HK1149511A - Freeze-dried coated moulded body - Google Patents

Description

The invention relates to freeze-dried moulds containing one or more active substances and, where appropriate, one or more scaffolding agents, where applicable, one or more auxiliary agents, and a coating containing at least one film forming agent; to methods for the manufacture of such freeze-dried moulds, to the combination of such freeze-dried moulds in kit-of-part devices together with aqueous solutions, and to the use of the freeze-dried moulds and the kit-of-part combinations for pharmaceutical and cosmetic applications.

In the freeze-drying process, a highly porous matrix is produced depending on the water content of the substance to be dried. Ice crystals are formed from the water contained in the matrix solution to be dried during the freeze-drying process, which after sublimation in the freeze-drying process determine the pore structures of the material. This pore structure results in a large internal surface, which is important for the rehydration behavior of the freeze-dried matrix. This usually leads to very high rehydration, depending on the material composition.In particular, in the manufacture of freeze-dried active substances or moulds, as known and commonly used for pharmaceutical or cosmetic applications, the mechanical stability and therefore the handling of the materials after the freeze-drying process plays a central role. In order to form form stable active substance matrices, the active substances to be dried must normally be supplemented with active substances which give the freeze-dried final product a certain mechanical strength. This is achieved by using reinforcing substances or polymers, called polymers, which are usually essential for cosmetic or pharmaceutical applications, in particular natural polymers, such as the polymers of the Bollo group or those based on plant-based polysaccharides.In general, the higher the proportion of scaffolding polymers, the higher the mechanical strength of the freeze-dried product and the lower the hydration rate.High concentrations of polymers therefore lead to mechanically stable and resistant, wear resistant and thus dust-free products with good handling, but which, due to the source behaviour of the polymers contained in them, take longer to fully wet.Low scaffolding concentrations, on the other hand, lead to products that can be fully used within a short time, but do not have sufficient mechanical stability and strength and thus provide extremely fragile and stable products.

Thus, the freeze-dried product available to date has always been a compromise between rapid dissolution and sufficient mechanical stability.

To stabilize freeze-dried materials with low mechanical strength, it is useful to apply a continuous, stable protective layer to the material, which allows the formation of moulds with a formula distribution consisting of an internal active substance core with very little or no structural polymer content and an outer polymer layer to stabilize the unstable active substance core.

The coating of moulds with film-forming or structural polymers to change the physical/chemical properties of these moulds, in particular to stabilize and influence the dissolution behaviour of such moulds, is well known and widely used in the pharmaceutical sector, e.g. in tablet coating technology, and has a wide range of applications. For example, tablets can be known to be produced with acid-resistant coatings to obtain gastric-resistant active substance formulations. Coatings that allow a controlled or delayed release of active substance are also known to produce so-called sustained release inhibitors.

The preparation of tablets is usually done in a three-step process. After the preparation of the tablets, they are coated in a second step with a coating dissolved in a solvent and in a third step the solvent is removed, for example by drying or evaporation. To apply this process to coating or coating, sufficient stability of the material to be coated is a prerequisite.

The state of the art has given rise to a number of well-known freeze-dried moulds and their manufacturing processes. For example, JP 2004-149468, EP 0081912 or US 4.305.502 describe active substance compositions stabilised by solid polymers which are characterised by their rapid solubility. However, these compositions are dried and packaged directly in the moulds or in the final packaging (e.g. bottles or blisters), which is due to the low mechanical stability of the moulds obtained by these processes.

Solid, readily soluble active substance preparations stabilised with scaffolding polymers are also known from DE 69227467 or JP 2003-238693, and from WO 04/011537 and WO 05/073296, where the preparations described herein have a sufficiently high level of stabilising polymer in the composition so that an additional stabilising coating is obviously not necessary and is not described. However, the comparatively high level of scaffolding agents in the formulations disclosed herein directly results from the disadvantage of comparatively poor transparency described above. Thus, unlike the formulations JP 2003-2383 and WO 05/073293, the preparations dissolve only by means of a single solvent.

Solid active substance preparations which are stabilised with polymer structural agents and dissolve on liquid supply and which are further modified in their physical/chemical properties by coating or coating are described in US 5,843,347 or also in US 5,578,307, US 5,405,616, EP 0701815 and DE 4201179. However, these documents reveal overlays which influence the active substance preparations in their dissolution behaviour to such an extent that rapid solubility can no longer be obtained. The overlays are intended instead for the manufacture of gastric-assisted preparations or for the provision of sustained release preparations, which is usually a significantly reduced solubility in physiological or biological media such as B-induced.The preparations described here do not therefore indicate any suitable coating technique which, while stabilizing the solid active substances, ensures or maintains rapid solubility. Furthermore, all the preparations described here necessarily contain scaffolding materials selected from the group of proteins. These proteinogenic scaffolding materials are essential for the stability of freeze-dried compounds, since they undergo a networking process known as dehydro-dry networking in the freeze-dry process.The mechanical stability of the freeze-dried pellets required for this process also requires a sufficiently high proportion of these scaffolding polymers and compounds with an active substance content < 50% by weight cannot be obtained by the process described here. Increased active substance content leads to a loss of mechanical stability of the freeze-dried mould, which makes it impossible, especially when using hydrophilic active substances, to subsequently coat them, as they collapse immediately during the coating attempt.

GB 1206033 also describes freeze-dried food moulds, in particular freeze-dried ice cream, which can be coated, for example, with chocolate, which could in principle be called a film forming agent. However, here too, the coating is only after the freeze-drying step, which can be carried out in mould tablets, which may have been coated with a film forming agent.

The methods described above for coating easily soluble solid active substance compounds are therefore only suitable for preparations which already have sufficient mechanical stability in themselves, but if particularly fragile and inherently unstable active substance compounds, in particular those which have no or only an extremely low proportion of structural or reinforcing polymer co-forming agents or a particularly high active substance content, are to be stabilised with a coating to achieve increased mechanical strength, the problem arises, first, that the preparations described above which are mechanically unstable solids are not accessible to other types of coating due to the mechanical drying process that is involved.

If freeze-dried moulds with the desired properties of high active substance content, low scaffolding co-forming, high dissolution rate and high or sufficient mechanical stability to provide single moulds, in particular for use as single unit dosage form, are to be stabilised by coating, it appears that hydrophilic coating solutions such as those based on glycerin increase the hygroscopicity, i.e. moisture sensitivity of the final product and also lead to an unstable coating, which is particularly evident in lubricating and abrasive films on packaging materials.The use of hydrophobic coatings, e.g. based on fats and oils, such as neutral oil, or based on hydrophobic polymers, as described in e.g. JP 54105289, reduces the dissolution behaviour of the active substance-containing moulds, particularly in aqueous media or physiological fluids such as saliva, to such an extent that the rate of dissolution is greatly delayed. This is particularly detrimental if rapid release of the active substance and thus rapid availability of the active substances is desired. For these reasons, a coating based on a hydrophilic, water-based coating composition is preferable. However, such a coating is not recommended for the purposes described above and is not recommended for the purposes described above.

One way of obtaining a hydrophilic coating on a rapidly soluble mould is to apply the coating to the frozen mould before freeze-drying. The advantage is that the ice structure of the composition gives the mould sufficient mechanical stability to withstand the mechanical stress during the coating process. Since the particularly fast solubility of the compositions is largely due to the pore structure of the freeze-dried compositions, and thus this rapid solubility potential is not yet present to a sufficient extent in the frozen state, coating the frozen compositions can also solve the problem of the rapid dissolution or moisture stability of the frozen moulds before coating with the coating agent.The coating solvent is removed along with the solvent of the composition, usually the water content of the active substance, in the subsequent freeze-drying step. This also increases the efficiency of the process, as compared to processes where the final product is subjected to a coating step, the additional work step to remove the coating solvent is saved. In addition, the method of coating the frozen moulds ensures that moisture sensitive active substances are protected by the low temperatures in the frozen mould, whereas such sensitive active substances are in already dried compositions when in contact with Co-Lol solvent, which may lead to a significant loss of active substance activity if exposed to this moisture.

Furthermore, the process of coating frozen moulds and subsequent freeze-drying results in a high degree of variability in the choice of active ingredient composition. The scaffolding structural polymers can be used in much lower concentrations. Ideally, they can even be completely eliminated, so that dry moulds are available that do not require structural polymers in the inner region of the moulds and are only mechanically stabilized by a thin polymer film-forming coating layer.

Fast-soluble solids coated in the frozen state are mentioned in the above-cited JP 54105289, but ice pellets are coated without subsequent freeze-drying; in addition, a hydrophobic coating is used, which is unfavourable for the application of active substances in aqueous systems for the reasons mentioned above; in addition, hydrophobic coatings for frozen moulds subsequently subjected to freeze-drying are unsuitable because the hydrophobic coating prevents or greatly restricts the liquid from seeping into the composition at sub-climate, which has a negative effect on the post-freeze pressure.

DE 10248314 and the corresponding WO 2004/035023 describe fast-soluble freeze-dried moulds of active substance-scaffolding mixtures for external use. The possibility of subjecting these moulds to a surface coating in the frozen state before freeze-drying is mentioned. However, only coatings for the application of an active substance or dye layer are mentioned and those which reduce the rate of dissolution of the moulds by interlacing the structural polymers in the mould on the basis of alginate. The possibility of mechanical stabilization of the moulds by coating, in particular by coating them with a film, is not revealed, as such a coating contains a high proportion of active polymers in the structure due to the presence of at least 10 elements in the mould.The possibility of obtaining stable freeze-dried moulds with high active substance contents and extremely low scaffolding proportions with sufficient mechanical stability by a thin film-forming coating is not disclosed in DE 10248314 or the corresponding WO 2004/035023. In particular, given the limited possibilities so far in incorporating a number of important and high temperature active substances for cosmetic or pharmaceutical applications, which are known to be extremely unstable to external influences such as light, temperature, oxidation or moisture, into cosmetic and pharmaceutical concentrations, there is a further high potential interest in bringing such unstable and high potency active substances into a highly degradable and high concentration form, which is known to be highly stable.provide high and long-term stability and thus good storage capacity, optimum and reproducible availability of active substance content throughout storage and administration time, and thus maximum safety and dosage availability in use.

In addition to effective stabilisation of the active substances, it is of particular interest to ensure that they are administered in the most appropriate and best suited form for the intended use, the choice of which form depends in particular on the type and location of application, the target group and their characteristics, the type and level of dosage of the active substances or their form of administration, and, for example, the physical and biochemical characteristics of the active substances, in particular their bioavailability and systemic effects, which must be taken into account.

In particular, forms of administration for external use and oral applications are of particular interest in the supply of such stable high potency active substances, whereby particularly suitable and preferred forms of administration for such applications are those that can be used in aqueous and/or aqueous formulations or environments and are readily soluble in such aqueous environments, particularly in oral systems.

Various methods, dosage forms and application systems have been developed to stabilise such unstable, easily degradable and/or easily degradable substances and to keep them available in the long term in cosmetic and/or pharmaceutical formulations for external or oral application, in particular methods for encapsulation of active substances, e.g. in liposomes, the use of special emulsion techniques or stabilising solvents or the provision of unstable active substances in delivery systems containing a stable derivative form or precursor and a transposition agent of the active substance from the precursor.

The disadvantages of these methods are the limited loading density, the complexity of manufacture, the contact of water-sensitive, water-soluble or water-insoluble active substances with the solvent water during storage time and the generally inadequate and unreliable and poorly reproducible release kinetics of the stabilised active substances from the formulations.

For highly concentrated dosage forms, there is also particular interest in so-called single-dose unit dosage forms, which allow simple and targeted dose application to the end user. 'single-dose unit dosage forms' means systems of application which, unlike powders or granules, contain the desired and necessary amount of active substance per unit of application in a single application unit such as tablets or capsules, without, however, entailing the disadvantages of poor solubility or lack of suitability for external application.

Thus, such readily soluble, freeze-dried moisture-stabilized single-dose unit application forms for the oral and/or external application of unstable active substances are becoming increasingly interesting in larger formats, especially when large amounts of active substances are to be administered.

There is therefore a need to provide well-doseable, large-format single-dose unit application forms with a high active substance load, in particular a load of unstable active substances and the lowest possible proportion of insoluble, suppressible carrier and thus the fastest possible and most complete solubility and maximum possible mechanical stability for cosmetic and pharmaceutical external and oral use.

The present invention was therefore intended to provide a composition in which extremely high amounts of active substances, particularly unstable active substances, could be stabilised in the long term and released and applied rapidly, efficiently, specifically and with high activity when used, with the stabilisation of the active substances being achieved preferably by freeze-drying of the active substance composition. The further objective was to design these stable active substance compositions in such a way that they would have a high mechanical strength and a sufficient size to be used in particular in cosmetic or pharmaceutical applications in the form of so-called single-dose or single-dose solutions. The aim of this was to reduce the proportion of the active substances used in such a way that the structure of the composition could be used in a way that would be as stable as possible for the final application or to be fully stabilized and, in particular, by ensuring that the final structure of the oral solution could be used in a manner that would not be able to be used in the final product, and to reduce the proportion of the active substances used in such a way as to achieve a complete and complete stability of the final application.

Surprisingly, it was found that it is possible to produce from DE 10248314 even such stable, large-format active substance-laden moulds containing active substance amounts with ≥ 50% by weight active substance content and < 10% by weight scaffolding content outside the amounts disclosed in DE 10248314 by compensating for the associated mechanical stability problems by coating the moulds.

By selecting a suitable film-forming hydrophilic coating and applying this coating to the frozen mould and then freeze-drying the coated frozen mould, a surprisingly stable freeze-dried highly concentrated active substance mould was obtained, which was further significantly improved in terms of solubility compared to systems already known, such as the one described in DE 10248314 due to the extremely low scaffolding content of the invention.

Neither DE 10248314 nor any of the other documents discussed here reveal solid freeze-dried moulds with such a high active substance content and a film-forming coating that have such good mechanical stability, resolution and size properties for use in cosmetic and pharmaceutical single dose applications.

The invention thus provides freeze-dried moulds containing one or more active substances and, where appropriate, one or more scaffolding agents, one or more auxiliaries, where appropriate, and a coating containing at least one film forming agent.

The invention also provides a method for the manufacture of such freeze-dried moulds, the combination of such freeze-dried moulds in kit-of-parts devices together with aqueous solutions, and the use of the freeze-dried moulds and kit-of-parts combinations for pharmaceutical and cosmetic applications.

For the purposes of the invention, a shape is a regularly shaped geometric body, e.g. in particular balls, squares, pyramids, stars, but also natural shapes, such as those in the form of animals, such as sea animals, such as sea stars, seafood, such as shells, etc. Plants and plant parts, such as leaves, etc. All these shapes are available after the procedure described below for the production of the shapes used in accordance with the invention. The invention prefers uniform regular spherical shapes, such as a spherical surface, because this is particularly useful when used with the film coil, which provides a particularly homogeneous and stable surface in terms of volume and is particularly suitable for mechanical transportation, especially in the form of a small ball, which is particularly stable and suitable for all types of mechanical applications.

The invention also includes a number of the moulds mentioned in the above container. It may also be a mixture of moulds of different geometries or sizes. The moulds may be packed individually, but preferably, especially in cosmetic applications, a number of moulds are in contact with each other in a container.

The volumes of the moulds used are not restricted by the method of their manufacture. The volumes are preferably at least about 0.1 cm3, preferably 0.3 cm3, preferably about 0.5 cm3, preferably about 0.6 cm3 and upwards, the volumes used are conveniently limited to about 6 cm3, preferably about 5 cm3, preferably about 4 cm3. The size of the moulds is determined, among other things, by the desired application form or the place of external application of the moulds. This allows for external cosmetic or pharmaceutical use the application on larger body surfaces or hair (e.g. direct application of the moulds against the back, etc., as a moisturizer) and the larger moulds where smaller parts of the body are preferable (e.g. moulds for use on the back, etc.).

The manufacture of oral application moulds also allows for size adjustment, for example by adapting the mould size to the appropriate target group, with the possibility of offering older users larger moulds with better handling and easier handling, and for example younger users or children who are in a proportionate relationship to their body size and age-related compliance in use.

The diameter of a mould (maximum distance between two points in a mould of any geometry) is preferably at least about 3 mm, preferably at least about 5 mm, preferably at least about 7 mm, preferably at least about 8 mm, preferably at least about 60 mm, preferably at least 50 mm, preferably at least 40 mm, preferably at least 20 mm. For the above reasons, a particularly preferred mould has a predominantly spherical geometry, with a diameter of the ball between 3 and 30 mm, preferably between 5 and 20 mm, preferably between 7 and 15 mm, preferably between 8 and 14 mm.

The freeze-dried moulds of the invention contain at least one or more active substances, preferably at least one active substance in a quantity ≥ 50% by weight in relation to the total coated freeze-dried composition. Active substances include, in particular, cosmetic or therapeutic or pharmaceutical active substances suitable for external use and for oral or oral application. Preferably, the moulds of the invention contain at least one cosmetic and/or pharmaceutical active substance. Accordingly, the freeze-dried moulds of the invention are preferably cosmetic or therapeutic agents.

Cosmetic molds or molds made with cosmetic active substances within the meaning of the invention are essentially means within the meaning of the Food, Consumer Goods and Feed Code (LFGB), i.e. substances or preparations of substances intended to be used externally on humans for the purpose of cleaning, care, or to affect the appearance or smell of the body, or to convey odour impressions, unless they are primarily intended to relieve or eliminate diseases, ailments, bodily injury or medical conditions. In this sense, the combined cosmetic molds used for the purpose of treatment are, for example, antiperspirants, lip balms, skin washers and body lotions, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, hair conditioners, etc.

Examples of cosmetically active compounds include, for example, anti-acne agents, antimicrobials, anti-transpiration agents, astringents, deodorants, hair removers, skin conditioners, skin smoothing agents, skin hydrating agents such as glycerin or urea, sunscreen, keratozymolytics, free radical inhibitors, anti-abortion agents, anti-slip agents, retreceptive agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-aging agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, anti-fouling agents, antifouling agents, anti-fouling agents, antifouling agents, antifouling agents, antifouling agents, antifouling agents, antifouling agents, etc.

In general, the plant extract is usually selected from the group consisting of solid plant extracts, liquid plant extracts, hydrophilic plant extracts, lipophilic plant extracts, individual plant ingredients; and mixtures thereof, such as flavonoids and their aglycides: rutin, quercetin, diosmin, calcium, hyperosid, (neo) purperidin, hesperitin, glyphosate (e.g. quercetin), ginseng (e.g. oligomers), procygenic (e.g. procygenic), buckwheat (e.g. B.e.g., R.e.g., R.e.g., Sophora), with or without oil (e.g. B.e.g., B.e.g., R.e.g., B.e.g., B.e.g., B.e.g., B.e.g., B.e.g., B.e.g., B.e.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., B.g., BFor example, alcohol extracts, fresh vegetable juice, press juice), eleuthercoccus senticosus, alkaloids: red wolfberry (e.g. prajmalin), green algae (e.g. vincamin); other phytopharmaceuticals: aloe, red chestnut (e.g. aescin), garlic (e.g. garlic oil), pineapple (e.g. bromelain), lycopene (e.g. beta-gensenosides), ginseng (e.g. extracted from silymarin), mouse root (e.g. ruscogen), baldy (e.g. valerian root, T. valerix), cacao (e.g. cacao) extract, hops (e.g. hops from garlic oil), lobster (e.g. bromelain), ginseng (e.g. ginseng extract, extracted from ginseng (e.g. from silymarin), rosehip root (e.g. roscogen), rosehip (e.g. valerian root), rosehip (e.g. cacao), rosehip (e. cacao) extract, rosehip (e. rosehip), rosehip (e. rosehip), rosehip (e. rosehip), rosehip (e.p), rosehip (e.p), rosehip (e.p), rosehip), rosehip (e.p), rosehip (e.p), rosehip (e.p), rosehip), rosehip (e.p), rosehip (e.p), rosehip), rosehip (e.p), rosehip (e.p), rosehip), rosehip (), rosehip (e.p), rosehip (), rose), rosehip (), rose), rose), rose), rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose, rose,Tagetes lucida, tea of the siems, Momordica charantia, and extracts of aloe vera.

The preferred cosmetic active substances are those which are highly unstable against degradation or decomposition, particularly due to moisture, and those which, in aqueous solution, produce an acid pH due to acidic groups in the active substance, so-called acidic active substances which have not been satisfactorily converted into stable forms even by freeze-drying processes, or only at very low concentrations or at very high cost, by a process at very low temperatures with very long drying times.

A particularly preferred active substance from the group of these unstable, acidic active substances, particularly used in cosmetics, is ascorbic acid or vitamin C and its derivatives or vitamin A and its derivatives.

Derivatives of ascorbic acid include in particular glycosides such as ascorbyl glucoside, or esters of ascorbic acid such as sodium or magnesium ascorbyl phosphate or ascorbyl palmitate and stearate, as well as, for example, L-ascorbic acid phosphates, alkali metal salts such as sodium and potassium salts of L-ascorbic acid phosphates; mineral mineral salts such as magnesium and calcium salts of L-ascorbic acid phosphates; trivalent metal salts such as aluminium salts of L-ascorbic acid phosphates; alkali metal salts of L-ascorbic acid phosphates; and sodium and calcium metal salts of L-ascorbic acid phosphates; and trivalent metal salts such as calcium and calcium metal salts of L-ascorbic acid phosphates; and sodium and calcium metal salts of L-ascorbic acid phosphates; and trivalent metal salts such as calcium and calcium salts of L-ascorbic acid phosphates; and calcium and calcium salts of L-ascorbic acid phosphates; and trivalent metal salts of L-ascorbic acid phosphates; and calcium and calcium salts of calcium and calcium salts of calcium and calcium salts of calcium salts of calcium and calcium salts of calcium salts of calcium salts of calcium salts of calcium and calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts of calcium salts

Unlike the moulds described above, which are mainly used in cosmetics, moulds (medicinal products) for therapeutic use are those containing at least one pharmaceutical or therapeutic, in particular a dermatological, active substance and which, within the meaning of the Law on medicinal products, are intended, inter alia, to cure, alleviate or prevent diseases, suffering, bodily injury or disorders.

For external use, active substances are mainly dermal active substances but also transdermal active substances, which include: products for the treatment of skin conditions, external analgesics such as dextropropoxyphens, pentazocine, pethidine, buprenorphine; anti-rheumatic/ antiphlogistic agents (NSARs) such as indomethacin, diclofenac, naproxen, ibuprofen, ketoprofen, flurbiprofen, salicylic acid and derivatives such as acetylsalicylic acid, juicam; steroidal steroids such as betamethylserine, dexamethasone, benkstylnis, ethinyl estradiol, external acetic acid, corticosteroid; all drugs used for external stimulation, including anti-inflammatory agents such as anti-bacterial agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-inflammatory agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, anti-viral agents, etc.

The preferred therapeutic agents for external use are analgesics, e.g. immunosuppressants, hormones, agents for the treatment of skin diseases such as neurodermatitis, atopic dermatitis, etc., and anti-herpes agents.

Therapeutic agents for oral or oral use may be selected from the group of antihistamines, antibiotics, peptide medicines, antifungal agents, bronchial agents such as antiasthmatics, antitussives, mucolytics, etc., antidiabetics such as glibenclamide, hormones, steroid hormones such as dexamethasone, herbicides such as digitoxin, cardiovascular agents such as beta-blockers, antiarrhythmic agents such as beta-ketones, antihypertensive agents such as calcium antagonists, psychotropic agents and antidepressants such as tricyclic antidepressants such as tricyclic antidepressants (NSM), anti-proliferative drugs such as lipoproliferative drugs such as lipoproliferative drugs such as dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea, dihydroxyurea,

A particularly favourable pharmaceutical active substance, used for both topical and oral or oral application, and selected from the group of unstable acidic substances, is salicylic acid and its derivatives such as acetylsalicylic acid (ASS). Other favourable unstable, acidic and freeze-point-lowering therapeutic agents are clofibromoic acid, ibuprofen, gemfibrozil, fenoprofen, naproxen, ketoprofen, indomethacin, bezafibrate, tolfenamic acid, diclofenac, meclophenoic acid, paracetamol, acetaminophen, acrivatin, acrylic acid, crolyn, ethanoic acid, penicillin, and their derivatives, and their derivatives, uric acid, uridine and urodiola.

The freeze-dried moulds of the invention are preferably ≥ 50% by weight, preferably ≥ 75% by weight, preferably ≥ 80% by weight, and preferably ≥ 90% by weight, respectively, based on the total composition of the freeze-dried coated mould.

In particular, these are active substances selected from the group of acidic active substances, i.e. active substances which, in aqueous solution, produce an acidic pH due to acidic groups in the active substance, and in particular active substances whose 1% by weight of solution or suspension in water at 20 °C has a pH < 7 or active substances which have a pKs value at 25 °C of ≤ 7.

The pKs value is the negative decadal logarithm of the acid constant Ks. The acid constant Ks is a substance constant and gives information on the extent to which a substance (HA) reacts in an equilibrium reaction with water under proteolysis: Other

HA stands for Brønsted acid, which can give off a proton H+ to a solvent such as water, leaving behind an anion A- More generally, the Brønsted definition also applies to non-aqueous systems, here it applies to any protonated solvent Y: Other

The acid constant Ks is the equilibrium constant of this reaction and is thus a measure of the strength of an acid. The stronger the acid, the more the reaction is shifted to the right.

The pKs value is determined by pH measurement in a so-called half titration. A solution of the acid of known concentration is presented and the pH value is measured, for example, by means of a pH probe. The acid is then partially neutralized with a measurement solution of a base of the same value as the acid presented. ${\mathrm{pK}}_S=-{\mathrm{lgK}}_S=-\lg \frac{c\left(H^{+}\right)\cdot c\left(A^{-}\right)}{c\left(\mathrm{HA}\right)}$

Since after adding half the amount of substance, c[A - ] = c[HA], for the so-called half titration point, pKs = pH.

Such acidic active substances have a high pH-dependent dissociation tendency, which results in the presence of the active substance in dissociated form and thus in high ionic concentration in neutral to alkaline pH ranges. Such an increased ionic concentration then results in a freeze-point-lowering effect, which has an adverse effect on the freeze-drying process. Compounds containing particularly high amounts of freeze-point-lowering substances. The freeze-point-lowering effects of such dissociated active substances result in the formation of frozen bodies in the form of very large ice rocks with a high proportion of non-saturated ice with high concentrations, which usually lead to partial collapse in a low-cost form or in a form that is not stable at high temperatures, or in a process that has only been modified by the use of such products at high temperatures, which can only be achieved by a very large ice rock with a high proportion of water-satisfying particles with high concentrations of non-saturated ice, which can be partially collapsed in a low-cost form or at high temperatures, which are usually not stable at high temperatures.

In a preferred embodiment, the freeze-dried moulds of the invention contain ≥ 50% by weight of an active substance from the ascorbic acid group and its derivatives in relation to the total composition of the freeze-dried coated mould.

In another preferred embodiment, the freeze-dried moulds of the invention contain ≥ 50% by weight of an active substance from the salicylic acid group and its derivatives, preferably from the acetylsalicylic acid group and its derivatives, in relation to the total composition of the freeze-dried mould.

The moulds of the invention preferably contain very small amounts up to a maximum of 25% by weight, preferably up to a maximum of 10% by weight of one or more scaffolding agents, depending on the total composition of the freeze-dried coated mould. Such scaffolding agents are generally so-called hydrocolloids, i.e. (partially) water-soluble/softening, natural or synthetic polymers, which are soluble in aqueous systems or viscous solutions. The scaffolding agents are selected from polysaccharides, mucopolysaccharides, animal heteroamines such as chitin or its derivatives, in particular from the glycosamines or glycogen, and the synthetic polysaccharide, for example, the polysaccharide or allyl glycoside, which is excluded from the group of polysaccharides.In particular, sodium alginate, carrageenan, pectin, carrier, guar gum, pullulan, trehalose, buckwheat flour, agar agar, gum arabic, xanthan, natural and modified starches such as cationic starch derivatives, dextrane, dextrin, maltodextrin, glucan, such as β-1,3-glucan, β-1,4-glucan, such as cellulose, mucopolysaccharides such as hyaluronic acid, etc., and animal polyamines such as chetherine or its derivatives, in particular chethalite. Synthetic polymers include, for example, polyethylene glycol, polyvinyl alcohol, polypropylene glycol, polypropylene glycol, polypropylene glycol, polypropylene glycol, especially polyethylene glycol, which can be readily synthesised with a solution of carboxylic acid, especially cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose-%, preferred < 2%, still preferred < 1,5% by weight, cellulose such as carboxymethylcellulose, hyaluronic acid and chitosan or cationically modified starch or cationically modified carboxymethylcellulose.

In a preferred embodiment, the freeze-dried moulds of the invention contain at least one scaffolding material selected from the group of cationic scaffolding materials, generally those scaffolding materials which have more positive than negative charges on their surface under physiological environmental conditions (room temperature, neutral pH range, aqueous environment).

In particular, cationally modified polymers include those in which at least one side group of the polymer backbone is replaced by cationic groups. According to the invention, preference is given in particular to cationally modified polymers with a degree of substitution (Sga) ≥ 1%. The degree of substitution can be determined according to the type of cationic group in the modified polymer by standard methods of analysis known to the expert and appropriate at the time.

In general, the term cationic polymers or scaffolding agents includes in particular modified chitinder derivatives, such as chitosan in particular, but also other chemically modified biopolymers, such as cationic celluloses, such as cationic carboxymethylcellulose or cationic starches.

Cationic biopolymers based on polysaccharides, such as cellulose or starch, include those in which some hydroxy groups in the polymer side chains are etherised with cationic groups or groups that can be converted into cationic groups by protonation in an acid medium.

In particular, when using active substances from the group of acidic substances, such as ascorbic acid and its derivatives or acetylsalicylic acid and its derivatives, the use of easily soluble cationic scaffolding agents such as chitosan or cationic starch derivatives or cationic cellulose derivatives (e.g. carboxymethylcellulose) is particularly preferable, where appropriate also in combination with other scaffolding agents mentioned above.

In a preferred embodiment, the use of scaffolding agents from the protein group is excluded.

The use of such hydrophilic, readily water-soluble scaffolding agents is preferred on the one hand for manufacturing purposes and, on the other hand, the use of such hydrophilic scaffolding agents leads to a high solubility of the formulation, e.g. in the mouth by saliva or, if water or aqueous solutions are added, to a high rate of decomposition and thus to an easy distribution on the skin. In particular, the use of readily soluble scaffolding agents in the preferred low levels of ≤ 10% by weight in relation to the total composition of the freeze-dried, coated mould can lead to a greater solubility of the moulding agents.

However, a clear distinction must be made between such polymer scaffolding materials which are present in a homogeneous distribution with the active composition, i.e. in the inner core region of the freeze-dried mould, and such polymers which form the outer coating. A particularly preferred embodiment mentioned above, which is made without scaffolding structural polymers, nevertheless has an outer coating of a film-forming polymer, as defined below.

Up to now, the use of small amounts of scaffolding substances in the active substance moulds of the invention was essential, compared with, for example, pure, dried, additive-free active substances, in order to provide the active substance immediately in an appropriate mechanically stable dosage form, which plays a role, in particular in external application, in terms of flexibility and handling.

The polysaccharides of the invention preferentially used as scaffolding materials have an appropriate average molar mass of about 103 to about 108, preferably about 104 to 107.

The freeze-dried moulds of the invention are preferably characterised by a scaffolding content of ≤ 25% by weight, preferably ≤ 10% by weight, preferably ≤ 5% by weight, in relation to the total composition of the freeze-dried coated mould.

The scaffolding products are compatible with the skin and mucous membranes and have no toxicological potential when applied externally or orally or orally, in particular they do not cause irritation or other intolerance reactions.

The scaffolding images, in particular the polysaccharides, may also have certain therapeutic effects, for example, the scaffolding agent (sodium alginate) of preference has some antiviral activity but is not an active substance within the meaning of the invention.

The moulds of the invention may also contain one or more excipients, if appropriate: fatty substances such as mineral oils such as paraffin oil or petroleum oil, silicone oils, vegetable oils such as coconut oil, almond oil, apricot oil, corn oil, jojoba oil, olive oil, avocado oil, sesame oil, cardamom oil, eucalyptus oil, rosemary oil, lavender oil, pine oil, thyme oil, mince oil, palm oil, orange blossom oil, soybean leaf oil, clove oil, rice oil, rapeseed oil and cosmetic oils, decorative oils and vegetable oil such as vitamin E, polyethylene, plant oils (including polyethylene, soybean oil, essential oil, corn oil, jojoba oil, olive oil, avocado oil, sesame oil, cardamom, eucalyptus oil, rosemary oil, lavender oil, lavender oil, pine oil, pine oil, thyme oil, palm oil, mince oil, orange oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm oil, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm, palm,

A particularly preferred excipient is neutral oil (Capryl/Caproic acid triglycerides).

Other excipients of preference according to the invention are mannitol, saltic acid and sodium chloride from the group of pH adjusting agents.

The excipients may be added to the moulds of the invention in amounts up to 50% by weight of the total composition.

The moulds of the invention shall preferably have a total percentage of active and excipients of ≥ 50% by weight, preferably ≥ 75% by weight, preferably ≥ 80% by weight, and preferably ≥ 90% by weight, based on the total composition of the freeze-dried coated mould.

The ratio of active substances to excipients in the freeze-dried coated forms is preferably approximately 10:1 to 100:1 and preferably approximately 20:1 to 50:1, with a ratio of 20:1 being particularly preferable and the total amount of active substances by weight in each case being proportional to the total amount of excipients by weight.

The moulds of the invention are intended for external cosmetic and pharmaceutical use and for oral or oral application to humans or animals. The external application is by moistening or dissolving the mould with water or an aqueous solution, which may contain one or more active substances and/or one or more excipients, if any. Depending on the liquid content and solubility of the mould material used, the mould may be completely dissolved to form a solution or decomposed to form a gel and then applied to the hair or skin.

Preferably, aqueous solutions which may also contain multi-alcohols are used for the dissolution, as well as those which are low viscous (have a viscosity < 50 mPa) and have no or only low oil content (< 10% by weight in relation to the total composition of the aqueous solution), and activator solutions which are free from earth alkalies, in particular calcium and/or magnesium ions (less than 1% by weight in relation to the total composition of the aqueous solution), and those with a pH between about 5 and 7.

According to the invention, the external application also includes the solution of the mould according to the invention in a quantity of water suitable for bathing application. However, the application is preferably carried out in such a way that the moulds with a small amount of about 0,5 to 5,0 ml or about 10 to 100 times the intrinsic weight of the mould are moistened directly on the skin or hair or in a suitable vessel, in the form of a solution or gel, and decompose there within ≤ 30 seconds and preferably dissolve completely and without residues. Preferably, the dissolution is carried out without mechanical action, e.g. by evaporation, recoiling, crushing or simply by massaging the mould or by applying a mechanical force to the surface of the mould, which is sufficient to produce a stable hydraulic effect and to activate the coating by means of a mechanical activation.

The present invention also relates to a combination containing at least one of the moulds used in accordance with the invention and at least one aqueous solution, possibly containing one or more active substances and/or one or more auxiliary substances (so-called activator solution), in a coherent spatial arrangement (application package, set, kit-of-parts, etc.). The active substance solution may, for example, be solutions of volatile active substances and/or auxiliary substances which, due to the manufacturing process, are not intended or cannot be introduced into the mould by freezing, such as a sub-drying, such as a partial etheric effect, a particle or a particle, etc. Such active substances and/or auxiliary substances may also be used to produce a moisture-resistant effect, for example, but cannot be processed in a hygroscopic or hydroscopic form, in particular because of the hygroscopic effect of the mould, and therefore cannot be used in a moist, hygroscopic or hygroscopic form, but may be used in a moist form, for example, because of the hygroscopic effect of the mould, and the hygroscopic effect of the mould, and the hygroscopic effect of the mould, and the mould, etc.

The design of such kit-of-parts combinations of the mould of the invention on the one hand and the active substance solution on the other may provide for the two components to be taken separately from the kit-of-parts package and combined and dissolved outside it for further use. However, it is also conceivable that a combination of the two components is made within the kit-of-parts package itself and the dissolved composition is then fed directly from this package to further cosmetic or pharmaceutical external, oral and/or oral use, preferably directly by the final consumer.

The moulds of the invention contain ≥ 50% by weight, preferably ≥ 75% by weight, preferably ≥ 80% by weight, and preferably ≥ 90% by weight of one or more active substances, based on the total composition of the freeze-dried coated mould, so that the amount of active substance indicated refers to a freeze-dried mould including the coating with the film forming agent.

Particular preference shall be given to moisture-insoluble and/or acidic active substances, such as ascorbic acid (vitamin C) and its derivatives and/or salicylic acid and its derivatives such as acetylsalicylic acid (ASS).

Err1:Expecting ',' delimiter: line 1 column 779 (char 778)

Depending on the quantity and type of active substances and/or excipients available, the mould according to the invention contains ≤ 25% by weight of a scaffolding material or preferably ≤ 10% by weight of a scaffolding material, based on the total weight of the coated freeze-dried mould, with a preference of ≤ 7% by weight or ≤ 5% by weight of the scaffolding material, with particular preference to polysaccharides such as sodium alginate or chitosan or also carboxymethylcellulose.

The integral proportion of scaffolding agents in the dry total composition can be determined by hydrolysis of the polymer chains present and subsequent quantitative chromatographic detection of the individual monomeric components. If this method cannot be used by a special combination of different scaffolding agents and special active and auxiliary substances, the quantitative polymer proportion can be determined mathematically by the difference between the total weight and the quantitatively determinable active and auxiliary substances and water.

The moulds may contain up to about 20% by weight of one or more auxiliary materials, preferably ≤ 15% by weight, preferably ≤ 10% by weight.

The moulds of the invention have a coating or coating with at least one filmmaker. The filmmakers include a particularly synthetic and natural polymer and copolymer such as the structural polymers listed under the hydrocolloids. Furthermore, semi-synthetic cellulose derivatives such as hydroxypropylmethylvinylvinyl, Polyvinyl (PVC), Polyvinyl acetate (PVC), Polyvinyl acetate (PVP), Shellac, PAPP, etc. can be used. In addition, polymers may be used, which are described in Seitz, J.A. Aqueous Film Coating [Encyclopedia of pharmaceutical technology, J.Swarbrick and J.C. Boylan; Marcel Dekker, New York (1988) 1; 337-349] and Cole, G.C. Introduction and overview of pharmaceutical coating, in Pharmaceutical Coating Technology, G. Cole, J. Hogan and M. Aulton; Taylor and Francis LTD., London (1995), 1-5. and in Aulton M., Mechanical Properties of film coats, pharmaceutical coating technology, G. Cole et.al., Taylor and Francis, London (1995), 280-362.

According to the invention, the film-forming agent is preferably selected from the group of hydrophilic polymers, preferably from the group of synthetic polymers, especially preferably from the group of vinylpyrrolidone vinyl acetate copolymers (e.g. Collidon VA64®).

The coating with the film-forming agent in the total freeze-dried composition including coating is preferably ≤ 10% by weight, preferably ≤ 7% by weight, and preferably ≤ 5% by weight of the coated freeze-dried composition.

The moulds may contain residues of water. However, since the active substances contained in the moulds are designed to be protected against moisture in particular and against moisture-related instability and dissolution, the water content should be kept as low as possible. Depending on the type of active substance (hydrophilic, hydrophobic), the water content may be up to 10% by weight. The water content may change after the mould is manufactured by freeze-drying during storage, usually increasing.

A particularly preferred moulding body contains: ≥ 50% by weight of one or more active substances, in particular acidic substances such as ascorbic acid (vitamin C) or its derivatives such as ascorbyl glucoside or salicylic acid or its derivatives such as acetylsalicylic acid (ASS) ≤ 25% by weight, preferably ≤ 10% by weight of one or more scaffolding agents, in particular polysaccharides such as sodium alginate, in particular calcium-free sodium alginate or cationic scaffolding agents such as chitosan and/or cationised starch or modified scaffolding agents such as carbamethylcellulose, in particular sodium carbamethylcellulose or cationised carbamethylcellulose®, and mixtures of polymer scaffolding agents of ≥ 20% by weight, in particular polymers of a content of less than or equal to 10% by weight, such as T-cylon and B-cylon, preferably with a hydrophobic filter (including a hydrophobic filter), and preferably with a weight of ≤ 10% by weight, in the form of a V-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-Cylon-C provided that the moulding body fully decomposes and dissolves in liquid for ≤ 30 seconds, preferably ≤ 20, preferably ≤ 10, and preferably ≤ 5 seconds, preferably without mechanical action.

Preferably the mould according to the invention, such as the one of the above composition, containing at least 50% by weight of one or more active substances, ≤ 25% by weight or ≤ 10% by weight of one or more scaffolding materials, and one or more auxiliary materials, if any, and coated with a film forming material a density of 0,005 g/cm3 to 0,8 g/cm3 preferably 0,01 g/cm3 to 0,8 g/cm3, a volume of 0,1 cm3 to 6 cm3, preferably 0,6 cm3 to 6 cm3, a diameter (maximum distance between two points of the moulding body) of at least 6 mm and/or a spherical shape, in particular a spherical shape.

The moulds of the invention are porous moulds with a homogeneous distribution of the ingredients in the core and a thin outer coating with a film-forming material.

In particular, it is conceivable to provide a system by coating and the resulting physical/chemical inhomogeneity of the overall body shape, which will consciously use this inhomogeneity or spatial separation into two phases to separate two phases until dissolution and thus complete homogenization of the entire body shape. This can be done by maintaining a chemical inhibition in the outer core and maintaining a chemical inhibition in the inner core.This prevents a reaction in the dry, storage state and only when activated by hydration or dissolution of the system leads to a mobilisation and thus reaction of the two previously separated immobilized reactants. This allows, for example, more stable active substance derivatives to be provided in the core of the composition and the chemical transposing agents that release the active but unstable active substances from these derivatives or precursors in the outer envelope. Spatial separation and immobilization in separate layers prevents a premature reaction. It is also possible to provide an attractive dye form by adding dyes in the envelope layer. The concentration of the dye is determined by the concentration of the dye.For example, a significantly higher colour is obtained with a low coating layer than if the same amount of colour was distributed homogeneously throughout the mould composition, which is advantageous for achieving good colour with low colour content without leaving undesirable colouring residues on the skin due to excessive colour content when applied externally.

The moulds of the invention, such as those mentioned above, are preferably dissolved with an aqueous liquid/activator solution containing: 70% or more by weight of water, at least 5% by weight of polyethylene alcohol, up to 10% by weight of one or more active substances, in particular those belonging to the group of cosmetic active substances, or 20% by weight of one or more excipients, in particular those belonging to the group of cosmetic oils, such as caprylic/caproic acid triglycerides or jojoba oil, having a pH of 5-7 and a content of earth alkalies, in particular calcium and/or magnesium ions, of less than 1% by weight.

Err1:Expecting ',' delimiter: line 1 column 159 (char 158)

The invention also relates to a process for the production of a freeze-dried coated mould characterised by coating the frozen mould and subsequently freezing the coated frozen mould. In particular, the invention relates to a process which shall include the following steps: (a) Preparation of an aqueous solution or suspension of one or more active substances, where appropriate one or more scaffolding agents, and where appropriate one or more auxiliary substances; (b) Pouring of the mixture into a mould; (c) Freezing of the mixture in the mould while preserving frozen moulds; (d) Removal of the frozen moulds from the mould and rounding of the frozen moulds where appropriate; (e) Spraying of the frozen moulds with a coating composition containing at least one film forming agent and at least one solvent and/or dispersive agent; (f) Freezing of the frozen moulds and drying of the frozen moulds with the film forming agent.

The manufacturing process should be such as to first prepare an aqueous solution of the active substances and, if necessary, mix a solution of the scaffolding agent by stirring, and then add and mix further excipients to the mixture, if necessary.

The amount of solids such as scaffolding agents, active substances and excipients in the solution or suspension has a significant influence on the density (weight of the mould relative to the volume of the geometric shape of the mould) of the mould obtained. Density is an important factor in determining the porosity of the mould and hence the rate of dissolution of the mould when moistened with water or an active and/or excipient solution.The higher the density of the solution, the lower the porosity of the mould, and vice versa. However, the porosity of the moulds does not depend solely on the material density. Rather, the material porosity is essentially a function of two parameters, the material density and the size of the ice crystal.

Since the coating of the frozen moulds produces inhomogeneous materials and the porous core inside the mould is shielded externally by a film-forming layer, the composition of the film coating and its behaviour in relation to the media used for the dissolution of the coated moulds is also of fundamental importance. In particular, porous film coatings allow the transport of liquids into the highly porous core and thus a rapid dissolution of the moulds. Since, in particular for cosmetic and pharmaceutical applications, preference is given to the use of aqueous-based solvent media, it is important to select the coating from the group of hydrophilic film coatings to avoid problems of coating and to prevent the dissolving of the mould.

From the point of view of density/porosity and rate of dissolution, the formulation and manufacture of the moulds of the invention are designed so that the densities of the moulds thus obtained are conveniently approximately 0,01 g/cm3 to 0,8 g/cm3, preferably about 0,015 g/cm3 to 0,5 g/cm3, preferably about 0,02 g/cm3 to 0,3 g/cm3.

The weight of the individual moulds depends of course on their size. In general, the weight of the individual moulds is about 10 to 300 mg, preferably 20 to 200 mg. For example, balls of 11 mm diameter have a weight in the range of preferably 20 to 160 mg, preferably 30 to 150 mg. For balls of other diameters, other preference ranges are calculated according to the change in volume.

The solution to be freeze-dried is preferably prepared by first preparing an aqueous solution of the active substances, wherein, if necessary, a solution of one or more scaffolding agents is mixed. Other excipients are then added to the mixture, if necessary. If oily active substances are used, they are preferably dissolved in oils (in particular squalene and triglycerides) used as excipients, and then replaced by the aqueous solution of the active substances or the scaffolding agent. This method has the advantage of providing temporary stable solutions or suspensions.

The resulting solution is then cast into molds which have cavities corresponding to the moulds of the desired geometric shapes. The mould is preferably made of rubber, silicone rubber, vulcanized rubber (rubber), etc. Rubber molds are preferred. The moulding materials may be coated, if necessary. The cavities of the moulds into which the solution is poured generally have the shape of the desired mould.

As the volume of solutions or suspensions filled in the cavities increases during freezing (density difference between water and ice), the cavities are usually not completely filled. This results in completely symmetrical moulds. This is not possible, for example, after the process by dripping into deep-cold solutions (such as liquid nitrogen), as there are asymmetrical temperature distributions, so that more or less strong deviations from a regular shape always result. However, such irregularly shaped moulds are not desirable especially in the field of cosmetic end products. This usually means that these untropically formed sub-cores undergo a mechanical after-treatment, which is always more likely to occur after such a process, as after-treatment is not required in a more or less regular form, especially in the case of the process with the untropically formed sub-cores.

After the solution is filled into the cavities of the mould, the solution or suspension is frozen. The cooling or freezing of the solution can be done in any way, such as by blowing with cold air, cooling by applying to a plate with a cooling solvent or also by immersing the moulds in liquid gases, such as by immersing them in liquid nitrogen. The rate of cooling affects the size of the ice crystals formed. These in turn affect the porosity distribution in the inner core of the moulded body.

The freezing temperature required depends, inter alia, on the degree of freeze-point reduction by the active substance (s) in the solution. It is preferable to keep the temperature below freezing from water to liquid nitrogen (- 196°C). The freezing temperature is preferably around -20 to -80°C, preferably -30 to -50°C. After freezing the solution or suspension, the moulds are removed from the mould and rounded if necessary. The coating is then carried out by testing the mould with an appropriate coating composition containing at least one film or film and at least one solvent and/or disperser.

The coating composition is preferably a composition of ≥ 15% alcohol by weight, ≤ 70% water by weight and ≥ 5% film by weight, each in relation to the total amount of coating composition.

The aqueous solution of the hydrophilic film forming medium may contain freeze-point reducing substances such as alcohols or salts, if necessary. The freeze-point reducing substances will prevent premature icing during the spraying process. In addition, these additives will briefly thaw the outside of the frozen mould and the film forming polymer can form a stable film firmly bonded to the frozen mould. Preference shall be given to freeze-point reducing substances which can be removed from the mould as part of the freeze-drying process.

If necessary, further soluble substances such as colours, active substances or excipients may be added to the mixture of water, alcohol and film, as well as suitable substances for the chemical transformation of active substance derivatives and/or precursors.

The moulds thus coated are then subjected to freeze-drying, which can be done in a familiar way by means of commonly known freeze-drying methods, such as those described in DE 4328329 C2, DE 4028622 C2 or DE 10350654 A1.

The invention includes in particular the following preferred embodiments: 1. freeze-dried moulds containing: one or more active substances and, where appropriate, one or more scaffolding agents, where applicable, one or more auxiliary substances, and a surface coating containing at least one film-forming agent.2. freeze-dried moulds of embodiment 1 with an active substance content ≥ 50% by weight, preferably ≥ 75% by weight, preferred ≥ 80% by weight, still preferred ≥ 90% by weight, based on the total composition of the frozen coated mould.3. freeze-dried moulds of one of embodiments 1 or 2 with an active and auxiliary substance content of 50% by weight, preferably ≥ 75% by weight, still preferred ≥ 80% by weight.4. freeze-dried moulds in one of the embodiments 1 to 3, with a ratio of active substances to excipients of 10:1 to 100:1 by weight, each in relation to the total amount of active substances in % by weight to the total amount of excipients in % by weight. 5. freeze-dried moulds in one of the embodiments 1 to 4, where a 1% by weight solution or suspension of the active substance in water at 20 °C has a pH < 7.6. freeze-dried moulds in one of the embodiments 1 to 4, where the active substance is separated from the group of active substances with a pKW of ≤ 25 °C.7. freeze-dried moulds in one of the forms 1 to 6, in which the active substance is selected from the group consisting of ascorbic acid and its derivatives, salicylic acid and its derivatives, in particular acetylsalicylic acid, clofibrinic acid, ibuprofen, gemfibrozil, phenoprofen, naproxen, ketoprofen, indomethacin, bezafibrate, tolfenamic acid, diclofenac, moclofenamic acid, paracetamol, acvastitretin, acrivastatin, azelaic acid, cromolyn, ethacrinic acid, furosemide, penicillin and its derivatives, vitamin A and its derivatives, acetone and its derivatives, risicroic acid and its derivatives, lipidic acid and ursodiol.8. Frozen moulds in the form 7, 8, acetic acid or its derivatives are exported in at least one of the forms 1 to 9.containing ≥ 50% by weight of an active substance of the ascorbic acid group and its derivatives in relation to the total composition of the freeze-dried coated formulation.10. freeze-dried formulation in one of the embodiments 1 to 8, containing ≥ 50% by weight of an active substance of the salicylic acid group and its derivatives, preferably in the acetylsalicylic acid group and its derivatives, in relation to the total composition of the freeze-dried coated formulation.11. freeze-dried formulation in one of the embodiments 1 to 10 with a scaffolding ratio ≤ 25% by weight, preferably ≤ 10% by weight, preferably ≤ 5%.Frozen moulds of one of the embodiments 1 to 12, in which the scaffolding material is selected from the group of hydrocolloids, preferably from the group of polysaccharides, polyaminosaccharides, glucosaminoglycans and/or synthetic polymers or mixtures thereof.14. Frozen moulds of embodiment 13, in which the scaffolding material is an alginate, preferably a sodium alginate, carboxymethylcellulose, cationally modified carboxymethylcellulose, cationally modified starch or chitosan or a combination thereof.15. Frozen moulds of one of the embodiments are 1 to 14, preferably from the group of violin proteins.16. Frozen moulds of a film-form containing ≤ 1 to 10% of the protein content of the embodiment 15.- 17, preferably ≤ 5 g/m2, in relation to the total composition of the freeze-dried coated mould, is.17. Freeze-dried moulds in one of the embodiments 1 to 16, in which the film forming agent is selected for coating from the group of hydrophilic polymers.18. Freeze-dried moulds in embodiment 17, in which the film forming agent is selected for coating from the group of synthetic polymers, preferably from the group of vinylpyrrolidone-vinylacetat-copolymers.19. Freeze-dried moulds in one of the embodiments 1 to 18, in which the liquid is dissolved in ≤ 30 secs, preferably ≤ 20 secs, preferably ≤ 10 secs, preferably ≤ 5 secs, are characterized by a fully dissolved volume of ≤ 1 to 20 volts, preferably after a single of the embodiments 1 to 18, preferably ≤ 1 to 5 secs.21 Process for the manufacture of a freeze-dried coated mould characterised by coating the frozen mould and subsequently freezing-drying the coated frozen mould.22. Process for the manufacture of a freeze-dried mould comprising the steps of preparing an aqueous solution or suspension of one or more active substances, where appropriate one or more preservatives and where appropriate one or more auxiliaries, e.g. in the form of a mixture of the mixture.Freeze drying of the frozen moulds coated with the film forming agent, forming the freeze-dried mould.23. Process in one of the embodiments 21 or 22, using a film forming agent selected from the group of hydrophilic polymers, preferably from the group of synthetic polymers, in particular preferably from the group of vinylpyrrolidone-lacetat-C.24. Process in which the solvent is a dispersant and water-alcohol.25. Process in which the film forming agent is a water-alcohol.25.in which the coating composition is ≥ 15% alcohol by weight, ≤ 70% water by weight and ≥ 5% film by weight, each in relation to the total amount of coating composition.26. freeze-dried moulds obtained by the process in one of the embodiments 21 to 25.27. use of the freeze-dried mould in one of the embodiments 1 to 20 or 26 as a cosmetic product.28. use of the freeze-dried mould in one of the embodiments 1 to 20 or 26 as a pharmaceutical product.29. use in embodiments 27 or 28 in which the application is external.30. use in one of the embodiments 27 to 29, in which the frozen mould is treated with water or a solution or a solution of any kind/of which is selected and applied to the hair or hair in a moisturizing agent and, if necessary, in a moisturizing agent ≤ 30 seconds and moistened and moistened to the skin.Use of the freeze-dried formulation in one of the embodiments 1 to 20 or 26 for oral or oral application of active substances.32. Kit-of-parts combination containing at least one freeze-dried formulation in one of the embodiments 1 to 20 or 26 and at least one aqueous solution containing one or more active substances and/or, where appropriate, one or more excipients, in a contiguous spatial arrangement.33. Use of the kit-of-parts combination in embodiment 32 as a cosmetic product.34. Use of the kit-of-parts combination in embodiment 32 as a therapeutic product.35. Use of one of the embodiments 27 to 31 and 33 to 34 directly by the end consumer.

The invention is illustrated by the following examples.

The Commission Example 1 Manufacture of a carboxymethylcellulose/ascorbic acid ball with subsequent coating

0,5 g	Carboxymethylcellulose
16,0 g	Ascorbinsäure
83,5 g	Wasser

0,5 g of carboxymethyl cellulose is added to 83,5 g of water by stirring and stirred until the carboxymethyl cellulose dissolves completely and homogeneously. Then, 16.0 g of ascorbic acid is added by stirring and the mixture with a pH ≤ 3.0 is kept at a temperature of 0-10 °C. The homogeneous (de-gassed) mixture is poured into molds, blown into cold air and frozen and mechanically processed if necessary. Frozen balls of approximately 11 mm in diameter are obtained, which can be stored in frozen containers at temperatures below -20 °C if necessary. The frozen moulds are homogenized in a refrigerated room at temperatures < - 10°C by shaking with a solution of: 80 g ethanol The test chemical is used to determine the concentration of the test substance in the test medium. 10 g of Collidon VA-64 The coated, deep-cooled balls are then subjected to freeze-drying, resulting in coated, mechanically stable freeze-dried moulds with Collidon VA-64.

The amount of coating agent and thus the mechanical stability of the freeze-dried mould can be easily controlled by the amount of coating agent sprayed.

Err1:Expecting ',' delimiter: line 1 column 165 (char 164)

Example 2 Manufacture of a chitosan/acetylsalicylic acid ball with subsequent coating

0,2 g	Chitosan
16,0 g	Acetylsalicylsäure
83,8 g	Wasser

After stirring, 16.0 g of acetylsalicylic acid are dispersed in the solution, the mixture having a pH ≤ 3.0 is kept at a temperature of 0-10 °C. The homogeneous (de-gassed) mixture is poured into molds, blown into cold air and then frozen and mechanically processed, if necessary. The frozen moulds are homogenized in a refrigerated room at temperatures < - 10 °C by shaking and blowing with cold air with a solution of:

85g	Ethanol
15g	Kollidon VA-64

Other The coated, deep-cooled balls are then subjected to freeze-drying. Collidon VA-64 is used to obtain coated, mechanically stable freeze-dried moulds. The amount of coating agent and thus the mechanical stability of the freeze-dried mould can be easily controlled by the amount of coating agent sprayed.

Err1:Expecting ',' delimiter: line 1 column 165 (char 164)

Example 3 Manufacture of ascorbic acid balls with subsequent coating

16,0 g	Ascorbinsäure
84,0 g	Wasser

16.0 g of ascorbic acid are dissolved in 84 g of water. The pH of the solution is ≤ pH 3.0 and the solution is kept at a temperature of 0-10 °C. The homogeneous (de-gaseous) solution is poured into molds, frozen by blowing cold air, removed from the mould and, if necessary, mechanically further processed. Frozen ascorbic acid balls with a diameter of about 11 mm are obtained, which can be stored frozen at temperatures below -20 °C if necessary. The frozen moulds are homogenized with a solution in a refrigerated room at a temperature < - 10 °C under shaking: Other

90g	Ethanol
10g	Kollidon VA-64

Other The coated, deep-cooled balls are then subjected to freeze-drying. Collidon VA-64 is used to obtain coated, mechanically stable freeze-dried moulds of ascorbic acid.

The amount of coating agent and thus the mechanical stability of the freeze-dried mould can be easily controlled by the amount of coating agent sprayed.

Err1:Expecting ',' delimiter: line 1 column 165 (char 164)

Example 4 Manufacture of a cationised starch/ascorbic acid ball with subsequent coating

2,0 g	kationisierte Stärke
1,0 g	Jojobaöl
16,0 g	Ascorbinsäure
81 ,0 g	Wasser

The 2,0 g of cationised starch is added to 81,0 g of water by stirring and stirred until the starch dissolves completely and homogeneously. Then, 16,0 g of ascorbic acid and 1 g of jojoba oil are added by stirring and the mixture with a pH ≤ 3,0 is kept at a temperature of 0-10 °C. The homogeneous (de-gassed) mixture is poured into molds, blown into cold air and frozen and mechanically processed if necessary. Frozen balls of approximately 11 mm in diameter are obtained, which can be stored in frozen containers at temperatures below -20 °C if necessary. The frozen moulds are homogenized with a solution in a refrigerated room at a temperature < - 10 °C under shaking: Other

80g	Ethanol
10g	RO-Wasser
10g	Kollidon VA-64

Other The coated, deep-cooled balls are then subjected to freeze-drying, resulting in coated, mechanically stable freeze-dried moulds with Collidon VA-64.

The amount of coating agent and thus the mechanical stability of the freeze-dried mould can be easily controlled by the amount of coating agent sprayed.

Err1:Expecting ',' delimiter: line 1 column 165 (char 164)

Claims (15)

1. Freeze-dried moulds containing one or more active substances and one or more scaffolding agents, where appropriate, one or more auxiliaries, where appropriate, and a coating containing at least one film-forming agent.
2. Freeze-dried moulds of claim 1 with an active substance content ≥ 50% by weight, preferably ≥ 75% by weight, preferably ≥ 80% by weight, and preferably ≥ 90% by weight, based on the total composition of the freeze-dried coated mould.
3. Freeze-dried moulds according to claim 1 or 2, where the active substance is selected from the group of acidic active substances with a pKs value at 25 °C of ≤ 7.
4. Freeze-dried moulds according to claims 1 to 3 of the total composition of the freeze-dried coated mould containing ≥ 50% by weight of an active substance from the group of ascorbic acid and its derivatives or from the group of salicylic acid and its derivatives, preferably from the group of acetylsalicylic acid and its derivatives.
5. Freeze-dried moulds according to one of the claims 1 to 4 with a scaffolding content ≤ 10% by weight, preferably ≤ 5% by weight, based on the total composition of the freeze-dried coated mould.
6. Freeze-dried moulds according to one of claims 1 to 5 which do not contain scaffolding agents.
7. Freeze-dried moulds according to claims 1 to 5, where the scaffolding material is selected from the group of hydrocolloids, preferably from the group of polysaccharides, polyaminosaccharides, glucosaminoglycans and/or synthetic polymers or mixtures thereof.
8. Freeze-dried moulds according to claim 7, where the scaffolding material is an alginate, preferably sodium alginate, carboxymethyl cellulose or chitosan or a mixture thereof.
9. Freeze-dried moulds according to any of the claims 1 to 8, where the proportion of coating with a film forming agent is ≤ 10% by weight, preferably ≤ 7% by weight, preferably ≤ 5% by weight, each in relation to the total composition of the freeze-dried coated mould.
10. Freeze-dried moulds according to any of claims 1 to 9 in which the film forming agent selected for coating is from the group of hydrophilic polymers preferably from the group of synthetic polymers, preferably from the group of vinylpyrrolidone-vinyl acetate copolymers.
11. Freeze-dried moulds according to any of the claims 1 to 10 which fully decompose in ≤ 30 seconds, preferably ≤ 20 seconds, preferably ≤ 10 seconds, preferably ≤ 5 seconds, when fed with liquid.
12. Process for the manufacture of a freeze-dried coated mould characterised by coating the frozen mould and subsequently freezing-drying the coated frozen mould.
13. Process for the production of a freeze-dried moulding body comprising the steps Other

    (a) a solution or suspension of one or more active substances, one or more scaffolding agents where appropriate and one or more excipients where appropriate, in an aqueous solution;

    (b) Casting the mixture into a mould

    (c) Freezing of the mixture in the mould, preserving frozen moulds

    (d) Removal of frozen moulds from the mould and, where appropriate, rounding

    (e) Spraying of the frozen moulds with a coating composition containing at least one film forming agent and at least one solvent and/or dispersant

    (f) Freeze-drying of the frozen moulds coated with the film forming machine to form the freeze-dried mould.
14. Use of the freeze-dried mould according to any of claims 1 to 11 as a cosmetic or pharmaceutical product.
15. Kit-of-parts combination containing at least one freeze-dried mould according to any of claims 1 to 11 and at least one aqueous solution containing one or more active substances and/or one or more excipients, as appropriate, in a co-located spatial arrangement.