Silicon dioxide-containing compositions and process for their preparation and use

A process for the incorporation of active materials into silicon dioxide-containing carrier materials, comprises encapsulating the active material with liquid polyalkoxysiloxane, polyorganoalkoxysiloxane or a mixture thereof and subsequently effecting hydrolytic polycondensation of the siloxane. The resultant enveloped active material has readily controllable release properties.

BACKGROUND OF THE INVENTION 
This invention concerns silicon dioxide-containing compositions and a 
process for the preparation thereof whereby active materials are 
incorporated therein such that the active materials are stabilized and/or 
their rate of liberation is controlled. 
In formulating active materials, especially pharmaceutical or pest 
combating agents, various processes have been employed to mask flavor, 
reduce volatility, stabilize against oxidative and/or hydrolytic 
decomposition, achieve better handling during production and 
administration etc. Recently, measures to control the rate of liberation 
of active materials, i.e., to achieve a desired retarding has received 
much attention, e.g., for the production of depot pharmaceuticals. The 
most important retardation technique involves binding of the active 
material to carrier substances or embedding of the pharmaceuticals in 
suitable encapsulating or matrix substances. 
When embedding into a matrix or binding onto a carrier via asorptive forces 
or ion exchange is employed, in addition to a large number of organic 
adjuvant materials (macromolecules, fats), inorganic materials such as 
barium sulphate, calcium sulphate, calcium phosphate, titanium dioxide and 
the like are also recommended. However, for the encapsulating of 
particles, organic substances, mostly natural, semi-synthetic or synthetic 
macromolecules, are used exclusively. A large range of suitable adjuvant 
materials is thereby available, comprising essentially hydrophilic 
colloids, such as gum arabic, gelatine, cellulose ethers or swellable 
materials, such as methacrylic acid derivatives, cellulose esters, as well 
as plastics, such as PVP, polyamide, polyethylene, polyacrylates, 
polystyrene and a series of other mixed polymers. 
In spite of this multiplicity of adjuvant materials, and of a highly 
developed technology, conventional formulations exhibit a series of 
disadvantages which, in part, considerably limit their application and 
also lessen the reliability of achieving the desired liberation features. 
This is especially true for conventional depot formulations. 
On the other hand, especially when organic adjuvant materials are used, 
liberation of the active material in the gastrointestinal tract is very 
difficult to control. This disadvantage is due to the fact that the 
liberation of the active material by diffusion from a matrix or through 
porous capsule walls or after dissolution of an encapsulating material, is 
very considerably dependent upon the conditions of the surroundings, such 
as e.g. pH, ion concentration, enzyme influences and the like. Due to 
these conditions, dissolution or swelling of the matrix or enveloping 
substances often occurs, whereby the ensuing nature and rate of liberation 
of the active material often cannot be anticipated. In many cases, the 
complete availability of the active materials is impaired by binding to 
carriers, whereby exact dosaging becomes difficult. 
On the other hand, compatibility of the active material with the carriers 
is often unsatisfactory, especially in the pharmaceutical field. For 
example, the adjuvant materials can burden the digestive tract or may even 
be fully incompatible for certain patients, e.g., those who must avoid 
sugars, fats, etc. Moreover, due to expansion and/or swelling of 
materials, unpleasant feelings of satiation can be produced and even 
potential danger can exist if the polymers used still contain residual 
parts of toxic components, such as, e.g., catalysts, accelerators, 
hardeners, plasticisers, stabilizers, filling materials or unreacted 
monomers. 
Furthermore, due to the very large number of recommended adjuvant and 
additional materials, an enormous number of combinations are possible. 
Consequently, the development of a pharmaceutical form for a new active 
material becomes a time-consuming and expensive proposition. In addition, 
the formulation process itself, e.g, microencapsulation, requires a high 
degree of precision with attendant complicated and expensive apparatus 
when reproducable results are required. 
SUMMARY OF THE INVENTION 
Accordingly, it is an object of this invention to provide a process of 
incorporating active materials into carriers which not only can be carried 
out with simple adjuvant materials, but which also permits the liberation 
behavior of the active materials in question to be directly controlled by 
selection of a few easily controllable parameters. 
It is another object of this invention to provide such a process which 
employes a readily compatible, non-toxic and non-digestable carrier 
material which retains its essential structure independent of the 
surrounding medium, and thereby renders possible a complete liberation of 
the active material, especially a pharmaceutical, with reproducible speed. 
Surprisingly, it has now been found that these objects can be achieved 
simply, by incorporating active materials in a novel manner into silicon 
dioxide-containing carrier materials. 
In a process aspect, this invention relates to a process for the 
incorporation of active materials into a silicon dioxide-containing 
carrier material, which comprises encapsulating the active materials, 
optionally together with additional carrier materials, with liquid 
polyalkoxy and/or polyorganoalkoxysiloxanes and subsequently effecting 
hydrolytic polycondensation of the enveloping material. 
Polyalkoxysiloxanes and polyorganoalkoxysiloxanes containing alkoxy groups 
having 1-4 carbon atoms are preferred. 
In a composition aspect, this invention relates to silicon 
dioxide-containing active material compositions which comprise active 
materials which are incorporated in silicon dioxide and/or 
organic-modified silicon dioxide as defined herein, produced by hydrolytic 
polycondensation of polyalkoxy- and/or polyorganoalkoxysiloxanes, the 
SiO.sub.2 having a selectable and reproducible pore structure. 
In a method of use aspect, this invention relates to a method of 
administering an active ingredient with a desired liberation rate which 
comprises administering the active ingredient incorporated in silicon 
dioxide and/or organic-modified silicon dioxide as defined herein, 
produced by hydrolytic polycondensation of polyalkoxy- and/or 
polyorganoalkoxysiloxanes, the SiO.sub.2 having a selectable and 
reproducible pore structure. 
DETAILED DISCUSSION 
The process of this invention and the compositions produced thereby exhibit 
a series of advantages. For the process, a very good reproducibility of 
results is achieved without use of expensive apparatus and/or complicated 
techniques. The carrier and enveloping material possess a precisely 
definable pore structure which can be reproducibly selected within a wide 
range. Moreover, they suffer no changes due to swelling in the 
physiological medium of the gastrointestinal tract. Excellent 
compatibility with the active ingredient is provided, since all of the 
starting materials and the final encapsulating material are fully 
compatible. In particular, however, the desired liberation behavior can be 
directly controlled by selection of a few easily controllable parameters, 
such as, the average particle diameter of the active material to be 
enveloped, the average particle diameter of the particles obtained after 
encapsulating, the layer thickness and average pore diameter of the 
polysilicic acid gel envelope surrounding the active material and also the 
nature of any organo groups introduced into the additional carrier and/or 
enveloping material. 
It is known that by hydrolytic polycondensation of polyalkoxy- or 
polyorganoalkoxysiloxanes, polysilicic acid gels with defined and directly 
controllable hollow space structures can be produced. See, for example, 
German Patent Specification No. 2,155,281 and published German Patent 
Application No. 2,357,184. A process is also known by which a non-porous 
material can be coated with a porous silicon dioxide. (See U.S. Pat. No. 
3,922,392 and references incorporated therein.) However, these processes 
are used exclusively to produce sorption materials for chromatography, so 
that no suggestion can be deduced from them that it could be advantageous 
to incorporate active materials into silicon dioxide-containing carrier 
materials. In particular, the prior art has failed to recognize that by 
use of the process according to this invention, the liberation behavior of 
active materials can be controlled. 
Surprisingly, however, using the process of this invention, quite varied 
types of liberation phenomena can be achieved. Thus, very rapid liberation 
of the active material to the surrounding medium can be effected. On the 
other hand, liberation of the active material can be, ab initio, delayed 
and made to remain constant over a period of time which can be controlled 
as desired. Alternatively, a definite proportion of the active material 
can be given off very rapidly as an initial dose while the remainder is 
continuously liberated over a comparatively long period of time, whereby 
not only the proportion of the initial dose but also the period of the 
continuous liberation can be selected. 
All these advantages can be achieved simply and without impairment of the 
active materials by appropriate hydrolytic polycondensation of the 
enveloping material applied in liquid form. Hitherto, such an 
incorporation or micro-encapsulation of active materials, precisely 
adapted to the particular liberation requirements, was not possible. 
The process of this invention can be modified in various ways, depending 
upon the desired liberation behavior of the active material. 
According to one process variant, the solid active material is dispersed in 
liquid polyalkoxy or polyorganoalkoxysiloxane. The dispersion is then 
subjected to a hydrolytic polycondensation. The resultant solid 
polysilicic acid gel, possibly organo modified, contains the active 
material. After it is dehydrated and dried, as a rule it is also ground 
and sieved. 
In an alternate aspect, the active material is dissolved, suspended, 
emulsified or otherwise dispersed in a solution of a polyalkoxy- or 
polyorganoalkoxysiloxane. This mixture is subsequently internally or 
externally catalysed to effect a hydrolytic polycondensation. After 
dehydration and drying, as above, the product particles are deaggregated, 
such as by grinding to render them suitable for use. 
In still another aspect of the process of this invention, the active 
material is suspended in liquid polyalkoxy- or polyorganoalkoxysiloxane. 
Subsequently, this suspension is dispersed, with stirring, in water 
containing a polycondensation catalyst. After a short time, the droplets 
which thereby form solidify into solid, spheroidal particles of enveloped 
active materials. Thereafter, they are optionally washed and then dried. 
Grinding is not generally required. 
In a further process aspect, the active material, together with a carrier 
material, can be encapsulated with a liquid film of polyalkoxy- or 
polyorganoalkoxysiloxane which, by subsequent hydrolytic polycondensation, 
condenses to a porous layer of polysilicic acid gel. As for the preceeding 
aspect, the only post-treatment is a drying process since the particle 
size is essentially predetermined by the carrier material. 
The starting materials for the process of this invention, are 
polyalkoxysiloxanes and/or polyorganoalkoxysiloxanes. There are known 
materials whose production is described, for example, in German Patent 
Specification No. 2,155,281 and published German Patent Application No. 
2,357,184 (U.S. Pat. No. 4,017,528), the disclosures of which are hereby 
incorporated by reference. Such starting materials wherein alkoxy is 
ethoxy are particularly preferred. 
According to these conventional processes, a tetraalkoxy- or 
organoalkoxysilane or a mixture thereof is conveniently dissolved in a 
water-miscible solvent, e.g., ethanol, and mixed, with stirring at room 
temperature, with an appropriate amount of water. proportions of 
ingredients and reaction conditions are selected in accordance with the 
cited references to obtain the desired molecular weights, viscosity, etc. 
of the polyalkoxysiloxanes and/or polyorganoalkoxysiloxanes produced. The 
latter serves as a starting material for the process of this invention. It 
is in partially polycondensed form as described fully in the foregoing 
references. The final complete condensation occurs during the process of 
this invention in forming the coating on the active material. 
To the silane are then added materials which provide hydrogen ions to cause 
hydrolysis. Carrying out this hydrolysis with aqueous hydrochloric acid is 
especially practical. The resultant homogeneous solution is stirred, while 
dry nitrogen is bubbled in, until a temperature increase can no longer be 
measured indicating the termination of the partial hydrolytic 
polycondensation, the extent of which is controlled, for example, by 
control of the amount of water added. The extent of condensation also 
controls the molecular weight and viscosity of the product obtained. Thus, 
the degree of completion of the polycondensation is determined by the 
desired values for these parameters. 
Most of the solvent is distilled off from the reaction mixture. The residue 
obtained, which mainly contains the polyalkoxy- or 
polyorganoalkoxysiloxane, is advantageously tempered at an elevated 
temperature, preferably in the range of from 120.degree. to 140.degree. 
C., for at least 24 hours. Subsequently, the tempered reaction product is 
treated, again at an elevated temperature (e.g. 150.degree. to 170.degree. 
C.), under reduced pressure (10.sup.-1 to 10.sup.-3 mm Hg) in order to 
remove traces of solvents, water and unreacted products. All these 
procedures take place under a nitrogen atmosphere. A storable polyalkoxy- 
or polyorganoalkoxysiloxane is obtained. Its Si atoms are partially 
cross-linked via Si-O-Si bridges. They also still possess alkoxy groups 
for further condensation, and possibly organo groups. The degree of 
cross-linking and thus also the viscosity and the molecular weight of the 
product depend upon the amount of water used and thus can be varied over a 
wide range. 
For the production of polyorganoalkoxysiloxanes, a very wide variety of 
organoalkoxysilanes can be used. The organo radical can essentially be 
chosen as desired. Basically, it need only possess stability to hydrolysis 
so that, during the production of the modified silicon dioxides, no 
undesirable change of the organic group takes place. Since the hydrolysis 
conditions to be employed are, however, very mild, the choice of a 
suitable organic radical is scarcely limited thereby. 
In general, suitable organoalkoxysilanes have the formula 
EQU R.sub.n -Si(OR.sup.1).sub.4-n 
wherein R is alkyl, aryl or aralkyl, R.sup.1 is alkyl of 1-4 carbon atoms 
and n is 1, 2 or 3, preferably 1. R may be substituted as discussed below. 
Especially preferred are organotriethoxysilanes, which possess especially 
good spatial cross-linking capability. When R is a relatively large and 
bulky organic radical, n is preferably 1. 
R preferably possesses at most 20 carbon atoms. Suitable alkyl radicals, 
have straight or branched chains. The former are preferred from the point 
of view of the use of the end products since the diffusion properties of a 
gel modified with straight chain alkyl radicals are in many cases better 
than those of a gel modified with bulkier branched chain alkyl radicals. 
Because of the ready availability of the starting materials, preferred 
aryl groups are phenyl and naphthyl, as well as substituted phenyl and 
naphthyl radicals. Preferred aralkyl radicals include benzyl and 
substituted benzyl radicals, as well as the corresponding naphthylmethyl 
radicals. 
Depending upon the properties desired in the end product, all R radicals 
can be variously substituted not only by functional but also by inert 
groups. Since these substituents do not impair the process of this 
invention, the selection of particular substituents is not critical and 
detailed listing is not given. In this regard, the process of this 
invention is highly immune to adverse effect from the presence of any 
substituent. Many suitable substituents are listed in the foregoing 
references. 
Depending upon the nature of the radical R in the starting material, there 
are obtained hydrophobic or hydrophilic organo-silicon dioxides. For 
example, with benzyl or phenyl triethoxysilane, a strong hydrophobic 
effect is achieved. On the other hand, hydrophilic organo-silicon dioxides 
are produced by the use of appropriately substituted 
organo-trialkoxysilanes or by appropriate substitution on the 
organo-silicon dioxides obtained. As a rule, according to known general 
principles, the more polar the substituents in the radical R are the more 
hydrophilic is the resulting organo-silicon dioxide and vice versa. 
By appropriate selection of the amount of the modifying organo component, 
the specific pore volume of the finally produced silicon dioxide can be 
controlled. With increasing content of organo component, the specific pore 
volume increases strongly. Furthermore, the relative increase of the 
specific pore volume is influenced by the size of the radical R of the 
organotrialkoxysilane, i.e., the specific pore volume increases with 
increasing size of the radical R. (See foregoing references.) 
The specific pore volume can also be selected by choice of a suitable 
average molecular weight or viscosity of the polyalkoxysiloxane employed. 
Polyalkoxysiloxanes with low viscosity are, in comparison with those with 
high viscosity, relatively slightly cross-linked. For a given content of 
organo components, the specific pore volume of an organo-silicon dioxide 
prepared with a low viscosity polyalkoxysiloxane is higher than that of 
the corresponding product obtained using highly viscous 
polyalkoxysiloxanes. Achievement of a specific pore volume may be 
accomplished by conventional procedures. 
For use in the process of the invention, those polyalkoxy- or 
polyorganoalkoxysiloxanes are especially preferred which possess an 
average molecular weight of about 600 to about 3000 g./mol, corresponding 
to a kinematic viscosity of about 5 to about 20,000 cSt. The molecular 
weight can be determined by conventional methods, e.g. with a steam 
pressure osmometer. The thus determined values are weight average 
molecular weights. 
The viscosity of a given polyalkoxy- or polyorganoalkoxysiloxane is 
directly related to the average molecular weight. Therefore, complete 
characterization of the polyalkoxy or polyorganoalkoxysiloxanes suitable 
for use in this invention, is accomplished by the foregoing specification 
of the nature of the alkoxy and the nature and content of optional organo 
groups, and by specification of the appropriate average molecular weight 
or viscosity selection of any of which determines the others. 
If the encapsulation is accomplished by suspending or dispersing the active 
material in the liquid polyalkoxy- or polyorganoalkoxysiloxane, active 
material particles having a size from about 50 to about 500 .mu.m. are 
generally employed. However, when dictated by the desired end uses, much 
larger and/or smaller particles can also be employed. Adjustment, of 
course, can be made for the added diameter due to the thickness of the 
coating. The viscosity of the polyalkoxy- or polyorganoalkoxysiloxane is 
chosen so that a uniform suspension is obtained. Therefore, the viscosity 
should preferably be greater than about 600 cSt. 
If the active material is enveloped by treatment with a solution of the 
polyalkoxy- or polyorganoalkoxysiloxane in an organic solvent, the 
viscosity of the siloxane used only plays a subordinate role. For example, 
the solubility of the siloxane decreases with increasing viscosity, i.e., 
molecular weight. Thus, the viscosity must be chosen accordingly. Suitable 
solvents include those which, on the one hand, are able to dissolve the 
polyalkoxy- or polyorganoalkoxysiloxane, on the other hand, are compatible 
with the active material used and which, in addition, after 
polycondensation has taken place, can easily be removed from the resultant 
product. Not only polar but also non-polar solvents can be used. Suitable 
solvents include alcohols, e.g., methanol, ethanol and n-propanol or 
isopropanol; ketones, e.g., acetone or methyl ethyl ketone; hydrocarbons, 
e.g., cyclohexane, n-pentane, benzene or toluene; ethers, e.g., diethyl 
ether, dioxane or tetrahydrofuran; and other solvents which satisfy the 
mentioned criteria. 
The amount of the solvent added should generally be sufficient to produce 
at least about 50% solutions of the polyalkoxy- or 
polyorganoalkoxysiloxane, preferably from 50 to 80%. If the active 
material is dispersed or suspended in the solution of the polyalkoxy- or 
polyorganoalkoxysiloxane and not dissolved the suitable particle sizes for 
the active material range from 50 to about 500 .mu.m. 
When the active materials are enveloped via active material/polysiloxane 
suspension and subsequently subjected to a polycondensation in aqueous 
phase, active material particles having a diameter of about 30 to about 
150 .mu.m. should be used. These particles are first suspended in the 
liquid polyalkoxy- or polyorganoalkoxysiloxane and subsequently this 
suspension is dispersed in the aqueous phase by vigorous stirring. Active 
material-containing polysiloxane droplets thereby result, the size of 
which are dependent upon the speed of stirring. Since the droplet size 
determines the size of the solid active material carrier which results 
from the subsequent polycondensation, the speed of stirring generally 
should be chosen by routine experimentation so that particles result with 
a diameter of from about 200 to about 1000 .mu.m. If final particles of 
other sizes are desired, different stirring rates can be employed. 
Adjustments for the thickness of the coating can also be made if 
necessary. 
In the suspension, the aqueous phase preferably contains ammonia as the 
polycondensation catalyst. By adjustment of the concentration of the 
catalyst, the pore structure of the resultant silica gel can be influenced 
as described in German Patent Specification No. 21 55 281. However, 
especially for readily water-soluble active materials catalyst 
concentrations should be selected to be as high as possible in order to 
achieve a solidification of the droplets in the shortest possible time, 
preferably a few minutes. This is achieved e.g. by an approximately 25% 
ammonia solution. As described in German Patent Specification No. 21 55 
281, the aqueous phase can also contain alcohol. However, it is preferred 
that no alcohol be added in order to inhibit the dissolution of the active 
material form the carrier particles. In addition or alternatively, 
materials can be added to reduce the solubility of the active material in 
the aqueous phase, e.g., common salt. 
As mentioned above, the active material together with a carrier material 
can be encapsulated with a thin film of a polyalkoxy- or 
polyorganoalkoxysiloxane. In this embodiment, for example, active 
material-containing carrier particles can be mixed with a solution of a 
polyalkoxy- or polyorganoalkoxysiloxane, whereupon, after removal of the 
solvent, e.g., under reduced pressure, polysiloxane remains behind as a 
thin film on the surface of the particles. Any of the above-mentioned 
solvents can be used. The solvent is preferably chosen so that the active 
material will not be separated from the carrier material. The liquid 
polyalkoxy- or polyorganoalkoxysiloxane can alternatively be directly 
applied to the carrier particles without solvents. 
The active material can be bound to the carrier material in various ways. 
For example, the active material can be adsorbed on a porous carrier 
material, can be pressed onto the carrier, can be microencapsulated in a 
carrier material or can be bound to the carrier in some other conventional 
manner. The ratio of this amount of active ingredient to carrier is 
generally from 100:1 to 1:100, preferably from 10:1 to 1:10 on a weight 
basis. 
Suitable carrier materials include conventional materials compatible with 
the active ingredient, e.g., pharmaceuticals, plant protectors, pesticides 
etc. However, spheroidal particles of porous silicon dioxide are 
preferred. The spheroidal, porous silicon dioxide particles are generally 
selected so that they liberate the active material practically without 
delay. Generally, for this purpose particles with a size of 50 to 500 
.mu.m. and with an average pore diameter of 20 to 400 A can be used. 
Generally, the particle size of the carrier is selected to correspond to 
the particle size desired for the final product in view of the end use. 
Adjustments for the thickness of the coating to be applied can also be 
made if required. The incorporation of the active material into the 
particles is conventional. For example, the porous silica gel particles 
can be brought into contact with a solution of the active material, 
whereby an adsorption equilibrium ensues. The particles are then separated 
having active material adsorbed on them. They are then dried. 
After the active material is enveloped with the liquid polyalkoxy- or 
polyorganoalkoxysiloxane, the latter is subjected to complete hydrolytic 
polycondensation in a known manner in the presence of water and a 
catalyst. (See foregoing references.) Suitable catalysts include acids and 
bases. Thus, for example, as for the partial polycondensation used to 
prepare the liquid starting materials hydrochloric acid can be used. Basic 
catalysts are preferred, e.g., alkali metal hydroxides. However, ammonia 
or ammonium hydroxide is especially preferred. Moreover, the active 
material itself can constitute the catalyst, especially when present in 
the form of a base having a pK.sub.b value of less than 6.5. 
From German Patent Specification No. 21 55 281 and published German Patent 
Application No. 23 57 184, it is known to add the catalyst together with 
an alcohol/water mixture. This procedure can be used in this invention 
with advantageous results, especially for polycondensations on enveloped 
carrier particles. However, for this use, the presence of an alcohol is 
not absolutely essential. The hydrolytic polycondensation, surprisingly, 
can also be effected by making water available in the form of water vapor. 
Thus, the reaction mixture can be exposed to a current of air previously 
passed through water. If the active material itself does not serve as 
catalyst, then the catalyst, e.g., ammonia gas, can also be supplied along 
with the water vapor-saturated air. 
During this complete hydrolytic polycondensation, the Si-O-alkyl groups, 
still present after the first condensation in the preparation of the 
starting materials, are hydrolysed to Si-OH groups and the corresponding 
alkanol. Adjacent Si-OH groups can then further crosslink, splitting off 
water and forming Si-O-Si bridges, so that finally a solid, porous 
polysilicic acid gel results which no longer contains alkoxy groups. This 
polysilicic acid gel will be either pure SiO.sub.2 or SiO.sub.2 modified 
by organo groups if the starting material contained a 
polyorganoalkoxysiloxane. 
By variation of the conditions used during the hydrolytic polycondensation, 
the pore structure of the resultant polysilicic acid gel can be selected 
in a known manner, e.g., by the selection of the nature and amount of the 
catalyst and of the amount of the optional solvent miscible with the 
polyalkoxy- or polyorganoalkoxysiloxane as disclosed in German Patent 
Specification No. 21 55 281. As a rule, the pore diameters of the 
polysilicic acid gels resulting from the hydrolytic polycondensation are 
between about 15 and about 400 A. 
Upon termination of the polycondensation, which usually is carried out at 
about 20.degree. to 80.degree. C. and can last from a few minutes up to 
several hours, the product is generally freed from adhering water, 
alcohol, optional solvent and catalyst. If further removal of such 
contaminants is necessary and/or advantageous, this can be easily 
accomplished by drying at an elevated temperature, e.g., 50.degree. to 
80.degree. C., and reduced pressure, e.g., up to 50 mm.Hg. If even trace 
amounts of these materials are to be removed, it may be necessary to 
extend the drying process over several hours. 
When the polycondensation does not involve discrete particles such as the 
carrier particles or the droplets dispersed in the aqueous phase, a 
deaggregation of the product into particles suitable for use is generally 
necessary. In general, this deaggregation can be performed by a simple 
grinding. By control of the fineness of the grinding and of an optional 
subsequent sieving, particles of an optimum size for the particular use 
can be obtained. 
The optimum particle size of the products produced by the process of this 
invention will vary very greatly according to the field of use and is 
selected in accordance with conventional considerations for each field. In 
this respect, there is no limitation of the process of this invention. For 
example, if pharmaceutically active materials for oral administration are 
prepared the final particles prepared by this invention will generally 
have sizes from about 200 to about 2000 .mu.m. However, for other fields 
of use, these values may be considerably larger or smaller. 
The active material content of the products produced by the process of this 
invention can also be varied within wide limits. Generally, contents 
between 1 and 30 wt.% are suitable. When required, contents above or below 
this range can of course be employed. A content of about 2 to 20% is 
preferred. These contents, of course, are achieved by the corresponding 
selection of proper weight ratio between active material and polyalkoxy- 
or polyorganoalkoxysiloxane, suitably adjusted for weight loss due to 
polycondensation. Typical such ratios are from 1:5 to 1:200, preferably 
from 1:5 to 1:50. 
The thickness of the enveloping layer is essentially dependent upon the 
amount of liquid polyalkoxy- or polyorganoalkoxysiloxane used with respect 
to the amount of active material or of active material plus carrier, and 
the particle size of the latter. In general, for the enveloping of active 
materials bound onto a carrier material, layer thicknesses from about 1 to 
about 20 .mu.m. are preferred. If the particles to be used are obtained by 
grinding, then no uniform layer thickness will result since the broken 
surfaces, formed randomly by the grinding, will provide varying distances 
between active material particles and exposed surfaces. Some of the active 
material particles will be only partially covered by the porous 
encapsulating layer. This phenomenon can be utilized when an increased 
initial dose followed by a slow liberation of the remaining content of 
active material is desired. Also when the active material carriers are 
obtained by dispersion of an active material/polysiloxane suspension in an 
aqueous phase, the active material is, as a rule, so non-uniformly 
distributed that no uniform layer thickness results. 
The liberation behavior of the active material carriers produced by the 
process of this invention can be controlled by variation of a series of 
parameters. Thus, as mentioned above, for active materials which have been 
incorporated by suspension in liquid polyalkoxy- or 
polyorganoalkoxysiloxane, and subsequent polycondensation, drying, 
grinding and sieving, liberation can be made to occur in such a manner 
that after a very rapid release of an initial dose, the remaining content 
is slowly given off over a comparatively long period of time. 
Surprisingly, for the pharmaceutical products produced by this process, at 
least when the content of active material is not too high, e.g., from 1 to 
15%, after the release of the initial dose, the liberation of the 
remainder takes place practically continuously. Moreover, its release 
curve does not display an asymptotic approximation to the limiting value 
of complete release, as observed in the case of other conventional matrix 
systems. That is, complete usage of the active ingredient can be achieved. 
For this system, the proportion of the initial dose is essentially 
determined by the choice of the relative particle sizes of the active 
material and of the active material carrier combination formed by the 
grinding step. Thus, for a given particle size of the active material, the 
finer one grinds the polysilicic acid gel the greater is the proportion of 
active material which is given off very rapidly as an initial dose since 
the surface area composed of active ingredient is thereby increased. This 
same effect, i.e., increase of the initial dose, can also be achieved for 
a given size of the active material carrier, by increasing the particle 
size of the active material. The nature of the subsequent continuous 
release, taking place after the liberation of the initial dose, can be 
controlled by selection of the reaction temperature of the 
polycondensation and by suitable choice of the polyalkoxy- or 
polyorganoalkoxysiloxane employed. An increase of the reaction temperature 
causes a simultaneous reduction of the initial dose and a more rapid 
continuous release. Temperature can be selected by routine parametric 
experimentation. Influence on the continuous release rate by the starting 
material siloxane is effected by suitable choice of hydrophobic and/or 
hydrophilic properties. 
Release takes place in a different manner when the active material is 
incorporated by dissolution in the liquid polyalkoxy- or 
polyorganoalkoxysiloxane optionally in the presence of additional 
solvents, followed by subsequent polycondensation, drying, grinding and 
sieving. Since a complete enveloping is achieved in this case, liberation 
is thereby essentially dependent upon the porosity which, in turn, can be 
conventionally controlled as indicated above, e.g., by the amount of 
solvent or catalyst added. For active material carriers obtained by 
dispersion of an active material/polysiloxane suspension in an aqueous 
phase and subsequent polycondensation, liberation takes place in a manner 
analogous to that from a matrix system but a marked initial phase is 
observed. The behavior displayed by matrix systems is also exhibited by 
the liberation of active material from the active material carriers which 
are formed by enveloping active material together with a carrier material, 
followed by polycondensation. 
For the latter process embodiment, liberation behavior can also be 
controlled by several other parameters. The thickness of the encapsulating 
layer (mantle) can be varied, for example by changing the ratio of the 
surface area of the carrier particles to the amount of polyalkoxy- or 
polyorganoalkoxysiloxane. As a rule, the layer thickness is varied between 
1 and 20 .mu.m. Furthermore, the pore size of the enveloping layer can be 
varied by the selection of the nature and amount of the catalyst used, 
such as is disclosed in German Patent Specification No. 21 55 281. 
According to this conventional technique, by selection of an hydroxyl ion 
concentration, which is preferably supplied by aqueous ammonia, in the 
range of from 1.times.10.sup.-3 to 1.5 moles per mole of Si in the 
polyalkoxy- or polyorganoalkoxysiloxane used, average pore diameters are 
obtained which lie in the range between about 30 and about 800 A.degree., 
respectively. 
The liberation behavior is also strongly influenced by nature of the organo 
groups introduced into the enveloping layer by employment of a 
polyorganoalkoxysiloxane in the process. The polysilicic acid gel 
resulting after the hydrolytic polycondensation is modified by organo 
groups not only in the interior but also on its surface. In this way, the 
hydrophilic or hydrophobic character of the enveloping layer can be varied 
in any desired manner by selection of appropriate hydrophilic or 
hydrophobic organo groups by conventional considerations. The diffusion of 
the active material through the enveloping layer can thereby be 
influenced. 
The active material carriers produced by the process of this invention can 
be used in numerous fields depending on the nature of the active 
ingredient. For example, pharmaceutical compositions with controllable 
active material liberation can be very advantageously produced for use in 
man and animals. Production of compositions for oral or rectal 
administration is preferred, but other active material carriers, e.g., for 
implantation, can also be readily produced. 
Active materials having other uses can also be incorporated with the same 
success, e.g., pest combatting agents, plant protection agents, 
fertilizers, dyestuffs, aroma-generating materials and others. Generally, 
the process of this invention can always be used when controlled 
liberation of the active material is required or desirable. 
The active material carriers can be used directly as produced by the 
process of this invention, but they also can be subsequently processed 
into a form suitable for the intended purpose. For example, they can be 
combined with additional carriers for adjuvant materials or even with 
additional active materials. The nature of the additional materials and 
the final form of the composition depend upon the conventional 
requirements of the field of use in question. For example, for production 
of pharmaceutical compositions, the active material carriers can be filled 
into capsules or pressed into dragees or tablets. 
By this invention, a simple process is thus available by which compositions 
can be prepared which are not only especially advantageous due to their 
stability and compatibility, but also in that the liberation behavior of 
the incorporated active material can be controlled in a reproducible 
manner by appropriate selection of a few, readily variable parameters. By 
suitable variation of the above-described process characteristics, a 
skilled worker, very quickly and in a systematic manner, can find an 
optimal solution for the most complex problems regarding the controlled 
liberation of an active ingredient for a given use. He need only carry out 
a few parametric-type experiments, since the influence of the process 
characteristics on the structure of the silicon dioxide-containing carrier 
material is known from the literature. For example, depot and retard 
forms, compositions acting over extended time periods and those with 
variable initial release doses can be produced.

Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extents. The following preferred specific embodiments are, 
therefore, to be construed as merely illustrative, and not limitative of 
the remainder of the disclosure in any way whatsoever. 
The liberation behavior indicated in the drawings was measured "in vitro" 
with 100 ml. of a desorption liquid (either aqueous hydrochloric acid of 
pH 2 or Sorensen's buffer of pH 7.4) at a temperature of 37.degree. C. and 
a stirring speed of 80 rotations per minute. 
EXAMPLE 1 
In 9 parts by weight of polyethoxysiloxane (kinematic viscosity 1000 cSt) 
was suspended, by stirring, one part by weight of codeine base (particle 
size 100 to 160 .mu.m.; pK.sub.b value 6.1). The stirring was continued 
until, with commencing polycondensation, the viscosity increased strongly. 
To complete the polycondensation, the mixture was flushed with water 
vapor-saturated air. Thereafter, the product was dried under reduced 
pressure over phosphorus pentoxide, ground and sieved to a desired 
particle size. 
The layer thickness of the enveloping layer was, on the average, about 50 
.mu.m. The pore diameter was, on the average, about 20 A. 
FIG. 1 shows: 
(a) the liberation of the active material from active material carriers 
having a particle size of 315 to 800 .mu.m. at a pH of 7.4 
(b) as (a), only a pH of 2 
(c) the liberation of the active material from active material carriers 
having a particle size of 800-2000 .mu.m., at a pH of 7.4. 
FIG. 1 shows that the liberation behavior is practically independent of the 
pH value but that the inital dose decreases with increasing particle size 
of the active material carrier. 
EXAMPLE 2 
The procedure of Example 1 was followed except that codeine base with a 
particle size of 315 to 800 .mu.m. was incorporated. 
Average layer thickness: above 50 .mu.m. 
Average pore diameter: above 100 A. 
FIG. 2 shows the liberation of the active material from active material 
carriers with a particle size of up to 800 .mu.m.: 
(a) in the case where active material of a particle size of 315-800 .mu.m. 
was employed. 
(b) (From Example 1) in the case where active material of a particle size 
of 100-160 .mu.m. was employed. 
FIG. 2 shows that, for a given particle size of the active material 
carrier, the initial dose increases with increasing particle size of the 
active material. 
EXAMPLE 3 
The procedure of Example 1 was used, except that the temperature during 
polycondensation was increased from 20.degree. to 80.degree. C. 
FIG. 3 shows the liberation of the active material at a pH of 7.4 from 
active material carriers having a particle size of 315-800 .mu.m.: 
in the case where (a), polycondensation took place at 20.degree. C. and 
(b), polycondensation took place at 80.degree. C. 
Because of the larger pores, the release in (a) is faster than in (b). 
Average layer thickness: 
(a) about 50 .mu.m. 
(b) about 50 .mu.m. 
Average Pore diameter: 
(a) about 20 A 
(b) about 15 A 
EXAMPLE 4 
The procedure of Example 1 was used, except the proportion of codeine base 
was varied from 5 to 20 weight percent relative to the amount of 
polyethoxysiloxane. 
FIG. 4 shows that, with increasing active material concentration, first the 
initial dose is increased and that, for a higher concentration, the 
liberation of the active material is similar to that which is typical for 
matrix systems, i.e., the liberation is not uniform after the initial 
stage. 
The size of the active material carrier was between 315 and 800 .mu.m.; 
liberation medium pH: 7.4. 
The active material carriers were characterized as follows: 
(a) 20 wt.% codeine in the polyethoxysiloxane, corresponding to 30 wt.% in 
the product 
average layer thickness: about 30 .mu.m. 
average pore diameter: about 20 A 
(b) 10 wt.% codeine in the polyethoxysiloxane, corresponding to 15 wt.% in 
the product 
average layer thickness: about 50 .mu.m. 
average pore diameter: about 20 A 
(c) 5 wt.% codeine in the polyethoxysiloxane, corresponding to 7.5 wt.% in 
the product 
average layer thickness: about 65 .mu.m. 
average pore diameter: about 20 A 
EXAMPLE 5 
One part by weight polyethoxysiloxane was mixed with one part by weight of 
a 10% solution of codeine in acetone and further treated as in Example 1. 
The product possessed an average pore diameter of about 20 A. 
FIG. 5 shows that the liberation of the active material from this 
composition proceeds without an initial stage and asymptotically 
approaches a limiting value. 
EXAMPLE 6 
The procedure of Example 1 was used except that, instead of codeine, 
ephedrine and chlorpromazine with particle diameters of 80 to 100 .mu.m. 
were used. 
FIG. 6 shows the liberation from active material carriers with a particle 
size of 315-800 .mu.m. at a pH of 7.4: 
(a) contains ephedrine 
average layer thickness: about 50 .mu.m. 
average pore diameter: about 20 A 
(b) contains chloropromazine 
average layer thickness: about 50 .mu.m. 
average pore diameter: about 20 A 
FIG. 6 shows that the rate of liberation of ephedrine is comparable with 
that of codeine (FIG. 1), whereas chlorpromazine is liberated 
substantially more slowly. 
EXAMPLE 7 
A suspension of 1 part by weight of benzoic acid (particle diameter from 
100 to 160 .mu.m.) in 9 parts by weight of polyethoxysiloxane (kinematic 
viscosity 6000 cSt) was exposed to an air current which had been passed 
through an aqueous 0.5 normal ammonia solution. After hardening, the mass 
was freed from adhering ammonia, water and alcohol under a reduced 
pressure (about 50 mm.Hg) and at a temperature of 30.degree. C. for 12 
hours. It was then ground and sieved. 
Potassium chloride and salicyclic acid was incorporated in the same way. 
FIG. 7 shows that the liberation of the active material from these 
compositions produced with an external catalyst takes place very quickly. 
The liberation medium was water and the particle size of the active 
material carrier was 315-800 .mu.m. 
(a) contains KCl 
average layer thickness: about 50 .mu.m. 
average pore diameter: about 15 A 
(b) contains benzoic acid 
average layer thickness: about 50 .mu.m. 
average pore diameter: about 20 A 
(c) contains salicylic acid 
average layer thickness: about 50 .mu.m. 
average pore diameter: about 15 A 
EXAMPLE 8 
10 g. of a microporous silicon dioxide having the following 
characteristics: 
specific surface area A.sub.BET =2,030 m.sup.2 /g. 
specific pore volume V.sub.p =0.56 ml./g. 
average pore diameter D=1.7 nm. 
particle size dp=100 to 125 .mu.m. 
were shaken for 3 days with 500 ml. of a 0.025 molar solution of codeine in 
Sorensen's phosphate buffer having a pH of 7.4. Thereby, 0.6 millimole of 
codeine were adsorbed per 1 g. of silica gel. The particles were separated 
off and dried. 
0.5 g. of the so produced sorbate were mixed with a solution of 0.3 g. of 
polyethoxysiloxane (kinematic viscosity 600 cSt) in 15 ml. of cyclohexane. 
After the cyclohexane was removed at room temperature under reduced 
pressure, 10 ml. of a water/ethanol mixture (5:1, parts by volume) and 0.5 
ml. of concentrated aqueous ammonia solution were added thereto, shaken 
intensively for 30 minutes, washed with 10 ml. of ether and dried for 12 
hours at 60.degree. C. 
In the same way, 0.5 g. of sorbate were coated with a 
polyphenylethoxysiloxane, which carried a phenyl group on 30% of the Si 
atoms, and further treated as above. 
FIG. 8 shows the liberation behavior 
(a) of the uncoated carrier 
(b) of the carrier enveloped with polysilicic acid gel 
average layer thickness: about 15 .mu.m. 
average pore diameter of the enveloping layer: about 50 A 
(c) of the carrier enveloped with polysilicic acid gel modified with phenyl 
groups 
average layer thickness: about 15 .mu.m. 
average pore diameter of the enveloping layer: about 50 A. 
FIG. 8 shows that the liberation of the active material, which takes place 
very quickly from the uncoated sorbate, is delayed by enveloping with 
polysilicic acid gel and is delayed even more by enveloping with 
polysilicic acid gel modified with phenyl groups. 
EXAMPLE 9 
A suspension of 1 part by weight of methyl red sodium (particle diameter of 
100 to 160 .mu.m.) in 9 parts by weight of polyethoxysiloxane (kinematic 
viscosity of 1200 cSt) was exposed to an air current which had been passed 
through an aqueous 0.01 normal ammonia solution. After hardening, the mass 
was further treated analogously to Example 7. 
FIG. 9 shows that methyl red sodium is liberated up to 90% within 3 hours. 
The liberation medium was water and the particle size of the active 
material carrier was 315-800 .mu.m. 
The product possessed an average layer thickness of 50 .mu.m.; and the 
average pore diameter was about 20 A. 
EXAMPLE 10 
7 Parts by weight of polyethoxysiloxane (kinematic viscosity of 1200 cSt) 
and 3 parts by weight of methylpolyethoxysiloane (prepared from 1 mole of 
tetraethoxysilane and 0.5 mole of methyltriethoxysilane), as well as 3.3 
parts by weight of a solution of 1 part by weight of benzoic acid in 2 
parts by weight of ethanol 99% were mixed. 
The solution was exposed to an air current which had been passed through an 
aqueous 0.01 normal ammonia solution. The further treatment of the batch 
was analogous to that used in Example 7. 
FIG. 10 shows the liberation of the benzoic acid from the active material 
carriers with a particle size of 315-800 .mu.m. whereby, as compared with 
pure SiO.sub.2 carriers (FIG. 7b), a strong delay of the liberation in the 
aqueous medium is shown, but also a lower availability is shown. 
EXAMPLE 11 
In 9 parts by weight of polyethoxysiloxane (kinematic viscosity of 1200 
cSt), there was suspended one part by weight of codeine (particle size: 
80-100 .mu.m.). This suspension was subsequently dispersed in a glass 
beaker in 100 parts by weight of 20 wt.% sodium chloride solution 
containing 25% aqueous ammonia, with strong stirring (1600 rpm). The 
droplets formed solidified in the course of about 2 minutes. The 
supernatant liquid was thereafter filtered off through a frit with 
suction. The remaining solid was washed with 50 ml. of a 30% sodium 
chloride solution an then dried for 12 minutes at 50.degree. C., 50 mm.Hg. 
Round spheroids were formed. 
The active material carrier was characterized as follows: 
particle size: 355-800 .mu.m 
average layer thickness: 50 .mu.m. 
average pore diameter: about 30 A 
FIG. 11 illustrates the liberation of codeine at a pH of 2 (HCl). It is 
characterized by a high rate of liberation at the outset and a further 
release corresponding to that of the "matrix" type. 
The preceding examples can be repeated with similar success by substituting 
the generically or specifically described reactants and/or operating 
conditions of this invention for those used in the preceding examples. 
From the foregoing description, one skilled in the art can easily ascertain 
the essential characteristics of this invention, and without departing 
from the spirit and scope thereof, can make various changes and 
modification of the invention to adapt it to various usages and conditions 
.