WO2020127281A1

WO2020127281A1 - A release system comprising a bioactive agent and a particulate material

Info

Publication number: WO2020127281A1
Application number: PCT/EP2019/085675
Authority: WO
Inventors: Dieter Lubda; Gert Fricker
Original assignee: Merck Patent Gmbh
Priority date: 2018-12-20
Filing date: 2019-12-17
Publication date: 2020-06-25

Abstract

The present invention relates to a release system comprising a bioactive agent and a particulate material, wherein the particulate material comprises macropores and the particulate material exhibits flowability. Furthermore, the present invention provides a method for the production of the present release system and a use.

Description

A release system comprising a bioactive agent and a particulate material

Field of the invention

The present invention relates to a release system comprising a bioactive agent and a particulate material, a process for producing the release system, and the use of the material for the administration of a bioactive agent.

Background Art

Inorganic materials are receiving a great interest in the field of biomedical science in the last few years. Two main routes have been traditionally used for drug intake: oral administration and injection. Traditional therapies are characterized by an increase of drug concentration in plasma when the intake takes place, followed by a decrease, leading to a sinusoidal drug concentration in the plasma as a function of continuous dosing during the duration of therapy.

Inorganic materials, especially bioceramics, have some porosity that can be used for drug delivery including chemically synthesized substances such as, for example, ibuprofen or nimodipine, but also biologically derived substances such as, for example, releasing growth factors or proteins. These materials are characterized by large specific surface areas, ordered pore systems, and narrow pore size distributions.

Depending of their pore size inorganic materials can be classified as microporous, mesoporous or macroporous. Within the meaning of the present application microporous materials are understood to have a pore size < 2 nm, mesoporous materials are understood to have a pore size from 2 to < 50 nm and macroporous materials are understood to have a pore size of at least 50 nm. In recent years ordered and non-ordered porous materials have been increasingly studied for the use as drug delivery systems.

One main approach for using mesoporous silica for the formulation of drug delivery systems is to increase the dissolution rate of poorly water-soluble or water-insoluble active pharmaceutical ingredients. Poorly water-soluble or insoluble active pharmaceutical ingredients usually have a very low bioavailability due to their poor solubility in digestive fluids causing incomplete absorption. This means, the rationale of using mesoporous silica for use in drug delivery systems is not only to increase the dissolution rate of poorly water- soluble or water-insoluble active pharmaceutical ingredients but also to improve their bioavailability by depositing the drug in it’s amorphous form onto the surface and within the pores of the carrier . Ordered mesoporous materials, which have been extensively studied, are e.g. MCM-41 (Mobil Composition of Matter number forty one) and SBA-15 (Santa Barbara Amorphous number fifteen). SBA-15 was first described by Zhao et al. and is the result of a templating procedure based on a hexagonal arrangement of amphiphilic block copolymers (D.Y. Zhao et al.: Triblock copolymer syntheses of mesoporous silica with periodic 5 to 30 nm, Science 279 (1998) 548-552). MCM-41 is obtained by the template action of long chain alkylammonium surfactant molecules (J.S. Beck et al.:

A new family of mesoporous molecular sieves prepared with liquid-crystal templates, J. Am. Chem. Soc. 114 (1992) 10834-10843). Typically, the pore diameter varies between 2 and 6 nm for MCM-41 and between 4 and 13 nm for SBA-15. In addition to the well-defined mesopore system, SBA-15 has a complementary pore system comprised of micropores (pore size < 2 nm). These micropores are located in the walls between adjacent mesopores and do not bridge the wall; they constitute dead end pores (J.S. Beck et al.: A new family of mesoporousmolecular sieves prepared with liquid-crystal templates, J. Am. Chem. Soc. 114 (1992) 10834-10843). Vallet-Regi et al. were one of the first to explore the drug release properties of these materials in an attempt to prolong the release of ibuprofen using MCM-41 as a carrier (M. Vallet-Regi et al.: A new property of MCM-41 : drug delivery system, Chem. Mater. 13 (2001 ) 308-311 ). The release kinetics of drugs from mesoporous silica carriers is dependent on several material characteristics including pore size (P. Horcajada et al.: Influence of pore size of MCM-41 matrices on drug delivery rate, Microporous

Mesoporous Mater. 68 (2004) 105- 09), pore connectivity (J. Andersson et al.: Influences of material characteristics on ibuprofen drug loading and release profiles from ordered micro- and mesoporous silica matrices,

Chem. Mater. 16 (2004) 4160-4167) and the chemical composition of the silica surface (B. Munoz et al.: MCM-41 organic modification as drug delivery rate regulator, Chem. Mater. 15 (2003) 500-503). WO 2006/026840 A2 discloses a controlled release delivery system wherein amorphous mesoporous non-fibrous silica is used as matrix carrier for the release of bioactive compounds and wherein such matrix carrier further comprises micropores having a mean size in the range of 0.4 to 2.0 nm.

WO 2005/000740 A2 discloses a crystalline mesoporous silica material comprising a framework of zeolite type micropores (designated as nanometer size building units), which does not give rise in Bragg type diffraction in x-ray diffraction, and its use for drug delivery.

Z.G. Shi et al. describe mesoporous silica particles for drug delivery, which beside the mesopores further contain very large macropores of several pm in diameter (Z.G. Shi et al.: Drug delivery devices based on macroporous silica spheres, Micropor. Mesopor. Mater. 126 (2011 ) 826-831 ). Due to its penetrable macropores the mesopores of such material can be sufficiently and efficiently loaded with drug. The silica particles described by said publication from Z.G. Shi et al. are produced by using sol-gel technique in combination with an emulsion method and phase separation as described by Z.G. Shi et al. in 2008 (Z.G. Shi et al.: Synthesis and characterization of hierarchically porous silica microspheres with penetrable macropores and tunable mesopores,

Micropor. Mesopor. Mater. 116 (2008) 701 ). In brief a solution containing tetraethoxyorthosilicate (TEOS), polyethylene oxide and hydrochloric acid are mixed and stirred and the ethanol resulting from the hydrolyzation of TEOS is removed by vacuum pumping for 4 h. Then the resulting solution is dispersed into paraffin oil under vigorous stirring. 20 hours later the resulting product was repeatedly washed with ethanol and water and subsequently calcined for 2 h at 600°C. The obtained calcined silica was size classified by using liquid elutriation involving the steps dispersion of the silica particles into water by ultrasonic treatment for 5 min., subsiding the particles in the dispersion by keeping it static for 2 hours, and discarding the upper water solution containing the small particles. Such size- classification was repeated for five times and the particles were collected.

WO 2012/156023 A1 describes a method for producing porous silica material containing both macropores and mesopores by using the sol-gel technique, as well as the use of the material in delivering a biologically active agent. In brief, the synthesis is carried out by dissolving a water- soluble polymer or another pore forming agent and a precursor for a matrix dissolving agent in a medium that promotes the hydrolysis of the

organometallic compound. The organometallic compound, or a mixture of organometallic which contains hydrolysable ligands to promote a hydrolysis reaction, is mixed. The mixture is then solidified through a sol-gel transition, whereby a gel is prepared which has three-dimensional interconnected phase domains: one rich in solvent and the other rich in inorganic. The documents WO 2014/072015 A1 and WO 2015/078552 A1 describe methods for preparing porous silica material containing both macropores and mesopores.

The particulate material as described in Z.G. Shi et al. , WO 2012/156023 A1 , WO 2014/072015 A1 and WO 2015/078552 A1 can be used for delivering a biologically active agent.

However, it is problematic to prepare pharmaceutical formulations in a conventional manner with these materials due to unsufficient flow or other physical particle properties.

Furthermore, the documents mentioned above are useful for providing small molecule drugs having a low water solubility. However, there are no data concerning high molecular drugs such as peptides and/or proteins which are very sensitive and are conventionally degraded if these drugs are orally administrated. Most of these peptides and/or proteins exhibit a high water-solubility but using conventional techniques for oral administration of these water-soluble peptides and/or proteins provide only poor blood levels of these peptides and/or proteins.

Object

Therefore, it is an object of the present invention to provide a release system being able to provide high amount of drug concentration in plasma when orally administrated. A further object of embodiments of the present invention is providing a release system for a bioactive having a high molecular weight, preferably a peptide and/or a protein. It is a special object of the present invention to provide a release system providing a high blood level of sensitive bioactive agents having a high molecular weight, preferably peptides and/or proteins. Another object of embodiments of the present invention is providing a release system which can be easily processed in conventional processing machines. This means, it is an object of the present invention to provide a release system which can be used for preparing tablets or capsules in conventional tabletting devices and/or devices for producing capsules.

It is an object of embodiments of the present invention to provide an efficient and/or cheap method for production of improved release system. The above objective is accomplished by a release system and a method for producing the same according to the present invention.

Summary of the invention Surprisingly, the inventors have found that a release system with all the features of present claim 1 solves one or more of the problems mentioned above.

Consequently, the present invention provides a release system comprising a bioactive agent and a particulate material, characterized in that the particulate material comprises macropores and the particulate material exhibits flowability. Formulations according to the invention including particulate material comprising macropores can be compacted to

administration form using a single punch or rotary tablet press or filled in capsules for further testing and use.

Preferably said release system of the present invention solves all the problems mentioned above at the same time. In another aspect, the present invention relates to a process for producing a release system. In another aspect, the present invention also relates to the use of a release system according to the present invention for orally administrating a drug, preferably a peptide or a protein. Detailed description of the invention

The present invention provides a release system comprising a bioactive agent and a particulate material, characterized in that the particulate material comprises macropores and the particulate material exhibits flowability.

Preferably, the flowability of the particulate material exhibits an angle of response below 50°, preferably below 47°. The angle of repose is measured according to DIN ISO 4324. For this measurement the bulk material is poured evenly from a small height through a funnel onto a horizontal surface. From the conjugated diameters D1 and D2 and the Height h of the pile the slope of angle a is calculated according to formula (4-1 ) a = arctane (4h / D1 + D2) (4-1 )

The measurement is carried out at least three times and the arithmetic mean value is calculated from the calculated individual values. The properties of the particulate materials related to flowability can be improved by addition of appropriate excipients. These excipients are well known in the art and these expedients preferably comprise no or an acceptable impact on the drug contained in the release system of the present invention. More preferably these excipients for improving the flowability include fumed silica, granular filling agents, granular binding agents etc.

The particulate material comprising the bioactive agent exhibits flowability, preferably having the same values as mentioned above. Surprisingly, the flowability enables the processing of the present release systems using conventional machines, e. g. machines for tableting the release system or machines for producing capsules using the release system. The flowability depends on features of the release system as known in the art, e.g. the particle size of the release system, the particle shape of release system and the bulk density of the particulate material as well as of the surface charge.

Bulk density is a property of powders, granules, and other "divided" solids, especially used in reference to mineral components (soil, gravel), chemical substances, (pharmaceutical) ingredients, foodstuff, or any other masses of corpuscular or particulate matter. It is defined as the mass of many particles of the material divided by the total volume they occupy. The total volume includes particle volume, inter-particle void volume, and internal pore volume.

Bulk density is not an intrinsic property of a particulate material; it can change depending on how the material is handled. For example, a powder poured into a cylinder will have a particular bulk density; if the cylinder is disturbed, the powder particles will move and usually settle closer together, resulting in a higher bulk density of the particulate material. For this reason, the bulk density of powders is usually reported both as "freely settled" (or "poured" density) and "tapped" density (where the tapped density refers to the poured density of the powder after a specified compaction process, usually involving vibration of the container.

In general, depending on their pore size particulate inorganic materials can be classified as microporous, mesoporous or macroporous. Within the meaning of the present application microporous materials are understood to have a pore size of less than 2 nm. Mesoporous materials are understood to have a pore size in the range from 2 to less than 50 nm and

macroporous materials are understood to have pore sizes of at least 50 nm. In one embodiment of the present invention, the pores of particulate materials suitable for the release system have a size of at least 50 nm. Said materials may have macropores of at least 55 nm, preferably of at least 100 nm, more preferably of at least 150 nm, even more preferably at least 250 nm. In an embodiment of the invention, the macropores of particulate materials suitable for the release system preferably have a size of at most 5000 nm, more preferably of at most 4800 nm, even more preferably of at most 2500 nm, more preferably of at most 1500 nm, more preferably of at most 1000 nm. More preferably the size of said macropores is in the range of 55 to 5000 nm, even more preferably the size is in the range of 100 to 4500 nm, even more preferably the size is in the range of 100 to 2500 nm, and even more preferably the size is in the range of 150 to 1500 nm. Most preferred are particulate materials having macropores in the range of 100 to 500 nm. The size of the macropores is measured by methods known in the art, such as scanning electron microscope (SEM) and/or by Hg-intrusion according to ISO 15901 -1 und DIN 66133 (or Ph. Eur. 8th edition, “Grundwerk” 2014) preferably by Hg-intrusion. The measurement is preferably performed using the device Quantachrome Poremaster. Preferably, the volume of the macropores of the particulate material is at least 0,2 cm³ per g of the particulate material, preferably at least 0,3 cm³ per g of the particulate material, more preferably at least 0,4cm³/g pure pore volume of particle without interparticle void volume. Preferably, the volume of the macropores of the particulate material is at most 3,0 cm³ per g of the particulate material, more preferably at most 2,0 cm³ per g of the particulate material, even more preferably at most 1 ,5 cm³ per g of the particulate material. The volume of the macropores is preferably measured by methods known in the art, such as by Hg-intrusion according to ISO 15901 -1 und DIN 66133.

Preferably, if a particulate material is used for the release system

comprising macropores a material is chosen having a narrow pore size distribution. In particular, those materials are preferably used whose macropore volume is provided by at least 50% of macropores having pore sizes in a range of at most 500 nm, preferably about 100 nm. The size distribution of the macropores is measured by methods known in the art, such as scanning electron microscope (SEM) and/or by Hg-intrusion according to ISO 15901 -1 und DIN 66133, preferably by Hg-intrusion.

In a further embodiment of the present invention a mesoporous material may be used for the release system. Preferably, this particulate material comprises mesopores and the volume of the mesopores is at most 0,75 cm³ per g of the particulate material, more preferably at most 0,25 cm³ per g of the particulate material measured by N2-Adsorption/ Desorption (BET- measurement according to (DIN 66131 und ISO 9277). Suitable particulate materials may preferably include meso- and

macropores, wherein the volume ratio of the macropores to those of the mesopores is at least 1 : 1 , preferably at least 2 : 1. In a particularly preferred embodiment, the particulate materials comprise a non- measurable amount of mesopores.

In a further embodiment of the present invention, the particulate material comprising macropores has a total (macropores plus interparticle or intergranular void volume) pore volume of at least 0,75 cm³ per g of the particulate material, preferably at least 1 ,5 cm³ per g of the particulate material measured according to Hg-intrusion according to ISO 15901 -1 und DIN 66133. Preferably, the particulate material comprising macropores has a total pore volume of at most 4,0 cm³ per g of the particulate material, more preferably at most 3,0 cm³ per g of the particulate material, even more preferably at most 2,2 cm³ per g of the particulate material measured according to Hg-intrusion according to ISO 15901 -1 und DIN 66133. The total pore volume includes the intergranular volume. The intergranular volume comprises conventionally an apparent pore size of at least 5 pm (5000 nm) and, hence the intergranular volume is easily distinguishable from the intragranular volume of the particulate material of the present release system. Preferably, the volume ratio of the volume of the macropores to the total pore volume is at least 0,2, preferably at least 0,3.

In a selected embodiment of the present invention a particulate material may be used comprising macropores having a surface area in the range of from 0,5 m²/g to 300 m²/g, preferably from 1 m²/g to 200 m²/g, more preferably from 3 m²/g to 50 m²/g, measured by N2 absorption according to DIN 66131 und ISO 9277. The measurement is preferably performed using the device Micromeritics ASAP 2420. In a specific embodiment of the present invention, the particulate material comprising macropores has preferably a poured density of at least 0,10 g/cm³, more preferably of at least 0,15 g/cm³ and even more preferably of at least 0,20 g/cm³. Preferably, the particulate material comprising macropores has preferably a poured density in the range of from 0,1 to 0,5 g/cm³, preferably from 0,15 to 0,4 g/cm³, more preferably from 0,2 to 0,35 g/cm³, most preferred the poured density is less than 0,30 g/cm³, measured according to DIN ISO 60. But poured density of this material is preferably not too low, otherwise the material could be too porous and the particles are too fragile, which would mean that the material may have a poor flowability and the tabettability may not be sufficient.

In a further embodiment of the present invention, the particulate material comprising macropores has preferably a tapped density of at least 0,2 g/cm³, more preferably of at least 0,3 g/cm³ and even more preferably of at least 0,42 g/cm³. Preferably, the particulate material comprising

macropores has preferably a tapped density in the range of from 0,2 to 0,7 g/cm³, more preferably from 0,3 to 0,6 g/cm³, most preferably the tapped density is less than 0,50 g/cm³ , measured according to DIN EN ISO 787- 11. But tapped density of this material is preferably not too low, otherwise the material could be too porous and the particles are too fragile, which would mean that the material may have a poor flowability and the tabettability may not be sufficient.

In a specific embodiment, the particulate material is an inorganic material, preferably an oxide, more preferably a silicon oxide, even more preferably the particulate material comprises at least 80 % by weight, most preferably at least 95% by weight SiCte. Preferably, the particulate material is based on Si0_2. The expression based on S1O2 indicates that the particulate material comprises at least 50 % by weight, more preferably the particulate material comprises at least 70 % by weight, even more preferably at least 95% by weight S1O2 and most preferably the particulate material essentially consists of SiCte.

In an embodiment of the present invention, at least one part of the surface area of the particulate material is hydrophilic. In a further embodiment of the present invention, at least a part of the surface area of the particulate material has hydrophobic properties.

The most recognizable definitions in surface science are hydrophobicity and hydrophilicity. In the Greek words, hydro means water, philicity means affinity, and phobicity means lack of affinity. In the scientific community, we have come to accept the definition that a surface is hydrophobic when its static water contact angle Q is >90° and is hydrophilic when Q is <90°. The static water contact angle is well known in the art and the measurement is disclosed in J. Phys. Chem. Lett. 2014, 5, 686-688). The static water contact angle is measured at 25°C. The hydrophilicity or the hydrophobicity of the surface of the particulate material can be achieved by methods known in the art. One other indication is the OH-number of the surface which depends on the production method of the particulate material. For increasing the hydrophobicity of the surface of the particulate materials a surface coating is preferably provided.

According to a specific embodiment of the present invention the surface area preferably having an OH-number of at least 1 pmol/m², more preferably of at least 2 pmol/m² and even more preferably of at least 3 pmol/m² .

According to a further embodiment the surface area preferably comprises an OH-number below 1 pmol/m², more preferably of at most 0,5 pmol/m². The number of OH groups determination is preferably carried out by means of 1 H NMR spectroscopy, as described in studies by Holik and Matejkova (M. Holik; B. Matejkova, J. Chromatography, 213 (1981 ), p 33).

Conventionally, a high OH-number correlates with a hydrophilic surface area while a low OH-number correlates with a hydrophobic surface area.

Processes for providing composite silicon oxide-based material by coating

In another embodiment, the particular material according to the present invention can be further surface modified by coating the surfaces of the constituent material with organic polymers to provide hydrophobic surface properties to the silicon oxide based material. Suitable methods are known to the person skilled in the art. Specifically, it is known to hydrophobically derivatize surfaces of S1O2 -based materials to produce hydrophobic chromatography materials wherein organic groups are attached to the surfaces by physical adsorption or chemisorption. These methods can also be applied here. In this context, there are a number of journal and patent publications in which a variety of

derivatizations are described. For example, publications by K. K. Unger disclose methods and materials for the hydrophobic derivatization of such surfaces.

Examples of organic polymers which can be used to prepare the silicon oxide- based composite materials are, for example, polystyrenes, polymethacrylates, polysiloxanes and derivatives thereof or copolymers of two or more suitable compounds, such as, for example, coatings of tetraalkoxysilane and/or methyltrialkoxysilane. Preference is given to chemi- or physisorbed polystyrenes, physisorbed poly(meth)acrylates or poly(meth)acrylic acid derivatives, such as, for example,

poly(methacrylate), poly(2-hydroxyethyl methacrylate), a copolymer of 2- hydroxyethyl methacrylate and ethyl methacrylate or poly(octadecyl methacrylate) and silanes, which are especially preferred.

A coating process which can be used to prepare the silicon oxide-based composite material can take place by

• polymerisation or polycondensation of physisorbed monomers and/or oligomers without formation of covalent bonds to the silicon oxide- based material,

• polymerisation or polycondensation of physisorbed monomers and/or oligomers with formation of covalent bonds to the silicon oxide-based material, · immobilisation (physisorption) of prepolymers without formation of bonds to the silicon oxide-based material or • chemisorption of prepolymers on the silicon oxide-based material.

A solution which is employed for the coating of the silicon oxide-based material accordingly comprises either organic prepolymers or monomers and/or oligomers. In addition, it typically comprises a suitable solvent and optional further constituents, such as, for example, free-radical initiators. It is referred to in accordance with the invention as coating solution.

Prepolymers here means that use is made of already oligomerised and/or polymerised compounds which, after introduction into the silicon oxide- based material, are not subjected to any further polymerisation reaction, i.e. are not cross-linked further with one another. Depending on the nature of the application, they are adsorbed onto the silicon oxide-based material (physisorption) or covalently bonded to the silicon oxide-based material (chemisorption).

By contrast, monomers and/or oligomers are compounds which are suitable for polymerisation or polycondensation and which are crosslinked or polymerised further by polymerisation of polycondensation after introduction into the silicon oxide-based material. Oligomers here are compounds which have already been generated in advance by crosslinking or polymerisation of monomers.

Processes for providing composite silicon oxide-based material by coating are known to the person skilled in the art and described, for example, in Handbuch der HPLC [Handbook of HPLC], Ed. K. K. Unger; GIT-Verlag ( 989) and Porous Silica, K. K. Unger, Elsevier Scientific Publishing

Company (1979). One process for the coating of particles includes the application of a polymer solution or a solution of monomer and free-radical initiator. The solvent is subsequently removed. Chemical Modification

According to a preferred embodiment the composite silicon-based material used for the release of biologically active agents is provided by reaction of the amorphous silicon oxide material with a silane compound capable of forming a covalent bond with a silanol group of the amorphous silicon oxide material.

Examples of silane compounds capable of forming covalent bonds by being reacted with a silanol groups of the amorphous silicon oxide materials include silazane, siloxane, or alkoxysilane, and partial hydrolysates of silazane, siloxane, or alkoxysilane, or oligomers such as polymerized dimers to pentamers of silazane, siloxane or cyclic-siloxane, alkoxysilane. Examples of suitable silazanes include hexamethyldisilazane and hexaethyldisilazane.

Examples of suitable siloxanes include hexamethyldisiloxane, 1 ,3- dibutyltetramethyldisiloxane, 1 ,3-diphenyltetramethyldisiloxane, 1 ,3- divinyltetramethyldisiloxane, hexaethyldisiloxane and 3- glycidoxypropylpentamethyldisiloxane.

Examples of alkoxysilanes include, for example, trimethylmethoxysilane, trimethylethoxysilane, trimethylpropoxysilane,

phenyldimethylmethoxysilane, chloropropyldimethylmethoxysilane, dimethyldimethoxysilane, methyltrimethoxysilane, tetramethoxysilane, tetraethoxysilane, tetrapropoxysilane, tetrabutoxysilane,

ethyltrimethoxysilane, dimethyldiethoxysilane, propyltriethoxysilane, n- butyltrimethoxysilane, n-hexyltrimethoxysilane, n-octyltriethoxysilane, n- octylmethyldiethoxysilane, n-octadecyltrimethoxysilane,

phenyltrimethoxysilane, phenylmethyldimethoxysilane,

phenetyltrimethoxysilane, dodecyltrimethoxysilane, n- octadecyltriethoxysilane, phenyltrimethoxysilane, diphenyldimethoxysilane. These silane compounds may be used individually or in combination of two or more types thereof. Silane compounds having reactive groups capable of bonding colloidal silica particles with the polymer while curing the curable composition of the present invention can enhance the properties of the cured article, so that such silane compounds are preferred.

According to a preferred embodiment of the invention the composite silicon oxide-based material used for the release of the biologically active agent is modified by reaction with a compound having the formula (I)

SiXnR¹(3-n)R² (I) wherein X is a reactive group,

R¹ is C1-C5 alkyl,

n is 1 , 2 or 3; and

R² is unsubstituted or substituted alkyl or aryl. X can be C1-C3 alkoxy, preferably methoxy or ethoxy or a halogen such as F, Cl, Br or J, preferably Cl.

In R² alkyl can be unbranched or branched alkyl having 1 to 20 C atoms, which optionally may be substituted by 1 , 2, 3 or 4 OH, Diol, NH2, Epoxy and/or CN whereby unbranched alkyl is preferred. Examples of suitable alkyl are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, n-decyl, n-dodecyl or n-octadecyl, whereby n-octyl and n-octadecyl are preferred. Aryl can be phenyl or phenylalkyl such as, for example phenylmethyl, phenylethyl, phenylpropyl or phenylbutyl, whereby phenylbutyl is preferred. According to a particularly preferred embodiment in the silane compound of formula (I) used for the modification independendly from each other X is methoxy, ethoxy or halogen, R² is n-octyl, n-octadecyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl or phenylbutyl. Therefore, one particularly preferred object of the invention is directed to the use of composite silicon oxide-based material for the release of biologically active agents, which is modified with a silane compound of formula (I), wherein independendly from each other

X is methoxy, ethoxy or halogen,

R² is n-octadecyl, n-octyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl or phenylbutyl.

Porous particles, as described above, which have been derivatized on their surfaces in this manner can advantageously serve as a matrix or as carrier materials for pharmaceutical active substances, in particular for poorly soluble active substances.

As has been described above, the present invention is particularly suitable for porous particulate particulate materials comprising macropores has an average size in the range of, 1 to 1000 pm, more preferably 1 to 500 pm, even more preferably 1 to 50 pm measured by laser diffraction method using a Mastersizer 3000 from Malvern [see: Laserbeugung - Parti Ikq^Gόb en verteilungen von Nanometern bis zu Millimetern; Malvern Instruments GmbH, (EinfCihrung und Produkte der Firma Malvern

Instruments)]. According to the present invention suitable porous, particulate material comprising macropores show an average particle size distribution with a D10 value of at least 0.5 pm, preferably of at least 1 pm and more preferably of at least 2 pm measured by laser diffraction method.

Furthermore, preferred particulate materials comprising macropores of the present invention have a D90 value of at most 1000 pm, preferably at most 800 pm and more preferably at most 500 pm measured by laser diffraction method according to the method of Malver using the apparatus mentioned above.

In a preferred embodiment, the particulate materials comprising

macropores have narrow particle size distributions, preferably the difference of the D90 value and the D10 value of the particles is at most 750 pm, preferably at most 500 pm, more preferably at most 250 pm and even more preferably at most 50 pm measured by laser diffraction method according to Malvern.

Suitable particulate material of the present invention comprising

macropores may have a non-spherical shape. In another embodiment, the macroporous particulate material may also have a spherical shape.

In addition to the particulate material, the present release system comprises at least one bioactive agent, wherein the bioactive agent is a substance having bioactivity. As a bioactive agent, not only a certain kind of drugs can be used. Various active substances can be used both individually and in combination. Thus, a porous particulate carrier can be loaded with one or more drugs, and different drugs may have different activities that

complement each other.

A bioactive agent being present in the release system can be any chemical substance or protein, which are capable of providing a local or systemic biological, physiological, or therapeutic effect in the subject to which it is applied. Preferred examples of a bioactive agent are pharmaceutical drugs, biological macromolecules, vaccines, vitamins or minerals. In terms of its activity the bioactive agent, being present in the release system, can be, for example an agent that act to control or prevent infection or inflammation, enhance cell growth and tissue regeneration, control tumor growth, act as an analgesic, promote anti-cell attachment or enhance bone growth, among other functions. Other suitable bioactive agents can include anti-viral agents, hormones, antibodies, or therapeutic proteins. Still other bioactive agents include prodrugs, which are agents that are not biologically active when administered but upon administration to a subject are converted to bioactive agents through metabolism or some other mechanism. Further suitable bioactive agents are vaccines, i.e. substances used to stimulate the production of antibodies and provide immunity against one or several diseases, prepared from the causative agent of a disease, its products, or a synthetic substitute, treated to act as an antigen without inducing the disease. According to a preferred embodiment of the invention the release delivery system contains a pharmaceutical drug. Therefore, one

embodiment of the invention is directed to a release delivery system, wherein the bioactive agent is a pharmaceutical drug. According to a further preferred embodiment of the invention the release delivery system contains a vaccine. Therefore, one embodiment of the invention is directed to a release delivery system, wherein the bioactive agent is a vaccine. In an embodiment, the release system of the present invention can be designed as modified release system. As used herein, the term "modified release" means that the release of the bioactive agent from the delivery system or a portion thereof upon contact of the dosage form or portion thereof with a liquid medium is different to the release of the same bioactive agent from a conventional immediate release formulation, wherein the release is mainly controlled by the solubility of the bioactive agent in the liquid medium. In one embodiment, the inorganic particulate material comprising macropores is suitable to increase the dissolution of bioactive agents, especially to increase the dissolution rate of poorly water-soluble or water- insoluble bioactive agents. Poorly water-soluble substances are understood to have a solubility in water of < 10 mg/ml, in particular < 5 mg/ml and more particularly < 1 mg/ml, practically water-insoluble or insoluble substances are those having a solubility in water of < 0.1 mg/ml. The term "water- solubility" or "solubility in water" in the present application refers to the respective solubility measured at 25°Celsius.

For example, U.S. Pharmacopoeia gives the following terms:

The thresholds to describe something as insoluble, or similar terms, may depend on the application. For example, one source states that substances are described as "insoluble" when their solubility is less than 0.1 g per 100 mL of solvent [see Pharmacopeia of the United States of America, 32nd revision, and the National Formulary, 27th edition," 2009, pp.1 to 12;

Rogers, Elizabeth; Stovall, Iris (2000). "Fundamentals of Chemistry:

Solubility". Department of Chemistry. University of Wisconsin. Retrieved 22 April 2015] In a further embodiment, the inorganic particulate material comprising macropores is especially designed to provide high blood levels of a bioactive agent having a high molecular mass, preferably a peptide and/or protein as described above and below. The bioactive agent having a high molecular mass can exhibit a high or a low water- solubility as described above and below.

Preferably, the bioactive agent is a pharmaceutical drug or a vaccine.

In another embodiment of the present invention, the release system comprising a bioactive agent and a particulate material comprising macropores can also comprise liquids (i.e. liquid pharmaceutical formulations or liquid APIs). In this case, the bioactive agent itself may be liquid or may be dissolved or formulated in a liquid formulation (e.g. oily, lipids, liposomes or aqueous formulations).

Accordingly a further object of the present invention is directed to a release system comprising a bioactive agent and a particulate material comprising macropores, wherein the bioactive agent is present in a liquid form.

Surprising improvements can be obtained with a bioactive agent exhibiting a molecular weight of at least 500 g/mol, preferably at least 750 g/mol, more preferably at least 1000 g/mol. It should be noted that conventional release systems are not able to provide a high blood level of a bioactive agent having a high molecular weight. Surprisingly, it is found that the present release system is able to provide high blood levels of high molecular weight bioactive agents, preferably peptides and/or proteins wherein the release system is orally administrated. That is, the present release system enables the transport of high molecular weight bioactive agents through the gastrointestinal tract. According to a further embodiment, the bioactive agent preferably exhibits a molecular weight of at most 1000000 g/mol, more preferably of at most 500000 g/mol, even more preferably of at most 250000 g/mol, even more preferably of at most 50000 g/mol, even more preferably of at most 25000 g/mol.

According to a specific embodiment, the present invention relates to corresponding formulations, wherein the bioactive agent has a water- solubility of about 10 mg/ml or less measured at 25 °C, preferably of about 5 mg/ml or less, more preferably from about 0.1 mg/ml to about 5 mg/ml,.

In a further embodiment, the bioactive agent has a water-solubility of about 10 mg/ml or more, preferably of about 15 mg/ml or more, measured at 25°C. Surprisingly, it is found that the present release system is suitable to provide high blood levels of water-soluble bioactive agents, preferably of peptides and/or proteins wherein the release system is orally administrated.

Preferably, the bioactive agent is a pharmaceutical drug belonging to the

Biopharmaceutics Classification System = BCS classes II, III or IV.

Surprisingly, according to the present invention, in the manner described here, it is also possible to combine active ingredients of higher molecular weight, as already mentioned above, with the porous particulate carrier.

Thus, according to the invention the bioactive agent is preferably a peptide and/or a protein, more preferably an Immunoglobulin G (IgG), such as Canakinumab, Bevazimumab, Adalimumab; an antigen-binding (Fab) fragment, such as Ranibizumab, Abciximab; an PEGylated antigen-binding (Fab) fragment, such as Certolizumab; Antibody-drug conjugates (ADC), such as Trastuzumab emtansine (T-DM1 ), Brentuximab vedotin,

Gemtuzumab osogamicin; a Fusion protein, such as Aflibercept, Abatacept, Etanercept; a Trifunctional antibody, such as Catumaxomab; A single-chain variable fragment (scFv), such as Blinatumomab; Buserelin, Nafarelin, Colistin, Cyclosporine A, Cytochrome C, Glutathione, Linaclotide,

Plecanatide, Taltirelin, Tyrothricin, Vancomycin, Octreotide, Cyclosporine, Desmopressin, Calcitonin, Insulin, Glucagon-like peptide-1 (GLP-1 ), human growth hormone (hGH), Parathyroid hormone (PTH) and analogues thereof, even more preferably Octreotide, Cyclosporine, Desmopressin, Calcitonin, Insulin, GLP-1 , hGH, PTH and analogues thereof. Peptide and/or protein analogues are compounds having essentially the same effect as the peptides and/or proteins. These compounds have a structure similar to that of another compound, but differing from it in respect to a certain component. These peptide and/or protein analogues are well-known in the art.

In some embodiments of the invention, the bioactive agent is present in an amount of from about 0.1 to about 75% by weight, preferably from about 0.2 to about 60% by weight, more preferably from about 5 to about 45% by weight most preferably from about 15 to about 35% by weight.

Preferably, the bioactive agent is present in the macropores of the particulate carrier material.

In a preferred embodiment of the present invention, the release system may comprise an additive, preferably a penetration enhancer, enzyme inhibitors and/or physical complex forming agents or a stabilizing additive to prevent e.g. degradation of the bioactive agent during loading or storage.

Preferred penetration enhancer preferably include e.g. medium chain fatty acids and their salts, such as capric acid and/or caprylic acid and their salts; benzoyl and salicyloyl derivatives of caprylic acid, butanoic acid, decanoic acid and their salts and/or amino derivatives such as sodium N-[8- (2-hydroxybenzoyl)amino] caprylate (SNAC), (N-(5-chlorosalicyloyl)-8- aminocaprylic acid (5-CNAC), 4-[(4-chloro-2-hydroxy- benzoyl)amino]butanoic acid (4-CNAB), N-(10-[2-hydroxybenzoyl]-amino) decanoic acid (SNAD) and their salts; L-carnitine alkyl (C12-C16) derivative (acylcarnitine) salts; aromatic alcohols, such as Propyl gallate, butylated hydroxy toluene, butylated hydroxy anisole; divalent ion chelating agents such as ethylenediamine tetraacetic acid (EDTA), diethylenetriamine pentaacetic acid (DTPA), etc.; ionic amphiphilic biosurfactants, e.g., bile salts, such as sodium deoxycholate, taurodeoxycholate, glycodeoxycholate, etc.; cationic polymers, such as N-trimethyl-chitosan chloride, etc.;

enterotoxin peptide derivatives, such as Zonula occludens toxin synthetic peptide derivative (AT1002), etc. Useful salts are pharmaceutically acceptable salts such as sodium and/or potassum salts.

Preferred enzyme inhibitors preferably include e. g. serpin, aprotinin, soybean trypsin inhibitor, camostat mesylate, chymostatin, duck

ovomucoid, chitosan-EDTA conjugates, citric acid, etc.

Preferred physical complex forming agents preferably include e. g. Benzoyl and salicyloy derivatives of aminocaprylic acid, aminobutanoic acid or aminodecanoic acid (e.g., SNAC, 5-CNAC, 4-CNAB, SNAD); medium chain fatty acids e. g. caprylic acid, etc..

It can be provided that the release system preferably does not comprise a liposome system. A liposome is a spherical vesicle having at least one lipid bilayer. Liposome systems are well known in the art. Preferably, the release system comprises a coating, more preferably an enteric coating. An enteric coating is well known in the art. Preferably, the enteric coating provides a physical barrier being insoluble in gastric medium but dissolves at enteric pH to release the bioactive agent, preferably the peptide and/or protein. Preferred compounds for providing an enteric coating are e.g. (Meth)acrylic copolymers, like EUDRAGIT L 100 and EUDRAGIT S 100, which are anionic copolymers based on methacrylic acid and methyl methacrylate, hydroxypropyl methylcellulose acetate succinate and/or Cellulose acetate phthalate derivatives, etc. The ratio of the free carboxyl groups to the ester groups is preferably in the range of 10:1 to 1 :10, more preferably 5:1 to 1 :5 and even more preferably 2:1 to 1 :3. (The ratio of the free carboxyl groups to the ester groups is e.g. approx.

1 :1 in EUDRAGIT^® L 100 and approx. 1 :2 in EUDRAGIT^®S 100. Another polymer used is HPMCAS, which is hydroxypropyl methylcellulose acetate succinate.

According to the invention, the bioactive agent may be placed in the macropores of the particulate material and the particulate material may be coated with a coating, preferably an enteric coating.

In a preferred embodiment, the release system is an oral administration form, preferably a tablet, a pellet, and/or a capsule.

In a more preferred embodiment, the release system is an oral

administration form and the oral administration form, preferably the tablet, the pellet, and/or the capsule, comprises a coating, preferably an enteric coating.

A further subject matter the present invention is a process for producing a release system according to the present invention, wherein a particulate material comprising macropores is loaded with a bioactive agent.

Loading

The bioactive agent can be applied onto the particulate material, preferably an inorganic particulate material by using the loading techniques known in the art. For example, the bioactive agent can be applied to the inorganic material by adsorption from a solution of the bioactive agent in a suitable solvent and subsequent separation. It can also be applied by wetness impregnation of the inorganic material with a concentrated solution of the bioactive agent in a suitable solvent, such as, for example, water, buffer, ethanol, CH2CI2 or acetone and subsequent solvent evaporation. Other suitable methods are carried out by by spray-drying or by dropping of a mixture of bioactive agent in a suitable solvent, or by heating of a mixture of the bioactive agent and the particulate material or by drug loading with supercritical fluids. The release system can be formulated as an oral, a topical or a parenteral administration form, preferably as an oral

administration form. Consequently, the invention is further directed to the use of the release system as described herein, wherein said system is an oral or a topical or a parenteral administration form, preferably an oral administration form.

Suitable forms for oral administration include tablets, capsules, powders, dragees, suspensions.

If an oral administration form is used, tablets, capsules and powders are preferred. Accordingly, the invention is also directed to a release system as described herein, wherein said release system is an oral application form, which is a tablet, a capsule, a powder, or a dragee, preferably a tablet or a capsule.

The release system is suitable to be used for the administration of at least one bioactive agent to a biological organism, preferably to a mammal, more preferably to a human. Accordingly, the invention is also directed to the use of the release system as described herein for the administration of at least one bioactive agent to a mammal, preferably to a human.

The application forms described above are well known in the art. For example, if the release system is in the form of a tablet or capsule, the bioactive agent loaded inorganic material can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders can be composed of the bioactive agent loaded inorganic material itself, which may be further comminuted, or can be prepared, for example, by mixing the bioactive agent loaded inorganic, which may have been comminuted, with a comminuted pharmaceutical excipient, such as, for example, an edible carbohydrate, such as, for example, polyols like sorbitol or mannitol, microcrystalline cellulose or other cellulose derivatives, superdisintegrates, polymers, starch, lactose. A flavour, preservative, dispersant and dye may likewise be present.

Capsules can be produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. A disintegrant or solubiliser, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica ment after the capsule has been taken. In addition, if desired or necessary, suitable binders, lubricants and disintegrants as well as dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose,

polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry- pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the active agent loaded in a inorganic, which may have been comminuted in a suitable manner, with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbent, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricant containing mixture is then pressed to give tablets. The bioactive agent loaded inorganic material can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.

According to the present invention, the bioactive agent may be liquid or it may be dissolved in a solvent and used in the present invention.

In a very preferred embodiment, the present invention provides a release system comprising a peptide and/or a protein preferably having a high molecular weight as bioactive agent and a particulate material comprising macropores being based on S1O₂ and the macropores of the particulate material are loaded with the bioactive agent and the release system comprises an enteric coating and the release system is orally administrable. The porous particulate material of the present invention can be prepared by any method known in the art, e. g. hydrolysation of a metalorganic compound such as a silane compound or soluble alkali silicate, preferably a water-glass. In a preferred embodiment, the particulate material is achieved with a process including the steps of:

(a) providing a soluble alkali silicate, preferably a water-glass;

(b) adding an acid to the soluble alkali silicate;

(c) solidifying the mixture through a sol-gel transition,

(d) washing the solidified silica hydrogel, preferably with an water;

(e) removing the liquid part by evaporation drying and/or heat-treatment;

(f) modifying the pore size distribution by appropriate post treatment.

The preparation of a porous particulate material based on S1O2 is known in the art. Therefore, the steps (a) to (f) can be achieved by a method as described in K.K. Unger, porous silica, Elsevier Scientific Publishing

Company, Amsterdam, Oxford, New York, 1979. Specific details for obtaining a porous silica are mentioned in Chapters 2.2 and 2.3, pages 40 to 53 in K.K. Unger, porous silica. The disclosure of K.K. Unger, porous silica is herewith enclosed by reference.

Preferably, the alkali silicate solution comprises a pH value above 11 , more preferably above 12 and even more preferably above 12.5.

The acid added to the soluble alkali silicate preferably is sulfuric acid and/or hydrochloric acid, more preferably sulfuric acid. The pH value of the acidified alkali silicate solution for precipitation of the S1O2 is preferably in the range of 3 to 8, more preferably 4 to 7. The step (f) is preferably achieved by hydrothermal treatment of silica hydrogels and xerogels. Furthermore, the step (f) is preferably achieved by controlled sintering preferably using a high-melting salt and washing out the salt after the treatment.

It can be provided that the bioactive agent is a peptide or protein and the peptide or protein is stabilized by a carbon hydrate, preferably a sugar, such as sucrose, trehalose etc.

A further subject matter of the present invention is the use of a release system according to the present invention for orally administrating a drug, preferably a peptide or a protein. Advantages

The embodiments of the drug release system according to the invention are distinguished over the prior art by one or more of the following surprising advantages:

1. The release system according to the invention provides a high blood level of a high molecular bioactive agent wherein the release system is orally administrated. This is especially true for peptides and/or proteins being sensitive to degradation in the gastrointestinal tract. Surprising improvements can be achieved by an enteric coating of the release system.

2. The release system according to the invention preferably comprises a particulate material being based on S1O2 which is obtained by a precipitating a soluble alkali silicate. These particulate material have a permission of the Food and Drug Administration (FDA) and, hence, the release system of the present invention provides astonishing improvements in view of pharmaceutical permissions.

3. The release system according to the invention can be achieved in an easy and cost-efficient manner.

4. The release system according to the invention can be processed

using conventional methods, so that cost advantages can also be achieved thereby. Surprisingly, the present release systems can be used for achieving tablets and capsules using conventional machines without undue burden.

These above-mentioned advantages are not accompanied by an undue impairment of the other essential properties.

It should be pointed out that variations of the embodiments described in the present invention fall within the scope of this invention. Each feature dis closed in the present invention can, unless this is explicitly excluded, be replaced by alternative features which serve the same, an equivalent or a similar purpose. Thus, each feature disclosed in the present invention is, unless stated otherwise, to be regarded as an example of a generic series or as an equivalent or similar feature.

All features of the present invention can be combined with one another in any way, unless certain features and/or steps are mutually exclusive. This applies, in particular, to preferred features of the present invention. Equally, features of non-essential combinations can be used separately (and not in combination).

It should furthermore be pointed out that many of the features, and in par ticular those of the preferred embodiments of the present invention, are themselves inventive and are not to be regarded merely as part of the em- bodiments of the present invention. For these features, independent pro tection can be sought in addition or as an alternative to each invention presently claimed. The teaching on technical action disclosed in the present invention can be abstracted and combined with other examples.

The invention is explained in greater detail below with reference to a working example, but without being restricted thereby.

Working Examples

Example 1

For of the preparation process of the microporous carrier several procedures are described in literature. Main method, beside the direct preparation of the porous structure, is the use of mesopores carrier with addition posttreatment to widen the pores. Widening of pores could be achieved by addition of high pressure using an autoclave in water or with addition of salt.

The autoclave method destroying the walls between the mesopores mechanically and resulting in bigger pores. The salt method dissolving the pore-walls after melting of the salt.

An S1O2 based particulate material is prepared by using 500 g mesoporous silica with a pore-diameter of at least 6 nm (DIN-ISO 15901 -2:2009 Bestimmung der PorengroBenverteilung und Porositat von Feststoffen mittels Quecksilberporosimetrie und Gasadsorption - Teil 2: Meso- und Makroporenanalyse mittels Gasadsorption) and 5 - 20 pm particle size measured by Malvern (Mastersizer 3000). To the silica 5% by weight of milled sodium chloride (10 g) was added and mixed intensively using an rotavapor instrumentation. To the mixture 100 ml of deionized water was added dropwise and evaporated after applying vacuum to the system. After removal of the water additional 2 h rotated for intensive homogenization of mixture.

The mixture was transferred into temperature resistant vessels and was place into an annealing furnace for further treatment.

The temperature of the furnace was increase over five hours to 850°C and kept constant for addition 1 hour. After cooling down to room temperature the particles were suspended in 5 L of deionized water and transferred onto a filter and washed until the passes water was chloride free.

Material was dried in a circulating air oven at 150°C during 20 hours.

The resulting pore-diameter of 460g of material was analyzed by Hg- intrusion according to ISO 15901 -1 und DIN 66133.

The macropores have a size of about 500 nm and comprise a volume of about 0.43 ml/g measured by Hg intrusion using a Quantachrome

Poremaster device. The total porevolume (macropores and interparticle pores) of 1.69ml_/g measured.

BET surface area SBET of about 3.1 m²/g measured by N2 absorption according to (DIN 66131 und ISO 9277) using the device Micromeritics ASAP 2420.

The particulate material comprises an angle of response (flowability) of 45° measured according to DIN ISO 4324.

The S1O2 based particulate material being achieved with the method mentioned above is loaded with Octreotide. The loading using 125 mg of silica is achieved by adding of a solution of 10mg Octreotide (Bachem: Octreotide Acetate, Art.No.: 4076320) in 1 mL of water by dropping the solution on the silica particles within 30 minutes using a rotating evaporator as mixing device without applying vaccum. The mixture was further rotated for additional 30 minutes at room-temperature. After the homogeneous distribution of Octreotide the mixture was shock frozen using a mixture of isopentane/ solid carbon dioxide. Removal of water took place by lyophilization during 40 hours at - 20°C and 0.28 mbar. Final drying over 8 hours 0°C and 0.28 mbar resulting to dry flowable particles.

In the next step, commercially available capsules (PCcaps® Capsule from Capsugel = Size 9) comprising the S1O2 based particulate being loaded for in vivo studies with Octreotide (100pg load) are produced according to by manually loading using the appropriate system provided by Capsugel (Capsules and Kit for Pre-Clinical Studies). The kit includes funnel, stand and tamper to fill capsules properly and reproducible.

The capsules are coated by dip coating with Eudragit L 100 using a 10% solution of polymer in water. The filled and closed capsule was dipped into the solution and dried using blow-dryer. Procedure was repeated three times for both side of the capsule. As alternative enteric capsules are commercially available.

The capsules are orally administrated to rats using a dosage of 100 pg Octreotide. After administration, the blood level of Octreotide has been measured by using the Octreotide (R -rs, pi), Enzyme Immunoassay Kit: Extraction Free, Lot-No.: A16612, SO-No.: 0127980 ELISA Kit provided from Peninsula Laboratories International, Inc. The values being obtained are shown in Figure 1. Example 2

An S1O2 based particulate material is prepared by using 500 g mesoporous silica with a pore-diameter of app 6nm and 5 - 20 pm particle size measured as indicated in example 1. To the silica 1.5% milled sodium chloride (10g) was added and mixed intensively using an rotavapor instrumentation. To the mixture 100ml of deionized water was added dropwise and evaporated after applying vacuum to the system. After removal of the water additional 2h rotated for intensive homogenization of mixture.

Material was dried in a circulating air oven at 150°C during 20 hours.

The macropores have a size of about 150 nm and comprise a volume of about 0.47 ml/g measured by Hg intrusion using a Quantachrome

Poremaster device. The total porevolume (macropores and interparticle pores) of 2.06ml_/g measured.

BET surface area SBET of about 22.6 m2/g measured by N2 absorption according to (DIN 66131 und ISO 9277) using the device Micromeritics ASAP 2420. Example 3

An S1O2 based particulate material is prepared by using 500 g mesoporous silica with a pore-diameter of app 6nm and 5 - 20 pm particle size measured by as indicated in example 1. To the silica 2% milled sodium chloride (10g) was added and mixed intensively using an rotavapor instrumentation. To the mixture 100ml of deionized water was added dropwise and evaporated after applying vacuum to the system. After removal of the water additional 2h rotated for intensive homogenization of mixture.

Material was dried in a circulating air oven at 150°C during 20 hours.

The macropores have a size of about 200 nm and comprise a volume of about 0.48 ml/g measured by Hg intrusion using a Quantachrome

Poremaster device. The total porevolume (macropores and interparticle pores) of 1.93ml_/g measured.

BET surface area SBET of about 12.2 m²/g measured by N₂ absorption according to (DIN 66131 und ISO 9277) using the device Micromeritics ASAP 2420. Comparative Example 1

Capsules comprising Octreotide are produced by filling the amount of pure Octreotide using an appropriate capsule filling device delivered together with capsules for in-vivo testing. The capsules are coated as mentioned in Example 1.

The capsules are orally administrated to rats using a dosage of 100 pg Octreotide acetate. After administration, the blood level of Octreotide has been measured as mentioned in Example 1 . The values being obtained are shown in Figure 1.

The Example 1 and the Comparative Example 1 show that the blood level of Octreotide being orally administrated using the release system of the present invention is much higher than the blood level provided by any other release system.

Example 4

An S1O2 based particulate material is prepared as mentioned in Example 1. The particulate material exhibits a size in the range of 5 to 20 pm measured as mentioned in Example 1. The macropores have a size of about 500 nm measured as mentioned in Example 1 and a BET surface area SBET of about 3.1 m²/g as mentioned in Example 1 . The macropores comprise a volume of about 0.43 ml/g measured by Hg intrusion using a

Quantachrome Poremaster device. The particulate material comprises an angle of response (flowability) of 45° measured according to Ph. Eur. / USP (2018). The S1O2 based particulate material being achieved with the method mentioned above is loaded with Cyclosporine A. The S1O2 based particulate material being achieved with the method mentioned above is loaded with Cyclosporine A (material was a gift from Novartis Basel) The loading 125 mg of silica is achieved by adding of a solution of 4mg Cyclosporine A in 0.5 mL of ethanol by dropping the solution on the silica particles within 30 minutes using a rotating evaporator. The mixture was further rotated for additional 30 minutes at room- temperature. After the homogeneous distribution of Cyclosporine A the mixture was shock frozen using a mixture of isopentane/ solid carbon dioxide. Removal of water took place by lyophilization during 40 hours at - 20°C and 0.28 mbar. Final drying over 8 hours 0°C and 0.28 mbar resulting to dry flowable particles .

In the next step, capsules comprising the S1O2 based particulate being loaded with Cyclosporine A are produced by filling the amount of

Cyclosporine A loaded Silica using an appropriate capsule filling device delivered together with capsules for in-vivo testing.

The capsules are coated by dip coating with Eudragit L 100 using a 10% solution of polymer in water. The filled and closed capsule was dipped into the solution and dried using blow-dryer. Procedure was repeated three times for both side of the capsule.

The capsules are orally administrated to rats using a dosage of 20 mg/kg Cyclosporine A (considering the weight of the rat 4mg are administered). After administration, the blood level of Cyclosporine A has been measured using established LC-MS method (with a lowest limit of sensitivity of

15ng/ml) . The values being obtained are shown in Figure 2. Processing Examples

Tableting of Silica prepared according raw material used Example 2 Example using single-punch and rotary tablet press

Table 1 : The mixture tested on the single-punch tablet press is prepared by mixing a following formulation:

Mixture was performed by adding the formulation mixture without lubricant into one turbula mixer T2A, (Willy A. Bachofen AG - Maschinenfabrik, Muttenz, Schweiz) and mixed 5 minutes/ 47 rpm to homogenize. The mixture is sieved using and 1 mm mesh size hand sieve and the lubricant (Parteck® LUB MST) is added after sieving using and 0.25mm mesh size hand sieve. Final mixing is performed using the turbula mixer T2A for 2 minutes/47 rpm. Tabletting single-punch tablet

Tableting is performed using single-punch tablet press Korsch EK 0 DMS (Korsch AG, Berlin, Deutschland) with tableting speed of 50 tablet/min. For tableting faceted flat tablet punches used 11 mm in diameter. Mass of tablet was 350mg and tableting punching pressure 5, 10, 20 & 30 kN used.

Analytical evaluation including tablet hardness with n=20 tablets (ERWEKA Multicheck 5.1 ), friction (according Ph. Eur.) using n=13 tablets with

ERWEKA TA420 and disintegration time with n=6 tablets (Biomation disi 4).

Table 2: Tablet hardness measurement

Table 3: Tablet friction measurement

Table 4: Disintegration time measurement

The mixture tested on the rotary tablet press is prepared by mixing a following formulation:

Table 5:

Mixture was performed by adding the formulation mixture without lubricant (Table 5) into an adequate mixer Elte 650 (Engelsmann AG Ludwigshafen Germany) and mixed 5 minutes with 35 rpm to homogenize. The mixture is sieved using and 1 mm mesh size hand sieve and the lubricant (Parteck^® LUB MST) is added after sieving using and 0.25mm mesh size hand sieve. Final mixing is performed using adequate mixer Elte 650 for 2 minutes with 36rpm.

Tabletting rotary tablet press

Tableting is performed using rotary tablet press Korsch PH 230/14 (Korsch

AG, Berlin, Deutschland) with rotation speed of 35 rpm. For tableting faceted flat tablet punches used 11 mm in diameter. Mass of tablet was

500mg and tableting punching pressure app. 10, 15, 20 & 30 kN used. Analytical evaluation including tablet hardness with n=20 tablets (ERWEKA Multicheck 5.1 ), friction (according Ph. Eur.) using n=13 tablets with

ERWEKA TA420 and disintegration time with n=6 tablets (Biomation disi 4).

Table 6: Tablet hardness measurement

Table 7: Tablet friction measurement

Table 8: Disintegration time measurement

Comparative Example 4

Cyclosporine A was loaded to Parteck® SLC 500 (a Si02 based particulate material having mesopores but no macropores commercially available) was loaded using following method: The loading of 125 mg of silica is achieved by adding of a solution of 4mg Cyclosporine A in 0.5 mL of ethanol by dropping the solution on the silica particles within 30 minutes using a rotating evaporator. The mixture was further rotated for additional 30 minutes at room-temperature. After the homogeneous distribution of Cyclosporine A the mixture was shock frozen using a mixture of

isopentane/ solid carbon dioxide. Removal of water took place by lyophilization during 40 hours at - 20°C and 0.28 mbar. Final drying over 8 hours 0°C and 0.28 mbar resulting to dry flowable particles . Capsules comprising the Parteck® SLC 500 being loaded with

Cyclosporine A are produced by filling the amount of Cyclosporine A loaded Silica using an appropriate capsule filling device delivered together with capsules for in-vivo testing. The capsules are coated as mentioned in Example 1.

The capsules are orally administrated to rats using a dosage of 20 mg/kg Cyclosporine A. After administration, the blood level of Cyclosporine A has been measured according to LC-MS method used in example 4. The values being obtained are shown in Figure 2.

The Example 2 shows that the blood level of Cyclosporine A being orally administrated using the release system of the present invention is much higher than the blood level provided by a release system comprising mesopores but no macropores.

Claims

Patent Claims

1. A release system comprising a bioactive agent and a particulate

material, characterized in that the particulate material comprises macropores and the particulate material exhibits flowability.

2. A release system according to Claim 1 , wherein the flowability of the particulate material exhibits an angle of response below 50°, preferably below 47°, measured according to Ph. Eur. / USP.

3. A release system according to Claim 1 or 2, wherein the macropores have a size of at least 50 nm, preferably at least 100 nm, preferably at least 250 nm, more preferably the size is in the range of 100 to 5000 nm, even more preferably the size is in the range of 150 to 2500 nm, even more preferably the size is in the range of 250 to 1500 nm.

4. A release system according to one or more of Claims 1 to 3, wherein the particulate material is an inorganic material, preferably an oxide, more preferably a silicon oxide, even more preferably the particulate material comprises at least 80 % by weight, most preferably at least 95% by weight SiCte.

5. A release system according to one or more of Claims 1 to 4, wherein the volume of the macropores of the particulate material is at least 0,2 cm³ per g of the particulate material, preferably at least 0,3 cm³ per g of the particulate material.

6. A release system according to one or more of Claims 1 to 5, wherein the particulate material comprises mesopores and the volume of the mesopores is at most 0,75 cm³ per g of the particulate material, preferably at most 0,25 cm³ per g of the particulate material.

7. A release system according to one or more of Claims 1 to 6, wherein that the particulate material comprising macropores has a volume average size in the range of 1 to 2000 pm, preferably 1 to 1000 pm, more preferably 1 to 500 pm, even more preferably 1 to 50 pm.

8. A release system according to one or more of Claims 1 to 7, wherein the volume ratio of the volume of the macropores to the total pore volume is at least 0.2, preferably at least 0.3.

9. A release system according to one or more of Claims 1 to 8, wherein particulate material comprising macropores has preferably a tapped density of at least 0.2, more preferably of at least 0.3 and even more preferably of at least 0.42 measured according to DIN EN ISO 787-11

10. A release system according to one or more of Claims 1 to 9, wherein the bioactive agent is a pharmaceutical drug or a vaccine.

11. A release system according to one or more of Claims 1 to 10, wherein the bioactive agent exhibits a molecular weight of at least 500 g/mol, preferably at least 750 g/mol, more preferably at least 1000 g/mol.

12. A release system according to one or more of Claims 1 to 11 , wherein the bioactive agent exhibits a molecular weight of at most 1000000 g/mol, preferably at most 500000 g/mol, more preferably at most 250000 g/mol.

13. A release system according to one or more of Claims 1 to 12, wherein the bioactive agent is a bioactive agent is a peptide and/or a protein, more preferably an Immunoglobulin G (IgG), such as Canakinumab, Bevazimumab, Adalimumab; an antigen-binding (Fab) fragment, such as Ranibizumab, Abciximab; an PEGylated antigen-binding (Fab) fragment, such as Certolizumab; Antibody-drug conjugates (ADC), such as Trastuzumab emtansine (T-DM1 ), Brentuximab vedotin, Gemtuzumab osogamicin; a Fusion protein, such as Aflibercept, Abatacept, Etanercept; a Trifunctional antibody, such as

Catumaxomab; A single-chain variable fragment (scFv), such as Blinatumomab; Buserelin, Nafarelin, Colistin, Cyclosporine A,

Cytochrome C, Glutathione, Linaclotide, Plecanatide, Taltirelin, Tyrothricin, Vancomycin, Octreotide, Cyclosporin, Desmopressin, Calcitonin, Insulin, Glucagon-like peptide-1 (GLP-1 ), human growth hormone (hGH), Parathyroid hormone (PTFI) and analogues thereof, even more preferably Octreotide, Cyclosporin, Desmopressin,

Calcitonin, Insulin, GLP-1 , hGH, PTH and analogues thereof.

14. A release system according to one or more of Claims 1 to 13, wherein the release system comprises a coating, preferably an enteric coating.

15. A release system according to one or more of Claims 1 to 14, wherein the release system is an oral administration form, preferably a tablet, a pellet, and/or a capsule.

16. A process for producing a release system according to one or more of

Claims 1 to 15, wherein a particulate material comprising macropores is loaded with a bioactive agent.

17. A use of a release system according to one or more of Claims 1 to 15 for orally administrating a drug, preferably a peptide or a protein.