, Tramadol, Tranilast, Trapidil, Trazodone, Trenbolone, Treosulfan, Trepibutone, Tretinoin, Tretinoin Tocoferil, Tretoquinol, Triacetin, Triamcinolone, Triamterene, Triazolam, Tribuzone, Trichloromethiazines, Trichloromethines, Triclofos , Triclosan, Tricylamol Chloride, Trientine, Trifluoroperazine, Trifluperidol, Triflupromazine, Trifluridine, Trifusal, Trihexyphenidyl, Trilostane, Trimazosin, Trimebutine, Trimecaine, Trmetazidine, Trimethadione, Trimethobenzamide, Trimethoprine, Trimmetozine, Trimetrexate, Trimipramine, Tripamide, Trioxysalin, Tripamide, Triptorelin, Tritiouzine, tropicamide , Troxipidine, Trypsin, Tryptohan, Tulobuterol, Tybamate, Tymazolines, Tylosin, Tyrothricin, Ubenimex, Ubidecarenone, Ulbetasol, Undecylenic Acid, Uramustine, Urapidil, Uredofos, Ursodeoxycholic Acid, Valethamate Bromide, Valnoctamide, Valproic Acid, Valpromide, Vancomycin, Venlafaxine, Veralipride , Verbenone, Vesnarinone, Vetrabutine, Vidarabine, Vigabatrin, Viloxazine, Viminol, Vinburnine, Vincamine, Vincristine, Vindesine, Vinorelbine, Vilynbital, Vinpocttine, Viquidile, Virginiamycin, Visnadine, Warfarin, Xamoterol, Xenbucine, Xipamide, Xylazine, Yohimbine, Zeranol, Zidovudine , Zipeprol, Zolimidine, Zolpidem, Zonisamide, Zopiclone, Zorubicin, Zotepine, Zuclopenthixol and Aciclocivir, Valaciclovir, Risedronate, Pamidronate, Zolidronate, Incadronate, Ibandronate, Tiludronate.

According to a further aspect, the present invention relates to a melt extrudate consisting of in a matrix containing sugars, sugar alcohols, sugar substitutes or mixtures thereof and difficult-to-disperse substance dissolved therein. The matrix preferably contains at least 30% of a recrystallizing sugar alcohol. 45 • · · · · · · · · ·

* · ♦ ♦ ♦ I »IM • · * · · t ·· ·

Preference is given to melt extrudates which are obtainable by the process according to the invention.

The Schmelextrudate invention are characterized in that the sensitive substances are completely encapsulated in the matrix. By crushing the Schmelzextrudates can remain in one or the other case a little material on the surface.

The extrudates according to the invention can be processed or ground directly into pellets or granules, usually monolithic or polynuclear microcapsules are obtained.

In order to obtain flavor protection, controlled release or enteric resistance, the above-mentioned particles may be coated with common film materials of different solubility. In this case, mainly cellulose derivatives are used.

The products according to the invention can be used in various fields, the further processing being carried out with the addition of customary, pharmaceutical or food-acceptable excipients and techniques. For example, the preparations according to the invention can be provided as tablets, dragees, film-coated tablets, or dissolving or orodispersible tablets which rapidly dissolve in the oral cavity in the saliva and accumulate the dissolved active substances or active agent particles in the oral mucosa in the most dispersed form.

However, the extrudates according to the invention can also be sprinkled directly onto food, e.g. on bread, yoghurt, fruit components, whereby the protection or taste protection is of particular importance.

The said solid solutions of difficult-to-disperse substances can be further processed into effervescent tablets, chewing gum or buccally resorbable tablets. 46 46 • • • • • • • * * * * * *

The invention will be explained in more detail with reference to the following examples and the drawing figures, to which it is of course not limited. 47 · · · · · · · · · · · · · · · · · ··· * ·

• · ♦ · · · t »I

Examples: 1 Thermal characterization of the individual substances 1.2 DSC analyzes:

task

First, DSC analyzes of individual sugar alcohols and sugar substitutes will be shown. Of interest is the glass transition of the sugar alcohol or to what proportion of this crystallized from the melt. To be examined are essentially the substances mannitol, sorbitol, xylitol and maltitol.

execution

For this purpose, the single substance was weighed in an amount between 1-6 mg in a DSC pan, melted in the 1st heating at a heating rate of 20 ° C / min at least 10 ° C above the melting point, then with a cooling rate of Cooled to at least 10 ° C under the glass transition at 20 ° C / min and re-measured in the 2nd heating at a heating rate of 20 ° C / min.

Evaluation and presentation of the results

Substance weight [mg] Melting point [° C] Melting range [° C] Mannitol 3.34 166 162-178 Xylitol 2.64 95 94-105 Sorbitol 3.061 97 84-110 Maltitol 2.64 148 143-159

Tab. 1: Data from the DSC analysis of various sugar alcohols and sugar substitutes 48 ···· ································································ * · · ·

Substance Glass transition [° C] Enthalpy of fusion [J / g] Recrystallization degree [%] Mannitol None Tg 287 100 Xylitol -19 241 0 Sorbitol 2 169 0 Maltitol 49 94 0

Tab. 2: Data from the DSC analysis of various sugar alcohols and sugar substitutes 1.3 Reconciliation in forced convection Task

As already mentioned, the recrystallization fraction depends strongly on the convection of the material. Thus, the apparatus in Fig. 3 should serve to investigate the recrystallization of the individual substances and to simulate the events in the extruder.

execution

The apparatus sat down from a two-necked flask or

Three-necked flask standing on a hot plate with oil bath together. The temperature profile was measured with a thermometer. Once the substance was completely melted, heating was stopped and the material was stirred with a KPG stirrer while stirring

Number of revolutions cooled to level 2 in the air. Of the

Recrystallization rate was subsequently determined via a cooling curve. Mannitol crystallized completely without stirring even from the melt and therefore did not have to be measured.

Evaluation and presentation of the results:

Substance Recrystallization Xylitol Compl. Recrystallization Sorbitol Incomplete .. Recrystallization Maltitol Incomplete. Recrystallization isomalt incomplete recrystallization

Tab. 3: Recrystallization in forced convection. 49 • · · · · ♦ · · · ♦ • ··········· ··· «« ·

It should be noted that also extrusion experiments were carried out, for example with sorbitol. All materials crystallize at a given convection, but not completely, as assumed for xylitol. By fully crystallized is meant that the crystals already formed act as seed crystals and for the rest

Ensure crystallization of the substance. Based on the extrusion process, this would mean that the crystals formed shear induced by the movement of the screws cause the complete crystallization of the strand after exiting the die head. A cooling curve is used to test xylitol for this property. 1.4 Cooling curve of xylitol Task

A cooling curve of xylitol is to be included. The cooling curve should only be recorded for xylitol because it is believed that this substance is able to crystallize completely from the melt under the influence of forced convection. All other substances, with the exception of mannitol, form mixtures of crystalline and amorphous regions. Upon storage, it can thus lead to molecular transport processes, recrystallization and consequently instability of the drug form.

execution

For this purpose, 60 g of a melt of xylitol in a three-necked flask were cooled while stirring with a KPG stirrer at level 2 in air and measured at intervals of half to one minute, the melt temperature.

Evaluation 50 ·····················································

It resulted in the cooling curve in Fig. 4 as a function of time. From a certain solids content (at 12 min), stirring had to be stopped because the mass became too viscous. However, xylitol remained at 83 ° C for another 20 minutes.

It can be deduced from this that xylitol is extrudable at a solids content at which the strand would completely crystallize upon exiting the die. 51 ···· · · · · · · · · · · · · · «« « ··· 2 Thermal Characterization of Matrix Mixtures 2.1 Theoretical Solution Suggestions and Task

The preceding thermal examination of the substances mentioned showed particular properties especially for mannitol and xylitol. As a result of these substances recrystallizing either on their own initiative or under convection, melt extrudates are obtained in this way which reach a certain hardness at room temperature and do not stick.

It could also sugar alcohols with a glass transition over at least 40 ° C are made the comparable

Show properties. These also crystallize under convection. Examples of this would be isomalt or maltitol, ie dimeric sugar alcohols, but in this case complete crystallization via melt extrusion would not be possible.

It is believed that the own crystals of a substance are best suited to vaccinate a crystallization and thus to accelerate.

The influence of the molecular transport processes that would take place in a partly amorphous, partly crystalline matrix could lead to instabilities (for example to the exclusion of the sensitive substances) and thus to a significant deterioration of the shelf life. For mannitol as well as xylitol, at least under convection, complete crystallization occurs. Thus, from the first investigations, a special significance of these two materials for the encapsulation of substances via melt extrusion can be recognized. As a result, we recommend that you continue to 52 • «« · # # · · · · · · «· · ·« · · · · · · · · · · · · · · · · · · · · · · II Μ Μ · t · * · substance (matrix) mixtures containing as main ingredient mannitol or xylitol.

Based on the processing conditions, the extruder should according to the material properties on a

Temperature profile can be adjusted, in which the melt is induced shear induced crystallization, wherein the corresponding solids content causes the complete crystallization after leaving the nozzle head.

Consequently, one aim of the thermal investigations of the matrix mixtures must be to find substances with which the melting range of mannitol or of xylitol can be extended in order to be able to better control the shear-induced crystallization during the extrusion. Narrow melting ranges cause increased risk of clogging of the extruder or a lack of recrystallization due to a low solids content and consequently no constant product quality.

Theoretical approaches to achieve this goal would be: rl · defects in the crystal lattice lead to deviations from the ideal crystal structure and thus to a broadened melting range.

The incorporation of low-melting and soluble in the melt of the main component substances leads to a broadening of the melting range. This effect is comparable with the broad melting range of a polymer. There, the flowable at lower temperature amorphous shares cause premature dissolution of the crystalline domains and thus the broadening. 53

Another goal of the following studies of mixtures of substances should be to reduce the melting point of the matrix and thus reduce the temperature load on the sensitive substances.

Theoretical approaches would be:

Admixing a substance which forms a eutectic mixture with the main component. · Admixture of low-melting substances, which serve as a plasticizer for the higher-melting sugar alcohol.

Delayed recrystallization due to defects in the crystal lattice. 2.3 Matrix mixtures with main component mannitol: DSC analyzes

execution

The two or more matrix components were mixed and triturated, weighed between 1-20 mg in a DSC pan. In the first heating run at a heating rate of 20 ° C / min melted at least 10 ° C above the melting point, then cooled at a cooling rate of 20 ° C / min to 40 ° C and below and further in the 2nd heating with a heating rate of Re-measure at 20 ° C / min. For evaluation, the 2nd heating run was used. 54: • · * · t ♦

Ml »· · · · · · · · · · · · · · · · · · · · · · · · ·

Mannitol 70% - glucose 30%

Fig. 5 shows the 2nd heating run of a mixture of glucose with mannitol. The exothermic peak shows a recrystallization, the second peak characterizes a melting point. Recrystallisation peak and melting peak show approximately the same value. Glucose is amorphous. The recrystallization content of mannitol is 100%. The melting range is greatly expanded and reaches a weight of only 1.20 mg above 35 ° C.

Furthermore, studies of mannitol with xylitol, sorbitol, maltitol and glucono-5-lactone are to be carried out. The data should be presented in the following table.

Mixture Containing Weighing [mgl Melting range Γ01 Gucono-δ-lactones 30% by weight 0.991 123-170 Xylitol equimolar 17.93 111-154 Maltitol 30% by weight 2.059 113-175 Sorbitol 33% by weight 11.64 120 165 sorbitol 5% by weight 2.25 149-173

Table 4: Summarized data from the DSC analyzes. 2.4 matrix mixtures with main constituent xylitol:

task

The melting point of xylitol is 94 ° C. The aim of the work described below was to find a way to further reduce the melting point in order to process even very thermally sensitive substances in the desired manner. For this purpose, a phase diagram of xylitol / mannitol is to be included. Subsequently, an eutectic mixture of xylitol / glucono-5-lactone and xylitol / mannitol / glucono-5-lactone is sought by DSC analyzes. 55: ··· ····

execution

The substances were dry mixed, melted and cooled with the apparatus described in Fig. 3 with stirring. It had to be stirred at a speed at which the mixture crystallized. When the crystallizing dough became too viscous, it was stirred manually. The cooled mixture was weighed into a mortar chopped 2-14 mg in a DSC pan and recorded only one heating run. Heating was at 10 ° C / min.

evaluation

In the phase diagram, the peak onset is plotted against the weight percent of mannitol.

A phase diagram is obtained (see Fig. 6). There are three phases in total.

Phase I: mannitol and xylitol are in solid form.

Phase II: Mannitol is partially solid, xylitol completely melted.

Phase III: Melt without solids.

A eutectic is present in a xylitol mixture containing 12% by weight of mannitol.

Furthermore, a eutectic mixture of xylitol containing 20% by weight of glucono-5-lactone (Figure 7) was found. FIG. 8 shows a mixture containing 23% by weight of glucono-5-lactone. Already visible is a second peak, namely that of the lactone. The melting point of the mixture is 86 ° C and could be lowered by 8 ° C compared to pure xylitol. The melting range extends from 70 to 95 ° C with a weight of 7.88 mg, so it is more advanced than pure

Xylitol, indicating better extrudability.

The melting point of xylitol was further reduced by a eutectic mixture of xylitol containing 9% by weight of glucono-5-lactone and 10% by weight of mannitol (FIG. 9). The peak onset gives 83 ° C and is therefore 11 ° C lower than for pure xylitol. 3 Melt Extrusion Experiments 3.1 Choice of Model Substances:

In order to test the suitability of the process for the use of volatile substances, Oleum Eucalypti was chosen as a model substance. This, in contrast to natural essential oils, is easy to analyze. The oil used contained 1,8-cineole as the main component and a-pinene as a minor component.

Glucono-delta-lactone was considered as a model substance for a substance which is difficult to disperse and thus serves as a model substance for a poorly water-soluble active substance.

The second model substance is a solution of vitamin D3 in peanut oil. Vitamin D3 is sensitive to thermal stress, exposure to light and oxidation by atmospheric oxygen. Consequently, the suitability of the method for the use of sensitive substances should be investigated. As anti-oxidant vitamin E acetate was added.

As a further model substance orange oil was used. Due to time constraints, a salary and homogeneity determination unfortunately could not be carried out. 57 • * · «« · · · 3.2 Experimental setup

The process and the plant are to be represented as follows (Fig. 10). The matrix mixture is weighed, mixed by hand, filled into the solids feeder and introduced from there into the extruder. The model substances are introduced via an HPLC pump in zones of different material pressure. 3.3 Extrusion tests for the encapsulation of sensitive substances

In 3.3 all experiments should be presented first. Subsequently, a detailed analysis report will verify the suitability of the process for the encapsulation of sensitive substances. 3.3.1 Presentation of the experiments

The following tables should describe the extrusion experiments in detail. The matrix mixtures, the corresponding process parameters and the temperature profile are to be displayed.

Sample No. Mannitol xylitol 1 60 0 2 60 0 3 60 0 4 60 0 5 60 0 6 60 0 7 59 0 8 60 0 9 66 10 10 66 5 11 66 5 12 71 0 13 71 0 14 50 0

Glucono-d-lactone maltodextrin 20 20 20 20 20 20 20 20 20 20 20 20 19 20 20 20 9 20 9 20 9 20 9 20 9 20 30 20 58 • * * • · t • ♦ * · • · * · · 15 50 0 30 20 16 50 0 30 20 17 0 71 9 20 18 0 76 9 15 19 0 80 0 20 20 10 81 9 0 21 0 80 0 20 22 0 80 0 20 23 0 80 0 20 24 0 80 0 20 25 0 71 9 20 26 0 80 0 20

Table 5: Matrix mixtures. All data in% by weight.

Sample No. Throughput [kg / h] Screw speed rpm rpm Torque [Nml Material pressure [bar] Oleum Eucalypti [mL / min. Orange peel oil [mL / min] Cholecal ciferol-Lsg [mL / min 1 3 150 40 9 0 0 0 2 3 150 34 8 3 0 0 3 3 253 33 6 6 0 0 4 3 253 33 6 9,9 0 0 5 3 251 33 6 3 0 0 6 3 251 33 6 2 0 0 7 3 251 33 6 0 3 0 8 3 251 33 6 0 3 0 9 3 252 21 2 0 3 0 10 3 252 27 2 0 2 0 11 3 252 27 2 0 3 0 12 3 251 36 5 0 0 0 13 3 150 46 9 0 0 0 14 5 250 59 9 9,9 0 0 15 5 156 76 1 9,9 0 0 16 3 251 50 1 2 0 0 17 3 150 35 ub 0 0 0 18 3 68 34 51 0 0 0 19 3 150 21 8 0 0 0 20 3 150 15 0 0 0 0 21 3 251 23 8 0 0 5 22 3 251 23 8 0 0 3 23 3 150 27 8 0 0 3 24 3 150 28 9 0 0 7 25 3 150 28 8 0 0 3 26 3 148 23 10 0 0 3

Tab. 6: Process parameters. The stated flow rate corresponds to the set flow rate at the HPLC pump. 59 59

• «· · · · * * *

Sample No. Heating zone 1 Heating zone 2 Heating zone 3 Heating zone 4 Heating zone 5 Heating zone 6 1 111 111 111 111 110 112 2 110 115 115 115 115 115 3 110 110 110 110 110 110 4 110 110 110 110 110 110 5 110 110 110 110 110 110 6 110 110 110 110 110 110 7 110 110 110 110 110 110 8 110 110 110 110 110 110 9 108 108 108 109 117 108 10 110 110 110 110 110 110 11 110 110 110 110 110 110 12 111 112 112 112 110 107 13 111 112 112 112 110 107 14 110 110 110 110 110 110 15 110 110 110 110 110 110 16 110 110 110 110 110 110 17 90 85 84 71 60 63 18 89 85 82 71 60 62 19 90 90 82 81 64 69 20 84 85 84 85 85 86 21 89 90 82 73 63 69 22 89 90 82 73 63 69 23 89 90 82 73 63 69 24 90 90 80 71 65 67 25 89 90 74 70 66 67 26 91 90 74 71 69 70

Tab. 7: Temperature profile. 3.3.2 Analysis Report Matrix

The analyzes described in this subchapter serve to qualitatively record the influence of various process parameters such as throughput, screw speed, temperature profile and the matrix composition on the extrudate obtained. The extruder is understood in this case to be a "black box". (Fig. 1), in whose inner events no insight can be taken. The objective is to obtain a product which is characterized in that the matrix materials were completely melted at least once (a solid solution is present in the extrudate). In this way, the largest amount of substance can be included.

In all cases, the parameters of interest were changed and all others, if possible, kept constant. The extrudate obtained is comminuted and analyzed (2-8) mg by DSC and interpreted. In all cases it is assumed that the admixed substance to be encapsulated does not represent a parameter influencing the process.

Influence of the temperature profile on the product

Samples 2 and 8 should be investigated with regard to the influence of the temperature profile on the target product described. Sample 2 was extruded isothermally on a temperature profile of 115 ° C.

Figure 11 shows a DSC analysis of Sample 2 before extrusion and Figure 12 shows a DSC after extrusion in the first heating run. It can be seen clearly that the 2 melt peaks of glucono-5-lactone and mannitol are merged into a single &quot; fusion &quot; So based on the sensitivity of the measurement is a solid solution. Retroactively this serves as proof that the material has been completely melted.

Sample 8 was extruded at an isothermal temperature profile of 110 ° C. The resulting extrudate shows, as shown in Fig. 13. * * * * * * * · · «I · · · · · · · · · · · · ·

· ··························································································································································· Comparison of the two samples shows that increasing the temperature from 110 ° C to 115 ° C can result in improved encapsulation efficiency (note that the torque of the two samples differs by only 1 Nm, and therefore only slightly different Temperature gradient leads).

Influence of the matrix mixture on the product

Described are samples 8, 9, 10 and 13. Figure 14 shows the DSC of the extrudate of sample no. 13.

The screw speed was maintained at 150 rpm, unlike samples 8, 9 and 10, because the material pressure and torque were already relatively high. It shows a solid solution of 9 wt .-% glucono-5-lactone in 71 wt .-%

Mannitol. The lower level of low-melting glucono-5-lactone leads to a higher melting point. The melting range begins only at 120 ° C. Nevertheless, there is a firm solution. This can be attributed to higher ones

Temperature gradients due to higher viscosity of the melt. The influence of pressure should also be considered. There are no further identifiable phase transitions in sample 13.

Sample No. 9 (Figure 15) contains 10% by weight of xylitol, 9% by weight.

Glucono-5-lactone, 20% by weight maltodextrin and 61% by weight

Mannitol and shows a wide and already beginning at 100 ° C melting range.

The DSC analysis shows a multiphase system. There are several discontinuities to see. The matrix was not completely melted. No defined decomposition products could be detected.

Sample 9 crystallized only very slowly after exiting the extruder. It is therefore assumed that the xylitol content solidifies only slowly. In sample 9, xylitol is present in crystalline form because no glass transition between -20 ° C and 0 ° C could be found.

For sample 10 (FIG. 16), the xylitol content was reduced to 5% by weight and the proportion of mannitol correspondingly increased. It forms a solid solution with a uniform peak and a melting range starting at 109 ° C, ie 10 ° C higher than comparatively in sample 9. Since the melting range also depends on the initial weight, care was taken to ensure that they differ only slightly. There are not any

Detection products of the matrix detectable.

In general, it can be stated that a matrix mixture which melts at low temperatures does not necessarily lead to a more homogeneous matrix in the end product, given unchanged process parameters.

Influence of the screw speed on the product

To be compared are the samples 14 and 15.

For sample 14 (Figure 17), the screw rotation number was maintained at 250 rpm for 1 and for sample 15 (Figure 18) at 150 rpm for 1. In both cases there is no fixed solution. However, the peak in Fig. 17 (sample 14) is much more uniform than that in Fig. 18 (sample 15). Higher number of revolutions of the screws means higher pressure and higher temperature gradients in the extruder. It can be seen that a greater proportion of the matrix of sample 14 was melted than in sample 15.

Following are still the extrudates, as the main component

Xylitol contains. Sample 18 (Figure 19) contains 9% by weight of glucono-5-lactone, 20% by weight of maltodextrin, and 71% by weight of xylitol, and does not show a single-phase system. It was shown in the thermal characterization of the substance (matrix) mixtures that a eutectic mixture should actually form. The higher melting glucono-5-lactone is expected to dissolve too slowly in the xylitol melt. Fig. 20 shows sample 24 consisting of 20% by weight of maltodextrin and 80% by weight of xylitol. As expected, a uniform melting peak of xylitol is formed. No deep glass transitions (degradation products of maltodextrin) were found. 3.3.3 Analysis report of the substances to be included

Samples 2-6 are to be examined for their content of oleum eucalypti and the efficiency of the encapsulation and regarding

Samples 22-25 should be analyzed for decomposition products, content, efficiency of encapsulation and homogeneity of vitamin D3.

The results should be summarized here. essential oils

In Samples 2-7, the content of α-pinene, 1,8-cineole and oleum eucalypti should be determined by HS / GC / MS and HS / GC / FID, respectively. The results are summarized again in Tables 22 and 23.

Sample Content Oleum [wt.%] 2 5.07 3 4.96 4 3.99 5 5.08 6 7.63

Tab. 8: Content of a-pinene, 1,8-cineole and oleum eucalypti in samples 2-7

Middle HS / ßP. / MS

The strand of sample 2 was crushed and kept in a closed vial at a temperature of 80 ° C for half an hour and then the gas phase was measured by gas chromatography. No volatiles were released from the matrix, indicating high efficiency of encapsulation.

Vitamin P3

All peaks in the chromatogram could be identified. Thus, no decomposition products were formed. In addition, the ratios of cholecalciferol to tocopherol acetate of the non-extruded oily formulation are similar to those in the extruded samples. In Table 9, the content of vitamin D3 will be summarized again.

Sample No. Content Cholecalciferol [mg / g] 22 0.44 23 0.59 25 0.47

Tab. 9: Content of vitamin D3 in samples 22, 23 and 25.

Fixed solution

Glucono-delta-lactone serves as a model substance for determining whether the process can serve to prepare solid solutions of poorly water-soluble pharmaceutical active ingredients.

Example:

A mixture containing 20% by weight of glucono-delta-lactone, 60% by weight of mannitol and 20% by weight of maltodextrin was introduced at a rate of 3 kg / h in a co-rotating twin-screw extruder with 6 temperature zones (Werner and Pfleiderer series ZSK 25).

Temperature settings of the heating zones (in 0 C):

Heating zone 1 Heating zone 2 Heating zone 3 Heating zone 4 Heating zone 5 Heating zone 6 110 110 115 115 115 115

The material solidified within the first minute after exiting the extruder.

Diagrams 11 and 12 show DSC analyzes of the mixture before and after the extrusion. The set temperatures of the individual heating zones are well below the melting point of the mixture. Nevertheless, a solid solution of glucono-delta-lactone forms in a matrix of 60% by weight of mannitol and 20% by weight of maltodextrin (uniform melting peak in the DSC).

Claims (25)

1. A process for the preparation of solid dispersions in a matrix containing sugar, sugar alcohols and / or sugar substitutes or Mixtures thereof, by extrusion through an extruder having one or more temperature zones, characterized in that the matrix with the substances to be entrapped is extruded at a temperature at which the sugars, sugar alcohols, sugar substitutes or mixtures thereof leave the extruder in a partially molten state. 2. A process for the encapsulation of substances in a matrix consisting of A) sugars, sugar alcohols, sugar substitutes, or mixtures thereof B) additives which can form a eutectic with A) and C) auxiliaries, wherein the matrix is mixed with the substances to be encapsulated, and the mixture is extruded dry and solvent-free at a temperature at which component A is partially melted. 3. The method according to any one of claims 1 or 2, characterized in that the substances with the matrix containing at least 20 wt.% Of a recrystallizing sugar alcohol, are mixed and the mixture is dry-melt and solvent-free melt-extruded. 4. The method according to any one of claims 1-3, characterized in that the substances are volatile and / or hydrolysis-sensitive and / or oxidation-sensitive and poorly dispersible, in particular pharmaceutical active ingredients, vitamins and oils, fats or waxes. 5. The method according to any one of claims 1 to 4, characterized in that the matrix contains mannitol, xylitol ^ maltitol, sorbitol, isomalt, lactitol, mono-, di- and trisaccharides, in particular glucose or fructose, or mixtures thereof. Process according to any one of claims 1-5, characterized in that the matrix contains a polysaccharide, in particular maltodextrin, modified starch, or mixtures thereof. 7. The method according to any one of claims 1-6, characterized in that the matrix contains your inner ester of an acid, in particular glucono-delta-lactone. 8. The method according to any one of claims 1 to 7, characterized in that the matrix contains emulsifiers, in particular sugar esters, lecithin, or mixtures thereof. 9. The method according to any one of claims 1 to 8, characterized in that the matrix independently 30-90%, preferably 50-80%, recrystallizing sugar alcohol, in particular mannitol or xylitol, 5-50%, preferably 10-30%, the inner Ester of an organic acid, 0-55%, preferably 10-30%, of a polysaccharide, in particular a hydrolysis product of starch or a modified starch. 10. The method according to any one of claims 1 to 10, characterized in that the matrix is mixed without prior melting with the substances. 11. The method according to any one of claims 1 to 10, characterized in that the Matix are mixed with the substances at a material pressure of at least 1, preferably at least 5 bar. 12. The method according to any one of claims 1-11, characterized gekennzeichet that the corresponding sugar alcohols are brought about forced convection in the extruder to crystallize. §8 • «·« ·· * · • · · · · · «4 I ··· * * · · · · 13. The method according to any one of claims 1 to 12, characterized in that the extrusion is extruded below the melting point of the matrix mixture. 14. The method according to any one of claims 1 to 13, characterized in that as substances to be encapsulated polyunsaturated fatty acids, omega fatty acids, fish oils, vitamins, perfumes, flavorings, essential oils, as well as solutions or dispersions of drugs or vitamins, especially vitamin D and Vitamin K in oils, fats or waxes, oily solutions of lipophilic drugs, or mixtures thereof, can be used. 15. The method according to any one of claims 2 to 14, characterized in that is extruded at a temperature profile, in which the components A and B are present partially melted. 16. The method according to any one of claims 2- 15, characterized in that is extruded below the melting point of the homogeneous mixture of component A and B. 17. The method according to any one of claims 1 to 16, characterized in that the constituents of component A form a solid solution in which the substances are dispersed. 18. The method according to any one of claims 2 to 17, characterized in that the constituents of component A with the component B form a solid solution in which the substances are dispersed. 19. The method according to any one of claims 1 to 18, characterized in that the matrix constituents form a solid solution in which the substances are dispersed. 20. The method according to any one of claims 2 to 19, characterized in that a recrystallizing sugar alcohol is used as component A. / 21. The method according to any one of claims 2 to 20, characterized in that is formed as the component A of a recrystallizing sugar alcohol and fructose, glucose, \ isomalt, maltitol, maltose, and the inner ester of an acid. 22. The method according to any one of claims 2 to 21, characterized in that maltodextrins or modified starches are used as component B. 23. The method according to any one of claims 1 to 22, characterized in that a co-rotating twin-screw extruder is used as the extruder. 24. The method according to any one of claims 1 to 23, characterized in that the resulting extrudate is comminuted during or after cooling .. 25. Melt extrudate consisting of substances encapsulated in a matrix containing sugar alcohols.