CA2128244C - Solid bodies containing active substances and a structure consisting of hydrophilic macromolecules, plus a method of producing such bodies - Google Patents

Abstract

The invention relates to accurately meterable shaped articles, for example granules or pellets, containing hydrophilic macromolecules, active compounds and optionally further pharmaceutically acceptable structure-forming substances and auxiliaries, the active compound being present in a matrix in dissolved, suspended or emulsified form, and a novel process for the production of these shaped articles, the process being particularly economically and ecologically acceptable, and use of the shaped articles as medicaments, in which the bioavailability, shelf life and tolerability is increased. Using the shaped articles or mixtures according to the invention, intermediates or final products for pharmacy, cosmetics, diagnosis, analysis or dietetics (healthcare) can additionally be advantageously prepared.

Description

21~

3.26.1994 Active compound-con~a;n;ng powder~, granule~ or pellet~ having a Lyd~ h;l;c macromGlecule ~tructure and proces~ for their production The invention relates to accurately meterable powders, granules or pellets comprising hydrophilic macromolecules, active compounds and optionally other pharmaceutically acceptable structure-forming substances and auxiliaries, the active compound being dissolved, suspended or emulsified in a matrix, and a novel process for the production of these powders, granules or pellets, and furthermore their use as a medicament, cosmetic, diagnostic or dietetic foodstuff (healthcare). Active compounds employed are preferably dihydropyridine deriva-tives, in particular nifedipine, nitrendipine or nisol-dipine.
Granules or pellets as shaped articles serve in the pharmaceutical industry mainly as intermediates for tableting. Shaping here should lead to a free-flowing, granular and dust-free product which, on account of its homogeneity, improves technological processing and dosage accuracy. Moreover, pellets, as a modern multiple-unit pharmaceutical form, for example filled into hard gelatin capsules, possess a number of advantages compared with single-unit pharmaceutical forms, such as e.g. tablets or coated tablets:
- They disperse uniformly in the gastrointestinal tract.
- On account of their small size shorter gastric residence times result in contra~t to monolithic pharma-ceutical forms, especially with enterically coated pharmaceutical forms.
- As individual aggregates they dissolve more rapidly in the gastrointestinal tract in contrast to a compressed tablet, which must first disintegrate into its granule particles.
- Pellets with differing release of active compound can be individually metered in mixed form.

ZlZ8~44 However, the fundamental problem of the necessary shaping of pulverulent-crystalline active compounds and auxiliaries to processable granules (pellets) as shaped articles underlies all processes of the prior art.
A distinction is made here between building up and breAk;ng down processes. It is common to all pro-cesses that until now granules or pellets as shaped articles were only obtA;neA via various and complicated partial steps.
In the breAk;ng down processes - presented in simplified form - the pharmaceutical substances and auxiliaries are first comminuted, brought to a uniform grain size by sieving and then mixed. Dry or moist granulation then takes place, in which the powder mixture is ayyLey~ted and then comminuted to give grains of granular material. In the next step, if necessary, it is dried and sieved again.
In the case of the building-up granules, grains of grAnl~lAr material are formed from the powdered pharma-ceutical substances and auxiliaries with continuousaddition of granulation fluid with simultaneous drying in a controlled process (e.g. fluidized bed process).
By means of subsequent, special ro~nA;ng pro-cesses (e.g. Marumerizer~), round, bead-shaped granule particles (pellets) are obtained. A disadvantage in this case is that in the ro~nA;ng of already prepared, un-shaped granule particles substance matter contA;n;ng pharmaceutical substance is lost and cannot be directly fed to the granulation process again. This is certainly a problem in terms of cost and disposal. At the same time, the mechanical shaping leads to a non-uniform product.
Special pelleting techniques are, for example, build-up dry pelleting by compaction and fluidized bed granulation, which produce very unsatisfactory results with respect to shape and mechanical strength of the pellets.
All these preparation processes are techno-logically complicated multi-step processes. They are 21282a~4 characterized by a multiplicity of process parameters of technological type, such as e.g. temperature, moisture content, homogeneity of the mixtures etc.
Furthermore, in all granulation and pelleting processes the use of a whole series of auxiliaries is necessary. Thus, for example, binders or granulation fluids must be employed to bring the powdered material into a solid, compact and processable form. The most accurate knowledge about the physicochemical behavior e.g. heat of solution, solubility or crystal formation ten~ncy and great experience in working with these substances is necessary to be able to assess the inter-action of these auxiliaries with one another and with the pharmaceutical substance in combination with all process parameters to be taken into account.
Thus the pharmaceutical requirements of granules (pellets) can often only be fulfilled by empirical tests dep~n~;ng on the pharmaceutical substance being processed and the administration form being formulated therefrom.
It is therefore understAn~Ahle that the a &erence to constant production conditions during the complicated process is very difficult. It is thus not possible, owing to the multiplicity of parameters to be taken into account, to find a suitable process for every pharma-ceutical substance in the case of the known production processes despite a high outlay on development and optimization.
If pellets or granules prepared according to the prior art are moreover considered from biopharmaceutical aspects, it can be seen that the pharmaceutical substance from these aggregated shaped articles can be made avail-able to the body only after deaggregation and subsequent release. The multiplicity of a &esive and b;n~;ng forces, which differ in principle, in granules illustrates this problem. As a result of har~n;ng binders during drying (moist granulation) or as a result of nintering or melt a &esion under action of pressure (dry granulation) solid bridges form whose b;n~;ng forces in the body must be overcome first in order to release the pharmaceutical substance from the pharmaceutical form at all.
Each preparation step in the processe~ of the prior art can thus have an unfavorable effect on the release of the active compound and thus on its bioavail-ability.
Looked at pharmacologically, dihydropyridine derivatives are amongst the calcium antagonists. They are indicated in a number of cardiovascular disorders, such as e.g. coronary heart disease, arterial hypertension, angina pectoris etc. The prescription frequency of about 700 million defined daily doses in 1989 very clearly confirms the market position of this substance group. The first representative of this group of dihydropyridine derivatives, nifedipine (dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate, C17H18N206) was supplemented in the meantime by a number of potent derivatives, the so-called "second-generation dihydropyridines", particularly nitrendipine, ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, C18H20N206 and nisoldipine, isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitro-phenyl)pyridine-3,5-dicarboxylate, C20H24N206.
The dosage of commercially available nifedipine immediate-effect medicaments when given in a single dose is customarily 5-10 mg; more recent dihydropyridine derivatives are in some cases given at a lower dose.
In order to bring dihydropyridines, particularly nifedipine, into an administration form which releases the active compound sufficiently rapidly in the body, pharmaceutical formulation development~ have frequently been proposed. These, however, are all compromises, because on the one hand the poor solubility or in~olu-bility of the~e active compounds in the physiological medium restrict~ or makes difficult their rapid release from pharmaceutical forms. On the other hand, the rapid release, however, is a prerequisite for an onset of action after administration which is as rapid as poss-ible. These processes are not unimportant for increasing patient compliance.

Z1282~4 Conventional, technological methods in the preparation of immediate-effect pharmaceutical forms of dihydropyridine derivatives, particularly nifedipine, are the following:
a) processing of the active compounds with solubilizers (surfactants) and additionally b) dissolution of the active compounds in organic solvents, e.g. polyether alcohols of tetrahydrofurfuryl alcohol.
Because of the known light sensitivity of the dihydropyridines, a conventional, colored soft gelatin capsule may be used e.g. as a carrier (light protection) for an abovementioned nifedipine solubilizate or a nifedipine solution in an organic solvent. After adminis-tration, the nifedipine should be released from the pharmaceutical form in fine form. It is to be considered here, however, that the active compound is then not actually free, but must first be released from its complex with the solubilizer, with the disadvantage that it is not sufficiently rapidly available to the body.
Additionally, there is also always the risk in this process that nifedipine precipitates under physiological conditions in relatively coarse crystalline form as soon as the solubilizer (surfactant) is no longer active.
Moreover, the use of surfactants or organic solvents is not completely safe from toxicological considerations.
Liquid nifedipine preparations able to form drops are also commercially available. For the patient, these nifedipine drops are a very popular administration form, particularly for elderly patients who find the swallowing of solid shaped articles (tablets, capsules) unpleasant or have difficulties with it. Moreover, they have the advantage of good meterability.
Although liquid pharmaceutical preparations, looked at technologically, are actually well conceived immediate-effect pharmaceutical forms (the process of the disintegration of solid, "single-unit" forms such as, for example, tablets or capsules does not apply), these preparations are not in keeping with the times in the 21Z8Z~4 case of the dihydropyridines on the one hand for the reasons already mentioned above (use of surfactants and/or organic solvents), and on the other hand for a further, even more far-reaching reason which is to be sought in this class of active compound itself. As is known, dihydropyridines are highly light-sensitive and tend to decompose, in particular in solutions.
Partial decomposition of the nifedipine as a result of admission of light, even before tAk; ng, is therefore never to be excluded particularly during with-drawal of nifedipine drops from the storage cont~; ner by the patient. Since this form of admini~tration, particu-larly in the case of elderly patients, is a very time-consuming process, the risk of decomposition of active compound before actual administration is thus addition-ally increased.
It is further to be taken into consideration that even the storage of nifedipine drop solutions in brown or dark-colored glass bottles may not offer adequate, relatively long storage stability (protection from admission of light!).
For dihydropyridine derivatives ~m;n;stration as an immediate-effect form having a rapid influx, the preparation itself being an active compound solution, is desirable or advantageous from pharmacological consider-ations. However, owing to the physicochemical properties of the active compound, such as, for example, inadequate water solubility, light sensitivity in solution etc., this administration form cannot be realized techno-logically or can only be realized in a ro~ln~out manner.
The present invention has the object of proposingnovel solids, a process for their production, and mixtures which on the one hand on account of their structure and composition improve the bioavailability and tolerability of pharmaceutical substances, are stable on storage, accurately meterable and present as a single or multiple unit and on the other hand can be prepared in an environmentally protective, simple and economical ~nne~, process the active compounds in a gentle manner and thus, Z1282~4 looked at all together, overcome the disadvantages of the prior art.
The present invention iB in particular based on the object of providing a medicament for oral adminis-tration of dihydropyridine derivatives, particularlynifedipine, which is suitable for rapid pharmaceutical substance release and overcomes the problems of the prior art.
This object is achieved according to the inven-tion by active compound-contA;n;ng solids which comprise the pharmaceutical substance in dissolved, emulsified or suspended form in a solid or semisolid matrix which mainly containa hydrophilic macromolecules of natural origin as structure-forming agents.
The hydrophilic macromolecules employed are:
collagen, gelatin, fractionated gelatin, collagen-hydrolyzates, gelatin derivatives, plant proteins, plant protein hydrolyzates, elastin hydrolyzates and combina-tions of the abovementioned substances with one another.
In particular, the present invention makes available active compound-contA;n;ng solids which com-prise a dispersion of at least one active compound or active compound mixture in a matrix which essentially includes a structure-forming agent comprising hydrophilic macromolecules selected from the group consisting of:
collagen, gelatin, fractionated gelatin, collagen hydro-lyzates, gelatin derivatives, plant proteins, plant protein hydrolyzates, elastin hydrolyzates and mixtures of the abovementioned substances.
This object is further achieved by a process for the production of active compound-contA;n;ng solids which comprises dissolving, emulsifying or 8U8p~n~; ng the active compound in a solution of the hydrophilic macromolecule (structure-forming agent) and shaping to give shaped articles.
The ~olids can be dried if required.
In particular, the present invention makes available a process for the production of solids con-tA;n;ng at least one active compound, which comprises 212824~

a) dissolving a structure-forming agent comprising hydrophilic macromolecules selected from the group consisting of:
collagen, gelatin, fractionated gelatin, collagen hydrolyzates, gelatin derivatives, plant proteins, plant protein hydrolyzates and elastin hydrolyzates in an aqueous and/or organic solvent, b) dispersing the active compound, c) AAA;ng the mixture of dissolved structure-forming agent and dispersed active compound obtA;n~A drop-wise to a deep-cooled liquid and thus shaping the solid.
Solid within the meAn~ng of the invention is understood as meAn; ng one which is selected from the group consisting of:
powders, granules, pellets and micropellets in essen-tially symmetrically built-up ayy,eyates.
According to the invention, uniformly round solids, in particular pellets, are particularly suitable for pharmaceutical applications, the term pellet prefer-ably comprising a grain size range from about 0.2 to 12 mm.
In the description of the invention the prop-erties, preparation and use are preferably presented with the aid of round pellets.
However, the person skilled in the art can also employ other solids from the group consisting of: pow-ders, granules, essentially symmetrically built-up aggre-gates, advantageously for the production, in particular, of pharmaceutical forms.
In addition, the object of the present invention is achieved by a mixture which contains at least one active compound and a structure-forming agent wherein the structure-forming agent is a hydrophilic macromolecule selected from the group consisting of:
collagen, gelatin, fractionated gelatin, gelatin deriva-tives, collagen hydrolyzates, plant proteins, plant protein hydrolyzates, elastin hydrolyzates, albumins, agar-agar, gum arabic, pectins, tragacanth, xanthan, Z12824~
g natural and modified starches, dextrans, dextrins, maltodextrin, chitosan, alginates, cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid and polymers of methacrylic acid and methacrylic acid esters; and their mixtures.
The active compound used according to the present invention is preferably a dihydropyridine derivative, in particular nifedipine, nitrendipine or nisoldipine.
Preferred ~mhodiments of the invention are described and claimed in the dependent claims.
The solid to semisolid or gelatinous pellets according to the invention are round, uniform shaped articles in the range from 0.2-12 mm. Pellets in the range from 0.2-2 mm are suitable for multiple unit dosage forms, pellets in the range from 2-12 mm can be used as a single unit dosage form.
With respect to medicament safety, exact dosage accuracy, homogeneity, tolerability and storage stability of the correspo~; ng pharmaceutical form are required by the pharmaceutical industry. With conventional medicament production, this st~n~rd is often only to be achieved with a high and cost-intensive outlay. The uniform grain size distribution of the claimed pellets, combined with a homogeneous dispersion of the pharmaceutical substance, improves the dosage accuracy distinctly compared with the prior art. Furthermore, the active compounds e_bedded in the pellet matrix are brought into a storage-stable form which has a high mechanical strength with low friability.
Sensitive active compounds are additionally reliably protected from external e$fects.
As shaped articles, the pellets according to the invention, which are distinguished by their homogeneous round and uniform shape, are visually very attractive on account of their harmonic total impression and can increase acceptance in the patient. By means of appro-priate coloring, the pellets, which appear clearly transparent and lustrous, opaque to transparent or non-transparent, can be developed to give unmistakable pharmaceutical specialties.

21282~

As a result of the advantageous protective colloid function of the claimed macromolecules and the simultaneous ~heAA; ng of the active compounds in the polymeric matrix structure, the tolerability is dis-tinctly increased, in particular in the case of mucousmembrane-irritating active compounds. Thus e.g. the irritation of the gastric mucous m~hrane by acetyl-salicylic acid can be effectively decreased by the mucous m~hrane-protective action of the claimed macromolecules (cf. Example 7). As a pharmaceutical form, the pellets described are palatable and easy to take orally.
Surprisingly, the release of the active agent takes place in the body without an advance disintegration process in all pharmaceutical substances independently of whether they are dissolved, suspended or emulsified in the pellets according to the invention as shaped articles, in contrast to conventional granules, pellets or tablets. In conventional preparations, the adhesive and b; nA; ng forces which make possible shaping at all must initially be overcome, in addition the sub-aggregates thus obt~; ne~ must be wetted and dissolved until the pharmaceutical substance is finally in an absorbable form. Dep~n~; ng on the nature of the auxiliaries used and the preparation process used, conventional solid pharmaceutical forms can reduce the bioavailability of active compounds significantly.
The dissolution process from the pharmaceutical form as a time-determining factor depends in the case of the pellets according to the invention as shaped articles exclusively on the nature and composition of the hydro-philic matrix system and can be modulated in the release rate. Immediate-effect forms which dissolve within a few seconds can thus be formulated even as sustained-release forms. The dissolution of the structure-forming agent is the rate-determining step.
In the case of hydrophobic or poorly soluble pharmaceutical substances, the hydrophilic macromolecules described improve the absorption or the bioavailability and can be coordinated according to the invention with "1282~a~

the particular pharmaceutical substance with respect to physicochemical and pharmaceutical properties.
In the case of pharmaceutical substances which under conventional conditions count as being poorly absorbable or having problematic bioavailability, a bioavailability increase of up to 100 to 150% can thus be achieved by incorporation, even as a simple dispersion, into a preparation according to the invention, in com-parison with a conventional preparation of the same dose of the pharmaceutical substance.
Obviously, the presence in a preparation accord-ing to the invention thus leads to a greatly increased (more effective) ab~orption of the pharmaceutical sub-stance dose under physiological conditions.
The pharmaceutical substance-cont~;n;ng péllets are exposed during the gentle preparation process (shap-ing) to low temperatures and only come into contact with an inert medium (liquid nitrogen). Alteration of the pharmaceutical substances or contamination with residues of cooling oils or organic solvents, such as is known, for example, of the classical soft gelatin capsule preparation, therefore does not take place.
From technological and biopharmaceutical aspects, the pellets described in principle fulfill all require-ments which are to be made of this dosage form:
- they are uniform in shape and color, - possess a narrow grain size distribution, - can be easily metered and filled, - have a high mechanical strength and shelf life, - release the pharmaceutical substance rapidly or in a modulated manner.
Within the me~n;ng of the invention - on their own or in mixtures - hydrophilic macromolecules from the group consisting of:
collagen, gelatin, fractionated gelatin, gelatin deriva-tives, collagen hydrolyzates, plant proteins, plant protein hydrolyzates and elastin hydrolyzates can be employed.
These biogenic substances are p~r~~ceutically 2~28Z44 acceptable and non-toxic. The matrix properties of said proteins can be adjusted within wide limits with accurate knowledge of their physicochemical behavior and thus lead to a medicament in which the respective active compound is present in optimum and reproducible form.
Gelatin is a scleroprotein obtained from collagen-cont~; n;ng material, which has different properties dep~n~; ng on the preparation process. It consists essentially of four molecular weight fractions which affect the physicochemical properties as a function of molecular weight and percentage weight content. The higher e.g. the content of microgel (107 to 108 D), the higher also the viscosity of the aqueous solution.
Commercially available types contain up to 10 percent by weight. The fractions of alpha-gelatin and its oligomers (9.5 x 104/105 to 106 D) are crucial for the gel solidity and are customarily between 10 and 40 percent by weight.
Molecular weights below that of alpha-gelatin are desig-nated as peptides and can amount to up to 80 percent by weight in conventional grades of gelatin (low-Bloom).
Gelatin possesses a temperature- and concentration-dependent reversible sol/gel conversion behavior which is dependent on the molecular composition.
As a measure of the gel formation power of the gelatin, it is internationally customary to give the Bloom number.
Low commercially available grades start at 50 Bloom, high-Bloom types are about 300 Bloom.
The chemical and physical properties vary depend-ing on the preparation process, particularly gently obtained types of gelatin (low content of dextrorotatory amino acids and peptides) having short sol/gel conversion rates and melting points above 37~C (measured as a 10%
strength solution).
Fractionated gelatin represents the special case of gelatin and is obtained from conventional gelatin by special preparation techniques, such as e.g.
ultrafiltration. The composition can be varied e.g. by removal of peptides (MW c 9.5 x 104 D) or by mixtures of individual fractions such as e.g. alpha ch~;n~, dimeric 2128~4~

and trimeric c~;nR or microgel.
Moreover, gelatin or fractionated gelatin has good surfactant properties with protective colloid action and emulsifying properties.
5Collagen in native form iR water-insoluble. By means of special preparation proce~ses there are today ~oluble types of collagen having an average molecular weight of about 300,000 D.
Gelatin derivatives are chemically modified gelatins, such as e.g. succinylated gelatin, which are used e.g. for plasma ~Yr~n~r8.
Collagen hydrolyzate is understood as me~n;ng a product obtained from collagen or gelatin by preRsure hydrolysis or enzymatically which no longer has sol/gel conversion power. Collagen hydrolyzates are readily cold water-soluble and the molecular weight composition can be between a few hundred D to below 9.5 x 104 D. Products obt~;ne~ by enzymatic routes are more homogeneous in molecular composition and additionally exhibit good surfactant and emulsifier action.
The plant proteinR and their hydrolyzates are newly developed products, which largely correRpond to the collagen hydrolyzates in their properties. They are preferably obta;neA from wheat and soybeans and possess, 25for example, molecular weights of about 200,000-300,000 D
and about 1,000-10,000 D respectively.
Ela~tin hydrolyzates are obtained enzymatically from elastin and consist of a single polypeptide chain.
On account of their high content of non-polar amino acid~
they can be used in lipophilic systems. Elastin hydro-lyzates have a molecular weight of about 2,000-3,000 D
and have great film-forming power on the skin.
When using vegetable proteins, plant protein hydrolyzates, ela~tin hydrolyzates, or collagen hydro-lyzateR (cold water-soluble gelatiris) or gelatins having a maximum in the molecular weight diRtribution of a few hundred D to below 105 D (variant A), the excipient material of the claimed R~pe~ articles after lyophilization carried out in a preferred embodiment of z~28~4~

the invention surprisingly forms a highly porous and at the same time mechanically stable matrix which dissolves rapidly and completely in cold water.
If the pharmaceutical substance is present in the matrix in dissolved or suspended form, all said hydrophilic macromolecules in the indicated molecular weight ranges are suitable according to the invention on their own or in mixtures. Emulsified pharmaceutical substances having rapid relea~e are advantageously prepared by use of collagen hydrolyzates with still present surfactant and emulsifier properties. Enzymati-cally obtained hydrolyzates which have a molecular weight between about 15,000 and 20,000 D are particularly suitable.
The rapid dissolution of the matrix recipes described is suitable for pharmaceutical immediate-effect forms in which the active compound can be present in a single or multiple dose.
For internal administration, instant preparations can advantageously be formulated from the pellets accord-ing to the invention as shaped articles. If e.g. the active compound is embedded in a rapidly dissolving matrix and pelletized, storage-~table pellets are obtained which (e.g. filled into a sachet) can be dissolved completely in cold water within a few seconds.
According to the invention, hydrophilic macromolecules with sol/gel-forming properties ~uch as e.g. gelatin and fractionated gelatin, which possess a maximum in the molecular weight distribution above 105 D, may also be suitable as structure-forming substances.
If the pharmaceutical substance is present in dissolved, suspended or emulsified form in a sol/gel-forming structural matrix (variant B) such as gelatin or fractionated gelatin, pellets are obt~;ne~ which release the active compound - dep~n~;ng on the molecular com-position of the type of gelatin used - rapidly or slowly in aqueous medium at 37~C.
In a further embodiment of the invention, additions of plasticizers of 1-50% (relative to the Z~8~4~

material to be processed) selected from the group con-sisting of: glycerol, propylene glycol, polyethylene glycols, triacetin, sorbitol, sorbitan mixtures, sorbitol solutions, glucose syrup and other polyols or sugar alco-hols, may be suitable. Said substances affect the matrixaccording to the invention with respect to consistency from solid to semisolid or gelatinous, its dissolution behavior and the viscosity. A particularly advantageously suitable plasticizer is sorbitol, which as a sweetener with non-cariogenic properties simultaneously serves as a flavor correctant.
In a particular embodiment of the invention, pellets comprising matrix materials with plasticizer additions of 20 to 50% (relative to the material to be processed) have pronounced bioA~he~ive properties.
Furthermore, it may be desirable to add to the described matrix materials lipophilic constituents, such as e.g. phospholipids for the formation of liposomes.
For pellets as shaped articles which dissolve in water at 37~C within a few minutes, types of gelatin are preferably selected whose peptide content is above 30%
and which have a maximum in the molecular weight dis-tribution at about 105 D to 106 D.
For the formulation of pellets having properties which delay release, types of gelatin having a peptide content of below 10% and a microgel content of 10-15% are suitable within the me~n;ng of the invention. Matrix materials or mixtures built up in this way possess a melting range from 35~C to 40~C, preferably above 37~C, in aqueous solution. Addition of plasticizers may be in the range between 1 and 30% (relative to the material to be proce~sed).
The following can be employed as additional structure-forming agents of 1-50% (relative to the material to be processed): albumins, agar-agar, gum arabic, pectins, tragacanth, xanthan, natural and mod-ified starches, dextrans, dextrins, maltodextrin, chito-san, alginates, alginate-calcium phosphates, cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone, 212824~

polyacrylic acid and polymers of methacrylic acid and methacrylic acid esters.
Celluloseacetate phthalate or hydroxypropyl-methylcellulose phthalate, azo-crosslinked polymeth-acrylate; polyurethane/sugar copolymers, a suitable sugarcomponent in particular being oligomeric galactom~nnAn~
or galactomannan derivatives which are then crosslinked with aliphatic diisocyanates; galactomannan derivatives such as ethyl- or acetylgalactom~nn~n~; polysaccharides crosslinked with adipic acid, lipophilic substances such as degradable mono-, di- and triglycerides; and erodable fatty alcohols.
In a further embodiment of the invention, 1-50%
strength additions of substances can be selected from this group in order to suit the physical or chemical properties of the matrix, such as e.g. the viscosity, the mechanical strength or the dissolution properties of the polymeric structure, to the active compound and the intended use. Thus, for example, using substances such as dextrans, modified starches, sugars and in particular mannitol, pellets according to the invention can be prepared which as a lyophilizate form a highly porous network. Macromolecules such as e.g. alginates, agar-agar and pectins can be used according to the invention for the additional retardation or modification of the release of active compound.
To this groundmass can be added further auxil-iaries and excipients suitable for pharmaceutical use, such as e.g. fillers, such as e.g. lactose, dispersants, such as e.g. disodium phosphate, pH correctants, such as e.g. disodium citrate, emulsifiers, such as e.g.
lecithin, stabilizers, such as e.g. ascorbic acid, cosolvents, such as e.g. polyethylene glycol, natural colorants, such a~ e.g. carotenoids, aromatizing sub-stances or flavor correctants, such as e.g. sugar substi-tutes, complex-forming agents or inclusion complex-forming agents, such as e.g. cyclodextrin.
In a particular embodiment of the matrix materials or mixtures indicated in variants A and B, 2~ 2824 4~

which can be built up with or without addition of plasticizer, pellet6 can be prepared by addition of enteric-resistant substances from the group: poly- and methacrylic acid derivatives, cellulose derivatives and their mixtures, which release the pharmaceutical sub-stance only after gastric passage, i.e. that the struc-ture-forming agent of the matrix mixture dissolves in a predetermined pH range.
Instead of the abovementioned enteric-resistant substances, substances can also be used which are only degraded after reaching a certain section of the intes-tine by enzymes present there. These are e.g. azo-crosslinkedpolymethacrylates; polyurethane/sugar copoly-mers, a suitable sugar component in particular being oligomeric galactom~nn~nR or galact~nn~n derivatives which are then crosslinked with aliphatic diisocyanates;
galactomannan derivatives such as ethyl- or acetylgal-act~~-nn~nQ; polysaccharides crosslinked with adipic acid .
Pellets according to the invention can be pre-pared in this manner which are particularly suitable for colonic pharmaceutical forms. After reaching the colon, a pellet matrix of this type is degraded enzymatically and the incol~o-ated pharmaceutical substance thus released in a controlled manner in this gastrointestinal section.
Further embodiments to colonic ph~ ceutical forms are found in particular in the international PCT
application W0 93/13753 of ALFATEC-Pharma GmbH of the same date.

In the case of alginate-cont~;n;ng basic recipes, by susp~n~;ng water-insoluble dicalcium hydrogen phos-phate [(Ca2(EP04) 2] e.g. to give a pE-neutral to slightly basic gelatin/alginate mixture pellets can be produced which have delayed release of the active compound. During gastric p~s~ge, the acidic medium dissolves the calcium 8~44 salt and crosslinks the alginate.
Furthermore, pharmaceutically acceptable hardeners, such as e.g. aldoses or citral, which after drying lead to crossl;nk;n~, can be added according to the invention to the structure-forming substances derived from collagen.
A suitable hardener is in particular xylose, as it makes possible a specifically controllable crosslink-ing of the pellet matrix. In this manner depot pharma-ceutical forms, eo-called sustA;n~-release pharma-ceutical forms, can be realized, it being possible according to the invention to set different release characteristics of the pharmaceutical substance with high reproducibility.
This modulation of pharmaceutical substance release is seen particularly clearly if the behavior of a crosslinked matrix of this type is looked at in aqueous medium. The pellets no longer dissolve in aqueous medium, on the contrary as a result of crossl;nk;ng (derivatiz-ation of the structure-forming agent) they show a more or less highly pronounced swelling behavior. This swelling behavior is now adjustable in a controlled manner via the amount of crossl;nk;ng agent added, i.e. by the extent of har~n;ng or via the selected har~n;ng conditions.
Different molecular fractions of a structure-forming agent derived from collagen can in this way be cross-linked very specifically and with high reproducibility.
On the one hand, pharmaceutical substance release profiles can thus be achieved according to the invention which correspond to the conventional diffusion from matrix formulations (square root law, compare Higuchi equation).
On the other hand, however, which is all the more surprising, using the same starting materials (structure-forming substances and crossl;nk;ng agents) a pharma-ceutical substance release profile of zero order (linear kinetics) can also be reproducibly established. In this special case a non-Fick~s diffusion from the matrix can be assumed, i.e. a swelling-controlled diffu~ion with a 282~4 transition from a vitreous matrix to a swollen matrix, the diffusion coefficient of the pharmaceutical substance in the matrix itself gradually increasing during the swelling process. Intermediate states between the two release profile~ shown can also be established.
As the pellets according to the invention, as shaped articles, possess high mechanical stability, they can be coated with pharmaceutically customary film-forming agents. The desired absorption section in the gastrointestinal tract can be specifically reached particularly advantageously by combination of matrix materials, which in particular have bioa&esive prop-erties, and film coatings (e.g. poly- and methacrylic acid derivatives) which dissolve in defined pH ranges.
Such bioA~he~ive properties can be produced, for example, by partial crossl;nk;ng of a matrix which i~
constructed from an auxiliary derived from collagen.
In~tead of Eudragits~ suitable film coatings made of substances which after reaching the colon are degraded by enzymes present there can also be employed. These are e.g. azo-crosslinked polymethacrylates; polyurethane/
sugar copolymers, a suitable sugar component in particu-lar being oligomeric galactomannans or galactomannan derivatives which are then crosslinked with aliphatic di-isocyanates; galactomannan derivatives such as ethyl- or acetylgalactomAnnAn~; polysaccharides crosslinked with adipic acid.
This procedure makes pos~ible the absorption of pharmaceutical ~ubstances with problematic bioavail-ability in a controlled manner. Furthermore, by combina-tions of film-forming agents, pellet mixtures can be pre-pared according to the invention which release the active compound from the pharmaceutical form in a pulsed manner.
The alreadymentioned bioavailability increase achievable according to the invention is surprisingly also provided in the case of controlled crossl; nk; ng Of a pellet matrix. According to the invention, pellet pharmaceutical forms with modulated or pulsed pharma-ceutical substance release can thus be advantageously 21~8Z~4 prepared with retention of the increased bioavailability of the pharmaceutical substance.
As is known, gelatin, depen~; ng on the prepar-ation process, possesses an isoelectric point in the acidic (gelatin type B) or in the alkaline range (gelatin type A). This property is utilized according to the invention for the direct formation of micro- or nano-capsules in the matrix material. Thus, when using gela-tins of opposite charge mixed with active compound-cont~;n;ng solution (e.g. at a pH of 6-7), microcapsules can be prepared by removing the solvent. When using types of gelatin or collagen derivatives having defined mol-ecular composition, three-dimensional crossl; n~; ng8 in the nanometer range can be carried out. Gelatins or collagen hydrolyzates can furthermore form conjugates with the active compound e.g. with an about 2-3% strength addition of salts.
The bioavailability increase of pharmaceutical substances according to the invention described at the beg; nn; ng can surprisingly even be achieved if a pharma-ceutical substance is present dispersed in a pellet matrix in coarsely disperse form.
When using micronized powders which are present dispersed in a pellet matrix according to the invention, a distinct bioavailability increase again results in comparison with a conventional suspension of a micronized powder. Thus, in example 8 an immediate-effect pharma-ceutical form on a pellet basis is described which contains ibuprofen. The bioavailability of this pellet preparation compared with a conventional, orally ~;n;8-tered suspension of micronized ibuprofen is increased by about 100% to 150% at the same dose. Obviously, the presence of a pharmaceutical ~ubstance in a preparation according to the invention advantageously leads to a greatly increased (more effective) absorption of the pharmaceutical substance under physiological conditions.
Active compounds having problematic bioavailability can be brought according to the invention in a further development form into a finely disperse form - 21 - ~ 2 4 ~ ~;
promoting absorption by direct and controlled precipi-tation of the active compound previously present in the matrix m~terial in dissolved form, e.g. by pH shift or removal of the solvent.
Suitable particularly finely disperse pharma-ceutical substance dispersions are colloidally disperse pharmaceutical substance systems (nanosols) whose prop-erties and preparation are described in numerous patent ~pplication~ of ALFATEC-Ph~rma GmbH (e.g. CAnA~;an a~lication CA 2,125,282 and further ~atent applications cited there) Pharmaceutically customary organic solvents and cosolvents which are preferably miscible in aqueous solution can be added to the claimed matrix materials if the active compound is water-insoluble.
By the combination of pellets which contain active compounds from different indication groups, combination preparations can be obtained, eg. by filling in customary hard gelatin capsules. ~seful combinations may be, for example:
dihydl~ylidine derivative t beta-sympathicolytic or diuretic.
Other intended uses are eg. filling into sachets to give beverage granules (beverage pellets) or use for the preparation of initial doses in depot ph~ ceutical forms etc.
Starting from a single product - the shaped articles according to the invention - a considerable technological breadth of application is thus provided.
In the following, the process for the preparation of the pellets according to the invention is described in greater detail.

'A

~ ~8~ ~

Further embodiments to this are contained in the parallel international (PCT) applications listed in the following:

CA 2,128,242 (WO 93/13754) CA 2,128,243 (WO 93/13761) 3, like the earlier PCT applications:

WO 93/10766 and WO 93/10767 of 12.04.1992.

In the simplest case, the process according to the invention for the production of active compound-cont~;n;n~ solids can be described by the following three process steps:
A

a) a structure-forming agent comprising hydrophilic macromolecules is dissolved in a solvent, b) the active compound is dispersed in this solution and c) the mixture of dissolved structure-forming agent and dispersed active compound obt~; ne~ is added dropwise to a deep-cooled inert liquefied gas and the solid is thus formed.
The first step of the process consists in dis-solving the hydrophilic macromolecule, in particulargelatin, fractionated gelatin, collagen hydrolyzates or gelatin derivatives or alternatively mixtures of macro-molecular substances, in a suitable solvent - water as a solvent is the choice to be preferred in most cases. The use of heat may be necessary here, such as e.g. with gelatin a temperature of 37~C or more, in order to obtain a gelatin 801.
Further auxiliaries and excipients, such as e.g.
fillers, such as e.g. lactose, dispersants, such as e.g.
disodium hydrogen phosphate, pH correctants, such as e.g.
disodium citrate, emulsifiers, such as e.g. lecithin, stabilizers, such as e.g. ascorbic acid, cosolvents, such as e.g. polyethylene glycol, natural colorants, such as e.g. carotenoids, aromatizing substances or flavor correctants, such as e.g. sugar substitutes, complex-forming agents or inclusion complex-forming agents, such as e.g. cyclodextrin are added.
Concentration ranges of the hydrophilic macromolecules, in particular gelatin, collagen hydro-lyzates or gelatin derivatives are preferably below 30%
(% by weight), e.g. in the range from 3-15%, relative to the material without active compound to be processed.
Corresro~; ngly the water content of the material to be processed is up to about 70% by weight or more.
-35 Concentration ranges of the additional structure-forming agents, such as, for example, dextrans, sucrose, glycine, lactose, polyvinylpyrrolidone, but in particular Z~28Z~

mannitol, are below 30% (% by weight), e.g. in the range from 0-15%, relative to the material without active compound to be processed. Preferably the content of additional structure-forming agent i~ not greater than the content of the actual structure-forming agent.
As filler components, these substances, in particular mannitol, however, can improve the stability of the polymeric structure in the pellets according to the invention and thus also its mechanical properties.
In the second step the dihydropyridine derivative is dispersed in as finely divided a form as possible in the solution of the hydrophilic macromolecule.
The system described in the second step is then added dropwise to a deep-cooled, easily evaporable liquid in the third step for shaping via a suitable metering system, preferably in an immersion bath cont~in;ng liquid nitrogen. Each discrete drop in this process a~sumes spherical shape, on the one hand even during free fall, on the other hand in the immersion bath as a result of the gas envelope formed around it or the system/gas interfacial tension, before complete freezing takes place. Precisely this rapid, but still controllably manageable freezing fixes the given state of the system instantly, i.e. no pharmaceutical substance can diffuse into the surrolln~i ng medium, dissolved pharmaceutical substance can no longer crystallize out, suspensions can no longer sediment, emulsions can no longer break, thermally sensitive or moisture-sensitive substances are cryopreserved, the excipient structure cannot contract, etc. The preparation process using an inert liquid gas thus has no disadvantageous effect on or change in the product as a consequence, which i~ a great advantage. The desired properties are maint~; n~ .
In an ~mhodiment of the proces~ step described in a), a material capable of forming drops, mainly compris-ing hydrophilic macromolecules as structure-forming agents, in particular plant proteins, plant protein hydrolyzates, collagen, gelatin, fractionated gelatin, elastin hydrolyzates, collagen hydrolyzates, gelatin Z~za24a~

derivatives or mixtureR of the abovementioned substances, and the active compound is prepared.
The active compound is initially dispersed, i.e.
dissolved, suspended or emulsified, e.g. in the structure-forming agent present in dissolved form, in particular plant proteins, plant protein hydrolyzates, collagen, gelatin, fractionated gelatin, gelatin deriva-tives, collagen hydrolyzates or elastin hydrolyzate, the nature and amount of the structure-forming agent employed and optionally the addition of further auxiliaries dep~n~;ng on the later intended use of the shaped article. The concentration of the excipient material may vary, for example, from 0.5 to 60% (g/g), preferably 0.5 to 30% (relative to the material to be processed). The use of heat in the temperature range from about 30~C to 60~C, preferably about 45~C, may be necessary e.g. when using gelatin in order to convert this into the 801 form.
Addition of additional structure-forming agents of from 1-50% (relative to the material to be processed) selected from the group consisting of: albumins, agar-agar, gum arabic, pectins, tragacanth, xanthan, natural and modified starches, dextrans, dextrins, maltodextrin, chitosan, alginates, cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid and polymers of methacrylic acid and methacrylic acid esters, cellulose acetate phthalate or hydroxypropylmethyl-cellulose phthalate, azo-crosslinked polymethacrylates;
polyurethane/sugar copolymers, a suitable Rugar component in particular being oligomeric galact~nn~nR or galacto-mannan derivatives which are then crosslinked in thealiphatic diisocyanates; galactomannan derivatives such as ethyl- or acetylgalactom~nn~nR; polysaccharides crosslinked with adipic acid; lipophilic substances such as degradable mono-, di- and triglycerides; and erodable fatty alcohols can furthermore be added to the matrix material.
In a further proceRs variant, additions of plasticizers of from 1-50% (relative to the material to be processed) may be added selected from the group 2~28244 consisting of: glycerol, propylene glycol, polyethylene glycols, triacetin, sorbitol, sorbitan mixtures, sorbitol solutions, glucose syrup and other polyols or sugar alco-hols.
Further auxiliaries and excipients suitable for pharmaceutical use, such as e.g. fillers, such as e.g.
lactose, dispersants, such as e.g. disodium hydrogen phosphate, pH correctants, such as e.g. disodium citrate, emulsifiers, such as e.g. lecithin, stabilisers, such as e.g. ascorbic acid, cosolvents, such as e.g. polyethylene glycol, natural colorants, such as e.g. carotenoids, aromatizing substances or flavor correctants, such as e.g. sugar substitutes, complex-forming agent~ or inclu-sion complex-forming agents, such as e.g. cyclodextrin can be added to this groun~ass.
Of course, the mixtures according to the inven-tion are suitable for immediate filling in liquid form according to the process step described in a) for shaping in cont~;ners, such as e.g. molds, soft gelatin capsules and suitable other coverings.
In one embodiment o$ the process step described in b), the matrix material described is added dropwise for ro~n~;ng (shaping) and shock deep-freezing in an immersion bath in the range from about -70~C to about -270~C, preferably from about -100~C to -220~C. The deep-cooled, in particular inert, liquid employed is prefer-ably liquid nitrogen, which does not alter the constitu-ents of the pellets. Round shaped articles (pellets) which after drying form a mech~n;cally stable matrix are formed in the deep-cooled liquid. Shaping is carried out by means of a suitable metering system. Each discrete drop in this process assumes spherical shape, on the one hand even during free fall, on the other hand in the immersion bath as a result of the gas envelope formed around it or the system/gas interfacial tension in the immersion bath, before complete freezing takes place.
Precisely this rapid, but still controllably manageable freezing fixes the given state of the system instantly, i.e. no active compounds can diffuse into the surro~n~;ng Z~282~4 medium, dissolved constituents can no longer crystallize out, suspensions can no longer sediment, emulsions can no longer break, thermally sensitive or moisture-sensitive active compounds are cryopreserved, and the excipient structure cannot contract, etc. The preparation process using an inert liquid gas thus has no disadvantageous effect on or change in the active compound or the matrix material as a consequence. The retention of the desired properties is thus of particular advantage. Furthermore the process operates without solvents, does not pollute the environment and can be carried out under sterile conditions.
Suitable metering systems are all devices which can produce discrete, uniform structures, e.g. drops, of predeterminable size.
If e.g. uncontrolled drop-formation devices are used, granules are obt~;ne~; when using suitable spray or atomization nozzles with metering pumps powders are preferably obtA;ne~ as shaped articles.
Metering devices with nozzles, which eject the material to be converted to drops at regular intervals or intermittently, can furthermore be used for the process according to the invention.
An additionally preferred embodiment of the process according to the invention employs the Cryopel~
process developed by Messer Griesheim GmbH (based on German Offenlegungsschrift 37 11 169). In conjunction with an immersion deep-freeze plant, the Cryopel~ plant, the conversion of the process according to the invention to the industrial scale is particularly simple in terms of apparatus. This plant, which can be operated with liquid nitrogen, is particularly distinguished by its economy. This plant is also suitable for sterile pro-duction. Continuous operation with low maintenance and cle~n;ng expenditure makes possible the economical conversion of the process according to the invention to the industrial scale.
Fig. 1 shows : a schematic representation in cutaway view of a device for carrying out the process Z15~8;~i~4 according to the invention; and Fig. 2 shows: a further embodiment of a device for carrying out the process according to the invention in schematic representation.
5Fig. 3 show~: schematically the processes which take place during the passive absorption of pharma-ceutical substances in the gastrointestinal membrane.
The Cryopel~ process developed by Messer Griesheim GmbH is shown schematically in Fig. 1. The matrix solution according to the invention, which con-tains the active compound in dissolved, emulsified or suspended form, is added dropwise to the liquid nitrogen bath 3 at -196~C from the heatable entry device 1 via callibrated nozzles and shaped to give round pellets with simultaneous shock deep-freezing. By means of the con-veyor belt 2 r~nn;ng continuously over deflecting rollers, the frozen product is discharged via the device 5. The metering of the liquid nitrogen is carried out by means of the supply line 7 and the resulting nitrogen gas escapes via the line 6. The insulation 4 encloses the entire system.
Fig. 2 shows a schematic representation of a process in which the active compound matrix dispersion, which is cold or heated to at most 60~C, is added drop-wise continuously via the supply line 9 by means of theheatable drop nozzles 10 in the insulated trough 11 contA;n;ng liquid nitrogen 12 by means of a controllable metering pump 8. The shock deep-frozen pellets are removed batchwise or continuously. Using this device highly viscous materials can be processed.
Should the system to be processed not be suffici-ently capable of flow or drop formation, a further addition of water (e.g. of 1-10% by weight) can be carried out, the processing temperature can be increased or else even pressure can be used during the metering. In the converse case (system of too low viscosity), reduced pressure or temperature reduction is to be used analogously. In this manner uniform formation is guaranteed, as well as detachment of the individual 21X8;~4~

drops.
The processing temperature can be varied within wide ranges, but in the case of thermolabile active compounds should be below 50~C.
Using the metering devices described, for example, materials whose viscosity varies within a wide range, e.g. 1 x 10-3 to 12.5 Pa x 8 (Pascalseconds) and higher, can thus be metered without problems.
Further deep-cooled inert liquified gases which are suitable for the process according to the invention can be e.g. liquid rare gases such as argon.
Dep~n~; ng on the metering system selected, a grain size uniformity of over 80% can be achieved which can be even further increased by classification.
By classification of the frozen and separated portions, these can be converted into the liquid state once more and pelleted again 80 that a loss-free pro-cedure is guaranteed.
In a preferred embodiment of the invention, the pellets are dried, two process variants resulting.
Process variant A:
The shaped articles frozen at -196~C (liquid nitrogen), e.g. pellets, are transferred to a freeze-drying plant. In this plant temperatures of 15~C below the sublimation point of water are selected with a pressure of 0.1 Pa to 103 Pa (0.001 to 1.03 mbar). The drying operation, which takes place in a conventional freeze-drying plant (co~n~er temperature -40~C) at -25~C and 33 Pa (0.33 mbar) in primary drying with sublimation of the water, frozen in amorphous form by the shock deep-freezing, from the matrix, leads after second-ary drying (desorption) to a final product having a highly porous network. As a result of the shock deep-freezing according to the invention, the water is largely prevented from forming a crystalline phase, as a result of which a solid finely disperse amorphous water phase is formed in the matrix. After the sublimation of the water present in this way, highly porous micropore-contA;n;ng networks are formed, which with respect to conventionally 21Z82~

freezing processes have a distinctly increased surface area. Compared with conventionally freeze-dried materials, such pellets are particularly easily soluble and are preferably suitable for the development of instant preparations.
Process variant B:
The frozen shaped articles, e.g. pellets, are thawed and conventionally dried. In this case it can be advantageous for accelerating the drying process and for keeping to low temperatures to work under vacuum (about 3,000-5,000 Pa (about 30-50 mbar)). Drying temperatures of up to 50~C can be selected, the temperature during the drying process not rising above 30~C in the pellet matrix as a result of the evaporation enthalpy of the liquid.
For conventionally dried pellets (process variant B) sol/gel-forming substances are necessary for the matrix which, in 801 form, are capable of forming drops and after cryopelleting or after thawing form a gel which is stable after drying. Addition of plasticizers effects the matrix material with respect to consistency. Pellets prepared in this way are distinguished by particularly cost-effective preparation, as the lyophilization process step is not absolutely necessary.
Lipophilic active substances can be particularly advantageously processed without addition of further emulsifiers, e.g. using ultrasonic homogenizers when using types of gelatin and collagen hydrolyzates of high molecular weights, before further processing to stable emulsions or microemulsions.
Lipophilic/oily active compounds can be e.g.:
garlic oil, cod-liver oil, vitamin E and further fat-soluble vitamins, hypericon oil, lecithin, juniper oil, omega-3-fatty acids, evening primrose oil, ethereal oils etc. With plant extracts whose active components exhibit both hydrophilic and lipophilic properties, the lipo-philic components are first emulsified in the matrix material and the water-soluble constituents are dissolved in the hydrophilic matrix material and then cryopelleted.
Owing to the increased viscosity of the matrix Z128Z~4 system, active compounds present in suspended form can be prevented from sedimenting by simple stirring and simul-taneously metered. Temperature-sensitive pharmaceutical substances are advantageously lyophilized.
The processing of the particular development forms of the invention indicated in the dependent claims such as e.g. formulations having controlled release or improved absorption, micro- and nanoencapsulation, precipitates, conjugate formation, film coatings and the preparation of pellets having bio~h~ive properties is carried out according to the general sense of the description and in coordination with the particular active compound.
The proces~ according to the invention itself can be carried out, looked at altogether, in a low maintenance and economical manner compared with the prior art. The cryopelleting, which is simple to carry out per se, surprisingly makes it possible clearly to surpass the prior art.
For carrying out the process according to the invention, it is sufficient in the simplest case to prepare an aqueous gelatin solution with a type of gelatin of the designated specification, to suspend the nifedipine or the dihydropyridine derivative homogene-ously therein in finely crystalline form, and to add the system dropwise via a suitable metering device to an immersion bath cont~;n;ng liquid nitrogen. The deep-frozen pellets formed in this way are then converted to the dry state by lyophilization.
In the context of the present invention it has advantageously been shown that finely disperse dihydro-pyridine precipitates can also be produced directly in the gelatin solution by precipitation from a solution of the dihydropyridine in a water-miscible and pharma-ceutically acceptable organic solvent, such as e.g.
alcohol. After removal of the alcohol (e.g. by evapor-ation), a procedure analogous to the procedure described is used in order to prepare the shaped articles according to the invention.

ZlZ8Z4~

For the combination preparations already men-tioned, dihydropyridine derivatives can be combined, for example, with beta-sympathicolytics or diuretics.
In the case of optically active substances, both their racemates and the enantiomerically pure components and mixtures thereof can be employed.
Owing to the great breac~th of variation of the invention, all pharmaceutical substances can be cont~;n~
in the matrix materials described if they exhibit no incompatibilities with the individual constituents of the recipe materials. The term pharmaceutical substance here is defined according to the invention as follows:
Pharmaceutical substances can be of synthetic or natural origin, can be both chemically homogeneous substances or substance mixtures, and combinations of various pharmacologically acti~e components. The term pharmaceutical substance, however, should further generally cover phytopharmaceuticals and plant extracte and finally also include hormones, vitamins and enzymes.
Enantiomerically pure active compounds or pseudo-racemates are also suitable according to the invention.
Active compounds from the dietetic foodstuffs sector (healthcare) and from the cosmetic sector can furthermore be used.
In the case of pharmaceutical substances suitable for the invention there is no limitation with respect to the indication groups whatsoever. In the following indication groups and some associated representatives are mentioned by way of example:
1. strong analgesics, e.g. morphine, dextropropoxyphen, pentazocine, pethidine, buprenorphine;
2. antirheumatics/anti-infl~ tories (NSAR), e.g.
indometacin, diclofenac, naproxen, ketoprofen, ibuprofen, flurbiprofen, acetylsalicylic acid, oxicams;
3. beta-sympathicolytics, e.g. propranolol, alprenolol, atenolol, bupranolol, salbutamol;
4. steroid hormones, e.g. betamethasone, dexamethasone, methylprednisolone, ethynylestradiol, medroxy-progesterone, prednisone, prednisolone;

z~.X8Z~

5. tranquillizers, e.g. oxazepam, diazepam, lorazepam;

6. alpha-sympathicolytics, e.g. ergotamine, dihydro-ergotamine, dihydroergotoxin;

7. hypnotics and sedatives, e.g. secbutabarbital, secobarbital, pentobarbital, doxylamine, diphenhydramine;

8. tricyclic antidepressants, e.g. imipramine, nortrip-tyline, clomipramine, amitryptiline;

9. neuroleptics, e.g. chlorproth;Y~n, chlorpromazine, haloperidol, triflupromazine;

10. antigout agents, e.g. benzbromarone, allopurinol;

11. antiparkinson agents, e.g. levodopa, ~mantA~;n~;

12. coronary therapeutics or calcium antagonists, e.g.
nifedipine and other dihydropyridine derivatives; nitric acid esters such as glycerol trinitrate, isosorbide mononitrate and isosorbide dinatrate; verapamil, gallo-pamil, molsidomine;

13. antihypertensives, e.g. clonidine, methyldopa,dihydralazine, diazoxide;

14. diuretics, e.g. mefruside, hydrochlorothiazide, furosemide, triamterene, spironolactone;

15. oral antidiabetics, e.g. tolbutamide, glibenclamide;

16. chemotherapeutics or antibiotics, e.g. penicillins such as ph~noYymethylpenicillin, amoxycillin, ampicillin, pivampicillin, bacampicillin, dicloxacillin, flucloxacil-lin; cephalosporins such as cefalexin, cefaclor; gyrase inhibitors such as n~ ;Y;C acid, ofloxacin, norfloYAc;n;
erythromycin, lincomycin, tetracycline, doxycycline, tri-methoprim, sulfame~hoY~7ole, chloramphenicol, rifampicin;

17. local anesthetics, e.g. benzocaine;

18. ACE inhibitors, e.g. enalapril, captopril;

19. mucolytics, e.g. acetylcysteine, ambroxole, brom-h~Y; ne;

20. antiasthmatics, e.g. theophylline;

21. mineral preparations, e.g. magnesium, calcium or potassium salts, iron preparations;

22. neurotropics, e.g. piracetam;

23. ulcer therapeutics, e.g. cimetidine, pirenzepine;

24. provitamins and vitamins, e.g. biotin, cyanocobal-amine, ergocalciferol, ascorbic acid, thiamine, z~824~

pyri~ox; n9, alpha-tocopherol, retinol, beta-carotene;

25. peptide pharmaceutical substances, e.g. insulin, interferons;

26. digitalis glycosides, e.g. digitoxin, digoxin;

27. antiemetics, e.g. metoclopramide;

28. enzymes, e.g. plasmin, deoxyribonuclease;

29. antiarrhythmics, e.g. prajmaline;

30. antiepileptics, e.g. phenytoin;

31. anticoagulants, e.g. phenprocoumon;

32. spasmolytics, e.g. papaverine;

33. antimycotics, e.g. clotrimazole;

34. hormones, e.g. calcitonin;

35. venotherapeutics, e.g. aescin;

36. immunosuppressants, e.g. cyclosporin;

37. tuberculostatics, e.g. rifampicin;

38. virustatics, e.g. am;no~mantane;

39. cytostatics, e.g. methotrexate;

40. vaccines, e.g. live poliomyelitis vaccine;

41. phytopharmaceuticals, e.g. Gingko biloba extract;

42. substances for the treatment of AIDS, such as e.g.
renin antagonists;

43. calcium antagonists, such as dihydropyridine deriva-tives, in particular nifedipine, nitrendipine or nisoldi-pine .
Compared with the prior art, active compounds having poor tolerability or problematic bioavailability, and also light-, oxidation-, hydrolysis- and temperature-sensitive substances such as e.g. poorly soluble pharma-ceutical substances, peptides, natural substances, enzymes, vitamins etc. can be processed particularly advantageously to give pharmaceutical forms according to the invention.
In order to explain the physiological background to the absorption of pharmaceutical substances in general and the improved absorption ratio of the pellet formu-lations according to the invention adequately, a con-sideration of the mechanism of the physiological absorption of pharmaceutical substances as is also presented in appropriate publications is initially Z~ ~8Z~

necessary. However, the present invention is neither tied to the following attempt at a scientific explanation of the phenomena occurring according to the invention nor can it be restricted thereby.
Passive pharmaceutical substance absorption take~
place according to the modern state of knowledge (theory according to Brodie et al.), if the following conditions exist:
a) the gastrointestinal membrane acts as a lipid barrier, b) the pharmaceutical substance is only absorbed in dissolved and ~nch~rged, i.e. nonionized form, c) acidic pharmaceutical substances are preferably absorbed in the stomach and basic pharmaceutical sub-stances preferably in the intestine.
After the oral uptake of a pharmaceuticalsubstance into the body, its absorption, i.e. the cross-ing into the general circulation (biophase) is h; n~ered to a great degree by physical barriers (see Fig. 3), namely - by the mucus layer and an aqueous layer adhering thereto - the cell membranes of the intestinal epithelial cells with the glycocalyx covalently bonded thereto and - the so-called "tight junctions" which connect the epithelial cells with one another on their apical sides.
These barriers presuppose that absorption of pharmaceutical substances takes place through the lipid bilayers fundamentally independently of their distri-bution mechanism and state of charge (so-called passive diffusion).
The epithelial cells of the entire gastro-intestinal tract are covered with a mucus layer which consists of mucins (glycoproteins), electrolytes, proteins and nucleic acids. In particular, the glyco-proteins form with the main component of the mucus, namely water, a viscous gel structure which primarily performs protective functions for the underlying epithelial layer. The mucus layer is bound to the apical 2~2824~

surface of the epithelial cells via the glycocalyx. The glycocalyx likewise has a glycoprotein structure which is covalently bound to components of the membrane bilayer of the epithelial cells. The brAnche~ polysaccharides of the glycocalyx, which are either directly covalently bonded to amphiphilic molecules of the double membrane or to proteins incorporated in the double m~hrane, possess charged N-acetylneuraminic acid and ~ulfate radical~ and are therefore negatively charged, which can lead to an electrostatic bond or repulsion of charged pharmaceutical substance molecules or of electrostatically charged particles. The epithelial cell membranes consist of phospholipid bilayers in which proteins are anchored via their hydrophobic regions. The phospholipid bilayers with their lipophilic content represent a further barrier for the transport of the pharmaceutical substances to be absorbed.
From this description, it clearly follows that charged pharmaceutical substance molecules or electro-statically charged particles therefore only have a verylow chance of being absorbed via the oral administration route.
The shaped articles according to the invention for the first time provide the technical te~ch;ng to form a system with which these abovementioned absorption barriers can be overcome.
Hydrophilic macromolecules, in particular gela-tin, are amphiphilic substances which, dep~n~;ng on the pE, have differing charge states. According to the invention, the hydrophilic macromolecule in the systems according to the invention can now be selected, or the pH
of the formulation can be coordinated, such that a positive state of charge results in the physiological medium. At least a partial neutralization of the negative surface charges of the glycocalyx can thus be achieved.
This neutralization phenomenon can become increasingly effective as a result of bio~he~ive propertie~ of the hydrophilic macromolecule, in particular gelatin.
As dissolved pharmaceutical substance molecules 2~28Z4~

can now pass through the glycocalyx l~nh;n~red without being bound or repelled by electrostatic effects, they thus also reach the surface of the epithelial cells and are available there in a high concentration.
Active, carrier-mediated transport mechanisms or phagocytosis can now also make a substantial contribution to absorption.
The use of the powders, granules, or pellets according to the invention as shaped articles can be effected e.g. by means of customary dosage systems in hard gelatin capsules or as granules in sachets. As a result of the good flowability and approximately round shape of the granules, good meterability can be guaranteed. When using pellets the tightest sphere packing in exact coordination of the bulk volume to the capsule size is possible, from which an improvement in dosage accuracy in the filling process results. Moreover, the addition of fillers can be dispensed with as a result of the appropriate selection of a certain pellet size.
The pellets having a size of 2-12 mm can be used according to the invention for a novel single-dose buccal, nasal or oral pharmaceutical form. Pellets employed orally are easily swallowable and can be sold in bottles with dosage dispensers in an environmentally compatible manner. In the case of buccal and nasal use, shaped article pellets with bio~h~sive properties are suitable.
Powders, granules or pellets - as shaped articles - comprising matrix materials which dissolve rapidly and completely in cold water, can be used -filled into sachets - as instant preparations for the pharmaceutical or dietetic sector (healthcare).
Surprisingly, utilizing the bio~h~Rive prop-erties of the sol/gel-forming agents, in particular gelatin, with the shaped articles according to the invention buccal and nasal formulation~ or pharmaceutical forms having pH-controlled release can be used.
A further use of these special granules or pellets as shaped articles is provided by their direct 2~82~4 compressibility to give tablets. The tablets thus obtained surprisingly show, with low friability and high bre~k;ng strength, complete dissolution within 5 minutes, e.g. 2 minutes, measured according to customary test methods (e.g. dissolution test apparatus according to USP). Surprisingly, the good dissolving properties of the structural matrix are also ret~; n~ after compressing.
The tablets dissolve directly without advance disin-tegration. In contrast to this, tablets compressed from conventional granules always disintegrate first into granule particles, which only then dissolve.
Tablet preparation from freeze-dried shaped articles according to the invention is of importance, for example, in the design of a pharmaceutical form for temperature-sensitive active compounds. Because of their sensitivity (e.g. heat inactivation etc.) such pharma-ceutical substances require particularly gentle pro-cessing processes, which advantageously can be very easily and simply ensured by the process according to the invention.
The application area for the shaped articles according to the invention is, of course, not only restricted to pharmaceutical purposes. Areas of use may also be in the biotechnological sector (cryopreservation of enzymes or bacteria, finished nutrient media in dried form etc.) and in the cosmetics sector (processing of plant extracts such as e.g. Aloe vera to give pellets offers the advantage of an ideal, dry transportation form for the moisture-sensitive extract and at the same time the naturally synthesized matrix system is particularly suitable as a constituent for ointments and creams).
Owing to the diverse variation and combination possibilities of the shaped articles according to the invention, the release of pharmaceutical substances in all intended uses indicated can be modulated within wide limits.
The following examples are intended to illustrate the invention in greater detail:

ZlZ82~4 Example 1:
Pharmaceutical substance: benzocaine Recipe of the groundmass to be processed:
210 g of gelatin 170 Bloom 50 g of dextran (molecular weight about 10,000) 29 g of sucrose 1 g of peppermint flavoring 710 g of distilled water 1000 g The gelatin powder is mixed with the peppermint flavoring, the water, which already contains the dextran and the sucrose in dissolved form, is added and after preliminary swelling at 50~C the mixture is melted. 10 g of micronized benzocaine are suspended in this solution with ultrasonication.
The solution i8 then deaerated in vacuo. By means of the Cryopel metering device it is added dropwise to an immersion bath cont~;n;ng liquid nitrogen and pellets are thus formed.
The shock deep-frozen, round pellet shaped articles are dried in a freeze-drying unit with primary drying at -50~C and 5 Pa (0.05 mbar) and secondary drying at 22~C.
78% of the pellets are in the size range from 0.8-1 mm.
The dried pellets are compressed directly on an eccentric press to give a lozenge having an average benzocaine content of 5 mg.
Example 2:
Pharmaceutical substance: potassium chloride Recipe of the groun~m~ss to be processed:
625 g of collagen hydrolyzate (molecular weight 2,000-3,000 D) 50 g of citric acid 2325 g of distilled water ______ 3000 g The collagen hydrolyzate and the citric acid are Z1~8Z4~1 dissolved in water with stirring. 190 g of potassium chloride are dissolved in this solution.
After defoaming in vacuo, the solution is added dropwise by means of the Cryopel metering device to an immersion bath conta;n;ng liquid nitrogen and pellets of size of on average 4 mm are thus formed.
The water is removed as in example 1 by subse-quent freeze-drying.
The pellets are pack~ged in air-tight sachets, 10 COrre8pQn~; ng to an individual dose of 1 g of potassium ions.
The contents of a sachet dissolve completely in water at room temperature within 30 sec.
Example 3:
Pharmaceutical substance: phPnoYymethylpenicillin potas-sium Recipe of the groundmass to be processed:
200 g of dextran (molecular weight about 60,000) 200 g of collagen hydrolyzate (molecular weight 2,000-3,000) 5 g of orange flavoring 250 g of mannitol 100 g of sucrose Distilled water to 2,500 g The constituents are mixed and dissolved in the water. 100 g of ph~no~ymethylpenicillin potassium are dissolved in this solution with stirring.
After defoaming in vacuo, the solution is addeddropwise by means of the Cryopel metering device to an immersion bath cont~;n;ng liquid nitrogen and pellets are thus formed. The water is removed by subsequent freeze-drying.
2.31 g of the dried pellets (correspon~;ng to an average content of ph~noxymethylpenicillin potassium of 270 mg) are used - sealed into individual sachets - as an instant beverage solution.
Example 4:
Example of a matrix material comprising gelatin and plasticizer, in which pharmaceutical substance to be Z~28Z44 processed can be dissolved.
Gelatin 150 Bloom 2.6 kg Spray-dried sorbitol 1.0 kg Dihydrocodeine hydrogen tartrate 0.1 kg Water 6.3 kg The active compound i~ dissolved completely in 1 kg of water with stirring. The gelatin granules are preswollen in the remaining amount of water and dissolved at 40~C, and sorbitol and the active compound solution are then added with stirring. After melting the gelatin and homogenizing the solution, pellets as described in example 1 are prepared by dropwise addition of the material to liquid nitrogen. The pellets are dried in the customary manner at temperatures between 20~C and 40~C
and then filled into opaque hard gelatin capsules having an average content of 10 mg of dihydrocoAe;ne tartrate.
In the dissolution test (apparatus according to USP XXI, 500 ml of water, 37~C, 50 rpm), the pharmaceutical form releases 70% of the active compound in 4.5 minutes.
The pellets obtA; ne~ are transparently clear and lustrous.
Example 5:
Example of a matrix material comprising gelatin and plasticizer, in which the pharmaceutical substance is present in emulsified form.
Gelatin 210 Bloom 2.6 kg Glycerol (85% strength) 1.25 kg ~-Tocopherol acetate 0.25 kg Water 6.9 kg The powdered gelatin is preswollen in cold water for 40 minutes and then dissolved at 50~C. Using an ultrasonic homogenizer, the active compound is emulsified in the gelatin solution at 50~C. The oil-in-water emul-sion is then mixed with glycerol and cryopelletized. The pellets obtained are dried as in Example 4. The pellets are metered into opa~ue hard gelatin capsules contA; n; ng 25 mg of ~-tocopherol acetate.
The pellets obtA; ne~ have an opaque and lustrous appearance.

2~8Z4~

Example 6:
Example for a matrix material comprising gelatin and plasticizer, in which the pharmaceutical substance can be suspended.
Gelatin 250 Bloom 2.5 kg Glycerol (85% strength) 1.0 kg Dexamethasone, micronized powder 0.025 kg Water 4.0 kg The soft gelatin material is preswollen in 1 kg of water and dissolved at 50~C after addition of the remaining water. The active compound is homogeneously dispersed in this solution with stirring and the ~olution i~ then mixed with the glycerol. The suspension obtained is cryopelletized. After customary drying the pellets are filled into hard gelatin capsules having a steroid content of 0.5 mg.
The pellets obt~; ne~ are transparent and lus-trous.
Example 7:
Example of a single-dose pharmaceutical form.
Mixture:
0.8 kg of gelatin 250 Bloom 0.8 kg of spray-dried sorbitol 0.8 kg of acetylsalicylic acid 1.6 kg of water The gelatin granules are preswollen for 30 minutes in the water and then di~solved at 70~C. The acetylsalicylic acid is di~persed in the solution obt~; ne~ and the sorbitol is then added.
The matrix material obtained is added dropwi~e to liquid nitrogen by means of the apparatus shown in Fig. 2 at a temperature of the nozzles of 70~C. The shock deep-frozen pellets are clas~ified with cooling and have a uniform size of 8 mm.
The round ~haped articles are filled into a dose dispenser and - dep~nA;ng on the indication - can be administered individually.
Pellets prepared in this way are palatable and increase the tolerability, in particular in the ca~e of z~zaz4~

cardiac infarct prophylaxis.
Example 8:
Production of an ibuprofen immediate-effect pharma-ceutical form based on pellets.
Demon~tration of the increased bioavailability.
Recipe:
400 g of ibuprofen USP XXII, micronized powder 400 g of gelatin powder 220 Bloom 1400 g of water The gelatin powder i8 preswollen for 45 min in the water and then dissolved at 60~C. The micronized ibuprofen i8 homogeneously dispersed in the gelatin solution and the re~ulting material i~ deaerated in vacuo.
The material is added dropwise to liquid nitrogen by means of the apparatus shown in Fig. 1 and pellets are thus formed. After drying at temperatures between 20~C
and 40~C the pellets are filled into hard gelatin cap-suleR cont~;n;ng 400 mg of ibuprofen.
In an in vivo hl~an study, the immediate-effect form described was comparatively tested against a commer-cially available ibuprofen immediate-effect formulation which contains 600 mg of ibuprofen (in micronized form).
The following average plasma concentration-time value~ re~ult, indicated in ~g of ibuprofen/ml of plasma.
Time (h) Formulation Comparison from Example 8 preparation 1 27.5 5 2.5 37 23 3 35 .... 22 17.5 15 7 8 ..... 6 Example 9:
Production of a flurbiprofen immediate-effect pharma-ceutical form based on pellet~, demonstration of the increased bioavailability.

Z~Z8;~44 Recipe:
50 g of flurbiprofen, micronized powder 50 g of gelatin powder 220 Bloom 175 g of water The gelatin powder i8 preswollen for 45 min in the water and then dissolved at 60~C. The micronized flurbiprofen i8 homogeneously dispersed in the gelatin solution and the resulting material is deaerated in vacuo.
The material is added dropwise to li~uid nitrogen by means of the apparatus shown in Fig. 1 and pellets are thus formed. After drying at temperatures between 20~C
and 40~C the pellets are filled into hard gelatin capsules cont~;n;ng 50 mg of flurbiprofen.
In an in vivo human study, the immediate-effect form described was comparatively tested against a commercially available flurbiprofen immediate-effect formulation which contains 50 mg of flurbiprofen (in micronized form).
The following average plasma concentration-time values result, indicated in ~g of flurbiprofen/ml of plasma.
Time (h) Formulation Comparison from Example 9 preparation 0.5 6.5 2 2 6 4.5 3 6 3.5 4.5 2 Example 10:
Pharmaceutical substance: nifedipine Recipe of the groundmass to be processed:
300 g of collagen hydrolyzate 750 g of mannitol 3950 g of distilled water The collagen hydrolyzate and the mannitol are dissolved in the dist. water with stirring. 100 g of micronized nifedipine are homogeneously suspended in this solution, if desired with addition of customary pharma-ceutical auxiliaries. After defoaming under vacuum, the z~.Z8Z44 euspension is shaped to give pellets by dropwise addition at room temperature by means of the Cryopel~ metering device to an i ersion bath contA;n;ng liquid nitrogen.
The water is removed by subsequent freeze-drying and round shaped articles are obtA;ne~, after classifi-cation, with an average nifedipine content of 2 mg.
These shaped articles disintegrate completely in water at room temperature (dissolution test apparatus according to USP, test medium 100 ml of water, 23~C) within 20 seconds and release the amount of nifedipine cont~; ne~ .
The dried shaped articles are filled into a dark-colored dose cont~;ne~ in which they are protected from entry of light and from which the desired dose can be removed.
Example 11:
The dried shaped articles from Example 10 are directly compressed in an eccentric press to give tablets having an average nifedipine content of 10 mg.
In a dissolution test apparutus according to USP
~900 ml of 0.1 N HCl, paddle, 75 rpm, 37~C), complete tablet dissolution and thus active compound release results within 5 minutes.
The pellets from Example 10 can alternatively be filled into opaque hard gelatin capsules having an average nifedipine content of 5 mg.
Example 12:
The recipe of the groundmass to be processed in Example 10 is altered as follows:
300 g of collagen hydrolyzate 60 g of polyvinylpyrrolidone R 15 100 g of sucrose 2540 g of distilled water The further working procedure is carried out analogously to Example 10.
The examples are only exemplary embodiments of the present invention. The person skilled in the art is accordingly also free to use or to prepare all pharma-ceutical, cosmetic or other shaped articles according to Z~Z8Z4~

the invention such as powders, granules, essentially symmetrical ay~ e~tes etc. if required within the scope of the present invention.

Claims (36)

claims

1. A process for the preparation of powders, granules or pellets containing at least one active compound having poor absorbability in vivo, which comprises a) dissolving a structure-forming agent comprising hydrophilic macromolecules selected from the group consisting of:
collagen, gelatin, fractionated gelatin, collagen hydrolyzates, gelatin derivatives, plant proteins, plant protein hydrolyzates, elastin hydrolyzates, in an aqueous or aqueous-organic solvent, b) dispersing the active compound and c) adding the mixture of dissolved structure-forming agent and dispersed active compound obtained dropwise to a deep-cooled inert liquefied gas and thus forming powders, granules or pellets, and d) drying the powders, granules or pellets thus formed by evaporation or sublimation of the solvent.

2. The process as claimed in claim 1, wherein the mixture is added dropwise to liquid nitrogen.

3. The process as claimed in claim 1 and/or 2, wherein a) a structure-forming agent selected from the group consisting of : gelatin, fractionated gelatin, collagen hydrolyzate, gelatin derivatives, and their mixtures is dissolved in a solvent.
b) a dihydropyridine derivative is dispersed (dissolved, suspended or emulsified) in the solution, c) the dispersion of structure-forming agent and dihydropylidine derivative is added dropwise to liquid nitrogen and powders, granules or pellets are thus formed, and d) the powders, granules or pellets thus formed are dried by evaporation or sublimation of the solvent.

4. The process as claimed in any one of claims 1 to 3, wherein drops in an approximately uniform predetermined shape are prepared from the dispersion by means of a metering system.

5. The process as claimed in any one of claims 1 to 4, wherein the powders, granules or pellets are freeze-dried.

6. The process as claimed in any one of claims 1 to 5, wherein the dispersion of active compound and structure-forming agent is treated with an additional structure-forming agent selected from the group consisting of:
albumins, agar-agar, gum arabic, pectins, tragacanth, xanthan, natural-and modified starches, dextrans, dextrins, maltodextrin, chitosan, alginates, cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid and polymers of methacrylic acid and methacrylic acid esters, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, azo-crosslinked polymethacrylates, polyurethane/sugar copolymers, a sugar component preferably oligomeric galactomannas or galactomannan derivatives which are then crosslinked with aliphatic diisocyanates, galactomannan derivatives such as ethyl- or acetyl-galactomannans, polysaccharides crosslinked with adipic acid, lipophilic substances such as degradable mono-, di- and triglycerides, erodable fatty alcohols; and their mixtures.

7. The process as claimed in any one of claims 1 to 6, wherein placticizers and flavor correctants selected from the group consisting of:
glycerol, propylene glycol, polyethylene glycol, triacetin, sorbitol, sorbitan mixtures, glucose syrup and their mixtures, are added to the mixture of structure-forming agent and active compound.

8. The process as claimed in any one of claims 1 to 7, wherein as a structure-forming agent gelatin having a maximum in the molecular weight distribution above 10 5 D
at at most 70°C is mixed with the active compound.

9. The process as claimed in any one of claims 1 to 8, wherein the active compound is introduced in dissolved, emulsified, suspended, microencapsulated, nanoencapsulated, microemulsified or finely disperse form or in conjugated form to the hydrophilic macromolecule.

10. The process as claimed in claims 1 or 3, wherein water is employed as a solvent.

11. An active compound-containing powder, granule or pellet, comprising a dispersion of at least one active compound or active compound mixture having poor absorbability in vivo in a matrix which essentially comprises structure-forming agent comprising hydrophilic macromolecules which are selected from the group consisting of:
collagen, gelatin, fractionated gelatin, collagen hydrolyzates, gelatin derivatives, plant proteins, plant protein hydrolyzates, elastin hydrolyzates, and their mixtures, which can be prepared by the process as claimed in any one of claims 1 to 10.

12. A powder, granule or pellet as claimed in claim 11, wherein the hydrophilic macromolecule is a thermoreversible sol/gel-forming agent.

13. A powder, granule or pellet as claimed in claim 11 or 12, wherein the matrix contains an additional structure-forming agent selected from the group consisting of: albumin, agar-agar, gum arabic, pectins, tragacanth, xanthan, natural and modified starches, dextrans, dextrins, maltodextrin, chitosan, alginates, cellulose derivatives, sugar, glycine, lactose, mannitol, polyvinylpyrrolidone, polyacrylic acid, polymers of methacrylic acid, polymers of methacrylic acid esters, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, azo-crosslinked polymethacrylates, polyurethane/sugar copolymers, a sugar component preferably oligomeric galactomannans or galactomannan derivatives which are then crosslinked with aliphatic diisocyanates, galactomannan derivatives such as ethyl- or acetylgalactomannans, polysaccharides cross-linked with adipic acid, lipophilic substances such as degradable mono-, di- and triglycerides, erodable fatty alcohols; and their mixtures.

14. A powder, granule or pellet as claimed in claim 13, wherein the active compound is a dihydropyridine derivative and the structure-forming agent comprises hydrophilic macromolecules selected from the group consisting of: gelatin, fractionated gelatin, a gelatin derivative, collagen hydrolyzate or their mixture; and the additional structure-forming agent is selected from the group consisting of: dextran, sugar, glycine, lactose, sorbitol, mannitol, polyvinylpyrrolidone, and their mixtures.

15. A powder, granule or pellet as claimed in any one of claims 11 - 14, wherein the matrix content of additional structure-forming agents is less than about 50% by weight.

16. A powder, granule or pellet as claimed in claim 11, comprising a pharmaceutically acceptable auxiliary or excipient for the matrix.

17. A powder, granule or pellet as claimed in claim 11, wherein it is present as a micropellet or an essentially symmetrical aggregate.

18. A powder, granule or pellet as claimed in claim 11, wherein it is present as a lyophilizate.

19. A powder, granule or pellet as claimed in claim 11, wherein it is rapidly dissolving; and wherein the matrix includes a hydrophilic macromolecule selected from the group consisting of:
plant proteins, plant protein hydrolyzates, elastin hydrolyzates, collagen hydrolyzates, cold water-soluble gelatins, gelatin derivatives; having a maximum in the molecular weight distribution of below 10 5 D.

20. A powder, granule or pellet as claimed in claim 11, wherein the matrix contains plasticizers and flavor correctants selected from the group consisting of:
glycerol, propylene glycol, polyethylene glycol, triacetin, sorbitol, sorbitan mixtures, glucose syrup;
and their mixtures.

21. A powder, granule or pellet as claimed in any one of claims 12 - 20, wherein the sol/gel-forming agent is a gelatin having a maximum in the molecular weight distribution above 10 5 D.

22. A powder, granule or pellet as claimed in claim 11, wherein the active compound is selected from the group consisting of:
pharmaceutical substances of synthetic or natural origin, cosmetics, preventive agents (healthcare), enzymes and microorganisms.

23. A powder, granule or pellet as claimed in claim 22, wherein the active compound is a dihydropyridine derivative.

24. A powder, granule or pellet as claimed in claim 23, wherein the dihydropyridine derivative is selected from the group consisting of: nifedipine, nitrendipine or nisoldipine.

25. A powder, granule or pellet as claimed in claim 22, wherein the active compound is present in dissolved, suspended, finely disperse, emulsified or microemulsified form or in the form of liposomes.

26. A powder, granule or pellet as claimed in one of claims 22 - 25, wherein the active compound is present as a conjugate with the hydrophilic macromolecule.

27. A powder, granule or pellet having controlled release as claimed in any one of claims 11 to 26, wherein the matrix has a melting range of between about 35°C and 40°C.

28. A powder, granule or pellet having controlled release as claimed in claim 27, wherein the matrix is present crosslinked with a pharmaceutically acceptable hardener selected from the group consisting of:
aldoses and citral.

29. A powder, granule or pellet having controlled release as claimed in claim 27 or 28, wherein the shaped articles contain an additional hydrophilic macromolecule as a structure-forming agent or film coating, which is selected from the group consisting of:
alginates, alginate-calcium phosphates, pectins, agar-agar, poly- and methacrylic acid derivatives, cellulose derivatives, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, azo-crosslinked polymethacrylates, polyurethane/sugar copolymers, a sugar component preferably oligomeric galactomannans or galactomannan derivatives which are then crosslinked with aliphatic diisocyanates, galactomannan derivatives such as ethyl- or acetylgalactomannans, polysaccharides crosslinked with adipic acid, lipophilic substances such as degradable mono-, di- and triglycerides and erodable fatty alcohols.

30. A powder, granule or pellet as claimed in claim 22, wherein the matrix is present in covered form.

31. The use of the powders, granules or pellets as claimed in claim 11 for the production of a cosmetic preparation.

32. The use of the powders, granules or pellets as claimed in claim 11 for the production of a preparation which is selected from the group consisting of:
pharmaceutical, diagnostic and analytical preparations.

33. The use of the powders, granules or pellets as claimed in claim 11 for the production of a preparation which is selected from the group consisting of : nasal, buccal and oral medicines.

34. A pharmaceutical preparation containing powders, granules or pellets as claimed in claim 11.

35. A cosmetic preparation containing powders, granules or pellets as claimed in claim 11.

36. A foodstuff preparation containing powders, granules or pellets as claimed in claim 11.