Title of Invention	" A PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION COMPRISING PYROGENICALLY PRODUCED SILICON DIOXIDE"
Abstract	A process for the preparation of a pharmaceutical composition comprising pyrogenically produced silicon dioxide as a glidant for pharmaceutical active constituents and/or auxiliary substance comprising the following steps: de-aerating or decompressing the pyrogenically produced silicon dioxide; compressing (compacting) the pyrogenically produced silicon dioxid by roller compaction to band-like intermediates (Schulpen) to have a tamped density (according to DIN EN ISO 787-11) of from 185 to 700 g/1; breaking the band-like intermediates(Schulpen); optionally grading or sieving the broken band-like intermediates(Schulpen); - combining the broken band-like intermediates (Schulpen) with at least one pharmaceutically active constituent.

Title of Invention

" A PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION COMPRISING PYROGENICALLY PRODUCED SILICON DIOXIDE"

Abstract

A process for the preparation of a pharmaceutical composition comprising pyrogenically produced silicon dioxide as a glidant for pharmaceutical active constituents and/or auxiliary substance comprising the following steps: de-aerating or decompressing the pyrogenically produced silicon dioxide; compressing (compacting) the pyrogenically produced silicon dioxid by roller compaction to band-like intermediates (Schulpen) to have a tamped density (according to DIN EN ISO 787-11) of from 185 to 700 g/1; breaking the band-like intermediates(Schulpen); optionally grading or sieving the broken band-like intermediates(Schulpen); - combining the broken band-like intermediates (Schulpen) with at least one pharmaceutically active constituent.

Full Text	Pharmaceutical compositions The present invention relates to the use of Schulpen of pyrogenic silicic acid in pharmaceutical compositions. The Schulpen are used in this connection in particular as glidants to improve the bulk flow of powders. In a medicament it is generally possible to distinguish two functionally different substance groups, namely active ingredients and auxiliary substances. Active ingredients are characterised by their specific pharmacological activity. They represent the active constituent of a medicament. As such, they are also identified quantitatively on the packaging and on the package leaflet. Auxiliary substances, on the other hand, have no pharmacological activity. They are necessary in order to enable a suitable form of administration, namely the medicament, to be produced for the active ingredient. In general, the medicament contains a plurality of auxiliary substances having different functions. For example, auxiliary substances are used as fillers, binders, disintegrators, glidants, lubricants or release agents. When developing stable, effective medicaments which are easy to handle from active ingredient(s) and auxiliary substances, there are a large number of auxiliary substances which can be used. Highly disperse, pyrogenic silicon dioxide, for example Aerosil", is frequently used in pharmaceutical and cosmetic compositions. In solid product forms it can be used as a flow regulator, adsorbent and drying agent; in liquid and . semi-liquid product forms it can be used as a suspension stabiliser, framework-forming agent and gel-forming agent. It can also be used to increase the mechanical stability and the rate of disintegration of tablets. In addition, it can improve the distribution of the active ingredient. A particular disadvantage when working with highly disperse silicon dioxide is the formation of dust, because very high demands have to be met in terms of cleanliness when producing pharmaceutical and cosmetic products. A further disadvantage is the agglomeration behaviour of highly disperse silicon dioxide, which causes the product to come together as a result of hydrogen bridges and electrostatic charging. This results in larger lumps which do not pass through the relatively small sieve openings typical for the pharmaceutical industry. This is a particular problem in the case of silicon dioxides which have been compressed in order to minimise dust formation and have a higher bulk and tamped density. Sieving is very important in order to eliminate foreign bodies in pharmaceutical products. As a result, modern automatic weighing and screening devices cannot be used, which increases the possibility of contamination from human handling. When using highly dispersed silicon dioxide in pharmaceutical compositions improved flowability of mixtures prepared therewith would also be desirable in order to be able to achieve greater metering accuracy, for example when producing tablets and capsules. As a result it would be possible on the one hand to achieve lower variance of tablet and capsule weights and on the other hand to improve the economy of processes that result in such forms of administration. The object of the present invention is to provide pharmaceutical compositions which avoid the disadvantages of the prior art. The object is achieved by producing and using pharmaceutical compositions which contain Schulpen of pyrogenic silicon dioxide as auxiliary substance and which have a low dust content and at the same time can readily be sieved. It has been found that, when working with the compositions according to the invention, almost no dust formation occurs, the Schulpen can readily be sieved and are not retained on the surface of the sieve, and the flowability of the compositions is equally as good as that of compositions according to the prior art. In addition, the mechanical stability of tablets is ensured, and even abrasion in the tablet-forming machine is reduced compared with the prior art. The Schulpen of pyrogenic silicon dioxide as auxiliary substance are preferably present in the composition according to the invention in an amount of from 0.1 to 10 wt.%. The composition according to the invention can additionally contain conventional auxiliary substances used in pharmacy, such as, for example, fillers such as carbohydrates, sugar alcohols, starches and starch derivatives; binders, such as, for example, gelatin, cellulose, polyvinylpyrrolidone derivatives; disintegrators, such as, for example, carboxy- methylcellulose, maize starch and sodium carboxymethyl starch; glidants, such as, for example, talcum or polyethylene glycols; lubricants and release agents, such as, for example, magnesium or calcium stearate or stearic acid. Processes for the production of pyrogenic silicon dioxide are to be found, for example, in Ullmann's Encyclopedia of Industrial Chemistry, Vol. A23, page 635 ff, 5th edition, 1993. By subsequent treatment with a surface-modifying reagent it is also possible for the silicon dioxide to acquire a surface that- has been rendered partially or completely hydrophobic. Processes relating thereto are to be found, for example, in DE-A 11 63 784, DE-A 196 16 781, DE-A 197 57 210 or DE-A 44 02 370. It is possible to use for the compositions according to the invention also mixtures of pyrogenic silicon dioxide with doped silicon dioxide having an SiO2 content of 90%, with mixed oxides having an SiO2 content of 90% or more and/or silicon dioxide that has been rendered hydrophobic. The subject of the invention is the use of Schulpen based on pyrogenically produced silicon dioxide in a pharmaceutical composition. In an embodiment of the invention, the pyrogenically produced silicon dioxide compacted to form Schulpen can have a tamped density (according to DIN EN ISO 787-11) of from 185 to 700 g/1. In a preferred embodiment of the invention, the tamped density (according to DIN EN ISO 787-11) can be from 200 to 450 g/1. Schulpen refers to the more or less band-like intermediates that are formed during roller compaction by pressing of the starting material. They are comminuted in a second step. The properties of the Schulpen can be influenced by the procedural parameter, such as the permitted mode of process control, the compaction force, the width of the gap between the two rollers and the pressure maintenance time, which is adjusted by appropriately changing the speeds of rotation of the press rollers. Compaction is understood as meaning mechanical compression without the addition of binders. In a particular embodiment of the invention, the Schulpen have a defined shape, whereby the size distribution can be adjusted by means of sieving. The pyrogenically produced silicon dioxide compacted to form Schulpen that is used according to the invention has high stability to transportation. The pyrogenically produced silicon dioxide compacted to form Schulpen and having a tamped density (according to DIN EN ISO 787-11) of from 185 to 700 g/1 can be produced by subjecting pyrogenically produced silicon dioxide to preliminary de-aeration, or pre-compression, compacting it to form Schulpen, breaking the Schulpen and optionally grading them. A diagrammatic representation of the process is shown in Figure 1. According to Figure 1, the pyrogenically produced silicon dioxide is de-aerated, or pre-compressed, in the "preliminary de-aeration" step by means of known methods. This step is necessary when an uncompressed pyrogenically produced, optionally freshly produced, silicon dioxide is used. If a pyrogenically produced silicon dioxide that has already been pre-compressed is used, the step of preliminary de-aeration can be omitted. The pyrogenically produced silicon dioxide that has been subjected to preliminary de-aeration is compressed (compacted) to the desired tamped density in the "compaction" step. After compaction, the Schulpen are broken. They can then be graded or sieved, if desired. The fines content obtained during sieving can be fed back to the preliminary de-aeration step. The starting material used in the preliminary de-aeration can be either an uncompressed or a pre-compressed silicon dioxide. Preliminary de-aeration can be carried out either before transportation or during transportation to the compaction step. Before transportation to the compaction step, preliminary de-aeration can be carried out by means of a pipe of a sintered material, such as, for example, sintered metal, to which a vacuum is applied. Preliminary de-aeration can also take place in the screw conveyor, it being possible for the screw conveyor to be located downstream of the device comprising a pipe to which a vacuum is applied. In a further emdodiment, the screw conveyor can be used as the only device for preliminary de-aeration. It is further possible for preliminary de-aeration to be carried out by means of a screw conveyor that is arranged inside a pipe to which a vacuum is applied. The pipe to which a vacuum is applied can consist of a sintered jacket, such as, for example, sintered metal. When the device consists of a preliminary de-aeration pipe, for example a pipe to which a vacuum is applied, and a screw conveyor located downstream, the preliminary de- aeration can take place in the pipe if uncompressed silicon dioxide is used. If pre-compressed silicon dioxide is used, preliminary de- aeration can likewise take place in the pipe. It is also possible to dispense with this preliminary de-aeration step. If only the screw conveyor is used for the preliminary de- aeration, pre-compressed silicon dioxide must be used. If preliminary de-aeration is carried out using the device comprising a screw, conveyor inside a pipe to which a vacuum is applied, it is possible to use both uncompressed silicon dioxide and pre-compressed silicon dioxide. Preliminary de-aeration of the pyrogenically produced silicon dioxide can further be carried out by means of filtration on a filter medium, such as, for example, a cloth or sintered material, such as, for example, sintered metal, sintered plastics material, sintered ceramics, porous glass, with continuous removal of the filter cake by, for example, a screw conveyor or a scraper. In an embodiment of the invention it is possible to use a sintered metal pipe with a metering screw. Preliminary de-aeration can also be carried out by means of sedimentation, the breaking up of solids bridges being assisted by superimposed vibration, sound or slow stirring. As starting material there can be used a hydrophilic pyrogenically produced silicon dioxide or a hydrophobic pyrogenically produced silicon dioxide. Hydrophobic pyrogenically produced silicon dioxide can be produced by means of surface modification. Surface modification can be effected using one or more compounds from the following group: a) organosilanes of the type (RO)3Si(CnH2n+1) and R = alkyl, for example methyl, ethyl, n-propyl,- isopropyl, butyl n = 1 - 20 b) organosilanes of the type R'x (R0)ySi (CnH2n+1) and R = alkyl, for example methyl, ethyl, n-propyl, isopropyl, butyl R' = alkyl, for example methyl, ethyl, n-propyl, isopropyl, butyl R' = cycloalkyl n = 1 - 20 x+y = 3 x = 1,2 Y =1,2 c) haloorganosilanes of the type X3Si(CnH2n+1) and X = Cl, Br n = 1 - 20 d) haloorganosilanes of the type X2(R') Si (CnH2n+1) and X = Cl, Br R' = alkyl, for example methyl, ethyl, n-propyl, isopropyl, butyl R' = cycloalkyl n =1-20 e) haloorganosilanes of the type X (R')2Si(CnH2n+1) and X = Cl, Br R' = alkyl, for example methyl, ethyl, R' = cycloalkyl n-propyl, isopropyl, butyl n =1-20 f) organosilanes of the type (RO)3Si(CH2)m-R' R = alkyl, such as methyl, ethyl, propyl m =0.1-20 R' = methyl, aryl (for example -C6H5, substituted phenyl radicals) R = alkyl, such as methyl, ethyl, propyl, butyl -SH -NR'R' (R' = alkyl, aryl; R' = H, alkyl, aryl; R'' = H, alkyl, aryl, benzyl, C2H4NR' ' R' ' ' ' where R" " = A, alkyl and R' ' ' = H, alkyl) g) organosilanes of the type (R")x(R0)ySi (CH2)m-R' R" = alkyl x+y = 2 = cycloalkyl x =1,2 y = 1,2 m = from 0.1 to 20 R' = methyl, aryl (for example -C6H5, substituted phenyl radicals) R = methyl, ethyl, propyl, butyl -SH - NR'R'R'' (R' = alkyl, aryl; R' = H, alkyl, aryl; R'' = H, alkyl, aryl, benzyl, C2H4NR'' R''' where R'' = A, alkyl and R''' = H, alkyl) h) haloorganosilanes of the type X3Si(CH2)m-R' X = Cl, Br m = 0.1 - 20 R' = methyl, aryl (for example -C6H5, substituted phenyl radicals) R = methyl, ethyl, propyl, butyl -SH i) haloorganosilanes of the type (R) X2Si(CH2)m-R' X = Cl, Br R = alkyl, such as methyl, ethyl, propyl m = 0.1 - 20 R' = methyl, aryl (e.g. -C6H5, substituted phenyl radicals) wherein R = methyl, ethyl, propyl, butyl -Sx- (CH2)3Si(OR)3, wherein R = methyl, ethyl, propyl, butyl and X = from 1 to 10 -SH j) haloorganosilanes of the type (R)2X Si(CH2)m-R' X = Cl, Br R = alkyl, such as methyl, ethyl, propyl, butyl m = 0.1 - 20 R' = methyl, aryl (e.g. -C6H5, substituted phenyl radicals) R = methyl, ethyl, propyl, butyl -SH k) silazanes of the type R = alkyl R' = alkyl, vinyl 1) cyclic polysiloxanes of the type D 3, D 4, D 5, wherein D 3, D 4 and D 5 are understood as being cyclic polysiloxanes having 3, 4 or 5 units of the type -0-Si(CH3)2-. E.g. octamethylcyclotetrasiloxane = D 4 m) polysiloxanes or silicone oils of the type R = alkyl, such as wherein n = from 1 to 20, aryl, such as phenyl and substituted phenyl radicals, H R' = alkyl, such as wherein n = from 1 to 20, aryl, such as phenyl and substituted phenyl radicals, H R" = alkyl, such as wherein n = from 1 to 20, aryl, such as phenyl and substituted phenyl radicals, H R'' = alkyl, such as CnH2n+1, wherein n = from 1 to 20, aryl, such as phenyl and substituted phenyl radicals, In an embodiment it is possible to use as starting material a pre-compressed pyrogenically produced silicon dioxide. The uncompressed pyrogenically produced silicon dioxide that is used can have a tamped density (according to DIN EN ISO 787-11) of less than 50 g/1, preferably from 20 to 30 g/1. The pre-compressed pyrogenically produced silicon dioxide that is used can have a tamped density (according to DIN EN ISO 787-11) of from 50 to 190 g/1, preferably from 100 to 150 g/1, wherein the tamped density (according to DIN EN ISO 787-11) in the case of a pre-compressed hydrophobic pyrogenically produced silicon dioxide can be from 90 to 120 g/1. The hydrophilic silicon dioxide that is used can have a tamped density (according to DIN EN ISO 787-11) of less than 50 g/1, preferably from 20 to 30 g/1, in the uncompressed state. In the pre-compressed state, the hydrophilic silicon dioxide can have a tamped density (according to DIN EN ISO 787-11) of from 50 to 190 g/1, preferably from 100 to 150 g/1. In the pre-compressed state, the hydrophobic silicon dioxide can have a tamped density (according to DIN EN ISO 787-11) of from 50 to 190 g/1, preferably from 90 to 120 g/1. The pyrogenically produced silicon dioxide that is used can have a primary particle size of from 5 to 50 nm and a BET surface area of from 40 to 400 m2/g, preferably from 100 to 250 m2/g. The water content of the pyrogenically produced silicon dioxide that is used can be less than 1 wt. %. The pyrogenically produced silicon dioxide can be pre- compressed by means of known methods and devices. For example, the devices according to US 4,325,686, US 4,877,595, US 3,838,785, US 3,742,566, US 3,762,851, US 3,860,682 can be used. In an embodiment, it is possible to use a pyrogenically produced silicon dioxide that has been pre-compressed by means of a press band filter according to EP 0280851 Bl or US 4,877,595. The pyrogenically produced Silicon dioxide can be transported to the compaction step by means of a screw, for example. This transport represents the forced guiding of the pyrogenically produced silicon dioxide into the roller gap of the compacting rollers. If a screw conveyor is not used, a pre-compressed pyrogenically produced silicon dioxide must be employed. If a screw conveyor is used, the pyrogenically produced silicon dioxide does not have to be pre-compressed because preliminary de-aeration takes place therein. In order to achieve high bulk weights of the -Schulpen it is possible to use a screw conveyor and a pre-compressed pyrogenically produced silicon dioxide. The screw conveyor used can be a screw with decreasing volume or with increasing pitch or with decreasing diameter. The screw conveyor can be enclosed in a pipe to which a vacuum is applied. This pipe can consist of a sintered jacket. Preliminary de-aeration of the silicon dioxide here takes place in the screw conveyor at the same time as transportation into the roller gap. Compaction to Schulpen can be carried out by means of two rollers, one or both of which can at the same time have a de-aerating function. It is possible especially to use two compacting rollers, which can be smooth. They can also be profiled. The profile can be present either only on one compacting roller or on both compacting rollers. The profile can consist of axis-parallel ribs. Alternatively, it can be troughs (indentations) of any desired form in any desired arrangement. In a further embodiment, at least one of the rollers can be a vacuum roller. In this embodiment, the roller can be covered with sintered metal. In order to carry out the de-aeration function, the roller can be produced from sintered metal or be covered with a filter medium, such as, for example, with a cloth. If the pyrogenically produced silicon dioxide can be de- aerated by means of the rollers, it is possible to dispense with the additional preliminary de-aeration, which can take place in the screw conveyor or the feed pipe. If the roller is used for preliminary de-aeration, the roller can have a smooth or profiled surface, it being possible for the surface to be only slightly ribbed in order to improve product intake. During compaction, uniform compression of the pyrogenically produced silicon dioxide is to be ensured in order to obtain Schulpen of uniform density. A device as shown in Figure 2 can be used for carrying out the compaction. According to Figure 2, the pyrogenically produced silicon dioxide is introduced by means of the pre-compressor screw 1 into the chamber 2 between the two rollers 3 and is compressed between the two rollers to form Schulpen. A device as described in document DE AS 1807714 can also be used for carrying out the process. During compaction, smooth rollers can preferably be used in order to avoid grit. It is further possible to use one or two rollers of sintered material, such as sintered metal or sintered ceramics, via which de-aeration can take place. After compaction, the Schulpen are broken. To this end there can be used a sieve granulator, which specifies the grain size by the mesh size of the sieve. The mesh size can - be from 250 µm to 20 mm. For breaking the Schulpen it is further possible to use a device having two rollers which rotate in opposite directions and have a defined gap between them, or a toothed roller. The broken Schulpen can be graded by means of a sifter, a sieve or a classifier. The fines content (particles smaller than 200 µm) can be separated off thereby. As sifters there can be used cross-flow sifters, counter- current deflecting sifters, etc. A cyclone can be used as classifier. The fines content (particles smaller than 200 µm) separated off during grading can be fed back into the process according to the invention. Determination of the dust content The dust content is determined according to DIN 55992-2. Prior to the measurement, a weighed amount of the Schulpen of the pyrogenically produced silicon dioxide to be tested is introduced into a feed system at the top end of the down pipe. This is closed at the bottom before the start of the measurement by flaps. The end of the down pipe is closed. At the start of the measurement, that flap is opened for a specific period of time so that the sample is able to fall into the down pipe. As it falls, and when it comes into contact with the bottom of the down pipe, the sample gives off dust into the air. The air currents during falling ensure that the dust is distributed uniformly in the pipe. The suspended material then begins to settle. At the bottom end of the down pipe, the light extinction caused by the suspended material is measured by a photometric sensor. The course of the sedimentation is indicated by a PC as a function of the time. In the case of the CIPACMT171 dust- measuring device, the extinction E (in %) is plotted directly as a function of the sedimentation time. In the case of the SP3 dust-measuring device from Lorenz, the dust number SZ is calculated according to the following formula (eq. 1) and plotted as a function of time. The dust number is a measure of the fine dust content of the sample. "Fine dust" here refers to the fraction whose rate of sedimentation in air is less than 1 m/16 s = 0.0625 m/s. A diagrammatic representation of the device used to determine the dust content is shown in Figure 3. In Figure 4, the fine dust content of the pyrogenically produced silicon dioxide compacted to form Schulpen that is used according to the invention and the fine dust contents of pyrogenic silicon dioxide that has been compressed by a different method are compared. The starting material employed for the silicon dioxide used according to the invention was a pyrogenically produced silicon dioxide that had been compressed by means of the press band filter according to EP 0280851 Bl. Figure 4 shows a measure of the particle size distribution and the mean particle size of the bulk powder or Schulpen, which are used with the according to the invention. This demonstrates that the Schulpen of the pyrogenically produced silicon dioxide that are used according to the invention settle significantly better and form significantly less dust than the granules according to EP 0 725037 A1. Figure 4 also shows a measure of the fine or suspended dust content. This demonstrates that the suspended dust content can be drastically reduced with the Schulpen used according to the invention. In the case of granules according to EP 075 037 A1, a large proportion remains suspended for a long time . Figure 5 shows the combined distribution (Q-3 distribution) of various granules according to EP 0 725 037 A1, None of these granules exhibits a mean particle size of 120 urn. Only the largest particles in this group are from 96 to 128 µm in size. This is less than 11 %. The Schulpen used according to the invention with X according to EP 0 725 037 Al in laser diffraction spectroscopy. In both cases it is ~ 35 µm. However, the Schulpen according to the invention produce significantly less dust. The fractions of the Schulpen were produced by sieve granulation using a sieve having a mesh size of 500 µm, with subsequent sieving on a 250 µm sieve. The fraction x fraction having a particle size of from 250 to 500 µm was the coarse material. Figure 6 shows the pyrogenically produced silicon dioxide compacted to form Schulpen that is used according to the invention, in its granular form after breaking and sieving. It has an angular shape. The granules according to DE 19601415 have a spherical appearance. In a preferred embodiment, the Schulpen used according to the invention have a tamped density of from 200 to 300 g/1. Such Schulpen then have the necessary strength not to disintegrate again in the subsequent steps. However, they can readily be dispersed again. Furthermore, the Schulpen that are obtained are porous. The Schulpen used according to the invention have an advantageously low dust content after breaking even without sieving or grading. The Schulpen used according to the invention have an agglomerate hardness of less than 50 N, measured using an ERWEKA 30. After breaking, the Schulpen used according to the invention do not exhibit a further dust content. Even during handling, transportation or storage, no further dust content is formed with the Schulpen used according to the invention. The pyrogenically produced silicon dioxide compacted to form Schulpen does not exhibit a fines content having a diameter of less than 200 µm after sieving. The pyrogenically produced silicon dioxide compacted to form Schulpen that is used according to the invention has a low dust content that is advantageous for all applications. It can be added to the mixtures without loss and without introducing dust. The pyrogenically produced silicon dioxide compacted to form Schulpen does not contain binder. The silicon dioxide utilized in the invention is of the very fine particle size variety. In the most preferred embodiments of the invention, the silicon dioxide utilized is a colloidal silicon dioxide. Colloidal silicon dioxide is a submicron fumed silica prepared by the vapor-phase hydrolysis (e.g., at 1110° C.) of a silicon compound, such as silicon tetrachloride. The product itself is a submicron, fluffy, light, loose, bluish-white, odorless and tasteless amorphous powder which is commercially available from a number of sources, including Cabot Corporation (under the tradename Cab-OSil); Degussa, Inc. (under the tradename AEROSIL) ; E.1. DuPont & Co.; and W.R. Grace & Co. Colloidal silicon dioxide is also known as colloidal silica, fumed silica, light anhydrous silicic acid, silicic anhydride, and silicon dioxide fumed, among others. A variety of commercial grades of colloidal silicon dioxide are produced by varying the manufacturing process. These modifications do not affect the silica content, specific gravity, refractive index, color or amorphous form. However, these modifications are known to change the particle size, surface areas, and bulk densities of the colloidal silicon dioxide products. The surface area of the preferred dass of silicon dioxides utilized in the invention ranges from about 50 m2/gm to about 500 m2/gm. The average primary particle diameter of the preferred dass of silicon dioxides utilized in the invention ranges from about 5 nm to about 50 run. However, in commercial colloidal silicon dioxide products, these particles are agglomerated or aggregated to varying extents. The bulk density of the preferred dass of silicon dioxides' utilized in the invention ranges from about 20 g/1 to about 100 g/1. Commercially available colloidal silicon dioxide products have, for example, a BET surface area ranging from about 50+15 m2/gm (AEROSIL OX50) to about 400±20 (Cab-O-Sil S-17) or 390+40 m2/gm (cab-o-sil EH-5). Commercially available particle sizes range from a nominal particle diameter of 7 nm (e.g., Cab-O-Sil S-17 or Cab-O-Sil EH-5) to an average primary particle size of 40 nm (AEROSIL OX50). The density of these products range from 72.0±8 g/1 (Cab-O-Sil S-17) to 36.8 g/1 (e.g., Cab-O-Sil M-5). The pH of the these products at 4% aqueous dispersion ranges from pH 3.5-4.5. The pyrogenic silicon dioxide serving as starting material is produced by feeding a volatile silicon compound through a nozzle into a detonating gas flame of hydrogen and air. Silicon tetrachloride is used in most cases. This substance hydrolyses under the influence of the water produced in the detonating gas reaction, to form silicon dioxide and hydrochloric acid. After leaving the flame the silicon dioxide enters a so-called coagulation zone in which the silicon dioxide primary particles and primary aggregates agglomerate. The product present as a form of aerosol in this stage is separated from the gaseous accompanying substances in cyclones and is then post-treated with moist hot air. The residual hydrochloric acid content can be reduced to below 0.025% by this process. The granular materials (Schulpen) based on pyrogenically produced silicon dioxide may also be silanised. The carbon content of the granular material is then preferably 0.3 to 15.0 wt. %. Halogenated silantes, alkoxysilanes, silazanes and/or siloxanes may be used for the silanisation. The following substances in particular may be used as halogenated silanes: halogenated organosilanes of the type halogenated organosilanes of the type halogenated organosilanes of the type halogenated organosilanes of the type (R)X2Si(CH2)m-R' R = Alkyl m = 0.1 - 20 R' = Alkyl, aryl (e.g. -C6H5) halogenated organosilanes of the type The following substances in particular may be used as alkoxysilanes: organosilanes of the type organosilanes of the typQ organosilanes of the type organosilanes of the type R" = Alkyl x+y = 2 x = 1.2 y = 1.2 The silane Si 108 trimethoxyoctylsilane may preferably be used as silanisation agent. The following substances in particular may be used as silazanes : Silazanes of the type: R = Alkyl R' = Alkyl, vinyl as well as for example hexamethyldisilazane. The following substances in particular may be used as siloxanes: cyclic polysiloxanes of the type D 3, D 4, D 5, e.g. octamethylcyclotetrasiloxane = D 4 polysiloxanes and/or silicone oils of the type: The silanisation may be carried out by spraying the Schulpen with the silanisation agent, which may optionally be dissolved in an organic solvent, for example ethanol, and then thermally treating the mixture at a temperature of 105° to 400° C. for a period of 1 to 6 hours. An alternative method of silanising the Schulpen involves treating the Schulpen with the silanisation agent in vapour form and then thermally treating the mixture at a temperature of 200 to 800 C. for a period of 0.5 to 6 hours. The thermal treatment may be carried out under a protective gas, such as for example nitrogen. The silanisation may be carried out continuously er batchwise in heatable mixers and dryers with spray devices. Suitable types of apparatus include for example ploughshare mixers, plate dryers, fluidised-bed dryers or turbulent-layer dryers. The physicochemical parameters Of the Schulpen, such as the specific surface, grain size distribution, pore volume, tamped density and silanol group concentration, pore distribution and pH value may be altered within the specified limits by varying the starting substances, spraying conditions, heat treatment and silanisation. One subject of the invention is the use of Schulpen based On pyrogenically produced silicon dioxide in a pharmaceutical composition. Thereby the pharmaceutical composition can be present in the form of a suspension, emulsion, aerosol, ointment, cream, gel, paste, suppository, stick, powder, topical powder, granular material, tablet, pastille, sugar-coated pill, film-coated tablet, hard gelatin capsule, soft gelatin capsule, extrudate, microcapsule or a microsphere. According to the invention the Schulpen can act as a glidant for pharmaceutical active constituents and/or auxiliary substances. A further subject of the invention is a pharmaceutical composition containing Schulpen based on pyrogenically produced silicon dioxide and at least one pharmaceutical active constituent. The pharmaceutical composition according to the invention can contain furthermore at least one pharmaceutical auxiliary substance. The silicon dioxide Schulpen may be used in combination with any arbitrary pharmaceutical active constituent. The following may be mentioned by way of example: a-proteinase inhibitor, abacavir, abciximab, acarbose, acetylsalicylic acid, acyclovir, adenosine, albuterol, aldesleukin, alendronate, alfuzosin, alosetrone, alprazolam, alteplase, ambroxol, amifostine, amiodarone, amisulprid, amlodipine, amoxicillin, amphetamine, amphotericin, ampicillin, amprenavir, anagrelide, anastrozole, ancrod, anti-haemophilia factor, aprotinin, atenolol, atorvastatin, atropine, azelastine, azithromycin, azulene, barnidipin, beclomethasone, benazepril, benserazide, beraprost, betamethasone, betaxolol, bezafibrate, bicalutamide, bisabolol, bisoprolol, botulinum toxin, brimonidine, bromazepam, bromocriptine, budesonide, bupivacaine, bupropion, buspirone, butorphanol, caber- goline,calcipotriene, calcitonin, calcitriol, camphor, candesartan, candesartan cilexetil, captopril, car- bamazepine, carbidopa, carboplatin, carvedilol, cefaclor, cefadroxil, cefaxitin, cefazolin, cefdinir, cefepime, cefixime, cefmetazole, cefoperazone, cefotiam, cefoxopran, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftriaxone, cefuroxime, celecoxib, celiprolol, cephalexin, cerivastatin, cetirizine, chloramphenicol, cilastatin, cilazapril, cimetidine, ciprofibrate, ciprofloxacin, cisapride, cisplatin, citalopram, clarithromycin, clavulanic acid, clindamycin, clomipramine, clonazepam, clonidine, clopidogrel, clotrimazole, clozapine, cromolyn, cyclophosphamide, cyclosporine, cyproterone, dalteparin, deferoxamine, desogestrel, dextroamphetamine, diazepam, diclofenac, didanosine, digitoxin, digoxin, dihydroergotamine, diltiazem, diphtheria protein, diphtheria toxoxide, divalproex, dobutamine, docetaxel, dolasetron, donepezil, dornase-a, dorzolamide, doxazosin, doxifluridin, doxorubicin, dydrogesterone, ecabet, efavirenz, enalapril, enoxaparin, eperisone, epinastin, epirubicin, eptifibatide, erythropoietin-a, erythropoietin- β, etanercept, ethinyl oestradiol, etodolac, etoposide, factor VIII, famciclovir, famotidine, faropeneme, felo- dipine, fenofibrate, fenoldopam, fentanyl, fexofenadin, filgrastim, finasteride, flomoxef, fluconazole, fludarabine, flunisolide, flunitrazepam, fluoxetine, flutamide, fluticasone, fluvastatin, fluvoxamine, fol- litropin-a, follitropin-ft, formoterol, fosinopril, furo- semide, gabapentin, gadodiamide, ganciclovir, gatifloxacin, gemcitabine, gestoden, glatiramer, glibenclamide, glimepiride, glipizide, glyburide, goserelin, granisetron, griseofulvin, hepatitis B antigen, hyaluronic acid, hycosin, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, hydroxychloroguine, hylan G-F 20, ibuprofen, ifosfamide, imidapril, imiglucerase, imipenem, immu- noglobulin, indinavir, indomethacin, infliximab, insulin, insulin human, insulin Lispro, insulin aspart, interferon β, interferon a, iodine 125, iodixanol, iohexol, iomeprol, iopromid, ioversol, ioxoprolen, ipratropium, ipriflavone, irbesartan, irinotecan, isosorbide, isotretinoin, isradipine, itraconazole, potassium chlorazepate, potassium chloride, ketorolac, ketotifen, whooping cough vaccine, coagulation factor IX, lamivudine, lamotrigine, lansoprazole, latanoprost, leflunomide, lenograstim, letrozole, leuprolide, levodopa, levofloxacin, levonorgestrel, levothyroxine, lidocaine, linezolid, lisinopril, lopamidol, loracarbef, loratadine, lorazepam, losartan, lovastatin, lysineacetylsalicylic acid, manidipin, mecobalamin, medroxyprogesterone, megestrol, meloxicam, menatetrenone, meningococcus vaccine, menotropine, meropenem, mesalamine, metaxalone, metformin, methylphenidate, methylprednisolone, metoprolol, midazolam, milrinone, minocycline, mirtazapine, misoprostol, mitoxantrone, moclobemid, modafinil, mometasone, montelukast, morniflumat, morphine, moxifloxacin, mycophenolate, nabumetone, nadroparin, naproxen, naratriptan, nefazodone, nelfinavir, nevirapine, niacin, nicardipine, nicergoline, nifedipine, nilutamide, nilvad- ipine, nimodipine, nitroglycerin, nizatidine, nore- thindrone, norfloxacin, octreotide, olanzapine, omeprazole, ondansetron, orlistate, oseltamivir, oestradiol, oestrogens, oxaliplatin, oxaprozin, oxolinic acid, oxybutynin, paclitaxel, palivizumab, pamidronate, pancrelipase, panipenem, pantoprazol, paracetamol, paroxetine, pentoxifylline, pergolide, phenytoin, pioglitazon, piperacillin, piroxicam, pramipexole, pravastatin, prazosin, probucol, progesterone, propafenone, propofol, propoxyphene, prostaglandin, quetiapine, quinapril, rabeprazol, raloxifene, ramipril, ranitidine, repaglinide, reserpine, ribavirin, riluzole, risperidone, ritonavir, rituximab, rivastigmin, rizatriptan, rofecoxib, ropinirol, rosiglitazone, salmeterol, saquinavir, sargramostim, serrapeptase, sertraline, sevelamer, sibutramin, sildenafil, simvastatin, somatropine, sotalol, spironolactone, stavudin, sulbactam, sulfaethidole, sulfamethoxazole, sulfasalazine sulpirid, sumatriptan, tacrolimus, tamoxifen, tamsulosin, tazobactam, teicoplanin, temocapril, temozolomid, tenecteplase, tenoxicam, teprenon, terazosin, terbinafine, terbutaline, tetanus toxoid, tetrabenazine, tetrazepam, thymol, tiagabine, tibolon, ticarcillin, ticlopidine, timolol, tirofiban, tizanidine, tobramycin, tocopheryl nicotinate, tolterodine, topiramate, topotecan, torasemid, tramadol, trandolapril, trastuzumab, triamcinolone, triazolam, trimebutin, trimethoprim, troglitazone, tropisetrone, tulobuterol, unoproston, urofollitropine, valacyclovir, valproic acid, valsartan, vancomycin, venlafaxine, verapamil, verteporfin, vigabatrin, vinorelbine, vinpocetine, vitamin A, vitamin D, vitamin E, vitamin K, voglibose, warfarin, zafirlukast, zaleplon, zanamivir, zidovudine, zolmitriptan, Zolpidem, zopiclone nutritional oils, essential fatty acids, non- essential fatty acids, extracts of plant or animal origin, oils of plant or animal origin and their derivatives. Pharmaceutical active constituents are however also understood to include other substances such as vitamins, provitamins, essential fatty acids, extracts of plant and animal origin and oils of plant and animal origin. Suitable active pharmaceutical ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anticoagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agent, anti-gout agents, anti- hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppresants, anti- protozoal agents, antithyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, B-blockers, cardiac inotropic agents, corticosteroids, diuretics, anti- parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolyses, lipid regulating agents, anti-anginal agents, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, anti- osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, extracts of plant or animal origin, oils of plant or animal origin, and mixtures thereof. A wide variety of therapeutically active agents can be used in conjunction with the present invention. The thera- peutically active agents (e.g. pharmaceutical agents) which may be used in the compositions of the present invention include both water soluble and water insoluble drugs. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), non-steroidal anti- inflammatory agents (e.g., naproxyn, diclofenac, indomethacin, ibuprofen, sulindac), antiemetics (e.g., metoclopramide), antiepileptics (e.g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti- tussive agents and expectorants (e.g., codeine phosphate), anti-asthmatics (e.g. theophylline), antacids, anti- spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluazide), antihypotensives (e.g., propranolol, clonidine), antihypertensives (e.g, clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine). The above list is not meant to be exclusive. A wide variety of locally active agents can be used in conjunction with the novel excipient described herein, and include both water soluble and water insoluble agents. The locally active agent (s) which may be included in the con- trolled release formulation of the present invention is intended to exert its effect in the environment of use, e.g., the oral cavity, although in some instances the active agent may also have systemic activity via absorption into the blood via the surrounding mucosa. The locally active agent(s) include antifungal agents (e.g., amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol, etc.), antibiotic agents (Penicillins, cephalosporins erythromycin, tetracycline, aminoglycosides, etc.), antiviral agents (e.g, acyclovir, idoxuridine, etc.), breath fresheners (e.g. chlorophyll), antitussive agents (e.g., dextromethorphan hydrochloride), anti-cariogenic compounds (e.g., metallic salts of fluoride, sodium monofluorophosphate, stannous fluoride, amine fluorides), analgesic agents (e.g., methylsalicylate, salicylic acid, etc.), local anesthetics (e.g., benzocaine), oral antiseptics (e.g., chlorhexidine and salts thereof, hexylresorcinol, dequalinium chloride, cetylpyridinium chloride), anti-flammatory agents (e.g., dexamethasone, betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone, etc.), hormonal agents (oestriol), antiplaque agents (e.g, chlorhexidine and salts thereof, octenidine, and mixtures of thymol, menthol, methysalicylate, eucalyptol), acidity reducing agents (e.g., buffering agents such as potassium phosphate lo dibasic, calcium carbonate, sodium bicarbonate, sodium and potassium hydroxide, etc.), and tooth desensitizers (e.g., potassium nitrate). This list is not meant to be exclusive. The solid formulations of the invention may also include other locally active agents, such as flavorants and sweeteners. Generally any flavoring or food additive such as those described in Chemicals Used in Food Processing, pub 1274 by the National Academy of Sciences, pages 63-258 may be used. A wide variety of pharmaceutically systemically active agents can be formulated e.g., vitamins, minerals, amino acids, essential trace elements, hormones and antagonists thereof, steroids, non-steroid anti-inflammatory agents, antineoplastic agents, antigens, antihistaminic agents, neuropharmacologic agents, including analgesics, vasodilators, anticoagulants, antimicrobial agents, antiviral agents, antifungal agents, antiparasitic agents, heavy metal antagonists, locally active drugs moderating the digestive tract, such as enzymes, antacids, histamine antagonists, diuretics and cardiovascular drugs. It is to be understood that the compositions of the invention may comprise more than one active drug substance, e.g. a combination of two or more drug substances. For example, a composition of the invention may comprise a therapeutic effective dose of drospirenone and a therapeu- tic effective dose of an estrogen. Further constituents of the pharmaceutical compositions according to the invention may include conventional auxiliary substances such as for example antioxidants, binders, emulsifiers, colouring agents, filmforming agents, fillers, odoriferous substances, flavouring 'substances, gelforming agents, preservatives, solvents, oils, powder bases, ointment bases, acids and salts for the formulation, replenishment and production of pharmaceutical compositions, lubricants, release agents, suppository bases, suspension stabilisers, sweetening agents, effervescent gases, emollients and sugar substitutes. Plant medicament preparations and homeopathic preparations are also included among the pharmaceutical compositions in which the silicon dioxide Schulpen may be used. The pharmaceutical compositions according to the invention may also include socalled retard and depot dosage forms with controlled release of active constituent. Moreover the pharmaceutical compositions according to the invention may also be part of therapeutic systems such as for example therapeutic systems for topical application and transdermal therapeutic systems. In a preferred embodiment the silicon dioxide Schulpen based on pyrogenic silicic acid serves as a glidant for improving the flow of pharmaceutical active constituents and/or excipients and/or mixtures thereof. The present invention is accordingly also directed to a mixture of the aforedescribed silicon dioxide Schulpen and at least one of these substances. The compositions according to the invention can be used in the form of solid, semi-solid and liquid product forms. Solid product forms are, for example, powders, granules, tablets and filled capsules. Examples of semi-solid product forms are creams, ointments, gels, pastes and "soft" gel Capsules. Liquid product forms are, for example, suspensions. Further suitable product forms can be suppositories and aerosols, for example. The term "glidant" may also mean that silicon dioxide Schulpen or fragments thereof coat solid particles of the material. The forCGS Of attraction between the particles are reduced and for example the flow behaviour is improved. Schulpen formed from pyrogenic silicic acids Can in particular complement or replace the conventional pyrogenic silicic acids that have been established in pharmaceutical practice for many years. For example, Schulpen of pyrogenic silicic acids may above all improve the production and properties of solid medicament forms. Also, they may advantageously be employed in the production of extrudates and replace for example other established auxiliary substances such as cellulose or polymers. The advantages of the Schulpen based on pyrogenically produced silicon dioxide compared to the known non- granulated pyrogenic silicic acids lie above all in their non-agglomerating behaviour, improved flowability, narrower and definable particle size distribution, and dust-free handling. In addition tablets produced therefrom have mechanical stability and disintegration behaviour properties as do tablets prepared with conventional highly disperse pyrogenic silicic acid. The invention will now be described in more detail with the aid of examples. Here too, AEROSIL was first compacted to form Schulpen and then sieve granulated. The fine-material fraction of the subsequent sieving was used. The AEROSIL Schulpen grain size of this fine-material fraction is less than 250 µm. Highly disperse pyrogenic silicic acids such as AEROSIL 200 Pharma or AEROSIL 200 Pharma VV 120 are frequently used as flow regulators in the production of medicaments. By adding small amounts of AEROSIL, the flow behaviour of an active ingredient carrier or auxiliary substance can be increased and accordingly its application-related properties, such as, for example, its metering ability, can be improved, Avicel PH-101 is a frequently used microcrystalline cellulose whose flow behaviour is improved by addition of small amounts of AEROSIL 200 (e.g. 0.5 %). The sieving behaviour and, above all, the sieve residue of the mixture of Avicel and AEROSIL is an important application-related property. A large sieve residue means that automatic weighing, sieving and metering devices cannot be used. In order to test these granules for AEROSIL Schulpen in comparison with AEROSIL 200 Pharma and AEROSIL 200 Pharma VV 120, the sieve residue of the following mixtures was studied. • Avicel® PH-101 without flow regulator (zero sample) • Avicel® PH-101 99.5% + 0.5% AEROSIL® 200 Pharma • Avicel® PH-101 99.5% + 0.5% AEROSIL® 200 VV Pharma • Avicel® PH-101 99.5% + 0.5% AEROSIL® Schulpen 250 (x The various components of the mixture were weighed directly onto a sieve having a mesh size of 0.71 mm. The mixture was first sieved through this sieve and thereby mixed slightly. The pulverulent mixtures were then mixed by means of a mixer (Turbula) at 46 rpm for a defined time (5, 10, 30, 60 minutes.) . In general, agglomerates break up during mixing, as a result of which the sieving ability generally improves with the mixing time. After the times defined above, the powder was sieved through, a 0.315 mm sieve and the sieve residue was determined in wt.%. This is shown in Figure 8 as a function of the mixing time. While pure Avicel passes through the sieve completely, the agglomerates in the case of AEROSIL 200 VV 120 Pharma and AEROSIL 200 Pharma are broken up by the mixing process only with difficulty. The sieving ability is relatively poor as a result. AEROSIL 200 VV 120 is compressed on a vacuum press band filter to a tamped density of approximately 120 g/1. However, the sieving behaviour worsens thereby. The AEROSIL Schulpen combine a good sieving and pouring ability with low dust formation. Accordingly, they have marked application-related advantages over AEROSIL 200 Pharma and AEROSIL 200 VV 120 Pharma. Further characteristic values for assessing the flow properties of various auxiliary substances such as microcrystalline cellulose (Avicel PH-101, FMB Biopolymers), starch and lactose monohydrate (Tablettose from Meggle) are AEROSIL Schulpen slightly better or equally as good as in the case of AEROSIL 200 Pharma or AEROSIL 200 VV 120 Pharma. The AEROSIL Schulpen exhibit a significantly better activity as flow regulators than AEROPERL. The measurement is called angle of repose and is used to determine the flow properties of powders. The angle of repose values are as follows: Avicel alone: 4 6.7° Avicel + 1 % VP AEROPERL 300' Pharma: 4 6.7° Avicel + 1 % AEROSIL® Granulate 500 (250 Avicel + 1 % AEROSIL® Granulate 250 (x A difference of 3° in the angle of repose is regarded as significant. AEROPERL produces no improvement in the flowability compared with Avicel alone. The difference of almost 10° between AEROPERL and the AEROSIL Schulpen is an enormous improvement. WE CLAIM : 1. A process for the preparation of a pharmaceutical composition comprising pyrogenically produced silicon dioxide as a glidant for pharmaceutical active constituents and/or auxiliary substance comprising the following steps: - de-aerating or decompressing the pyrogenically produced silicon dioxide; compressing (compacting) the pyrogenically produced silicon dioxid by roller compaction to band-like intermediates (Schulpen) to have a tamped density (according to DIN EN ISO 787-11) of from 185 to 700 g/1; - breaking the band-like intermediates(Schulpen); optionally grading or sieving the broken band-like intermediates(Schulpen); - combining the broken band-like intermediates (Schulpen) with at least one pharmaceutically active constituent. 2. The process as claimed in claim 1 wherein the pharmaceutical composition is present in the form of a suspension, emulsion, aerosol, ointment, cream, gel, paste, suppository, stick, powder, topical powder, granular material, tablet, pastille, sugarcoated pill, film- coated tablet, hard gelatin capsule, soft gelatin capsule, extrudate, microcapsule or a microsphere. 3. The process as claimed in claims 1 or 2 wherein the pharmaceutical composition contains at least one further pharmaceutical auxiliary substance. 4. The process as claimed in any of the preceding claims wherein the band-like intermediates (Schulpen) have a tamped density (according to DIN EN ISO 787-11) of from 200 to 450 g/1- ABSTRACT Title: "A PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION COMPRISING PYROGENICALLY PRODUCED SILICON DIOXIDE" A process for the preparation of a pharmaceutical composition comprising pyrogenically produced silicon dioxide as a glidant for pharmaceutical active constituents and/or auxiliary substance comprising the following steps: de-aerating or decompressing the pyrogenically produced silicon dioxide; compressing (compacting) the pyrogenically produced silicon dioxid by roller compaction to band-like intermediates (Schulpen) to have a tamped density (according to DIN EN ISO 787-11) of from 185 to 700 g/1; breaking the band-like intermediates(Schulpen); optionally grading or sieving the broken band-like intermediates(Schulpen); - combining the broken band-like intermediates (Schulpen) with at least one pharmaceutically active constituent.

Full Text

Pharmaceutical compositions
The present invention relates to the use of Schulpen of
pyrogenic silicic acid in pharmaceutical compositions. The
Schulpen are used in this connection in particular as
glidants to improve the bulk flow of powders.
In a medicament it is generally possible to distinguish two
functionally different substance groups, namely active
ingredients and auxiliary substances.
Active ingredients are characterised by their specific
pharmacological activity. They represent the active
constituent of a medicament. As such, they are also
identified quantitatively on the packaging and on the
package leaflet.
Auxiliary substances, on the other hand, have no
pharmacological activity. They are necessary in order to
enable a suitable form of administration, namely the
medicament, to be produced for the active ingredient. In
general, the medicament contains a plurality of auxiliary
substances having different functions. For example,
auxiliary substances are used as fillers, binders,
disintegrators, glidants, lubricants or release agents.
When developing stable, effective medicaments which are
easy to handle from active ingredient(s) and auxiliary
substances, there are a large number of auxiliary substances which can be used.
Highly disperse, pyrogenic silicon dioxide, for example
Aerosil", is frequently used in pharmaceutical and cosmetic
compositions. In solid product forms it can be used as a
flow regulator, adsorbent and drying agent; in liquid and .
semi-liquid product forms it can be used as a suspension
stabiliser, framework-forming agent and gel-forming agent.
It can also be used to increase the mechanical stability

and the rate of disintegration of tablets. In addition, it
can improve the distribution of the active ingredient.
A particular disadvantage when working with highly disperse
silicon dioxide is the formation of dust, because very high
demands have to be met in terms of cleanliness when
producing pharmaceutical and cosmetic products.
A further disadvantage is the agglomeration behaviour of
highly disperse silicon dioxide, which causes the product
to come together as a result of hydrogen bridges and
electrostatic charging. This results in larger lumps which
do not pass through the relatively small sieve openings
typical for the pharmaceutical industry. This is a
particular problem in the case of silicon dioxides which
have been compressed in order to minimise dust formation
and have a higher bulk and tamped density.
Sieving is very important in order to eliminate foreign
bodies in pharmaceutical products. As a result, modern
automatic weighing and screening devices cannot be used,
which increases the possibility of contamination from human
handling.
When using highly dispersed silicon dioxide in
pharmaceutical compositions improved flowability of
mixtures prepared therewith would also be desirable in
order to be able to achieve greater metering accuracy, for
example when producing tablets and capsules. As a result it
would be possible on the one hand to achieve lower variance
of tablet and capsule weights and on the other hand to
improve the economy of processes that result in such forms
of administration.
The object of the present invention is to provide
pharmaceutical compositions which avoid the disadvantages
of the prior art.

The object is achieved by producing and using
pharmaceutical compositions which contain Schulpen of
pyrogenic silicon dioxide as auxiliary substance and which
have a low dust content and at the same time can readily be
sieved.
It has been found that, when working with the compositions
according to the invention, almost no dust formation
occurs, the Schulpen can readily be sieved and are not
retained on the surface of the sieve, and the flowability
of the compositions is equally as good as that of
compositions according to the prior art. In addition, the
mechanical stability of tablets is ensured, and even
abrasion in the tablet-forming machine is reduced compared
with the prior art.
The Schulpen of pyrogenic silicon dioxide as auxiliary
substance are preferably present in the composition
according to the invention in an amount of from 0.1 to
10 wt.%.
The composition according to the invention can additionally
contain conventional auxiliary substances used in pharmacy,
such as, for example, fillers such as carbohydrates, sugar
alcohols, starches and starch derivatives; binders, such
as, for example, gelatin, cellulose, polyvinylpyrrolidone
derivatives; disintegrators, such as, for example, carboxy-
methylcellulose, maize starch and sodium carboxymethyl
starch; glidants, such as, for example, talcum or
polyethylene glycols; lubricants and release agents, such
as, for example, magnesium or calcium stearate or stearic
acid.
Processes for the production of pyrogenic silicon dioxide
are to be found, for example, in Ullmann's Encyclopedia of
Industrial Chemistry, Vol. A23, page 635 ff, 5th edition,
1993.

By subsequent treatment with a surface-modifying reagent it
is also possible for the silicon dioxide to acquire a
surface that- has been rendered partially or completely
hydrophobic. Processes relating thereto are to be found,
for example, in DE-A 11 63 784, DE-A 196 16 781, DE-A
197 57 210 or DE-A 44 02 370.
It is possible to use for the compositions according to the
invention also mixtures of pyrogenic silicon dioxide with
doped silicon dioxide having an SiO2 content of 90%, with
mixed oxides having an SiO2 content of 90% or more and/or
silicon dioxide that has been rendered hydrophobic.
The subject of the invention is the use of Schulpen based
on pyrogenically produced silicon dioxide in a
pharmaceutical composition.
In an embodiment of the invention, the pyrogenically
produced silicon dioxide compacted to form Schulpen can
have a tamped density (according to DIN EN ISO 787-11) of
from 185 to 700 g/1.
In a preferred embodiment of the invention, the tamped
density (according to DIN EN ISO 787-11) can be from 200 to
450 g/1.
Schulpen refers to the more or less band-like intermediates
that are formed during roller compaction by pressing of the
starting material. They are comminuted in a second step.
The properties of the Schulpen can be influenced by the
procedural parameter, such as the permitted mode of process
control, the compaction force, the width of the gap between
the two rollers and the pressure maintenance time, which is
adjusted by appropriately changing the speeds of rotation
of the press rollers.
Compaction is understood as meaning mechanical compression
without the addition of binders. In a particular embodiment

of the invention, the Schulpen have a defined shape,
whereby the size distribution can be adjusted by means of
sieving.
The pyrogenically produced silicon dioxide compacted to form Schulpen that is used according to the invention has
high stability to transportation.
The pyrogenically produced silicon dioxide compacted to
form Schulpen and having a tamped density (according to DIN
EN ISO 787-11) of from 185 to 700 g/1 can be produced by
subjecting pyrogenically produced silicon dioxide to
preliminary de-aeration, or pre-compression, compacting it
to form Schulpen, breaking the Schulpen and optionally
grading them.
A diagrammatic representation of the process is shown in Figure 1.
According to Figure 1, the pyrogenically produced silicon
dioxide is de-aerated, or pre-compressed, in the
"preliminary de-aeration" step by means of known methods.
This step is necessary when an uncompressed pyrogenically
produced, optionally freshly produced, silicon dioxide is
used.
If a pyrogenically produced silicon dioxide that has
already been pre-compressed is used, the step of
preliminary de-aeration can be omitted.
The pyrogenically produced silicon dioxide that has been
subjected to preliminary de-aeration is compressed
(compacted) to the desired tamped density in the
"compaction" step.
After compaction, the Schulpen are broken. They can then be
graded or sieved, if desired.

The fines content obtained during sieving can be fed back
to the preliminary de-aeration step.
The starting material used in the preliminary de-aeration
can be either an uncompressed or a pre-compressed silicon
dioxide.
Preliminary de-aeration can be carried out either before
transportation or during transportation to the compaction
step.
Before transportation to the compaction step, preliminary
de-aeration can be carried out by means of a pipe of a
sintered material, such as, for example, sintered metal, to
which a vacuum is applied.
Preliminary de-aeration can also take place in the screw
conveyor, it being possible for the screw conveyor to be
located downstream of the device comprising a pipe to which
a vacuum is applied.
In a further emdodiment, the screw conveyor can be used as
the only device for preliminary de-aeration.
It is further possible for preliminary de-aeration to be
carried out by means of a screw conveyor that is arranged
inside a pipe to which a vacuum is applied. The pipe to
which a vacuum is applied can consist of a sintered jacket,
such as, for example, sintered metal.
When the device consists of a preliminary de-aeration pipe,
for example a pipe to which a vacuum is applied, and a
screw conveyor located downstream, the preliminary de-
aeration can take place in the pipe if uncompressed silicon
dioxide is used.
If pre-compressed silicon dioxide is used, preliminary de-
aeration can likewise take place in the pipe. It is also

possible to dispense with this preliminary de-aeration
step.
If only the screw conveyor is used for the preliminary de-
aeration, pre-compressed silicon dioxide must be used.
If preliminary de-aeration is carried out using the device
comprising a screw, conveyor inside a pipe to which a vacuum
is applied, it is possible to use both uncompressed silicon
dioxide and pre-compressed silicon dioxide.
Preliminary de-aeration of the pyrogenically produced
silicon dioxide can further be carried out by means of
filtration on a filter medium, such as, for example, a
cloth or sintered material, such as, for example, sintered
metal, sintered plastics material, sintered ceramics,
porous glass, with continuous removal of the filter cake
by, for example, a screw conveyor or a scraper. In an
embodiment of the invention it is possible to use a
sintered metal pipe with a metering screw.
Preliminary de-aeration can also be carried out by means of
sedimentation, the breaking up of solids bridges being
assisted by superimposed vibration, sound or slow stirring.
As starting material there can be used a hydrophilic
pyrogenically produced silicon dioxide or a hydrophobic
pyrogenically produced silicon dioxide.
Hydrophobic pyrogenically produced silicon dioxide can be
produced by means of surface modification.
Surface modification can be effected using one or more
compounds from the following group:
a) organosilanes of the type (RO)3Si(CnH2n+1) and
R = alkyl, for example methyl, ethyl, n-propyl,-
isopropyl, butyl
n = 1 - 20

b) organosilanes of the type R'x (R0)ySi (CnH2n+1) and
R = alkyl, for example methyl, ethyl,
n-propyl, isopropyl, butyl
R' = alkyl, for example methyl, ethyl,
n-propyl, isopropyl, butyl
R' = cycloalkyl
n = 1 - 20
x+y = 3
x = 1,2
Y =1,2
c) haloorganosilanes of the type X3Si(CnH2n+1) and

X = Cl, Br
n = 1 - 20
d) haloorganosilanes of the type X2(R') Si (CnH2n+1) and

X = Cl, Br
R' = alkyl, for example methyl, ethyl,
n-propyl, isopropyl, butyl
R' = cycloalkyl
n =1-20
e) haloorganosilanes of the type X (R')2Si(CnH2n+1) and

X = Cl, Br
R' = alkyl, for example methyl, ethyl,
R' = cycloalkyl
n-propyl, isopropyl, butyl
n =1-20
f) organosilanes of the type (RO)3Si(CH2)m-R'
R = alkyl, such as methyl, ethyl, propyl
m =0.1-20
R' = methyl, aryl (for example -C6H5, substituted
phenyl radicals)
R = alkyl, such as methyl, ethyl, propyl,

butyl
-SH
-NR'R' (R' = alkyl, aryl; R' = H,
alkyl, aryl; R'' = H, alkyl, aryl, benzyl,
C2H4NR' ' R' ' ' ' where R" " = A, alkyl and
R' ' ' = H, alkyl)
g) organosilanes of the type (R")x(R0)ySi (CH2)m-R'
R" = alkyl x+y = 2
= cycloalkyl x =1,2
y = 1,2
m = from 0.1 to 20
R' = methyl, aryl (for example -C6H5, substituted
phenyl radicals)

R = methyl, ethyl, propyl, butyl
-SH - NR'R'R'' (R' = alkyl, aryl; R' = H,
alkyl, aryl; R'' = H, alkyl, aryl, benzyl,
C2H4NR'' R''' where R'' = A, alkyl and
R''' = H, alkyl)
h) haloorganosilanes of the type X3Si(CH2)m-R'
X = Cl, Br
m = 0.1 - 20
R' = methyl, aryl (for example -C6H5, substituted
phenyl radicals)

R = methyl, ethyl, propyl, butyl
-SH

i) haloorganosilanes of the type (R) X2Si(CH2)m-R'
X = Cl, Br
R = alkyl, such as methyl, ethyl, propyl
m = 0.1 - 20
R' = methyl, aryl (e.g. -C6H5, substituted
phenyl radicals)

wherein R = methyl, ethyl, propyl, butyl
-Sx- (CH2)3Si(OR)3, wherein R = methyl, ethyl,
propyl, butyl and X = from 1 to 10
-SH
j) haloorganosilanes of the type (R)2X Si(CH2)m-R'
X = Cl, Br
R = alkyl, such as methyl, ethyl, propyl, butyl
m = 0.1 - 20
R' = methyl, aryl (e.g. -C6H5, substituted
phenyl radicals)
R = methyl, ethyl, propyl, butyl
-SH
k) silazanes of the type
R = alkyl
R' = alkyl, vinyl

1) cyclic polysiloxanes of the type D 3, D 4, D 5, wherein
D 3, D 4 and D 5 are understood as being cyclic
polysiloxanes having 3, 4 or 5 units of the type
-0-Si(CH3)2-.
E.g. octamethylcyclotetrasiloxane = D 4

m) polysiloxanes or silicone oils of the type

R = alkyl, such as wherein n = from 1 to 20,
aryl, such as
phenyl and substituted phenyl radicals, H
R' = alkyl, such as wherein n = from 1 to 20,
aryl, such as
phenyl and substituted phenyl radicals, H
R" = alkyl, such as wherein n = from 1 to 20,
aryl, such as
phenyl and substituted phenyl radicals, H
R'' = alkyl, such as CnH2n+1, wherein n = from 1 to 20,
aryl, such as
phenyl and substituted phenyl radicals,

In an embodiment it is possible to use as starting material
a pre-compressed pyrogenically produced silicon dioxide.
The uncompressed pyrogenically produced silicon dioxide
that is used can have a tamped density (according to DIN EN
ISO 787-11) of less than 50 g/1, preferably from 20 to
30 g/1. The pre-compressed pyrogenically produced silicon
dioxide that is used can have a tamped density (according
to DIN EN ISO 787-11) of from 50 to 190 g/1, preferably
from 100 to 150 g/1, wherein the tamped density (according
to DIN EN ISO 787-11) in the case of a pre-compressed
hydrophobic pyrogenically produced silicon dioxide can be
from 90 to 120 g/1.
The hydrophilic silicon dioxide that is used can have a
tamped density (according to DIN EN ISO 787-11) of less
than 50 g/1, preferably from 20 to 30 g/1, in the
uncompressed state.
In the pre-compressed state, the hydrophilic silicon
dioxide can have a tamped density (according to DIN EN ISO
787-11) of from 50 to 190 g/1, preferably from 100 to
150 g/1.
In the pre-compressed state, the hydrophobic silicon
dioxide can have a tamped density (according to DIN EN ISO
787-11) of from 50 to 190 g/1, preferably from 90 to
120 g/1.
The pyrogenically produced silicon dioxide that is used can
have a primary particle size of from 5 to 50 nm and a BET
surface area of from 40 to 400 m2/g, preferably from 100 to
250 m2/g.
The water content of the pyrogenically produced silicon
dioxide that is used can be less than 1 wt. %.

The pyrogenically produced silicon dioxide can be pre-
compressed by means of known methods and devices. For
example, the devices according to US 4,325,686, US
4,877,595, US 3,838,785, US 3,742,566, US 3,762,851, US
3,860,682 can be used.
In an embodiment, it is possible to use a pyrogenically
produced silicon dioxide that has been pre-compressed by
means of a press band filter according to EP 0280851 Bl or
US 4,877,595.
The pyrogenically produced Silicon dioxide can be
transported to the compaction step by means of a screw, for
example.
This transport represents the forced guiding of the
pyrogenically produced silicon dioxide into the roller gap
of the compacting rollers. If a screw conveyor is not used,
a pre-compressed pyrogenically produced silicon dioxide
must be employed.
If a screw conveyor is used, the pyrogenically produced
silicon dioxide does not have to be pre-compressed because
preliminary de-aeration takes place therein.
In order to achieve high bulk weights of the -Schulpen it is
possible to use a screw conveyor and a pre-compressed
pyrogenically produced silicon dioxide.
The screw conveyor used can be a screw with decreasing
volume or with increasing pitch or with decreasing
diameter.
The screw conveyor can be enclosed in a pipe to which a
vacuum is applied. This pipe can consist of a sintered
jacket. Preliminary de-aeration of the silicon dioxide here
takes place in the screw conveyor at the same time as
transportation into the roller gap.

Compaction to Schulpen can be carried out by means of two
rollers, one or both of which can at the same time have a
de-aerating function.
It is possible especially to use two compacting rollers,
which can be smooth. They can also be profiled. The profile
can be present either only on one compacting roller or on
both compacting rollers.
The profile can consist of axis-parallel ribs.
Alternatively, it can be troughs (indentations) of any
desired form in any desired arrangement.
In a further embodiment, at least one of the rollers can be
a vacuum roller. In this embodiment, the roller can be
covered with sintered metal.
In order to carry out the de-aeration function, the roller
can be produced from sintered metal or be covered with a
filter medium, such as, for example, with a cloth.
If the pyrogenically produced silicon dioxide can be de-
aerated by means of the rollers, it is possible to dispense
with the additional preliminary de-aeration, which can take
place in the screw conveyor or the feed pipe.
If the roller is used for preliminary de-aeration, the
roller can have a smooth or profiled surface, it being
possible for the surface to be only slightly ribbed in
order to improve product intake.
During compaction, uniform compression of the pyrogenically
produced silicon dioxide is to be ensured in order to
obtain Schulpen of uniform density.
A device as shown in Figure 2 can be used for carrying out
the compaction.
According to Figure 2, the pyrogenically produced silicon
dioxide is introduced by means of the pre-compressor screw

1 into the chamber 2 between the two rollers 3 and is
compressed between the two rollers to form Schulpen.
A device as described in document DE AS 1807714 can also be
used for carrying out the process.
During compaction, smooth rollers can preferably be used in
order to avoid grit. It is further possible to use one or
two rollers of sintered material, such as sintered metal or
sintered ceramics, via which de-aeration can take place.
After compaction, the Schulpen are broken. To this end
there can be used a sieve granulator, which specifies the
grain size by the mesh size of the sieve. The mesh size can -
be from 250 µm to 20 mm.
For breaking the Schulpen it is further possible to use a
device having two rollers which rotate in opposite
directions and have a defined gap between them, or a
toothed roller.
The broken Schulpen can be graded by means of a sifter, a
sieve or a classifier. The fines content (particles smaller
than 200 µm) can be separated off thereby.
As sifters there can be used cross-flow sifters, counter-
current deflecting sifters, etc.
A cyclone can be used as classifier.
The fines content (particles smaller than 200 µm) separated
off during grading can be fed back into the process
according to the invention.
Determination of the dust content
The dust content is determined according to DIN 55992-2.

Prior to the measurement, a weighed amount of the Schulpen
of the pyrogenically produced silicon dioxide to be tested
is introduced into a feed system at the top end of the down
pipe. This is closed at the bottom before the start of the
measurement by flaps. The end of the down pipe is closed.
At the start of the measurement, that flap is opened for a
specific period of time so that the sample is able to fall
into the down pipe. As it falls, and when it comes into
contact with the bottom of the down pipe, the sample gives
off dust into the air. The air currents during falling
ensure that the dust is distributed uniformly in the pipe.
The suspended material then begins to settle. At the bottom
end of the down pipe, the light extinction caused by the
suspended material is measured by a photometric sensor. The
course of the sedimentation is indicated by a PC as a
function of the time. In the case of the CIPACMT171 dust-
measuring device, the extinction E (in %) is plotted
directly as a function of the sedimentation time. In the
case of the SP3 dust-measuring device from Lorenz, the dust
number SZ is calculated according to the following formula
(eq. 1) and plotted as a function of time.

The dust number is a measure of the fine dust content of
the sample. "Fine dust" here refers to the fraction whose
rate of sedimentation in air is less than 1 m/16 s =
0.0625 m/s.
A diagrammatic representation of the device used to
determine the dust content is shown in Figure 3.
In Figure 4, the fine dust content of the pyrogenically
produced silicon dioxide compacted to form Schulpen that is

used according to the invention and the fine dust contents
of pyrogenic silicon dioxide that has been compressed by a
different method are compared.
The starting material employed for the silicon dioxide used
according to the invention was a pyrogenically produced
silicon dioxide that had been compressed by means of the
press band filter according to EP 0280851 Bl.
Figure 4 shows a measure of the particle size distribution
and the mean particle size of the bulk powder or Schulpen,
which are used with the according to the invention. This
demonstrates that the Schulpen of the pyrogenically
produced silicon dioxide that are used according to the
invention settle significantly better and form
significantly less dust than the granules according to EP
0 725037 A1.
Figure 4 also shows a measure of the fine or suspended dust
content. This demonstrates that the suspended dust content
can be drastically reduced with the Schulpen used according
to the invention. In the case of granules according to EP
075 037 A1, a large proportion remains suspended for a long
time .
Figure 5 shows the combined distribution (Q-3 distribution)
of various granules according to EP 0 725 037 A1, None of
these granules exhibits a mean particle size of 120 urn.
Only the largest particles in this group are from 96 to
128 µm in size. This is less than 11 %.
The Schulpen used according to the invention with
X according to EP 0 725 037 Al in laser diffraction
spectroscopy. In both cases it is ~ 35 µm.
However, the Schulpen according to the invention produce
significantly less dust.

The fractions of the Schulpen were produced by sieve
granulation using a sieve having a mesh size of 500 µm,
with subsequent sieving on a 250 µm sieve. The fraction
x fraction having a particle size of from 250 to 500 µm was
the coarse material.
Figure 6 shows the pyrogenically produced silicon dioxide
compacted to form Schulpen that is used according to the
invention, in its granular form after breaking and sieving.
It has an angular shape.
The granules according to DE 19601415 have a spherical
appearance.
In a preferred embodiment, the Schulpen used according to
the invention have a tamped density of from 200 to 300 g/1.
Such Schulpen then have the necessary strength not to
disintegrate again in the subsequent steps. However, they
can readily be dispersed again.
Furthermore, the Schulpen that are obtained are porous.
The Schulpen used according to the invention have an
advantageously low dust content after breaking even without
sieving or grading.
The Schulpen used according to the invention have an
agglomerate hardness of less than 50 N, measured using an
ERWEKA 30.
After breaking, the Schulpen used according to the
invention do not exhibit a further dust content. Even
during handling, transportation or storage, no further dust
content is formed with the Schulpen used according to the
invention. The pyrogenically produced silicon dioxide
compacted to form Schulpen does not exhibit a fines content
having a diameter of less than 200 µm after sieving.

The pyrogenically produced silicon dioxide compacted to
form Schulpen that is used according to the invention has a
low dust content that is advantageous for all applications.
It can be added to the mixtures without loss and without
introducing dust.
The pyrogenically produced silicon dioxide compacted to
form Schulpen does not contain binder.
The silicon dioxide utilized in the invention is of the
very fine particle size variety. In the most preferred
embodiments of the invention, the silicon dioxide utilized
is a colloidal silicon dioxide. Colloidal silicon dioxide
is a submicron fumed silica prepared by the vapor-phase
hydrolysis (e.g., at 1110° C.) of a silicon compound, such
as silicon tetrachloride. The product itself is a
submicron, fluffy, light, loose, bluish-white, odorless
and tasteless amorphous powder which is commercially
available from a number of sources, including Cabot
Corporation (under the tradename Cab-OSil); Degussa, Inc.
(under the tradename AEROSIL) ; E.1. DuPont & Co.; and W.R.
Grace & Co. Colloidal silicon dioxide is also known as
colloidal silica, fumed silica, light anhydrous silicic
acid, silicic anhydride, and silicon dioxide fumed, among
others. A variety of commercial grades of colloidal
silicon dioxide are produced by varying the manufacturing
process. These modifications do not affect the silica
content, specific gravity, refractive index, color or
amorphous form. However, these modifications are known to
change the particle size, surface areas, and bulk
densities of the colloidal silicon dioxide products.
The surface area of the preferred dass of silicon dioxides
utilized in the invention ranges from about 50 m2/gm to
about 500 m2/gm. The average primary particle diameter of
the preferred dass of silicon dioxides utilized in the
invention ranges from about 5 nm to about 50 run. However,
in commercial colloidal silicon dioxide products, these

particles are agglomerated or aggregated to varying
extents. The bulk density of the preferred dass of silicon
dioxides' utilized in the invention ranges from about 20
g/1 to about 100 g/1.
Commercially available colloidal silicon dioxide products
have, for example, a BET surface area ranging from about
50+15 m2/gm (AEROSIL OX50) to about 400±20 (Cab-O-Sil S-17)
or 390+40 m2/gm (cab-o-sil EH-5). Commercially available
particle sizes range from a nominal particle diameter of 7
nm (e.g., Cab-O-Sil S-17 or Cab-O-Sil EH-5) to an average
primary particle size of 40 nm (AEROSIL OX50). The density
of these products range from 72.0±8 g/1 (Cab-O-Sil S-17) to
36.8 g/1 (e.g., Cab-O-Sil M-5). The pH of the these
products at 4% aqueous dispersion ranges from pH 3.5-4.5.
The pyrogenic silicon dioxide serving as starting material
is produced by feeding a volatile silicon compound through a
nozzle into a detonating gas flame of hydrogen and air.
Silicon tetrachloride is used in most cases. This substance
hydrolyses under the influence of the water produced in the
detonating gas reaction, to form silicon dioxide and
hydrochloric acid. After leaving the flame the silicon
dioxide enters a so-called coagulation zone in which the
silicon dioxide primary particles and primary aggregates
agglomerate. The product present as a form of aerosol in this
stage is separated from the gaseous accompanying substances
in cyclones and is then post-treated with moist hot air. The
residual hydrochloric acid content can be reduced to below
0.025% by this process.
The granular materials (Schulpen) based on pyrogenically
produced silicon dioxide may also be silanised. The carbon
content of the granular material is then preferably 0.3 to
15.0 wt. %. Halogenated silantes, alkoxysilanes, silazanes
and/or siloxanes may be used for the silanisation.

The following substances in particular may be used as
halogenated silanes:

halogenated organosilanes of the type
halogenated organosilanes of the type
halogenated organosilanes of the type

halogenated organosilanes of the type (R)X2Si(CH2)m-R'

R = Alkyl
m = 0.1 - 20
R' = Alkyl, aryl (e.g. -C6H5)

halogenated organosilanes of the type
The following substances in particular may be used as
alkoxysilanes:
organosilanes of the type

organosilanes of the typQ
organosilanes of the type

organosilanes of the type
R" = Alkyl
x+y = 2
x = 1.2
y = 1.2

The silane Si 108 trimethoxyoctylsilane
may preferably be used as silanisation agent.
The following substances in particular may be used as
silazanes :
Silazanes of the type:

R = Alkyl
R' = Alkyl, vinyl
as well as for example hexamethyldisilazane.
The following substances in particular may be used as
siloxanes:
cyclic polysiloxanes of the type D 3, D 4, D 5, e.g.
octamethylcyclotetrasiloxane = D 4

polysiloxanes and/or silicone oils of the type:

The silanisation may be carried out by spraying the Schulpen with the silanisation agent, which may optionally
be dissolved in an organic solvent, for example ethanol,
and then thermally treating the mixture at a temperature
of 105° to 400° C. for a period of 1 to 6 hours.
An alternative method of silanising the Schulpen involves
treating the Schulpen with the silanisation agent in
vapour form and then thermally treating the mixture at a
temperature of 200 to 800 C. for a period of 0.5 to 6
hours. The thermal treatment may be carried out under a
protective gas, such as for example nitrogen.
The silanisation may be carried out continuously er
batchwise in heatable mixers and dryers with spray
devices. Suitable types of apparatus include for example
ploughshare mixers, plate dryers, fluidised-bed dryers or
turbulent-layer dryers.

The physicochemical parameters Of the Schulpen, such as
the specific surface, grain size distribution, pore
volume, tamped density and silanol group concentration,
pore distribution and pH value may be altered within the
specified limits by varying the starting substances,
spraying conditions, heat treatment and silanisation.
One subject of the invention is the use of Schulpen based
On pyrogenically produced silicon dioxide in a
pharmaceutical composition.
Thereby the pharmaceutical composition can be present in
the form of a suspension, emulsion, aerosol, ointment,
cream, gel, paste, suppository, stick, powder, topical
powder, granular material, tablet, pastille, sugar-coated
pill, film-coated tablet, hard gelatin capsule, soft
gelatin capsule, extrudate, microcapsule or a microsphere.
According to the invention the Schulpen can act as a
glidant for pharmaceutical active constituents and/or
auxiliary substances.
A further subject of the invention is a pharmaceutical
composition containing Schulpen based on pyrogenically
produced silicon dioxide and at least one pharmaceutical
active constituent.
The pharmaceutical composition according to the invention
can contain furthermore at least one pharmaceutical
auxiliary substance.
The silicon dioxide Schulpen may be used in combination
with any arbitrary pharmaceutical active constituent. The
following may be mentioned by way of example:
a-proteinase inhibitor, abacavir, abciximab, acarbose,
acetylsalicylic acid, acyclovir, adenosine, albuterol,
aldesleukin, alendronate, alfuzosin, alosetrone,
alprazolam, alteplase, ambroxol, amifostine, amiodarone,

amisulprid, amlodipine, amoxicillin, amphetamine,
amphotericin, ampicillin, amprenavir, anagrelide,
anastrozole, ancrod, anti-haemophilia factor, aprotinin,
atenolol, atorvastatin, atropine, azelastine, azithromycin,
azulene, barnidipin, beclomethasone, benazepril,
benserazide, beraprost, betamethasone, betaxolol,
bezafibrate, bicalutamide, bisabolol, bisoprolol, botulinum
toxin, brimonidine, bromazepam, bromocriptine, budesonide,
bupivacaine, bupropion, buspirone, butorphanol, caber-
goline,calcipotriene, calcitonin, calcitriol, camphor,
candesartan, candesartan cilexetil, captopril, car-
bamazepine, carbidopa, carboplatin, carvedilol, cefaclor,
cefadroxil, cefaxitin, cefazolin, cefdinir, cefepime,
cefixime, cefmetazole, cefoperazone, cefotiam, cefoxopran,
cefpodoxime, cefprozil, ceftazidime, ceftibuten,
ceftriaxone, cefuroxime, celecoxib, celiprolol, cephalexin,
cerivastatin, cetirizine, chloramphenicol, cilastatin,
cilazapril, cimetidine, ciprofibrate, ciprofloxacin,
cisapride, cisplatin, citalopram, clarithromycin,
clavulanic acid, clindamycin, clomipramine, clonazepam,
clonidine, clopidogrel, clotrimazole, clozapine, cromolyn,
cyclophosphamide, cyclosporine, cyproterone, dalteparin,
deferoxamine, desogestrel, dextroamphetamine, diazepam,
diclofenac, didanosine, digitoxin, digoxin,
dihydroergotamine, diltiazem, diphtheria protein,
diphtheria toxoxide, divalproex, dobutamine, docetaxel,
dolasetron, donepezil, dornase-a, dorzolamide, doxazosin,
doxifluridin, doxorubicin, dydrogesterone, ecabet,
efavirenz, enalapril, enoxaparin, eperisone, epinastin, epirubicin, eptifibatide, erythropoietin-a, erythropoietin-
β, etanercept, ethinyl oestradiol, etodolac, etoposide,
factor VIII, famciclovir, famotidine, faropeneme, felo-
dipine, fenofibrate, fenoldopam, fentanyl, fexofenadin,
filgrastim, finasteride, flomoxef, fluconazole,
fludarabine, flunisolide, flunitrazepam, fluoxetine,
flutamide, fluticasone, fluvastatin, fluvoxamine, fol-
litropin-a, follitropin-ft, formoterol, fosinopril, furo-

semide, gabapentin, gadodiamide, ganciclovir, gatifloxacin,
gemcitabine, gestoden, glatiramer, glibenclamide,
glimepiride, glipizide, glyburide, goserelin, granisetron,
griseofulvin, hepatitis B antigen, hyaluronic acid,
hycosin, hydrochlorothiazide, hydrocodone, hydrocortisone,
hydromorphone, hydroxychloroguine, hylan G-F 20, ibuprofen,
ifosfamide, imidapril, imiglucerase, imipenem, immu-
noglobulin, indinavir, indomethacin, infliximab, insulin,
insulin human, insulin Lispro, insulin aspart, interferon
β, interferon a, iodine 125, iodixanol, iohexol, iomeprol,
iopromid, ioversol, ioxoprolen, ipratropium, ipriflavone,
irbesartan, irinotecan, isosorbide, isotretinoin,
isradipine, itraconazole, potassium chlorazepate, potassium
chloride, ketorolac, ketotifen, whooping cough vaccine,
coagulation factor IX, lamivudine, lamotrigine,
lansoprazole, latanoprost, leflunomide, lenograstim,
letrozole, leuprolide, levodopa, levofloxacin,
levonorgestrel, levothyroxine, lidocaine, linezolid,
lisinopril, lopamidol, loracarbef, loratadine, lorazepam,
losartan, lovastatin, lysineacetylsalicylic acid,
manidipin, mecobalamin, medroxyprogesterone, megestrol,
meloxicam, menatetrenone, meningococcus vaccine,
menotropine, meropenem, mesalamine, metaxalone, metformin,
methylphenidate, methylprednisolone, metoprolol, midazolam,
milrinone, minocycline, mirtazapine, misoprostol,
mitoxantrone, moclobemid, modafinil, mometasone,
montelukast, morniflumat, morphine, moxifloxacin,
mycophenolate, nabumetone, nadroparin, naproxen,
naratriptan, nefazodone, nelfinavir, nevirapine, niacin,
nicardipine, nicergoline, nifedipine, nilutamide, nilvad-
ipine, nimodipine, nitroglycerin, nizatidine, nore-
thindrone, norfloxacin, octreotide, olanzapine, omeprazole,
ondansetron, orlistate, oseltamivir, oestradiol,
oestrogens, oxaliplatin, oxaprozin, oxolinic acid,
oxybutynin, paclitaxel, palivizumab, pamidronate,
pancrelipase, panipenem, pantoprazol, paracetamol,
paroxetine, pentoxifylline, pergolide, phenytoin,

pioglitazon, piperacillin, piroxicam, pramipexole,
pravastatin, prazosin, probucol, progesterone, propafenone,
propofol, propoxyphene, prostaglandin, quetiapine,
quinapril, rabeprazol, raloxifene, ramipril, ranitidine,
repaglinide, reserpine, ribavirin, riluzole, risperidone,
ritonavir, rituximab, rivastigmin, rizatriptan, rofecoxib,
ropinirol, rosiglitazone, salmeterol, saquinavir,
sargramostim, serrapeptase, sertraline, sevelamer,
sibutramin, sildenafil, simvastatin, somatropine, sotalol,
spironolactone, stavudin, sulbactam, sulfaethidole,
sulfamethoxazole, sulfasalazine sulpirid, sumatriptan,
tacrolimus, tamoxifen, tamsulosin, tazobactam, teicoplanin,
temocapril, temozolomid, tenecteplase, tenoxicam, teprenon,
terazosin, terbinafine, terbutaline, tetanus toxoid,
tetrabenazine, tetrazepam, thymol, tiagabine, tibolon,
ticarcillin, ticlopidine, timolol, tirofiban, tizanidine,
tobramycin, tocopheryl nicotinate, tolterodine, topiramate,
topotecan, torasemid, tramadol, trandolapril, trastuzumab,
triamcinolone, triazolam, trimebutin, trimethoprim,
troglitazone, tropisetrone, tulobuterol, unoproston,
urofollitropine, valacyclovir, valproic acid, valsartan,
vancomycin, venlafaxine, verapamil, verteporfin,
vigabatrin, vinorelbine, vinpocetine, vitamin A, vitamin D,
vitamin E, vitamin K, voglibose, warfarin, zafirlukast,
zaleplon, zanamivir, zidovudine, zolmitriptan, Zolpidem,
zopiclone nutritional oils, essential fatty acids, non-
essential fatty acids, extracts of plant or animal origin,
oils of plant or animal origin and their derivatives.
Pharmaceutical active constituents are however also
understood to include other substances such as vitamins,
provitamins, essential fatty acids, extracts of plant and
animal origin and oils of plant and animal origin.
Suitable active pharmaceutical ingredients are not limited
by therapeutic category, and can be, for example,
analgesics, anti-inflammatory agents, antihelminthics,

anti-arrhythmic agents, anti-bacterial agents, anti-viral
agents, anticoagulants, anti-depressants, anti-diabetics,
anti-epileptics, anti-fungal agent, anti-gout agents, anti-
hypertensive agents, anti-malarials, anti-migraine agents,
anti-muscarinic agents, anti-neoplastic agents, erectile
dysfunction improvement agents, immunosuppresants, anti-
protozoal agents, antithyroid agents, anxiolytic agents,
sedatives, hypnotics, neuroleptics, B-blockers, cardiac
inotropic agents, corticosteroids, diuretics, anti-
parkinsonian agents, gastrointestinal agents, histamine
receptor antagonists, keratolyses, lipid regulating
agents, anti-anginal agents, Cox-2 inhibitors, leukotriene
inhibitors, macrolides, muscle relaxants, anti-
osteoporosis agents, anti-obesity agents, cognition
enhancers, anti-urinary incontinence agents, nutritional
oils, anti-benign prostate hypertrophy agents, essential
fatty acids, non-essential fatty acids, extracts of plant
or animal origin, oils of plant or animal origin, and
mixtures thereof.
A wide variety of therapeutically active agents can be
used in conjunction with the present invention. The thera-
peutically active agents (e.g. pharmaceutical agents)
which may be used in the compositions of the present
invention include both water soluble and water insoluble
drugs. Examples of such therapeutically active agents
include antihistamines (e.g., dimenhydrinate,
diphenhydramine, chlorpheniramine and dexchlorpheniramine
maleate), analgesics (e.g., aspirin, codeine, morphine,
dihydromorphone, oxycodone, etc.), non-steroidal anti-
inflammatory agents (e.g., naproxyn, diclofenac,
indomethacin, ibuprofen, sulindac), antiemetics (e.g.,
metoclopramide), antiepileptics (e.g., phenytoin,
meprobamate and nitrezepam), vasodilators (e.g.,
nifedipine, papaverine, diltiazem and nicardirine), anti-
tussive agents and expectorants (e.g., codeine phosphate),

anti-asthmatics (e.g. theophylline), antacids, anti-
spasmodics (e.g. atropine, scopolamine), antidiabetics
(e.g., insulin), diuretics (e.g., ethacrynic acid,
bendrofluazide), antihypotensives (e.g., propranolol,
clonidine), antihypertensives (e.g, clonidine,
methyldopa), bronchodilators (e.g., albuterol), steroids
(e.g., hydrocortisone, triamcinolone, prednisone),
antibiotics (e.g., tetracycline), antihemorrhoidals,
hypnotics, psychotropics, antidiarrheals, mucolytics,
sedatives, decongestants, laxatives, vitamins, stimulants
(including appetite suppressants such as
phenylpropanolamine). The above list is not meant to be
exclusive.
A wide variety of locally active agents can be used in
conjunction with the novel excipient described herein, and
include both water soluble and water insoluble agents. The
locally active agent (s) which may be included in the con-
trolled release formulation of the present invention is
intended to exert its effect in the environment of use,
e.g., the oral cavity, although in some instances the
active agent may also have systemic activity via
absorption into the blood via the surrounding mucosa.
The locally active agent(s) include antifungal agents
(e.g., amphotericin B, clotrimazole, nystatin,
ketoconazole, miconazol, etc.), antibiotic agents
(Penicillins, cephalosporins erythromycin, tetracycline,
aminoglycosides, etc.), antiviral agents (e.g, acyclovir,
idoxuridine, etc.), breath fresheners (e.g. chlorophyll),
antitussive agents (e.g., dextromethorphan hydrochloride),
anti-cariogenic compounds (e.g., metallic salts of
fluoride, sodium monofluorophosphate, stannous fluoride,
amine fluorides), analgesic agents (e.g., methylsalicylate,
salicylic acid, etc.), local anesthetics (e.g.,
benzocaine), oral antiseptics (e.g., chlorhexidine and
salts thereof, hexylresorcinol, dequalinium chloride,

cetylpyridinium chloride), anti-flammatory agents (e.g.,
dexamethasone, betamethasone, prednisone, prednisolone,
triamcinolone, hydrocortisone, etc.), hormonal agents
(oestriol), antiplaque agents (e.g, chlorhexidine and salts
thereof, octenidine, and mixtures of thymol, menthol,
methysalicylate, eucalyptol), acidity reducing agents
(e.g., buffering agents such as potassium phosphate lo
dibasic, calcium carbonate, sodium bicarbonate, sodium and
potassium hydroxide, etc.), and tooth desensitizers (e.g.,
potassium nitrate). This list is not meant to be exclusive.
The solid formulations of the invention may also include
other locally active agents, such as flavorants and
sweeteners. Generally any flavoring or food additive such
as those described in Chemicals Used in Food Processing,
pub 1274 by the National Academy of Sciences, pages 63-258
may be used.
A wide variety of pharmaceutically systemically active
agents can be formulated e.g., vitamins, minerals, amino
acids, essential trace elements, hormones and antagonists
thereof, steroids, non-steroid anti-inflammatory agents,
antineoplastic agents, antigens, antihistaminic agents,
neuropharmacologic agents, including analgesics,
vasodilators, anticoagulants, antimicrobial agents,
antiviral agents, antifungal agents, antiparasitic agents,
heavy metal antagonists, locally active drugs moderating
the digestive tract, such as enzymes, antacids, histamine
antagonists, diuretics and cardiovascular drugs.
It is to be understood that the compositions of the
invention may comprise more than one active drug substance,
e.g. a combination of two or more drug substances. For
example, a composition of the invention may comprise a
therapeutic effective dose of drospirenone and a therapeu-
tic effective dose of an estrogen.

Further constituents of the pharmaceutical compositions
according to the invention may include conventional
auxiliary substances such as for example antioxidants,
binders, emulsifiers, colouring agents, filmforming agents,
fillers, odoriferous substances, flavouring 'substances,
gelforming agents, preservatives, solvents, oils, powder
bases, ointment bases, acids and salts for the formulation,
replenishment and production of pharmaceutical
compositions, lubricants, release agents, suppository
bases, suspension stabilisers, sweetening agents,
effervescent gases, emollients and sugar substitutes.
Plant medicament preparations and homeopathic preparations
are also included among the pharmaceutical compositions in
which the silicon dioxide Schulpen may be used.
The pharmaceutical compositions according to the invention
may also include socalled retard and depot dosage forms
with controlled release of active constituent. Moreover
the pharmaceutical compositions according to the invention
may also be part of therapeutic systems such as for example
therapeutic systems for topical application and
transdermal therapeutic systems.
In a preferred embodiment the silicon dioxide Schulpen
based on pyrogenic silicic acid serves as a glidant for
improving the flow of pharmaceutical active constituents
and/or excipients and/or mixtures thereof. The present
invention is accordingly also directed to a mixture of the
aforedescribed silicon dioxide Schulpen and at least one of
these substances.
The compositions according to the invention can be used in
the form of solid, semi-solid and liquid product forms.
Solid product forms are, for example, powders, granules,
tablets and filled capsules. Examples of semi-solid product
forms are creams, ointments, gels, pastes and "soft" gel

Capsules. Liquid product forms are, for example,
suspensions. Further suitable product forms can be
suppositories and aerosols, for example.
The term "glidant" may also mean that silicon dioxide
Schulpen or fragments thereof coat solid particles of
the material. The forCGS Of attraction between the particles
are reduced and for example the flow behaviour is improved.
Schulpen formed from pyrogenic silicic acids Can in
particular complement or replace the conventional pyrogenic
silicic acids that have been established in pharmaceutical
practice for many years. For example, Schulpen of pyrogenic
silicic acids may above all improve the production and
properties of solid medicament forms. Also, they may
advantageously be employed in the production of extrudates
and replace for example other established auxiliary
substances such as cellulose or polymers.
The advantages of the Schulpen based on pyrogenically
produced silicon dioxide compared to the known non-
granulated pyrogenic silicic acids lie above all in their
non-agglomerating behaviour, improved flowability, narrower
and definable particle size distribution, and dust-free
handling. In addition tablets produced therefrom have
mechanical stability and disintegration behaviour
properties as do tablets prepared with conventional highly
disperse pyrogenic silicic acid.
The invention will now be described in more detail with the
aid of examples.
Here too, AEROSIL was first compacted to form Schulpen and
then sieve granulated. The fine-material fraction of the
subsequent sieving was used. The AEROSIL Schulpen grain
size of this fine-material fraction is less than 250 µm.
Highly disperse pyrogenic silicic acids such as AEROSIL 200
Pharma or AEROSIL 200 Pharma VV 120 are frequently used as

flow regulators in the production of medicaments. By adding
small amounts of AEROSIL, the flow behaviour of an active
ingredient carrier or auxiliary substance can be increased
and accordingly its application-related properties, such
as, for example, its metering ability, can be improved,
Avicel PH-101 is a frequently used microcrystalline
cellulose whose flow behaviour is improved by addition of
small amounts of AEROSIL 200 (e.g. 0.5 %). The sieving
behaviour and, above all, the sieve residue of the mixture
of Avicel and AEROSIL is an important application-related
property. A large sieve residue means that automatic
weighing, sieving and metering devices cannot be used. In
order to test these granules for AEROSIL Schulpen in
comparison with AEROSIL 200 Pharma and AEROSIL 200 Pharma
VV 120, the sieve residue of the following mixtures was
studied.
• Avicel® PH-101 without flow regulator (zero sample)
• Avicel® PH-101 99.5% + 0.5% AEROSIL® 200 Pharma
• Avicel® PH-101 99.5% + 0.5% AEROSIL® 200 VV Pharma
• Avicel® PH-101 99.5% + 0.5% AEROSIL® Schulpen 250
(x The various components of the mixture were weighed directly
onto a sieve having a mesh size of 0.71 mm. The mixture was
first sieved through this sieve and thereby mixed slightly.
The pulverulent mixtures were then mixed by means of a
mixer (Turbula) at 46 rpm for a defined time (5, 10, 30,
60 minutes.) . In general, agglomerates break up during
mixing, as a result of which the sieving ability generally
improves with the mixing time. After the times defined
above, the powder was sieved through, a 0.315 mm sieve and
the sieve residue was determined in wt.%. This is shown in Figure 8 as a function of the mixing time.

While pure Avicel passes through the sieve completely, the
agglomerates in the case of AEROSIL 200 VV 120 Pharma and
AEROSIL 200 Pharma are broken up by the mixing process only
with difficulty. The sieving ability is relatively poor as
a result. AEROSIL 200 VV 120 is compressed on a vacuum
press band filter to a tamped density of approximately
120 g/1. However, the sieving behaviour worsens thereby.
The AEROSIL Schulpen combine a good sieving and pouring
ability with low dust formation. Accordingly, they have
marked application-related advantages over AEROSIL 200
Pharma and AEROSIL 200 VV 120 Pharma. Further
characteristic values for assessing the flow properties of
various auxiliary substances such as microcrystalline
cellulose (Avicel PH-101, FMB Biopolymers), starch and
lactose monohydrate (Tablettose from Meggle) are AEROSIL
Schulpen slightly better or equally as good as in the case
of AEROSIL 200 Pharma or AEROSIL 200 VV 120 Pharma.
The AEROSIL Schulpen exhibit a significantly better
activity as flow regulators than AEROPERL. The measurement
is called angle of repose and is used to determine the flow
properties of powders. The angle of repose values are as
follows:
Avicel alone: 4 6.7°
Avicel + 1 % VP AEROPERL 300' Pharma: 4 6.7°
Avicel + 1 % AEROSIL® Granulate 500 (250 Avicel + 1 % AEROSIL® Granulate 250 (x A difference of 3° in the angle of repose is regarded as
significant. AEROPERL produces no improvement in the
flowability compared with Avicel alone. The difference of
almost 10° between AEROPERL and the AEROSIL Schulpen is an
enormous improvement.

WE CLAIM :
1. A process for the preparation of a pharmaceutical composition comprising pyrogenically
produced silicon dioxide as a glidant for pharmaceutical active constituents and/or auxiliary
substance comprising the following steps:
- de-aerating or decompressing the pyrogenically produced silicon dioxide;
compressing (compacting) the pyrogenically produced silicon dioxid by roller
compaction to band-like intermediates (Schulpen) to have a tamped density
(according to DIN EN ISO 787-11) of from 185 to 700 g/1;
- breaking the band-like intermediates(Schulpen); optionally grading or sieving the
broken band-like intermediates(Schulpen);
- combining the broken band-like intermediates (Schulpen) with at least one
pharmaceutically active constituent.

2. The process as claimed in claim 1 wherein the pharmaceutical composition is present in
the form of a suspension, emulsion, aerosol, ointment, cream, gel, paste, suppository,
stick, powder, topical powder, granular material, tablet, pastille, sugarcoated pill, film-
coated tablet, hard gelatin capsule, soft gelatin capsule, extrudate, microcapsule or a
microsphere.
3. The process as claimed in claims 1 or 2 wherein the pharmaceutical composition contains
at least one further pharmaceutical auxiliary substance.
4. The process as claimed in any of the preceding claims wherein the band-like intermediates
(Schulpen) have a tamped density (according to DIN EN ISO 787-11) of from 200 to 450
g/1-

ABSTRACT

Title: "A PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL
COMPOSITION COMPRISING PYROGENICALLY PRODUCED SILICON DIOXIDE"
A process for the preparation of a pharmaceutical composition comprising pyrogenically
produced silicon dioxide as a glidant for pharmaceutical active constituents and/or auxiliary
substance comprising the following steps:
de-aerating or decompressing the pyrogenically produced silicon dioxide;
compressing (compacting) the pyrogenically produced silicon dioxid by roller
compaction to band-like intermediates (Schulpen) to have a tamped density
(according to DIN EN ISO 787-11) of from 185 to 700 g/1;
breaking the band-like intermediates(Schulpen); optionally grading or sieving the
broken band-like intermediates(Schulpen);
- combining the broken band-like intermediates (Schulpen) with at least one
pharmaceutically active constituent.

" A PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION COMPRISING PYROGENICALLY PRODUCED SILICON DIOXIDE"

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