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

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.

This application is a 371 of PCT/DE93/00038 filed Jan. 18, 1993. 
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 derivatives, in particular nifedipine, 
nitrendipine or nisoldipine. 
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 
contrast to monolithic pharmaceutical 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. 
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 breaking down processes. 
It is common to all processes that until now granules or pellets as shaped 
articles were only obtained via various and complicated partial steps. 
In the breaking 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 aggregated 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 granular material are 
formed from the powdered pharmaceutical substances and auxiliaries with 
continuous addition of granulation fluid with simultaneous drying in a 
controlled process (e.g. fluidized bed process). 
By means of subsequent, special rounding processes (e.g. Marumerizer.RTM.), 
round, bead-shaped granule particles (pellets) are obtained. A 
disadvantage in this case is that in the rounding of already prepared, 
unshaped granule particles substance matter containing 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 technologically complicated multi-step 
processes. They are 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 tendency and great experience in working with these substances 
is necessary to be able to assess the interaction 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 depending on the pharmaceutical substance 
being processed and the administration form being formulated therefrom. 
It is therefore understandable that the adherence 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 pharmaceutical 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 
available to the body only after deaggregation and subsequent release. The 
multiplicity of adhesive and binding forces, which differ in principle, in 
granules illustrates this problem. As a result of hardening binders during 
drying (moist granulation) or as a result of sintering or melt adhesion 
under action of pressure (dry granulation) solid bridges form whose 
binding 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 processes of the prior art can thus have an 
unfavorable effect on the release of the active compound and thus on its 
bioavailability. 
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, 
C.sub.17 H.sub.18 N.sub.2 O.sub.6) 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, 
C.sub.18 H.sub.20 N.sub.2 O.sub.6 and nisoldipine, isobutyl methyl 
1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate, 
C.sub.20 H.sub.24 N.sub.2 O.sub.6. 
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 developments have 
frequently been proposed. These, however, are all compromises, because on 
the one hand the poor solubility or insolubility of these active compounds 
in the physiological medium restricts 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 possible. These processes are not unimportant for 
increasing patient compliance. 
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 administration, 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 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 taking, is therefore never to be excluded particularly during 
withdrawal of nifedipine drops from the storage container by the patient. 
Since this form of administration, particularly in the case of elderly 
patients, is a very time-consuming process, the risk of decomposition of 
active compound before actual administration is thus additionally 
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 administration as an immediate-effect form 
having a rapid influx, the preparation itself being an active compound 
solution, is desirable or advantageous from pharmacological 
considerations. 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 
technologically or can only be realized in a roundabout manner. 
The present invention has the object of proposing novel 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 manner, process the active compounds in a gentle manner and 
thus, looked at all together, overcome the disadvantages of the prior art. 
The present invention is in particular based on the object of providing a 
medicament for oral administration of dihydropyridine derivatives, 
particularly nifedipine, which is suitable for rapid pharmaceutical 
substance release and overcomes the problems of the prior art. 
This object is achieved according to the invention by active 
compound-containing solids which comprise the pharmaceutical substance in 
dissolved, emulsified or suspended form in a solid or semisolid matrix 
which mainly contains hydrophilic macromolecules of natural origin as 
structure-forming agents. 
The hydrophilic macromolecules employed are: collagen, gelatin, 
fractionated gelatin, collagenhydrolyzates, gelatin derivatives, plant 
proteins, plant protein hydrolyzates, elastin hydrolyzates and 
combinations of the abovementioned substances with one another. 
In particular, the present invention makes available active 
compound-containing solids which comprise 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 hydrolyzates, 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-containing solids which comprises dissolving, emulsifying or 
suspending the active compound in a solution of the hydrophilic 
macromolecule (structure-forming agent) and shaping to give shaped 
articles. 
The solids can be dried if required. 
In particular, the present invention makes available a process for the 
production of solids containing at least one active compound, 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 and elastin 
hydrolyzates in an aqueous and/or organic solvent, 
b) dispersing the active compound, 
c) adding the mixture of dissolved structure-forming agent and dispersed 
active compound obtained dropwise to a deep-cooled liquid and thus shaping 
the solid. 
Solid within the meaning of the invention is understood as meaning one 
which is selected from the group consisting of: 
powders, granules, pellets and micropellets in essentially symmetrically 
built-up aggregates. 
According to the invention, uniformly round solids, in particular pellets, 
are particularly suitable for pharmaceutical applications, the term pellet 
preferably comprising a grain size range from about 0.2 to 12 mm. 
In the description of the invention the properties, 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: powders, granules, essentially symmetrically 
built-up aggregates, 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 derivatives, collagen 
hydrolyzates, plant proteins, plant protein hydrolyzates, elastin 
hydrolyzates, 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; and their mixtures. 
The active compound used according to the present invention is preferably a 
dihydropyridine derivative, in particular nifedipine, nitrendipine or 
nisoldipine. 
Preferred embodiments 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 corresponding pharmaceutical 
form are required by the pharmaceutical industry. With conventional 
medicament production, this standard 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 embedded 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 effects. 
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 appropriate coloring, the 
pellets, which appear clearly transparent and lustrous, opaque to 
transparent or nontransparent, can be developed to give unmistakable 
pharmaceutical specialties. 
As a result of the advantageous protective colloid function of the claimed 
macromolecules and the simultaneous embedding of the active compounds in 
the polymeric matrix structure, the tolerability is distinctly increased, 
in particular in the case of mucous membrane-irritating active compounds. 
Thus e.g. the irritation of the gastric mucous membrane by acetylsalicylic 
acid can be effectively decreased by the mucous membrane-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 binding forces which make possible shaping at all must 
initially be overcome, in addition the subaggregates thus obtained must be 
wetted and dissolved until the pharmaceutical substance is finally in an 
absorbable form. Depending 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 
hydrophilic 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 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 comparison with a conventional 
preparation of the same dose of the pharmaceutical substance. 
Obviously, the presence in a preparation according to the invention thus 
leads to a greatly increased (more effective) absorption of the 
pharmaceutical substance dose under physiological conditions. 
The pharmaceutical substance-containing pellets are exposed during the 
gentle preparation process (shaping) 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 requirements 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 meaning of the invention--on their own or in 
mixtures--hydrophilic macromolecules from the group consisting of: 
collagen, gelatin, fractionated gelatin, gelatin derivatives, collagen 
hydrolyzates, plant proteins, plant protein hydrolyzates and elastin 
hydrolyzates can be employed. 
These biogenic substances are pharmaceutically 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-containing material, 
which has different properties depending 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 
(10.sup.7 to 10.sup.8 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.times.10.sup.4 
/10.sup.5 to 10.sup.6 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 designated 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 depending 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.degree. 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&lt;9.5.times.10.sup.4 D) or by mixtures of individual fractions such as 
e.g. alpha chains, dimeric and trimeric chains or microgel. 
Moreover, gelatin or fractionated gelatin has good surfactant properties 
with protective colloid action and emulsifying properties. 
Collagen in native form is water-insoluble. By means of special preparation 
processes there are today soluble 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 expanders. 
Collagen hydrolyzate is understood as meaning a product obtained from 
collagen or gelatin by pressure 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.times.10.sup.4 D. Products obtained by 
enzymatic routes are more homogeneous in molecular composition and 
additionally exhibit good surfactant and emulsifier action. 
The plant proteins and their hydrolyzates are newly developed products, 
which largely correspond to the collagen hydrolyzates in their properties. 
They are preferably obtained from wheat and soybeans and possess, for 
example, molecular weights of about 200,000-300,000 D and about 
1,000-10,000 D respectively. 
Elastin hydrolyzates are obtained enzymatically from elastin and consist of 
a single polypeptide chain. On account of their high content of non-polar 
amino acids they can be used in lipophilic systems. Elastin hydrolyzates 
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, elastin 
hydrolyzates, or collagen hydrolyzates (cold water-soluble gelatins) or 
gelatins having a maximum in the molecular weight distribution of a few 
hundred D to below 10.sup.5 D (variant A), the excipient material of the 
claimed shaped articles after lyophilization carried out in a preferred 
embodiment of 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 
release are advantageously prepared by use of collagen hydrolyzates with 
still present surfactant and emulsifier properties. Enzymatically 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 according to the invention as shaped articles. 
If e.g. the active compound is embedded in a rapidly dissolving matrix and 
pelletized, storage-stable 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 such as e.g. gelatin and fractionated gelatin, which possess a 
maximum in the molecular weight distribution above 10.sup.5 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 obtained which release the 
active compound--depending on the molecular composition of the type of 
gelatin used--rapidly or slowly in aqueous medium at 37.degree. C. 
In a further embodiment of the invention, additions of plasticizers of 
1-50% (relative to the material to be processed) selected from the group 
consisting of: glycerol, propylene glycol, polyethylene glycols, 
triacetin, sorbitol, sorbitan mixtures, sorbitol solutions, glucose syrup 
and other polyols or sugar alcohols, may be suitable. Said substances 
affect the matrix according 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 bioadhesive 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.degree. 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 distribution at about 10.sup.5 D to 10.sup.6 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 meaning of the invention. Matrix materials 
or mixtures built up in this way possess a melting range from 35.degree. 
C. to 40.degree. C., preferably above 37.degree. C., in aqueous solution. 
Addition of plasticizers may be in the range between 1 and 30% (relative 
to the material to be processed). 
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 modified starches, 
dextrans, dextrins, maltodextrin, chitosan, alginates, alginate-calcium 
phosphates, cellulose derivatives, polyvinyl alcohol, 
polyvinylpyrrolidone, polyacrylic acid and polymers of methacrylic acid 
and methacrylic acid esters. 
Celluloseacetate phthalate or hydroxypropylmethylcellulose phthalate, 
azo-crosslinked polymethacrylate; polyurethane/sugar copolymers, a 
suitable sugar component in particular being 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. 
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 auxiliaries 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 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. 
In a particular embodiment of the matrix materials or mixtures indicated in 
variants A and B, which can be built up with or without addition of 
plasticizer, pellets 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 
substance only after gastric passage, i.e. that the structure-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 intestine by enzymes present there. These are e.g. azo-crosslinked 
polymethacrylates; polyurethane/sugar copolymers, a suitable sugar 
component in particular being oligomeric galactomannans or galactomannan 
derivatives which are then crosslinked with aliphatic diisocyanates; 
galactomannan derivatives such as ethyl- or acetylgalactomannans; 
polysaccharides crosslinked with adipic acid. 
Pellets according to the invention can be prepared 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 
incorporated pharmaceutical substance thus released in a controlled manner 
in this gastrointestinal section. 
Further embodiments to colonic pharmaceutical forms are found in particular 
in the international PCT application titled "Peptidarzneistoffe 
enthaltende Formkorper und ihre Herstellung sowie deren Verwendung" 
(Shaped articles containing peptide pharmaceutical substances, their 
preparation and their use) of ALFATEC-Pharma GmbH of the same date. 
In the case of alginate-containing basic recipes, by suspending 
water-insoluble dicalcium hydrogen phosphate (Ca.sub.2 (HPO.sub.4).sub.2 
! e.g. to give a pH-neutral to slightly basic gelatin/alginate mixture 
pellets can be produced which have delayed release of the active compound. 
During gastric passage, the acidic medium dissolves the calcium salt and 
crosslinks the alginate. 
Furthermore, pharmaceutically acceptable hardeners, such as e.g. aldoses or 
citral, which after drying lead to crosslinking, 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 crosslinking of the pellet matrix. In this 
manner depot pharmaceutical forms, so-called sustained-release 
pharmaceutical 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 crosslinking (derivatization 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 crosslinking agent added, i.e. by the 
extent of hardening or via the selected hardening conditions. Different 
molecular fractions of a structure-forming agent derived from collagen can 
in this way be crosslinked 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 crosslinking 
agents) a pharmaceutical 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 diffusion with a 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 profiles 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 bioadhesive properties, and film coatings (e.g. poly- and methacrylic 
acid derivatives) which dissolve in defined pH ranges. 
Such bioadhesive properties can be produced, for example, by partial 
crosslinking of a matrix which is constructed from an auxiliary derived 
from collagen. 
Instead of Eudragits.RTM. 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 particular 
being oligomeric galactomannans or galactomannan derivatives which are 
then crosslinked with aliphatic diisocyanates; galactomannan derivatives 
such as ethyl- or acetylgalactomannans; polysaccharides crosslinked with 
adipic acid. 
This procedure makes possible the absorption of pharmaceutical substances 
with problematic bioavailability in a controlled manner. Furthermore, by 
combinations of film-forming agents, pellet mixtures can be prepared 
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 
crosslinking of a pellet matrix. According to the invention, pellet 
pharmaceutical forms with modulated or pulsed pharmaceutical substance 
release can thus be advantageously prepared with retention of the 
increased bioavailability of the pharmaceutical substance. 
As is known, gelatin, depending on the preparation 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 gelatins of opposite charge mixed with active 
compound-containing 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 molecular composition, three-dimensional 
crosslinkings 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 beginning can surprisingly even be achieved if 
a pharmaceutical 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 pharmaceutical form on a 
pellet basis is described which contains ibuprofen. The bioavailability of 
this pellet preparation compared with a conventional, orally administered 
suspension of micronized ibuprofen is increased by about 100% to 150% at 
the same dose. Obviously, the presence of a pharmaceutical substance 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 promoting absorption by direct and controlled precipitation 
of the active compound previously present in the matrix material in 
dissolved form, e.g. by pH shift or removal of the solvent. 
Suitable particularly finely disperse pharmaceutical substance dispersions 
are colloidally disperse pharmaceutical substance systems (nanosols) whose 
properties and preparation are described in numerous patent applications 
of ALFATEC-Pharma GmbH (e.g. PCT Application PCT/DE92/01010 and further 
PCT 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. Useful combinations may be, 
for example: 
dihydropyridine derivative+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 
pharmaceutical 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. 
Further embodiments to this are contained in the parallel international 
(PCT) applications listed in the following. The contents of these parallel 
PCT applications, filed on the same date at the German patent office by 
the same inventors and applicants: 
internal reference: P/81AL2740, Title: "Pflanzenextrakt(e) enthaltende 
Formkorper, insbesondere Pellets und ihre pharmazeutische oder kosmetische 
Verwendung", (Shaped articles containing vegetable extract(s), in 
particular pellets, and their pharmaceutical or cosmetic use), PCT/DE93/ 
claimed Priorities: 
German patent application P 42 01 179.5 of 1.17.1992, U.S. Ser. No. 
07/876,876 of 4.30.1992, U.S. Ser. No. 07/876,866 of 4.30.1992 U.S. Pat. 
No. 5,401,502 and German patent application P 42 01 172.8. 
internal reference: P/81AL2742, Title: "Verfahren zur Herstellung von 
Weichgelatinekapseln nach einem Tropfverfahren", (Process for the 
production of soft gelatin capsules by a drip-feed process), PCT/DE93/ 
claimed Priorities: 
German patent application P 42 01 178.7 of 1.17.1992 and U.S. Ser. No. 
07/876,863 of 4.30.1992 U.S. Pat. No. 5,254,294 
internal reference: P/81AL2743, Title: "Peptidarzneistoffe enthaltende 
Pellets and ihre Herstellung sowie deren Verwendung" (Pellets containing 
peptide pharmaceutical substances, their production and their use) 
PCT/DE93/ claimed Priorities: 
German patent application P 42 01 179.5 of 1.17.1992 and U.S. Ser. No. 
07/876,865 of 4.30.1992 now abandoned 
are hereby also made a part completely in terms of contents for the 
disclosure of the present application, like the earlier PCT applications: 
PCT/DE92/01010, PCT/DE92/01012, PCT/DE92/01014, PCT/DE92/01016, 
PCT/DE92/01007, PCT/DE92/01008, PCT/DE92/01015, PCT/DE92/01013, 
PCT/DE92/01009, PCT/DE92/01011 of 12.4.1992. 
In the simplest case, the process according to the invention for the 
production of active compound-containing solids can be described by the 
following three process steps: 
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 obtained is added dropwise to a deep-cooled inert liquefied gas 
and the solid is thus formed. 
The first step of the process consists in dissolving the hydrophilic 
macromolecule, in particular gelatin, 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.degree. C. or more, in 
order to obtain a gelatin sol. 
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 hydrolyzates 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. Correspondingly the water content 
of the material to be processed is up to about 70% by weight or more. 
Concentration ranges of the additional structure-forming agents, such as, 
for example, dextrans, sucrose, glycine, lactose, polyvinylpyrrolidone, 
but in particular 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 is 
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 containing 
liquid nitrogen. 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, 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 surrounding 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 
is a great advantage. The desired properties are maintained. 
In an embodiment of the process step described in a), a material capable of 
forming drops, mainly comprising hydrophilic macromolecules as 
structure-forming agents, in particular plant proteins, plant protein 
hydrolyzates, collagen, gelatin, fractionated gelatin, elastin 
hydrolyzates, collagen hydrolyzates, gelatin derivatives or mixtures 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 derivatives, collagen hydrolyzates 
or elastin hydrolyzate, the nature and amount of the structure-forming 
agent employed and optionally the addition of further auxiliaries 
depending 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.degree. 
C. to 60.degree. C., preferably about 45.degree. C., may be necessary e.g. 
when using gelatin in order to convert this into the sol 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, agaragar, 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 hydroxypropylmethylcellulose 
phthalate, azo-crosslinked polymethacrylates; polyurethane/sugar 
copolymers, a suitable sugar component in particular being oligomeric 
galactomannans or galactomannan derivatives which are then crosslinked in 
the 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 can furthermore be added to the matrix material. 
In a further process variant, additions of plasticizers of from 1-50% 
(relative to the material to be processed) may be added selected from the 
group consisting of: glycerol, propylene glycol, polyethylene glycols, 
triacetin, sorbitol, sorbitan mixtures, sorbitol solutions, glucose syrup 
and other polyols or sugar alcohols. 
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 agents or inclusion 
complex-forming agents, such as e.g. cyclodextrin can be added to this 
groundmass. 
Of course, the mixtures according to the invention are suitable for 
immediate filling in liquid form according to the process step described 
in a) for shaping in containers, such as e.g. molds, soft gelatin capsules 
and suitable other coverings. 
In one embodiment of the process step described in b), the matrix material 
described is added dropwise for rounding (shaping) and shock deep-freezing 
in an immersion bath in the range from about -70.degree. C. to about 
-270.degree. C., preferably from about -100.degree. C. to -220.degree. C. 
The deep-cooled, in particular inert, liquid employed is preferably liquid 
nitrogen, which does not alter the constituents of the pellets. Round 
shaped articles (pellets) which after drying form a mechanically 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 surrounding 
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 
obtained; when using suitable spray or atomization nozzles with metering 
pumps powders are preferably obtained 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.RTM. process developed by Messer Griesheim 
GmbH (based on German Offenlegungsschrift 37 11 169). In conjunction with 
an immersion deep-freeze plant, the Cryopel.RTM. 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 production. Continuous 
operation with low maintenance and cleaning expenditure makes possible the 
economical conversion of the process according to the invention to the 
industrial scale.

The Cryopel.RTM. process developed by Messer Griesheim GmbH is shown 
schematically in FIG. 1. The matrix solution according to the invention, 
which contains the active compound in dissolved, emulsified or suspended 
form, is added dropwise to the liquid nitrogen bath 3 at -196.degree. 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 
conveyor belt 2 running 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.degree. 
C., is added dropwise continuously via the supply line 9 by means of the 
heatable drop nozzles 10 in the insulated trough 11 containing 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 sufficiently 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 drops. 
The processing temperature can be varied within wide ranges, but in the 
case of thermolabile active compounds should be below 50.degree. C. 
Using the metering devices described, for example, materials whose 
viscosity varies within a wide range, e.g. 1.times.10.sup.-3 to 12.5 
Pa.times.s (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. 
Depending 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 so that a 
loss-free procedure 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.degree. C. (liquid nitrogen), e.g. 
pellets, are transferred to a freeze-drying plant. In this plant 
temperatures of 15.degree. C. below the sublimation point of water are 
selected with a pressure of 0.1 Pa to 10.sup.3 Pa (0.001 to 1.03 mbar). 
The drying operation, which takes place in a conventional freeze-drying 
plant (condenser temperature -40.degree. C.) at -25.degree. 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 
secondary 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-containing networks are formed, which 
with respect to conventionally 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.degree. C. can be selected, the temperature during the drying process 
not rising above 30.degree. 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 sol 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 lipophilic 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 system, active compounds 
present in suspended form can be prevented from sedimenting by simple 
stirring and simultaneously 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 bioadhesive properties is carried out according to the 
general sense of the description and in coordination with the particular 
active compound. 
The process 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 homogeneously therein in finely crystalline 
form, and to add the system dropwise via a suitable metering device to an 
immersion bath containing 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 dihydropyridine precipitates can also be produced 
directly in the gelatin solution by precipitation from a solution of the 
dihydropyridine in a water-miscible and pharmaceutically acceptable 
organic solvent, such as e.g. alcohol. After removal of the alcohol (e.g. 
by evaporation), a procedure analogous to the procedure described is used 
in order to prepare the shaped articles according to the invention. 
For the combination preparations already mentioned, 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 breadth of variation of the invention, all 
pharmaceutical substances can be contained 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 active components. The term 
pharmaceutical substance, however, should further generally cover 
phytopharmaceuticals and plant extracts and finally also include hormones, 
vitamins and enzymes. 
Enantiomerically pure active compounds or pseudoracemates 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-inflammatories (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, medroxyprogesterone, prednisone, prednisolone; 
5. tranquillizers, e.g. oxazepam, diazepam, lorazepam; 
6. alpha-sympathicolytics, e.g. ergotamine, dihydroergotamine, 
dihydroergotoxin; 
7. hypnotics and sedatives, e.g. secbutabarbital, secobarbital, 
pentobarbital, doxylamine, diphenhydramine; 
8. tricyclic antidepressants, e.g. imipramine, nortriptyline, clomipramine, 
amitryptiline; 
9. neuroleptics, e.g. chlorprothixen, chlorpromazine, haloperidol, 
triflupromazine; 
10. antigout agents, e.g. benzbromarone, allopurinol; 
11. antiparkinson agents, e.g. levodopa, amantadine; 
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, 
gallopamil, 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 
phenoxymethylpenicillin, amoxycillin, ampicillin, pivampicillin, 
bacampicillin, dicloxacillin, flucloxacillin; cephalosporins such as 
cefalexin, cefaclor; gyrase inhibitors such as nalidixic acid, ofloxacin, 
norfloxacin; erythromycin, lincomycin, tetracycline, doxycycline, 
trimethoprim, sulfamethoxazole, chloramphenicol, rifampicin; 
17. local anesthetics, e.g. benzocaine; 
18. ACE inhibitors, e.g. enalapril, captopril; 
19. mucolytics, e.g. acetylcysteine, ambroxole, bromhexine; 
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, cyanocobalamine, ergocalciferol, 
ascorbic acid, thiamine, pyridoxine, 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. aminoadamantane; 
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 derivatives, in particular 
nifedipine, nitrendipine or nisoldipine. 
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 
pharmaceutical 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 formulations according to the invention adequately, a 
consideration of the mechanism of the physiological absorption of 
pharmaceutical substances as is also presented in appropriate publications 
is initially 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 takes 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 
uncharged, i.e. nonionized form, 
c) acidic pharmaceutical substances are preferably absorbed in the stomach 
and basic pharmaceutical substances preferably in the intestine. 
After the oral uptake of a pharmaceutical substance into the body, its 
absorption, i.e. the crossing into the general circulation (biophase) is 
hindered 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 distribution mechanism and state of charge (so-called passive 
diffusion). 
The epithelial cells of the entire gastrointestinal tract are covered with 
a mucus layer which consists of mucins (glycoproteins), electrolytes, 
proteins and nucleic acids. In particular, the glycoproteins 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 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 branched polysaccharides of the glycocalyx, 
which are either directly covalently bonded to amphiphilic molecules of 
the double membrane or to proteins incorporated in the double membrane, 
possess charged N-acetylneuraminic acid and sulfate radicals 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 electrostatically charged particles therefore only 
have a very low chance of being absorbed via the oral administration 
route. 
The shaped articles according to the invention for the first time provide 
the technical teaching to form a system with which these abovementioned 
absorption barriers can be overcome. 
Hydrophilic macromolecules, in particular gelatin, are amphiphilic 
substances which, depending on the pH, 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 
bioadhesive properties of the hydrophilic macromolecule, in particular 
gelatin. 
As dissolved pharmaceutical substance molecules can now pass through the 
glycocalyx unhindered 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 bioadhesive 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 bioadhesive properties of the sol/gel-forming 
agents, in particular gelatin, with the shaped articles according to the 
invention buccal and nasal formulations 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 compressibility to give tablets. The tablets thus 
obtained surprisingly show, with low friability and high breaking 
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 retained after compressing. The tablets 
dissolve directly without advance disintegration. 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 pharmaceutical substances 
require particularly gentle processing 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: 
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.degree. C. the mixture is melted. 10 
g of micronized benzocaine are suspended in this solution with 
ultrasonication. 
The solution is then deaerated in vacuo. By means of the Cryopel metering 
device it is added dropwise to an immersion bath containing 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.degree. C. and 5 Pa (0.05 
mbar) and secondary drying at 22.degree. 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 groundmass 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 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 containing liquid nitrogen 
and pellets of size of on average 4 mm are thus formed. 
The water is removed as in example 1 by subsequent freeze-drying. 
The pellets are packaged in air-tight sachets, corresponding 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: phenoxymethylpenicillin potassium 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 
phenoxymethylpenicillin potassium are dissolved in this solution with 
stirring. 
After defoaming in vacuo, the solution is added dropwise by means of the 
Cryopel metering device to an immersion bath containing liquid nitrogen 
and pellets are thus formed. The water is removed by subsequent 
freeze-drying. 
2.31 g of the dried pellets (corresponding to an average content of 
phenoxymethylpenicillin 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 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 is dissolved completely in 1 kg of water with stirring. 
The gelatin granules are preswollen in the remaining amount of water and 
dissolved at 40.degree. 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.degree. C. and 40.degree. C. 
and then filled into opaque hard gelatin capsules having an average 
content of 10 mg of dihydrocodeine tartrate. In the dissolution test 
(apparatus according to USP XXI, 500 ml of water, 37.degree. C., 50 rpm), 
the pharmaceutical form releases 70% of the active compound in 4.5 
minutes. 
The pellets obtained 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 
.alpha.-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.degree. C. Using an ultrasonic homogenizer, the active 
compound is emulsified in the gelatin solution at 50.degree. C. The 
oil-in-water emulsion is then mixed with glycerol and cryopelletized. The 
pellets obtained are dried as in Example 4. The pellets are metered into 
opaque hard gelatin capsules containing 25 mg of .alpha.-tocopherol 
acetate. 
The pellets obtained have an opaque and lustrous appearance. 
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.degree. C. after addition of the remaining water. The active compound 
is homogeneously dispersed in this solution with stirring and the solution 
is 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 obtained are transparent and lustrous. 
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 
dissolved at 70.degree. C. The acetylsalicylic acid is dispersed in the 
solution obtained and the sorbitol is then added. 
The matrix material obtained is added dropwise to liquid nitrogen by means 
of the apparatus shown in FIG. 2 at a temperature of the nozzles of 
70.degree. C. The shock deep-frozen pellets are classified with cooling 
and have a uniform size of 8 mm. 
The round shaped articles are filled into a dose dispenser and--depending 
on the indication--can be administered individually. 
Pellets prepared in this way are palatable and increase the tolerability, 
in particular in the case of cardiac infarct prophylaxis. 
EXAMPLE 8 
Production of an ibuprofen immediate-effect pharmaceutical form based on 
pellets. 
Demonstration 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 is preswollen for 45 min in the water and then dissolved 
at 60.degree. C. The micronized ibuprofen is homogeneously dispersed in 
the gelatin solution and the resulting material is 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.degree. C. and 40.degree. C. the pellets are filled into hard 
gelatin capsules containing 400 mg of ibuprofen. 
In an in vivo human study, the immediate-effect form described was 
comparatively tested against a commercially available ibuprofen 
immediate-effect formulation which contains 600 mg of ibuprofen (in 
micronized form). 
The following average plasma concentration-time values result, indicated in 
.mu.g of ibuprofen/ml of plasma. 
______________________________________ 
Formulation Comparison 
Time (h) from Example 8 
preparation 
______________________________________ 
1 27.5 5 
2 35 19 
2.5 37 23 
3 35 22 
5 17.5 15 
7 8 6 
9 5 5 
______________________________________ 
EXAMPLE 9 
Production of a flurbiprofen immediate-effect pharmaceutical form based on 
pellets, demonstration of the increased bioavailability. 
Recipe: 
50 g of flurbiprofen, micronized powder 
50 g of gelatin powder 220 Bloom 
175 g of water 
The gelatin powder is preswollen for 45 min in the water and then dissolved 
at 60.degree. C. The micronized flurbiprofen is homogeneously dispersed in 
the gelatin solution and the resulting material is 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.degree. C. and 40.degree. C. the pellets are filled into hard 
gelatin capsules containing 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 
.mu.g of flurbiprofen/ml of plasma. 
______________________________________ 
Formulation Comparison 
Time (h) from Example 8 
preparation 
______________________________________ 
0.5 6.5 2 
1 8 6 
2 6 4.5 
3 6 3.5 
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 pharmaceutical 
auxiliaries. After defoaming under vacuum, the suspension is shaped to 
give pellets by dropwise addition at room temperature by means of the 
Cryopel.RTM. metering device to an immersion bath containing liquid 
nitrogen. 
The water is removed by subsequent freeze-drying and round shaped articles 
are obtained, after classification, 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.degree. C.) within 20 seconds and release the amount of nifedipine 
contained. 
The dried shaped articles are filled into a dark-colored dose container 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 0.1N HCl, 
paddle, 75 rpm, 37.degree. 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 K 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 pharmaceutical, cosmetic or other shaped articles according to the 
invention such as powders, granules, essentially symmetrical aggregates 
etc. if required within the scope of the present invention.