Silicone particles for drug delivery

Abstract

The present invention relates to a process for preparing silicon particles containing at least one active pharmaceutical ingredient, the process comprising: a) preparing silicon particles by chemical vapor deposition (CVD); b) loading the silicon particles prepared in step a) with at least one active pharmaceutical ingredient.

Description

[Technical field]

[0001] The present invention relates to a process for the manufacture of silicon particles containing at least one active pharmaceutical ingredient. In particular, the present invention relates to a process in which the silicon particles are prepared by a process comprising a chemical vapor deposition step. The present invention further relates to particles produced by the process, pharmaceutical compositions comprising said particles and the use of said particles and compositions in therapy, particularly drug delivery. [Background technology]

[0002] Drugs sold in pharmacies or used by patients are generally referred to as drug products in regulatory and scientific terms. Drug products contain two groups of components: drug substances and drug additives or excipients. Drug substances are biologically / pharmacologically active ingredients, while drug additives or excipients are per se inactive ingredients present in drug products to ensure the safety, efficiency and / or ease of use of the drug substance. For example, antibiotic drug substances cannot be injected into the bloodstream as solid materials and therefore are typically dissolved in water as drug additives or excipients and prepared as injectable drug products. The efficacy and safety of a drug product always depends on both the properties of the drug substance and the properties of the excipients. This technical field is often referred to as drug formulations or galenical formulations.

[0003] A drug product may contain one or more drug substances. Such drug substance(s) may be in the form of free drug substance, pharma- ceutically acceptable salt, crystalline or amorphous material, or may be encapsulated in one or more complex compounds. For a given substance, various pharma- ceutically acceptable salts can be prepared using different acids or bases in different ratios, resulting in different salts with different chemical properties such as aqueous solubility, dissolution rate and stability. However, the therapeutic index for different salts of a given substance is the same. The same is true for all possible crystalline forms, amorphous materials and inclusion complexes for a given drug substance. It is not uncommon for one drug substance to exist in different forms in different drug products so that it can be adapted to different routes of administration.

[0004] The field of drug formulations is a complex scientific field for all routes of administration. For oral routes of administration, it may be important that the drug substance is released very quickly, for example, sublingual tablets containing nitroglycerin to treat angina in patients with coronary artery disease. Advantages of using sublingual tablets include reduced first-pass metabolism and rapid action of the drug substance. Oral products that release the drug substance in the mouth, typically in the form of lozenges, are useful, for example, for the treatment of infections and / or pain in the mouth or throat. Classical capsules and tablets release the drug substance in the intestine, which is subsequently absorbed from the small intestine and sometimes partially from the intestine. The main problems associated with this type of pharmaceutical formulation include instability of the drug substance in the intestine due to low pH and / or gastric enzymes, local toxicity or irritation of the intestinal wall caused by the drug substance, or very low water solubility / low dissolution rate of the drug substance. The first two aspects can be improved by the presence of an enteric coating, ensuring that the drug substance dissolves in the intestine and not in the stomach. The topic of low aqueous solubility / low dissolution rate is a common challenge for several old and many new potential drug substances. The result is poor oral bioavailability, leading to the development of many drug candidates with interesting clinical profiles being abandoned.

[0005] For both oral and alternative routes (e.g., parenteral administration), several options using various excipients and mixtures of such excipients have been suggested to ensure a safe and effective drug product with good user convenience. Currently, there are a large number of excipients with various qualities used in commercial pharmaceutical products. However, for many drug substances, clinically useful formulations have not been developed to date.

[0006] One excipient that can be used in pharmaceuticals is silica (silicon dioxide). In the form of hydrophobic silicon dioxide, this compound has several functions, including anti-caking agent, emulsion stabilizer, glidant, suspending agent and viscosity enhancer. In the form of anhydrous silicon dioxide, this compound can act as adsorbent, anti-caking agent, desiccant, emulsion stabilizer, glidant, suspending agent, tablet and capsule disintegrant or thickener. In the form of hydrated silicon dioxide, this compound has several functions, including adsorbent, anti-adhesion agent, anti-caking agent, desiccant, direct compression excipient, flavor enhancer, gelling agent, glidant, plasticizer, solubilizer, suspending agent, tablet and capsule disintegrant and taste masking agent.

[0007] Silicon-containing particles have also been investigated as potential drug delivery excipients. Typically, these particles are silicon dioxide particles, but some studies have focused on silicon particles in which the silicon has the oxidation number 0 (i.e., silicon 0 particles) and is therefore not in the form of silicon oxide. However, such particles may contain some silicon oxide due to natural oxidation of the silicon 0 surface. The particles are typically prepared by ball milling of silicon materials manufactured for the electronics industry, such as semiconductors. Most of these silicon particles are porous particles that are produced by etching the particles before or after milling, for example using hydrofluoric acid (HF).

[0008] Silicon-0 materials can also be prepared by the so-called chemical vapor deposition (CVD) process, in which a silicon-containing gas, e.g. silane (SiH4), is pyrolyzed into silicon-0 solid material. One option is to grind this solid material into small size particles. Silicon-0 particles produced by centrifugal chemical vapor deposition are described, for example, in WO 2013 / 048258 and by Lumenet al in Eur. J. Pharm. and Biopharm. 158 (2021) 254-265. Lumenet al relates to a study on the intravenous administration of silicon particles without therapeutic agents. The findings demonstrated that the cCVD production method provides nanoparticles with physical and biological qualities comparable to conventional grinding methods, but the CVD particles were found to be more toxic than non-CVD particles.

[0009] The inventors have unexpectedly found that silicon particles produced by a direct CVD process as described in WO 2013 / 048258 are attractive for use in drug delivery without a subsequent grinding process. Compared to the state of the art in the pharmaceutical field, the potential advantages of using such particles in drug delivery include: high drug loading, improved drug release profile, improved stability and / or good safety profile.

[0010] During the growth of CVD silicon particles, both gas species and other nuclei are removed. These other nuclei grow into nanospheres that preserve some internal order upon entrapment. If growth is performed at high temperatures >650°C, the particles become crystalline. If growth is performed at lower temperatures, the particles become amorphous. Amorphous particles may be crystallized after growth, but higher temperatures are required to post-crystallize the particles. The exact post-production crystallization temperature depends on the growth conditions and the size of the grown particles. However, all pure silicon particles will crystallize above 770°C.

[0011] All particles are produced from decomposing electronic grade silane gas with a purity of 99,999999% SiH4, so the material produced is pure silicon. All removal and growth is done in an environment where only Si and H atoms are present, so the internal boundaries between the domains are pure. This is true both when the domains are amorphous or crystalline. It is possible to see these domains, for example by examination with a transmission electron microscope. If the sample is crystalline, either as grown crystalline or crystalline that has crystallized after growth, the domains are particularly transparent. The purity, the lack of internal oxidation, and the spherical shape of the primary particles are all intrinsic properties of particles grown by CVD. The main difference between c-CVD and other CVD particles is the narrower size distribution, especially in combination with the amorphous structure. It is possible to achieve a narrow size distribution by using high energy supply, for example by a laser or plasma torch growth zone, and short growth times. However, by performing the growth control in this way, a crystalline structure with substantially larger crystals is always obtained.

[0012] The main difference between CVD particles and milled particles is the spherical nature of the primary particles and the lack of sharp edges of CVD particles. CVD particles grow from gas in the process, but for clarity, can be considered as Hale growth. The spherical nature of the Hale is the result of the same primary growth mechanism, gas entrapment, and smaller solid domains that eventually form a complete Hale sphere. Milled silicon particles can be seen as the equivalent of milling ice cubes, for clarity. Both CVD and milled particles can contain crystalline domains, but for CVD particles, these domains are all small, of narrow size distribution, the particles are spherical, and the internal surfaces are not oxidized or contaminated. For crushed particles, internal crystalline domains may be present, but the size and distribution vary. Crushed particles are formed by breaking up larger particles, and therefore essentially always have sharp edges. If internal surfaces were present, they would see atoms other than Si and H, and therefore would always be more contaminated than direct electronic grade Si particles. Milling is also difficult to do without substantial internal oxidation. The simplest analytical methods to distinguish between CVD and fractured particles are scanning or transmission electron microscopy, or by X-ray diffraction to identify a completely amorphous structure. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2013 / 048258 [Non-patent literature]

[0014] [Non-Patent Document 1] Lumenet al. Eur. J. Pharm. and Biopharm. 158 (2021) 254-265 Summary of the Invention [Problem to be solved by the invention]

[0015] To aid in the analysis, purity measurements by inductively coupled plasma mass spectrometry (ICPMS) can be performed to verify the purity of the particles. Spherical, pure, non-oxidized amorphous or nanocrystalline particles must be produced by CVD and cannot be achieved by crushing. [Means for solving the problem]

[0016] [Summary of the Invention] In a first aspect, the present invention relates to a process for preparing silicon particles containing at least one active pharmaceutical ingredient, the process comprising: a) preparing silicon particles by chemical vapor deposition (CVD); b) loading the silicon particles prepared in step a) with at least one active pharmaceutical ingredient.

[0017] In a further aspect, the present invention provides silicon particles comprising at least one active pharmaceutical ingredient prepared according to the process defined above.

[0018] In another aspect, the present invention provides a pharmaceutical composition comprising silicon particles as defined hereinbefore and one or more pharma- ceutically acceptable carriers, diluents or excipients.

[0019] In a further aspect, the present invention provides a silicon particle as defined above or a pharmaceutical composition as defined above for use in therapy.

[0020] In yet another aspect, the present invention provides silicon particles as defined above or a pharmaceutical composition as defined above for use in drug delivery. [Brief description of the drawings]

[0021] [Figure 1] c Silicon particles with an average diameter of 300 nm produced by CVD. [Diagram 2]The silicon article has a primary particle size (median mean diameter) of about 30 nm. The dynamic light scattering (DLS) size of these particles is about 150 nm, and BET analysis gives an average particle size of about 40 nm. [Diagram 3] 1 is an SEM image of amorphous agglomerated cCVD Si particles. [Figure 4] 47. Rapamycin release versus time for Example 47. [Diagram 5] 48. Rapamycin release versus time for Example 48. [Figure 6] 49. Rapamycin release versus time for Example 49. [Figure 7] 6 is Rapamycin release versus time for Examples 50 and 51. [Figure 8] In Example 52, HPLC analysis / chromatogram for identification of rapamycin, no degradation peaks. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] [Definition] The term "drug substance" as used herein refers to any biologically and / or pharmacologically active compound, including prodrugs thereof. Any stereoisomers, or pharma- ceutically acceptable salts or solvates thereof, are included in the term. The term drug substance includes any drug substance that has received regulatory approval, drug substances currently in development, and drug substances that are commercially available.

[0023] The term "drug product" refers to a composition comprising at least one drug substance and at least one excipient (ie, a pharmaceutical composition).

[0024] The term "regulatory approved" refers to a drug product that is, or has been, regulatory approved for sale in at least one country.

[0025] The term "under regulatory development" refers to drug products that are known to be in development with a view to obtaining regulatory approval.

[0026] The term "pharmaceutical composition", including "drug product", refers to a composition that contains at least one active pharmaceutical ingredient and at least one excipient.

[0027] The term "pharmaceutical acceptable" refers to compounds and mixtures thereof that are acceptable for use in drug products. All excipients used in drug products that have been approved by regulatory agencies are pharmaceutical acceptable.

[0028] The term "excipient" refers to a compound for use in a pharmaceutical product that is not itself biologically active in the amounts present when the pharmaceutical product is used as intended or in accordance with regulatory approval.

[0029] The term "complex" refers to a compound that contains at least two different molecules that are bound to each other by additional bonds other than the covalent bonds and classical ionic bonds in simple salts. One typical example is a cyclodextrin complex.

[0030] The term "cyclodextrin" refers to a compound of cyclic oligosaccharides consisting of a macrocyclic ring of glucose subunits linked by α-1,4 glycosidic bonds. α (alpha)-cyclodextrin contains six glucose subunits, β (beta)-cyclodextrin contains seven glucose subunits, and γ (gamma)-cyclodextrin contains eight glucose subunits. Unsubstituted cyclodextrin (alpha, beta, and gamma) compounds are produced from starch by enzymatic processes. Substituted cyclodextrin derivatives are produced by semi-synthetic processes.

[0031] The term "0 silicon-containing particles" refers to particles in which at least 50% of the silicon is at an oxidation level of 0, not 4 like silica.

[0032] The term "low molecular weight compound" refers to a compound having a molecular weight below 3000 Daltons.

[0033] The term "biological drug substance" refers to a drug substance produced by a living organism. The term does not include substances naturally produced by plants. The term includes semi-synthetic drug substances, such as drug / toxin conjugates of monoclonal antibodies. This term is a controlled term.

[0034] The term "food additive" refers to any food product in the market.

[0035] "Silicon particles of the invention" are understood to be silicone particles which contain at least one active pharmaceutical ingredient.

[0036] The term cCVD-SP is used to denote "centrifugally deposited chemical vapor deposition silicon particles" and refers to silicon particles prepared by a centrifugation process. In particular, the term refers to silicon particles prepared by a CVD process in a reactor, the reactor comprising a reactor body and a rotating device operably disposed in the reactor, the rotating device configured to rotate the reactor about an axis during production of the silicon-containing particles.

[0037] The term PcCVD-SP is used to denote "porous centrifugation chemical vapor deposition silicon particles" and refers to silicon particles prepared by the centrifugation method, followed by a process such as etching to prepare the porosity of the particle.

[0038] [Mode for carrying out the invention] The present invention relates to a process for preparing silicon particles containing at least one active pharmaceutical ingredient, the process comprising: a) preparing silicon particles by chemical vapor deposition (CVD); b) loading the silicon particles prepared in step a) with at least one active pharmaceutical ingredient.

[0039] [Step a)—Chemical Vapor Deposition (CVD)] A CVD process is a process in which a gas is converted into a solid material, typically a film, under various conditions. Step a) of the process of the present invention preferably comprises preparing silicon particles by CVD from a silicon-containing reactive gas, such as silane or trichlorosilane.

[0040] In a preferred embodiment of the present invention, the CVD process in step a) does not include a milling step b).

[0041] In particular, the CVD process of step a) is preferably carried out in a reactor, the reactor comprising a reactor body and a rotation device operably arranged in the reactor, the rotation device being configured to rotate the reactor about an axis during the production of said silicon-containing particles, hereinafter referred to as cCVD-SP (Centrifugal Chemical Vapor Deposition Silicon Particles).

[0042] In a further preferred embodiment of the present invention, the CVD process of step a) is carried out in a reactor, the reactor comprising a reactor body and a rotating device operatively arranged in the reactor, the rotating device configured to rotate the reactor about an axis during the production of said silicon-containing particles, hereinafter referred to as cCVD-SP, optionally followed by an etching process to prepare the porosity of the particles. Such particles are herein referred to as PcCVD-SP (Porous centrifuge Chemical Vapor Deposition Silicon Particles).

[0043] One preferred embodiment of the present invention relates to porous non-etched cCVD-SP. Such particles are typically formed by forming stable agglomerates of smaller particles.

[0044] Another preferred embodiment of the present invention relates to non-porous, unetched cCVD-SP particles.

[0045] Yet another preferred embodiment of the present invention relates to porous amorphous non-etched cCVD-SP particles.

[0046] Yet another preferred embodiment of the present invention relates to non-porous, amorphous, non-etched cCVD-SP particles.

[0047] The etching process for producing PcCVD-SP from cCVD-SP is similar to other well-known etching processes for silicon particles described in the literature, for example hydrofluoric acid-based methods. The particle surface may be modified to exhibit desired properties, including chemical or thermal oxidation or coating.

[0048] Particularly preferred methods for the preparation of silicon particles in step a) are disclosed in WO2013048258 and WO2018052318 and are briefly described below.

[0049] In this preferred process, step a) is carried out in a reactor comprising a reactor body which can be rotated about an axis with the aid of a rotating device operably arranged in the reactor, at least one side wall surrounding the reactor body, at least one inlet for a reaction gas, at least one outlet for a residual gas, and at least one heating device operably arranged in the reactor, characterized in that during operation for the production of silicon particles by CVD, the reactor comprises a layer of particles inside at least one side wall.

[0050] Thus, the process of step a) preferably comprises: - generating a particle layer from a silicon-containing reaction gas in a reactor or introducing particles to form an inner particle layer on an inner wall surface of the reactor; - introducing a reactive gas for chemical vapor deposition; - nucleating particles within the reactor chamber.

[0051] The formed particles capture the precursor gas and grow until their weight drives them to the wall where the temperature is lower and further growth is inhibited. The particles are then removed from the wall in the gas flow and collected on a filter. The particles are then removed from the filter by sending a gas pressure pulse in the reverse direction through the filter. The particles are collected in an inert state for further processing.

[0052] Depending on the application, the particles can be inertly coated or exposed to air to form a thin native oxide layer on the particles. Further processing may include etching the particles in HF with or without subsequent coating depending on the application. However, preferably, the particles are not subjected to an etching process.

[0053] In particles formed from the milling of electronic grade silicon wafers, the average crystallite size of the material is orders of magnitude larger than the particle size. For CVD formed particles, the average crystallite size is tunable. It is possible to have one or a few crystallites in each particle, to have many nanocrystallites in each particle, or to have a completely disordered amorphous structure. This is tunable by the process, so that a particular crystallinity or average crystallite size can be selected for a particular application or following further processing. For example, the etch rate depends on the crystallite size and orientation, as well as the defect distribution and frequency within each crystallite.

[0054] The particle decomposition time depends to some extent on the number of crystal interfaces that reach the surface, in other words, the number of oxidation channels through which oxidation can propagate downward along the material, as well as how imperfect the individual crystals are. The more defects and interfaces there are, the easier it is to both reach individual silicon atoms and oxidize them. Since these are tunable properties in CVD-produced materials, it is possible to tailor the material to any particular application in a completely different way than crushed large crystal materials, which are given these properties. Especially in applications where rapid biodegradation is desired, CVD particles have substantial advantages over classical crushed crystalline silicon.

[0055] [Step b)-Filling] The silicon particles produced in step a) are then loaded with at least one active pharmaceutical ingredient in step b). This loading step b) can be carried out by any suitable method known in the art. Typically, however, step b) comprises mixing the silicon particles obtained in step a) with at least one active pharmaceutical ingredient in a solvent.

[0056] The solvent is ideally one in which the silicon particles are dispersed and the active pharmaceutical ingredient is at least partially soluble. Typically the solvent is an aqueous solvent (i.e., comprises, and preferably consists of, water).

[0057] The mixing step may be carried out at ambient temperature (e.g., 20-30° C.) or at elevated temperature (e.g., 40-80° C., e.g., 50-70° C.). Typically, mixing is carried out in a sonicator, but may be carried out by any suitable method known in the art.

[0058] cCVD-SP and PcCVD-SP containing at least one drug substance are typically isolated as a dry product by evaporation, lyophilization, fluid bed, spray drying, or any other method known in the art. If the cCVD-SP and PcCVD-SP containing at least one drug substance are intended for use as a non-dried material, the drying step described above is optional.

[0059] [silicon] The silicon in the silicon particles of the present invention (preferably cCVD-SP and / or PcCVD-SP) is present in at least 50% by weight as elemental silicon (silicon with oxidation number 0) based on the total weight of silicon. A more preferred form of silicon in the silicon particles is at least 70% by weight as elemental silicon, even more preferably at least 80% by weight as elemental silicon, based on the total weight of silicon. Another preferred aspect regarding the form of silicon in the particles is that the amount of elemental silicon and silicon dioxide is greater than 80%, more preferably greater than 90%, and most preferably greater than 95% based on the total weight of silicon.

[0060] Silane and other silicon-containing gases used in the preparation of the present particle in CVD process are very toxic.As a component in drugs, it is very important that the amount of silicon-containing gas is very low in the present particle.Therefore, another preferred embodiment of the form of silicon in the particle of the present invention is that the amount of silicon-containing gas in the particle is less than 10wt%, more preferably less than 5wt%, most preferably less than 2wt% of the total weight of silicon in the particle.

[0061] The elemental silicon in the particles of the present invention may be in amorphous or crystalline form. The elemental silicon in the particles produced by the CVD process is mainly in the form of amorphous elemental silicon at ambient temperature, but particles containing crystalline silicon can be prepared directly by CVD at high temperatures (e.g., above 630°C) and longer reaction times. The particles containing crystalline silicon prepared from the CVD method are typically in the form of polycrystalline material (crystal size about 1.5 nm), while the crushed crystalline particles typically consist of one crystal of silicon.

[0062] The crystalline versus amorphous form of silicon can be routinely determined by X-ray diffraction analysis (XRD analysis). The amorphous form of silicon can be converted to the crystalline form of silicon by heating to relatively high temperatures (e.g., above 650° C.).

[0063] In certain embodiments, elemental silicon is present in crystalline form based on the total weight of elemental silicon, in some embodiments typically greater than 60% by weight, in some embodiments greater than 80% by weight, and finally in some embodiments greater than 90% by weight.

[0064] In other embodiments, the silicon particles comprise elemental silicon in amorphous form relative to the total weight of elemental silicon, including in some embodiments greater than 80% by weight, in some embodiments greater than 90% by weight, in some embodiments greater than 95% by weight, and finally, in some embodiments greater than 99% by weight in amorphous form.

[0065] One preferred embodiment of this aspect of the invention is where the silicon particles are cCVD-SP or PcCVD-SP.

[0066] One of the most preferred embodiments of this aspect of the invention is where the silicon particles are cCVD-SP comprising silicon in amorphous form, such as in the weight % ranges defined above.

[0067] Another most preferred embodiment of this aspect of the invention is where the silicon particles are cCVD-SP that are not produced by an etching process, particularly not by a hydrogen fluoride (HF) etching process, i.e., the silicon particles are not etched.

[0068] In the final form of the most preferred embodiment of this aspect of the invention, the silicon particles comprise amorphous silicon, such as in the weight percent ranges defined above, and are not etched.

[0069] [Particle size] The process of the invention allows to prepare silicon particles with a "tailor-made" particle size. A typical median mean particle size of the silicon particles of the invention can be less than 500 nm, for example 30-300 nm, using the technique of Dynamic Light Scattering (DLS), for example using an instrument such as a Zetasizer. The given particle size relates to the final silicon particle loaded with one or more drug substances and optionally excipients and coatings. The particles consist of single particles partly clustered together via bonds and partly loosely. Figures 1-3 show examples of particles.

[0070] The polydispersity index can also vary from almost monodisperse particles to particles with a very broad particle size distribution.

[0071] The preferred particle size of the silicon particles of the present invention generally varies depending on the indication and the route of administration. For intravenous administration, the particles should typically have an average particle size of less than 500 nm, more preferably less than 200 nm. For intramuscular injection, the average particle size should preferably be less than 10 μm, typically less than 5 μm. For subcutaneous administration and ophthalmic use, the average particle size should typically be less than 5 μm. For nasal application, the average particle size should typically be less than 50 μm. For pulmonary administration (inhalation), the average particle size should typically be less than 15 μm, and for oral administration, the average particle size should typically be less than 500 μm.

[0072] [Porosity] The silicon particles of the present invention may be non-porous (cCVD-SP) or porous (PcCVD-SP). The most preferred particles according to the present invention are porous particles. In all embodiments, it is preferred if the particles are prepared by a non-etching process. Porous particles for drug delivery can be prepared by forming stable agglomerates of smaller particles, so-called stable particle clusters.

[0073] The porosity of the PcCVD-SP can vary over a wide range depending on the choice of drug substance, the indication and the route of administration. Porosity is a measure for the volume of pores. A PcCVD-SP with a porosity of 50% has a pore volume that is 50% of the total PcCVD-SP volume. The porosity of the PcCVD-SP can typically be between 20% and 90%. In certain embodiments, the porosity is greater than 40%, typically greater than 50%, preferably greater than 60%, more preferably greater than 70%, especially greater than 80%, for example 90%. In other embodiments, the porosity is preferably about 50% or less.

[0074] The pore size of the PcCVD-SP can vary from microporous particles through mesoporous particles to macroporous particles depending on the nature of the drug substance, the dose of the drug substance, the indication, the form of the drug product and the route of administration. Typical average pore sizes of PcCVD-SP for loading the drug substance are between 1 nm and 200 nm. In one embodiment of the invention, the average pore size is between 1 and 10 nm, in another embodiment, the typical pore size is between 5 and 20 nm, in yet another embodiment, the typical pore size is between 10 and 50 nm, and finally, in yet another embodiment, the typical pore size is between 2 and 50 nm.

[0075] In one embodiment, the particles are microporous. In this embodiment, preferably at least 2% by volume of the pores are micropores, more preferably at least 5% by volume, even more preferably at least 10% by volume, in particular at least 20% by volume, such as at least 50% by volume, based on the total pore volume.

[0076] In another embodiment, the particles are mesoporous, in which preferably at least 2% by volume of the pores are mesopores, more preferably at least 5% by volume, even more preferably at least 10% by volume, in particular at least 20% by volume, such as at least 50% by volume, based on the total pore volume.

[0077] In a further embodiment, the particles are macroporous, in which preferably at least 2% by volume of the pores are macropores, more preferably at least 5% by volume, even more preferably at least 10% by volume, in particular at least 20% by volume, such as at least 50% by volume, based on the total pore volume.

[0078] [Particle Surface and Coating] The particle surface may typically be in the form of elemental silicon, more preferably in the form of a layer of silicon oxide, where the elemental silicon on the particle surface has undergone a natural or chemical oxidation process. The surface may also be covered by a layer of drug molecules that are covalently or non-covalently bonded to the silicon-containing material. The surface may also be covered by a coating material that includes carbon, preferably in the form of an organic coating. The organic coating may be bonded to the silicon-containing material by covalent or non-covalent bonds. The coating chemistry of silicon particles is well known in the art.

[0079] The optional coating may have one or more different functions such as: The coating can protect silicon particles from degradation Coatings can control the release profile of the drug substance Coatings can affect the biodistribution of particles after administration Coatings may improve loading of API into silicon-containing particles Coatings may form the basis for covalent bonding of drug substances to the coating material

[0080] The coating may, from a chemical point of view, have one or more of the following properties: - Hydrophilic coatings, for example in the form of covalently attached polyethylene glycol chains. A particle surface that is positively charged at physiological pH. This can typically be obtained by the attachment of aliphatic amino groups to the particle surface. A particle surface that is negatively charged at physiological pH. This can typically be achieved by attachment of carboxyl groups to the particle surface. Enzymatically degradable coatings. Typical coatings include, for example, coatings containing ester groups. · Coatings that contain a monolayer of coating molecules. Coatings that contain multiple layers of coating molecules. Coatings based on monomeric compounds Coatings based on polymer compounds Coatings based on phospholipids and / or other lipid derivatives. Coatings based on proteins, peptides or amino acids or their derivatives. Coatings based on sugar molecules, including monosaccharides, disaccharides, oligosaccharides (including cyclodextrins and polysaccharides).

[0081] The surface area of ​​the silicon particles of the present invention varies. The surface area is much higher for porous particles (PcCVD-SP) than for non-porous particles (cCVD-SP). The surface area of ​​the particles prior to loading with at least one active pharmaceutical ingredient can be up to 1000 m per gram of particle. 2 may be also possible.

[0082] Preferred coatings include surfactants such as, for example, ceteareth, cetearyl, ceteth, cocamide, isosteareth, laureth, lecithin, oleth, PEG-20 almond glycerides, PEG-20 methyl glucose sesquistearate, PEG-25 hydrogenated castor oil, PEG-40 sorbitan peroleate, PEG-60 almond glycerides, PEG-7 olivate, PEG-7 glyceryl cocoate, PEG-8 dioleate, PEG-8 laurate, PEG-8 oleate, PEG-80 sorbitan laurate, polysorbates, and pluronics.

[0083] [drug substance] The silicon particles of the present invention comprise one or more active pharmaceutical ingredients. The silicon particles may comprise only one active pharmaceutical ingredient, but it is also possible that more than one active pharmaceutical ingredient is present, for example two or three active pharmaceutical ingredients.

[0084] A preferred embodiment of the present invention relates to a cCVD-SP that contains one drug substance.

[0085] A more preferred embodiment of the present invention relates to a PcCVD-SP that contains one active pharmaceutical ingredient.

[0086] Another preferred embodiment of the present invention relates to a cCVD-SP that contains two drug substances.

[0087] A more preferred embodiment of the present invention relates to a PcCVD-SP that contains two drug substances.

[0088] Another preferred embodiment of the present invention relates to a cCVD-SP that contains three or more drug substances.

[0089] A more preferred embodiment of the present invention relates to a PcCVD-SP that contains three or more drug substances.

[0090] Drug substances used in accordance with the present invention include any drug substance, regulatory approved drug substance, as well as any drug substance under development for prophylactic use and / or treatment of disease.

[0091] In one embodiment, the drug substance is preferably selected from the group consisting of anti-cancer drugs, drugs having an effect on the immune system, anti-fungal drugs, antibiotics, anti-viral drugs, drugs for the treatment of CNS-related diseases, anti-diabetic drugs, drugs for the treatment of pain and steroid drugs.

[0092] One preferred aspect of the present invention relates to a drug for the prophylactic use and / or treatment of diseases related to the gastrointestinal system and metabolism. Such drug substances are typically included in ATC group A. Drug substances for the treatment of diseases related to the gastrointestinal system and metabolism include anti-infectives and antiseptics for local oral treatment, corticosteroids for local oral treatment, and other drugs for local oral treatment.

[0093] Drug substances for the treatment of acid-related disorders include drugs for peptic ulcer and gastroesophageal reflux disease (GORD), such as H2 receptor antagonists, e.g., cimetidine, ranitidine, famotidine, nizatidine, niperotidine, roxatidine, ranitidine bismuth citrate, and lafutidine, prostaglandins, e.g., misoprostol and enprostil, such as omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole, dexlansoprazole, dexrabeprazole, and Antacids include proton pump inhibitors such as vonoprazan, including combinations for the eradication of Helicobacter pylori, and other drugs for peptic ulcer and gastroesophageal reflux disease (GORD), including other drugs for acid-related disorders such as carbenoxolone, sucralfate, pirenzepine, methiosulfonium chloride, bismuth subcitrate, proglumide, gefarnate, sulglycotide, acetoxolone, zolimidine, troxipide, bismuth subnitrate, arginic acid, rebamipide, carbenoxolone, and gefarnate.

[0094] Drug substances for the treatment of functional gastrointestinal disorders include antispasmodics such as belladonna alkaloids and their derivatives.

[0095] Other relevant drug substances include antiemetics such as ondansetron and other serotonin (5HT3) antagonists, drug substances for the treatment of bile and liver related disorders, constipation relief drug substances including laxatives, drug substances for the treatment of diarrhea, anti-obesity drug substances and gastrointestinal digestive agents including enzymes.

[0096] Drugs for the treatment of diabetes include insulin and analogs, including fast acting injectable insulins and analogs, such as, for example, insulin (human), insulin (bovine), insulin (porcine), insulin lispro, insulin aspart, and insulin glulisine (including injectable insulin and analogs), including intermediate acting injectable insulins and analogs, such as, for example, insulin (human), insulin (bovine), insulin (porcine), insulin lispro (including insulin and injectable analogs), including intermediate or long acting injectable insulins and analogs in combination with fast acting, such as, for example, insulin (human), insulin (bovine), insulin (porcine), insulin lispro, insulin aspart, insulin degludec, and insulin aspart (including insulin and injectable analogs), including long acting injectable insulins and analogs, such as, for example, insulin (human), e.g. insulin (bovine), insulin (porcine), insulin glargine, insulin detemir, insulin degludec, insulin glargine, and lixisenatide, and insulin degludec and liraglutide.Other non-insulin hypoglycemic agents include biguanides, such as phenformin, metformin and buformin; sulfonylureas, such as glibenclamide, chlorpropamide, tolbutamide, glibornuride, tolazamide, carbutamide, glipizide, gliquidone, gliclazide, methahexamide, glisoxepide, glimepiride and acetohexamide; heterocyclic sulfonamides, such as glymidine; alpha-glucosidase inhibitors, such as acarbose, miglitol and voglibose; thiazolidinediones, such as troglitazone, rosiglitazone, pioglitazone and lobeglitazone; These include dipeptidyl peptidase 4 (DPP-4) inhibitors such as linagliptin, gemigliptin, evogliptin and teneligliptin; glucagon-like peptide-1 (GLP-1) analogues such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide and veinaglutide; sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, sotagliflozin and luseogliflozin; and other diabetes related drug substances such as guar gum, repaglinide, nateglinide, pramlintide, benfluorex, mitiglinide and tolrestat.

[0097] Vitamins include any vitamin within the group: vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, and vitamin K.

[0098] Another preferred embodiment of the present invention relates to drugs for the prophylactic use and / or treatment of diseases related to blood and blood-forming organs. Such drug substances are typically included in ATC group B. These drug substances include vitamin K antagonists, such as warfarin, including dicoumarol, phenindione, and heparin, platelet coagulation inhibitors, such as picotamide, clopidogrel, ticlopidine, acetylsalicylic acid, and dipyridamole, direct thrombin inhibitors, such as desirudin, lepirudin, argatroban, melagatran, ximelagatran, bivalirudin, and dabigatran etexilate, antithrombin agents, including direct factor Xa inhibitors, such as rivaroxaban, apixaban, edoxaban, and betrixaban, and other antithrombotic agents.

[0099] Another preferred embodiment of the present invention relates to drugs for preventive use and / or treatment of diseases related to the cardiovascular system. Such drug substances are typically included in ATC group B. Drug substances related to the cardiovascular system include cardiac therapies such as cardiac glycosides, antiarrhythmics, inotropes and vasodilators. Drug substances for the treatment of hypertension include beta-blockers such as metoprolol and atenolol, diuretics such as hydrochlorothiazide, calcium antagonists such as amlodipine and nifedipine, ACE inhibitors such as enalapril and captopril, angiotensin II receptor antagonists such as losartan, candesartan and valsartan, lipid modifying agents such as simvastatin, atorvastatin and ezetimibe.

[0100] Another preferred embodiment of the present invention relates to drugs for the preventive use and / or treatment of skin-related diseases, including dermatological drugs. Such drug substances are typically included in ATC Group D.

[0101] Another preferred embodiment of the present invention relates to a drug for the preventive use and / or treatment of diseases related to the urogenital system, including sex hormones. Such drug substances are typically included in the ATC G group. Such drug substances include, for example, gynecological anti-infectives and antiseptics, imidazole derivatives such as metronidazole, clotrimazole, econazole and ornidazole, triazole derivatives such as terconazole, antibiotics such as natamycin, amphotericin B and candicidin, contraceptives and sex hormones such as estrogens, progestogens, androgens and antiandrogens.

[0102] Another preferred embodiment of the present invention relates to drugs for the prophylactic use and / or treatment of hormone-related diseases. Such drug substances are typically included in ATC group H. Hormones for systemic use include pituitary and hypothalamic hormones, corticosteroids and other hormones in clinical use.

[0103] Another preferred embodiment of the present invention relates to drugs for the prophylactic use and / or treatment of diseases associated with anti-infective agents such as antibacterial, antifungal and antiviral agents. Such drug substances are typically included in ATC Group H.

[0104] Antibacterial agents include drug substances such as tetracyclines, chloramphenicol, beta-lactam antibacterials such as penicillins and cephalosporins, sulfonamides and trimethoprim, macrolides, lincosamides and strepogramins, aminoglycoside antibacterials, quinoline antibacterials.

[0105] Antifungal agents include, for example, substances such as imidazole derivatives, triazole derivatives, nystatin, and amphotericin B.

[0106] Antiviral agents include, for example, agents such as thiosemicarbazones, non-reverse transcriptase inhibitors nucleosides and nucleotides, cyclic amines, phosphate derivatives, protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, neuraminidase inhibitors, integrase inhibitors, antivirals for the treatment of HCV infection.

[0107] Another preferred aspect of the present invention relates to drugs for the prophylactic use and / or treatment of diseases associated with antineoplastic and immunomodulatory substances. Such drug substances are included in ATC Group L.

[0108] Antitumor drugs are included in the ATC group L1. A preferred embodiment of the present invention relates to drugs within the ATC group L01.

[0109] Examples of anti-cancer drugs include alkylating agents such as cyclophosphamide, chlorambucil, melphalan, chlormethine, ifosfamide, trofosfamide, prednimustine, bendamustine, busulfan, treosulfan, mannosulfan, thiotepa, triaziquone, carboquone, carmustine, lomustine, semustine, streptozocin, fotemustine, nimustine, ranimustine, uramustine, etoglucide, mitobronitol, pipobroman, temozolomide, and dacarbazine, such as methotrexate, raltitrexate, and the like. antimetabolites such as vinblastine, vincristine, vindesine, vinorelbine, vinflunine, vintafolide, etoposide, teniposide, demecolcine, paclitaxel, docetaxel, paclitaxel poliglumex, and cabazitaxel; plant alkaloids and other natural products, such as cel, topotecan, irinotecan, etrinotecan pegol, belotecan, and trabectedin; cytotoxic antibiotics and related substances, such as dactinomycin, doxorubicin, daunorubicin, epirubicin, aclarubicin, zorubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, amrubicin, pixantrone, bleomycin, plicamycin, mitomycin, and ixabepilone; BCR-A inhibitors, such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib; BL tyrosine kinase inhibitors, e.g. epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors such as gefitinib, erlotinib, afatinib, osimertinib, rociletinib, olmutinib, dacomitinib, icotinib; B-Raf serine-threonine kinase (BRAF) inhibitors, e.g. vemurafenib, dabrafenib, encorafenib; anaplastic lymphoma kinase (ALK) inhibitors, e.g. crizotinib, ceritinib, alectinib, brigatinib, lorlatinib; e.g. trametinib, cobimetinib, binimetinib;Mitogen-activated protein kinase (MEK) inhibitors, such as selumetinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, ribociclib, and abemaciclib; mammalian target of rapamycin (mTOR) kinase inhibitors, such as temsirolimus, everolimus, and ridaforolimus; human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitors, such as lapatinib, neratinib, and tucatinib; Janus-related kinase (JAK) inhibitors, such as ruxolitinib and fedratinib; Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, such as ibrutinib, cediranib, and tivozanib; Bruton's tyrosine kinase (BTK) inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib; phosphatidylinositol-3-kinase (Pi3K) inhibitors, such as idelalisib, copanlisib, and alpelisib; sunitinib, sorafenib, pazopanib, vandetanib, regorafenib, masitinib, cabozantinib, lenvatinib, nintedanib, midostaurin, xarutinib, larotrectinib, gil Protein kinase inhibitors such as other protein kinase inhibitors such as teritinib, entrectinib, pexidartinib, erdafitinib, capmatinib, avapritinib, ripretinib, pemigatinib, tepotinib, other antineoplastic agents such as platinum compounds such as cisplatin, carboplatin, oxaliplatin, satraplatin, and polyplatinol, methylhydrazines such as procarbazine, edrecolomab, rituximab, trastuzumab, gemtuzumab ozogamicin, cetuximab, bevacizumab, panitum Mumab, catumaxomab, ofatumumab, ipilimumab, brentuximab vedotin, pertuzumab, trastuzumab emtansine, obinutuzumab, dinutuximab beta, nivolumab, pembrolizumab, blinatumomab, ramucirumab, necitumumab, elotuzumab, daratumumab, mogamulizumab, inotuzumab ozogamicin, olaratumab, durvalumab, bermekimab, avelumab, atezolizumab, cemiplimab, moxetumab passudotox, tafasitamab, enfortumab vedotin, polatuzumab vedotin, isatuximab,Monoclonal antibodies such as belantamab mafodotin, dostarlimab and trastuzumab deruxtecan, sensitizers used in photodynamic / radiotherapy such as porfimer sodium, methyl aminolevulinate, aminolevulinic acid, temoporfin, efaproxiral, padeliporfin, retinoids for cancer treatment such as tretinoin, alitretinoin, bexarotene, proteasome inhibitors such as bortezomib, carfilzomib, ixazomib, histone deacetylase (HDAC) inhibitors such as vorinostat, romidepsin, panobinostat, belinostat, entinostat, hedgehog pathway inhibitors such as vismodegib, sonidegib, glasdegib, e.g. olaparib, niraparib, rucaparib, talazoparib , poly(ADP-ribose) polymerase (PARP) inhibitors such as veliparib, e.g., amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine, pentostatin, masoprocol, estramustine, mitoguazone, tiazofurin, mitotane, pegaspargase, arsenic trioxide, denileukin diftitox, celecoxib, anagrelide, oblimerse Other anti-cancer drugs include cefotaxime, cytomagene seradenovec, omacetaxine mepeccate, eribulin, aflibercept, talimogene laherparepvec, venetoclax, vosaroxin, plitidepsin, epacadostat, enasidenib, ivosidenib, selinexor, tagraxofusp, lurbinectedin, axicabtagene ciloleucel, and tisagen luclucel.

[0110] Drug substances for endocrine therapy include hormones and antihormones. These drug substances are included in ATC group L02.

[0111] Immunostimulants are included in ATC group L03. A preferred embodiment of the present invention relates to drugs in ATC group L03. Immunostimulants include colony stimulating factors such as filgrastim, molgramostim, sargramostim, lenograstim, ancestim, pegfilgrastim, lipegfilgrastim, valgrastim, empegfilgrastim, and pegteograstim, interferon alpha, interferon beta, interferon gamma, interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon beta-1a, interferon alpha-2b, interferon alpha-n2, interferon beta-1a, interferon alpha-2b, interferon alpha-n1, interferon beta-1a, interferon alpha-2b, interferon alpha-n2, interferon alpha-n1, interferon beta-1a, interferon alpha-2b, interferon alpha-n1, interferon alpha-2b, interferon alpha-n2, interferon alpha-n1 ... interferons such as interferon beta-1b, interferon alfa con-1, peginterferon alfa-2b, peginterferon alfa-2a, albainterferon alfa-2b, peginterferon beta-1a, cepegininterferon alfa-2b, lobgininterferon alfa-2b, interleukins such as aldesleukin and oprelvekin, other immune stimulants such as lentinan, rokinimex, BCG vaccination, pegademase, pidotimod, poly I:C, poly IC LC, thymopentin, immunocyanin, tasonermin, melanoma vaccine, glatiramer acetate, histamine, mifamuratide, plerixafor, sipuleucel-T, clidanimod, dasiprotimut-T and elapegademase.

[0112] Immunosuppressants are included in ATC group L04. A preferred embodiment of the present invention relates to drugs in ATC group L04. Immunosuppressants include, for example, muromonab-CD3, antilymphocyte immunoglobulin (horse), antithymocyte immunoglobulin (rabbit), mycophenolic acid including mycophenolate mofetil, sirolimus, leflunomide, alefacept, everolimus, gusperimus, efalizumab, avetimus, natalizumab, abatacept, eculizumab, belimumab, fingolimod, belatase. Selective immunosuppressants such as etanercept, infliximab, afelix, cefotaxime, tofacitinib, teriflunomide, apremilast, vedolizumab, alemtuzumab, begelomab, ocrelizumab, baricitinib, ozanimod, emapalumab, cladribine, imlifidase, siponimod, ravulizumab, upadacitinib, filgotinib, itacitinib, and invigelizumab Tumor necrosis factor alpha (TNF-alpha) inhibitors such as momab, adalimumab, certolizumab pegol, golimumab and opinercept; interleucin inhibitors such as daclizumab, basiliximab, anakinra, rilonacept, ustekinumab, tocilizumab, canakinumab, briakinumab, secukinumab, siltuximab, brodalumab, ixekizumab, sarilumab, sirulumab, guselkumab, tildrakizumab, risankizumab and satralizumab; calcineurin inhibitors such as cyclosporine, tacrolimus and voclosporin; other immunosuppressants such as azathioprine, thalidomide, methotrexate, lenalidomide, pirfenidone, pomalidomide, dimethyl fumarate and dalvadostrocel.

[0113] Another preferred embodiment of the present invention relates to drugs for the preventive use and / or treatment of diseases related to the muscular and skeletal systems, including anti-inflammatory and anti-rheumatic compounds and immunomodulators. Such drug substances are included in ATC group M. Drug substances related to the muscular and skeletal systems include anti-inflammatory and anti-rheumatic compounds, such as non-steroidal anti-inflammatory compounds including indomethacin, diclofenac, ibuprofen and naproxen, and muscle relaxants.

[0114] Another preferred embodiment of the present invention relates to drugs for the prophylactic use and / or treatment of diseases related to the nervous system. Such drug substances are included in ATC Group N. Drug substances related to the nervous system include anesthetics, analgesics, antiepileptics, antiparkinsonian drug substances, psychotropic drugs, psychoanalgesics, and other drug substances having an effect on the nervous system. Some examples of drug substances and drug substance classes related to the nervous system include opioids, e.g., natural opium alkaloids like morphine, codeine, and oxycodone, and synthetic compounds like pethidine, ketobemidone, and fentanyl, antiepileptics, e.g., barbiturates, hydantoin derivatives, oxazolidine derivatives, succinimide derivatives, benzodiazepine derivatives, carboxamide derivatives, and fatty acid derivatives, antiparkinsonian drugs like anticholinergics and dopamine agonists, tranquilizer-like antipsychotics, anxiolytics and hypnotics and sedatives, psychostimulants like antidepressants, psychostimulants, drug substances used in ADHA, nootropics, psychostimulants, and anti-dementia drugs.

[0115] Another preferred embodiment of the present invention relates to drugs for the prophylactic use and / or treatment of diseases related to the respiratory system. Such drug substances are included in ATC group R. Drug substances related to the respiratory system include nasal compositions, throat compositions, drugs for the treatment of obstructive pulmonary diseases such as asthma and COPD, cough and cold compositions and antihistamines.

[0116] Another preferred embodiment of the present invention relates to drugs for prophylactic use and / or treatment of diseases in the ear and eye. Such drug substances are included in ATC Group S.

[0117] In particularly preferred embodiments, the at least one drug substance is selected from the group consisting of atorvastatin, simvastatin, losartan, valsartan, candesartan, enalapril, atenolol, propranolol, hydrochlorothiazide, cyclosporine, amphotericin B, diltiazem, phenoxymethylpenicillin, azithromycin, rapamycin, griseofulvin, chloramphenicol, erythromycin, acyclovir, nystatin, phenytoin, phenobarbital, ampicillin, celecoxib, prednisolone, and metformin.

[0118] A highly preferred embodiment of the present invention relates to a cCVD-SP comprising one or more active pharmaceutical ingredients, which active pharmaceutical ingredients are poorly soluble in water.

[0119] In particularly preferred embodiments of the present invention, the one or more active pharmaceutical ingredients are in the form of a complex with a cyclodextrin.

[0120] The most frequently used drug complexes in clinical applications are complexes with cyclodextrins. Cyclodextrins are cyclic oligosaccharides containing 6 to 8 glucose subunits. α (alpha)-cyclodextrin contains 6 glucose subunits, β (beta)-cyclodextrin contains 7 glucose subunits, and γ (gamma)-cyclodextrin contains 8 glucose subunits. Any cyclodextrin or derivative thereof can be used in the present invention. The most preferred cyclodextrins are β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and 4-sulfobutyl-β-cyclodextrin.

[0121] A preferred embodiment of the present invention relates to a cCVD-SP comprising one active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is in the form of a complex with cyclodextrin.

[0122] A more preferred embodiment of this aspect of the invention relates to a cCVD-SP comprising one active pharmaceutical ingredient, said active pharmaceutical ingredient being in the form of a complex with β-cyclodextrin or a derivative thereof.

[0123] An even more preferred embodiment of this aspect of the invention relates to a PcCVD-SP that includes one drug substance in the form of a complex with cyclodextrin β-cyclodextrin or a derivative thereof.

[0124] A preferred embodiment of the present invention relates to a cCVD-SP comprising two active pharmaceutical ingredients, at least one of which is in the form of a complex with a cyclodextrin.

[0125] A more preferred embodiment of this aspect of the invention relates to a PcCVD-SP which comprises two drug substances, at least one of which is in the form of a complex with β-cyclodextrin or a derivative thereof, as an LA-SP.

[0126] A preferred embodiment of the present invention relates to a cCVD-SP comprising three or more drug substances, at least one of which is in the form of a complex with a cyclodextrin.

[0127] A more preferred embodiment of this aspect of the invention relates to a PcCVD-SP which comprises three or more drug substances, at least one of which is in the form of a complex with β-cyclodextrin or a derivative thereof.

[0128] The present invention further relates to a method for preparing cCVD-SP or PcCVD-SP loaded with at least one drug cyclodextrin complex, comprising mixing the cCVD-SP or PcCVD-SP with at least one drug cyclodextrin complex at ambient temperature in a solvent in which the particles are dispersed and in which the drug cyclodextrin complex is at least partially soluble.

[0129] Another preferred method for preparing cCVD-SP or PcCVD-SP loaded with at least one drug-cyclodextrin complex is characterized by mixing the cCVD-SP or PcCVD-SP with cyclodextrin at ambient temperature in a solvent in which the particles are dispersed and in which the drug-cyclodextrin complex is at least partially soluble, optionally followed by isolating the particles, followed by forming a drug-cyclodextrin complex within the particles by mixing the cCVD-SP or PcCVD-SP with the drug substance in a solvent in which the particles are dispersed and in which the drug is at least partially soluble.

[0130] The silicon particles of the present invention preferably contain at least one drug substance in an amount of 5-50 wt%, more preferably 15-40 wt%, based on the total weight of the silicon particles. When more than one drug substance is present, it will be understood that these weight % ranges refer to the combined weight % of all drug substances present. Furthermore, when one or more of the drug substances is in the form of a cyclodextrin complex, the weight % ranges cited above should be based on the total weight of the cyclodextrin complex.

[0131] Composition and Use The present invention further relates to a pharmaceutical composition comprising silicon particles as defined above and one or more pharma- ceutically acceptable carriers, diluents or excipients, such carriers, diluents and excipients being well known in the art.

[0132] The excipients used in the pharmaceutical compositions of the present invention vary depending on the nature of the composition. In addition to water, excipients for suspensions of cCVD-SP or PcCVD-SP are typically selected from among sodium chloride or other physiologically acceptable salts, sugars, surfactants, antioxidants, flavors, sweeteners and pH adjusters.

[0133] Silicon particles and compositions thereof can be used in therapy, especially in drug delivery.Thus, the present invention relates to nanoparticles according to the present invention for use in therapy.In a further embodiment, the present invention relates to nanoparticles according to the present invention for use in the treatment or prevention or diagnosis of certain disorders and diseases.Examples of disorders or diseases that can be treated or prevented according to the present invention include cancers such as lung cancer, breast cancer, prostate cancer, brain cancer, head and neck cancer, ovarian cancer, skin cancer, testicular cancer, pancreatic cancer, colorectal cancer, kidney cancer, cervical cancer, gastrointestinal cancer, bladder cancer, and combinations thereof, pain-related diseases, diabetes, hypertension, and immune-related diseases.

[0134] The nanoparticles or compositions thereof are preferably administered in a therapeutically effective amount. A "therapeutically effective amount" refers to the amount of nanoparticles necessary to treat or prevent a particular disease or disorder. Any route of administration can be used to deliver the nanoparticles to a subject. Suitable routes of administration include intramuscular injection, transdermal administration, inhalation, topical application, oral administration, rectal or vaginal administration, intratumoral administration, and parenteral administration (e.g., intravenous, peritoneal, intraarterial, or subcutaneous). A preferred route of administration is injection.

[0135] For oral administration, aqueous suspensions, tablets and capsules are the most preferred formulations, and for dermal use, creams and ointments are the preferred pharmaceutical formulations.For injection, the most preferred injections are intravenous, intramuscular and subcutaneous injections.Injection formulations are typically in the form of sterile aqueous suspensions.Pulmonary formulations according to the present invention in the form of dry powder for inhalation are typically in the form of single or multiple doses, or in the form of a suspension of particles.Ophthalmic products are typically sterile aqueous suspensions of particles, while typical compositions for nasal administration can be dry particles or aqueous suspensions.

[0136] Typically, oral capsules containing cCVD-SP or PcCVD-SP are capsules prepared from gelatin or hydroxypropylmethylcellulose (HPMC).Typical excipients in such capsules include lactose, microcrystalline cellulose, and inorganic salts.

[0137] Typically, tablets containing cCVD-SP or PcCVD-SP can be instantaneous disintegrating tablets, controlled release tablets and sustained release tablets. Typical excipients in tablets include, for example, corn starch, lactose, glucose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.

[0138] The exact dosage and frequency of administration will depend, as is well known to those skilled in the art, on the particular nanoparticles used, the active agent and the optimal targeting agent, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of the disorder and general physical condition of the particular patient, as well as other medications that the individual may be taking. Furthermore, it will be apparent that the effective daily amount may be increased or decreased depending on the response of the subject being treated and / or depending on the evaluation of the physician prescribing the nanoparticles according to the present invention.

[0139] One embodiment of the present invention relates to a pharmaceutical composition comprising drug-loaded cCVD-SP or PcCVD-SP. The pharmaceutical composition may be any pharma- ceutical acceptable formulation, depending on the route of administration. For oral administration, aqueous suspensions, tablets and capsules are the most preferred formulations, and for dermatological use, creams and ointments are the preferred pharmaceutical formulations. For injection, the most preferred injections are intravenous, intramuscular and subcutaneous injections. The injectable formulations are typically in the form of a sterile aqueous suspension. Pulmonary formulations according to the present invention in the form of a dry powder for inhalation are typically in the form of a single or multiple dose, or in the form of a suspension of particles. Ophthalmic products are typically sterile aqueous suspensions of particles, while typical compositions for nasal administration may be dry particles or aqueous suspensions.

[0140] In one embodiment, the pharmaceutical composition is formulated for parenteral administration, such as injection or infusion.

[0141] One preferred embodiment of this aspect of the invention relates to a pharmaceutical composition comprising cCVD-SP or PcCVD-SP.

[0142] A more preferred embodiment of this aspect of the invention relates to pharmaceutical compositions comprising cCVD-SP or PcCVD-SP that contain at least one drug substance in the form of a free drug substance or a pharma- ceutically acceptable salt thereof.

[0143] An even more preferred embodiment of this aspect of the invention is where the pharmaceutical composition comprises cCVD-SP or PcCVD-SP containing at least one drug substance in the form of a free drug substance or, if the silicon is in amorphous form, a pharma- ceutically acceptable salt thereof.

[0144] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises a cCVD-SP containing at least one active ingredient in the form of a free active ingredient or a pharma- ceutically acceptable salt thereof, and the silicon is in amorphous form.

[0145] Another even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises a non-etched cPCVD-SP comprising at least one active ingredient in the form of a free active ingredient or a pharma- ceutically acceptable salt thereof, and the silicon is in amorphous form.

[0146] Another preferred embodiment of this aspect of the invention relates to a pharmaceutical composition comprising cCVD-SP or PcCVD-SP that contains at least one active pharmaceutical ingredient in the form of a cyclodextrin complex.

[0147] An even more preferred embodiment of this aspect of the invention relates to a pharmaceutical composition comprising cCVD-SP or PcCVD-SP which comprises at least one active pharmaceutical ingredient in the form of a cyclodextrin complex in which the silicon is in amorphous form.

[0148] A further preferred embodiment of this aspect of the invention relates to a pharmaceutical composition comprising cCVD-SP or PcCVD-SP which comprises at least one active pharmaceutical ingredient in the form of a cyclodextrin complex in which said silicon is in crystalline form.

[0149] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises a cCVD-SP which comprises at least one active pharmaceutical ingredient in the form of a cyclodextrin complex in which the silicon is in amorphous form.

[0150] Another preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises a cCVD-SP comprising at least one active pharmaceutical ingredient in the form of a cyclodextrin complex, wherein the silicon is in crystalline form.

[0151] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises cCVD-SP or PcCVD-SP containing at least one active pharmaceutical ingredient in the form of a β-cyclodextrin complex, and the silicon is in amorphous form.

[0152] A further preferred embodiment of this aspect of the invention is where the pharmaceutical composition comprises cCVD-SP or PcCVD-SP containing at least one active pharmaceutical ingredient in the form of a β-cyclodextrin complex, and the silicon is in crystalline form.

[0153] In one particularly preferred embodiment of the present invention, the pharmaceutical composition defined above is formulated for oral administration, for example as a tablet, capsule or suspension.

[0154] A more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises cCVD-SP or PcCVD-SP, which comprises at least one drug substance in the form of a free drug substance.

[0155] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises cCVD-SP or PcCVD-SP containing at least one drug substance in the form of a free drug substance, and the silicon is in amorphous form.

[0156] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises a cCVD-SP containing at least one drug substance in the form of a free drug substance, and the silicon is in amorphous form.

[0157] Another even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises a non-etched cPCVD-SP containing at least one drug substance in the form of a free drug substance, and the silicon is in amorphous form.

[0158] Another more preferred embodiment of this aspect of the invention is where the pharmaceutical composition comprises cCVD-SP or PcCVD-SP, which comprises at least one active pharmaceutical ingredient in the form of a cyclodextrin complex.

[0159] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises cCVD-SP or PcCVD-SP containing at least one active pharmaceutical ingredient in the form of a cyclodextrin complex, and the silicon is in amorphous form.

[0160] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises a cCVD-SP which comprises at least one active pharmaceutical ingredient in the form of a cyclodextrin complex in which the silicon is in amorphous form.

[0161] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises cCVD-SP or PcCVD-SP containing at least one active pharmaceutical ingredient in the form of a β-cyclodextrin complex, and the silicon is in amorphous form.

[0162] A further preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises a cCVD-SP that includes at least one active pharmaceutical ingredient in the form of an unsubstituted β-cyclodextrin complex.

[0163] A further preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises a non-etched PcCVD-SP that contains at least one active pharmaceutical ingredient in the form of an unsubstituted β-cyclodextrin complex.

[0164] An even more preferred embodiment of this aspect of the invention is where the pharmaceutical composition comprises a cCVD-SP containing at least one active pharmaceutical ingredient in the form of an unsubstituted β-cyclodextrin complex, a 2-hydroxypropyl-β-cyclodextrin complex, or a 4-sulfobutyl-β-cyclodextrin complex.

[0165] In an even more preferred embodiment of this aspect of the invention, the pharmaceutical composition comprises a non-etched cCVD-SP that includes at least one active pharmaceutical ingredient in the form of an unsubstituted β-cyclodextrin complex, a 2-hydroxypropyl-β-cyclodextrin complex, or a 4-sulfobutyl-β-cyclodextrin complex.

[0166] Most embodiments of this aspect of the invention are those in which the pharmaceutical composition comprises a cCVD-SP that includes at least one active pharmaceutical ingredient in the form of an unsubstituted β-cyclodextrin complex, a 2-hydroxypropyl-β-cyclodextrin complex, or a 4-sulfobutyl-β-cyclodextrin complex.

[0167] The BCS (Biopharmaceutic Classification System) is a system for distinguishing drugs based on their water solubility and oral permeability, and BCS Class II drug substances are compounds that have low water solubility but high oral permeability. See, e.g., Amidon GL, Lennernaes H, Shah VP, Crison JR (March 1995) "A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability" Pharm. Res. 12(3):413-20.

[0168] A highly preferred embodiment of this aspect of the invention relates to a pharmaceutical composition of cCVD-SP comprising a drug substance, wherein the drug substance is classified as BCS class II.

[0169] A further highly preferred embodiment of this aspect of the invention relates to a pharmaceutical composition of non-etched PcCVD-SP comprising a drug substance, said drug substance being classified as a BCS Class II drug substance.

[0170] Oral bioavailability of drug substances varies from nearly 0% to nearly 100%. Absolute bioavailability of some of the more frequently used drugs are: atorvastatin (12% bioavailability), simvastatin (less than 5% bioavailability), losartan (33% bioavailability), valsartan (25% bioavailability), candesartan (40% bioavailability), enalapril (60% bioavailability), atenolol (40-50% bioavailability), propranolol (26% bioavailability), hydrochlorothiazide (70% bioavailability), cyclosporine (very low bioavailability), amphotericin B (very low bioavailability), diltiazem (40% bioavailability), phenoxymethylpenicillin (50% bioavailability), azithromycin (40% bioavailability), and metformin (50-60% bioavailability).

[0171] In the context of formulating a pharmaceutical composition for oral administration, the following represent preferred embodiments.

[0172] Another highly preferred embodiment of the present invention relates to a pharmaceutical composition of cCVD-SP comprising a drug substance, the drug substance having a low oral bioavailability per se, typically less than 50%, more preferably less than 30%, more preferably less than 20%, and most preferably less than 10%.

[0173] A highly preferred embodiment of this aspect of the invention relates to a pharmaceutical composition of PcCVD-SP comprising a drug substance, the drug substance being a drug substance that has a low bioavailability per se, typically less than 50%, more preferably less than 30%, more preferably less than 20%, and most preferably less than 10%.

[0174] Another highly preferred embodiment of the present invention relates to pharmaceutical compositions of cCVD-SP that contain a drug substance that has very low aqueous solubility, typically less than 100 mg per liter, more preferably less than 50 mg per liter, even more preferably less than 10 mg per liter, and most preferably less than 5 mg per liter.

[0175] Another highly preferred embodiment of this aspect of the invention relates to pharmaceutical compositions of PcCVD-SP that contain a drug substance that has very low water solubility, typically less than 100 mg per liter, more preferably less than 50 mg per liter, even more preferably less than 10 mg per liter, and most preferably less than 5 mg per liter.

[0176] The list of drugs that are almost insoluble or have very low water solubility is extensive. Some examples of these well-known drugs that are in clinical use around the world include, but are not limited to, simvastatin, lovastatin, celecoxib, naproxen, ibuprofen, estradiol, testosterone, finasteride, glipizide, ketoconazole, methylprednisolone, mometolazone, triamcinolone, griseofulvin, and amphotericin B.

[0177] Another highly preferred embodiment of the present invention relates to a pharmaceutical composition of cCVD-SP comprising an active ingredient having a partition coefficient value (the amount of a substance that dissolves in the aqueous versus organic phase, giving a measure of its hydrophobic / hydrophilic properties), logP, greater than 2.5, more preferably greater than 3.0, even more preferably greater than 3.5, even more preferably greater than 4.0, and most preferably greater than 4.5.

[0178] Another highly preferred embodiment of this aspect of the invention relates to a pharmaceutical composition of PcCVD-SP comprising a drug substance having a log P of greater than 2.5, more preferably greater than 3.0, even more preferably greater than 3.5, even more preferably greater than 4.0, and most preferably greater than 4.5.

[0179] Some typical examples of well-known drugs in clinical use include the following drug substances with known high log P values: amiodarone (logP 7.81), amitriptyline (logP 4.41), amlodipine (logP 3.01), antazoline (logP 3.58), ariprazole (logP 3.76), atomoxetine (logP 3.36), bacampicillin (logP 3.52), benzphetamine (logP 3.84), benztropine (logP 4.04), bitolterol (logP 4.04), and ribavirin (logP 4.06). 4.16), bosentan (logP4.36), bromodiphenhydramine (logP4.03), brompheniramine (logP3.24), bufuralol (logP3.54), bupivacaine (logP3.31), butacaine (logP4.62), buclamol (logP3.81), butorphanol (logP3.54), carbenoxolone (logP6.63), carvedilol (logP4.11), Chlorcyclizine (logP 3.24), chlorpromazine (logP 5.35), chlorprothixene (logP 5.31), cinchonine (logP 3.69), citalopram (logP 3.47), clofibrate (logP 3.88), clopenthixol (logP 3.91), clotrimazole 4.92), clozapine (logP 3.94), cyclozocine (logP 3.52), cyclobenzaprine (logP 3.69), ogP6.19), cyproheptadine (logP4.92), darifenicin (logP4.92)P3.78), deserpidine (logP4.95), desipramine (logP3.97), desloratadine (logP3.50), dextrobrompheniramine (logP3.24), dextrofenfluramine (logP3.55), dextromethorphan (logP3.89), dibenzepine (logP3. 26), dibucaine (logP 4.40), diclofenac (logP 4.55), dicloxacillin (logP 3.10), dicyclomine (logP 4.64), diethadine (logP 5.55), diflunisal (logP 3.65), dihydroergocryptine (logP 6.37), dihydroergocristine (logP 6.55), dihydroergotamine (logP 5.69), dilevalol (logP 3.09), diltiazem (logP4.73), dimethisoquine (logP4.04), diperodone (logP4.65), diphenhydramine (logP3.27), difenoxin (logP3.97), diphenoxylate (logP4.51), diphenylpyraline (logP3.43), dipipanone (logP5.10), dipyridamole (logP3.35), donepezil (logP3.91), doxepin (logP3.85), droperidol (logP3.10), duloxetine (logP4.81), emetine (logP3.82), Enalapril (logP 3.25), enalaprilat (logP 3.63), entacapone (logP 3.02), ergotamine (logP 7.37), estrone (logP 3.62), ethopropazine (logP 4.77), etidocaine (logP 3.57), etomidate (logP 3.05), fenclofenac (logP 4.59), fenfluramine (logP 3.55), fenprofen (logP 3.72), fentanyl (logP 3.68), fesoterodine (logP 5.08), fexofenadine (logP 3.7 3), finasteride (logP 3.83), flurbiprofen (logP 3.66), fluphenaic acid (logP 5.22), flumisole (logP 4.26), fluoxetine (logP 3.93), flupentixol (logP 3.67), fluphenazine enanthate (logP 7.29), fluphenazine (logP 3.92), flurazepam (logP 4.84), flutamide (logP 3.52), fusidic acid (logP 5.76), fluvoxamine (logP 3.71), glibenclamide (logP 3.08), glyburide (logP 3.09), logP3.08), haloperidol (logP3.76), hexylcaine (logP3.65), hycanthone (logP3.81), ibuprofen (logP3.50), imipramine (logP4.35), indacaterol (logP3.88), indomethacin (logP4.25), iocetamic acid (logP4.57), iodipamide (logP5.10), iodoquinol (logP4.10), iopanoic acid (logP4.65), iprindole (logP5.02), irbesartan (logP5.25), ketamine (logP3.01), ketoconazole (logP 4.04), levallorphan (logP 3.85), liverphanol (logP 3.26), liothyronine (logP 3.91), lisinopril (logP 3.47), loperamide (logP 4.15), loratadine (logP 3.90), losartan (logP 3.46), maprotiline (logP 4.36), meclizine (logP 5.28), meclofenamic acid (logP 5.44), medazepam (logP 3.89), mefenamic acid (logP 4.83), mepazine (logP 5.04), methadone (lo gP3.93), methdilazine (logP4.64), methotrimeprazine (logP4.94), metolazone (logP3.16), miconazole (logP4.97), midazolam (logP3.80), montelukast (logP5.81), nabilone (logP7.25), nebivolol (logP4.08), nelfinavir (logP7.28), nortriptyline (logP3.97), novobiocin (logP3.74), olanzapine (logP3.08), orphenadrine (logP3.33), oxybutynin (logP5.0 5), oxyphenylbutazone (logP 3.28), pamaquine (logP 4.38), penbutolol (logP 4.02), pentazocine (logP 4.15), pergolide (logP 3.90), perphenazine (logP 3.94), perhexylene (logP 6.46), phencyclidine (logP 4.25), phenindamine (logP 3.81), phenindione (logP 3.19), phenothiazine (logP 4.15), phenoxybenzamine (logP 3.69), phentolamine (logP 4.08), phenylbutazone ( logP 3.38), phenyltoloxamine (logP 3.46), pimozide (logP 5.57), pipradrol (logP 3.61), pivampicillin (logP 3.88), plusgel (logP 4.31), prazepam (logP 3.70), prochlorperazine (logP 4.65), promazine (logP 4.69), promethazine (logP 4.89), proparasin (logP 3.46), propoxyphene 8LogP 4.10), pyrathiazine (logP 4.15), pyrobutamine (logP 4.57), quinacrine (logP 5.59), resperidone (logP 3.04), reserpine (logP 3.65), salmeterol (logP 3.71), salsalate (logP 3.29), sertraline (logP 5.08), solifenacin (logP 3.70), spiperone (logP 3.25), sufentanil (logP 3.95), sulfasalazine (logP 3.05), tamoxifen (logP 5.13), tetracaine (logP 3.75), tetrahydrocannabinol (logP 6.84), thiopropazinic acid (logP 4.76), thioridazine (logP 5.90), thiothixene (logP 3.72), L-tyrosine (logP 4.72), tiagabine (logP 4.03), ticlinfen (logP 3.05), trotelidin (logP 5.23), trifluoperazine (logP 4.62), triflupromazine (logP 5.16), trimeprazine (logP 5.04), trimipramine (logP 4.71), triprolidine (logP 3.25), troleandomycin (logP 3.46), vardanafil (logP 3.64), valsartan (logP 4.02), verapamil (logP 4.02), vinblastine (logP 5.92), vincristine (logP 5.75), vindesine (logP 4.94), warfarin (logP 3.13), and zimeldine (logP 3.07). All logP values ​​are calculated logP values ​​from Foye's Principles of Medicinal Chemistry. (Thomas L. Lemke, David A. Williams, Victoria F. Roche and S. William Zito), Seventh Edition, Lippincott Williams & Wilkins (2011).

[0180] [Brief description of the drawings] [Figure 1] Silicon particles with an average diameter of 300 nm produced by cCVD. [Figure 2] A silicon article with a primary particle size (median mean diameter) of about 30 nm. The dynamic light scattering (DLS) size of these particles is about 150 nm, and BET analysis gives an average particle size of about 40 nm. [Figure 3] SEM image of amorphous agglomerated cCVD Si particles.

[0023] FIG. 4: Rapamycin release versus time for Example 47.

[0023] FIG. 5: Rapamycin release versus time for Example 48.

[0023] FIG. 6: Rapamycin release versus time for Example 49.

[0023] FIG. 7. Rapamycin release versus time for Examples 50 and 51. [Figure 8] HPLC analysis / chromatogram for identification of rapamycin in Example 52, showing no degradation peaks.

[0181] The invention will now be described in more detail in the following non-limiting examples.

[0182] [Example] All silicon particles are produced by CVD in a reactor, the reactor comprising a reactor body and a rotation device operably disposed in the reactor, the rotation device configured to rotate the reactor about an axis during production in accordance with WO2013048258.

[0183] When used for the preparation of filled silicon particles, the mortar and pestle were cleaned in 2M sodium hydroxide and washed with water prior to the preparation of a new batch of silicon particles.

[0184] PDI is the polydispersity index.

[0185] All drug release experiments, except for the rapamycin experiments, were carried out with an excess of drug substance in purified water and the samples were rotated on a rotating table at room temperature.

[0186] Samples for HPLC analysis were centrifuged at 13,000 rpm for 30 minutes prior to further sample preparation.

[0187] [Intermediate 1 Atorvastatin calcium 2-hydroxypropyl-β-cyclodextrin complex (1:4.2)] Atorvastatin calcium (DDL, 559 mg, 0.48 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Aldrich, mw 1380, 2.76 g, 2 mmol) were mixed volumetrically in a mortar. A mixture of water / ethanol (1:1 (v / v)) was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 50° C. A white powder containing 17% (w / w) atorvastatin calcium was isolated.

[0188] [Intermediate 2 Griseofulvin 2-hydroxypropyl-β-cyclodextrin complex (1:3)] Griseofulvin (DDL, 352 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 4.38 g, 3 mmol) were mixed volumetrically in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 7.4% (w / w) griseofulvin was isolated.

[0189] [Intermediate 3: Chloramphenicol 2-hydroxypropyl-β-cyclodextrin complex (1:3)] Chloramphenicol (DDL, 323 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 4.38 g, 3 mmol) were mixed volumetrically in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder was isolated containing 6.9% (w / w) chloramphenicol.

[0190] [Intermediate 4 Erythromycin 2-hydroxypropyl-β-cyclodextrin complex (1:3)] Erythromycin (DDL, 733 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 4.38 g, 3 mmol) were mixed volumetrically in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 14.3% (w / w) erythromycin was isolated.

[0191] [Intermediate 5 Losartan potassium 2-hydroxypropyl-β-cyclodextrin complex (1:3)] Losartan potassium (DDL, 461 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 4.38 g, 3 mmol) were volumetrically mixed in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 9.5% (w / w) losartan potassium was isolated.

[0192] [Intermediate 6 Atorvastatin calcium 2-hydroxypropyl-β-cyclodextrin complex (1:3)] Atorvastatin calcium (DDL, 461 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 4.38 g, 3 mmol) were volumetrically mixed in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder was isolated containing 20.9% (w / w) atorvastatin calcium.

[0193] [Intermediate 7 Acyclovir 2-hydroxypropyl-β-cyclodextrin complex (1:1)] Acyclovir (DDL, 225 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 1.46 g, 1 mmol) were mixed volumetrically in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60°C. A white powder containing 13.4% (w / w) acyclovir was isolated.

[0194] [Intermediate 8 Nystatin 2-hydroxypropyl-β-cyclodextrin complex (1:1)] Nystatin (DDL, 773 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 1.46 g, 1 mmol) were volumetrically mixed in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 32.4% (w / w) nystatin was isolated.

[0195] [Intermediate 9 Celecoxib 2-hydroxypropyl-β-cyclodextrin complex (1:1)] Celecoxib (DDL, 381 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 1.46 g, 1 mmol) were volumetrically mixed in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 20.7% (w / w) celecoxib was isolated.

[0196] [Intermediate 10 Erythromycin 2-hydroxypropyl-β-cyclodextrin complex (1:1)] Erythromycin (DDL, 733 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 1.46 g, 1 mmol) were mixed volumetrically in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 33.4% (w / w) erythromycin was isolated.

[0197] [Intermediate 11 Griseofulvin 2-hydroxypropyl-β-cyclodextrin complex (1:1)] Grisofulvin (Sigma Aldrich, 352 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 1.46 g, 1 mmol) were mixed volumetrically in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 19.4% (w / w) griseofulvin was isolated.

[0198] [Intermediate 12 Griseofulvin 2-hydroxypropyl-β-cyclodextrin complex (1:2)] Grisofulvin (Sigma Aldrich, 176 mg, 0.5 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 1.46 g, 1 mmol) were mixed volumetrically in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 10.8% (w / w) griseofulvin was isolated.

[0199] [Intermediate 13 Phenytoin 2-hydroxypropyl-β-cyclodextrin complex (1:1.2)] Phenytoin (DDL, 252 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 1.752 g, 1.2 mmol) were volumetrically mixed in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 12.6% (w / w) phenytoin was isolated.

[0200] [Intermediate 14 Phenobarbital 2-hydroxypropyl-β-cyclodextrin complex (1:1.2)] Phenobarbital (DDL, 232 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 1.752 g, 1.2 mmol) were mixed volumetrically in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder was isolated containing 11.7% (w / w) phenobarbital.

[0201] [Intermediate 15 Phenytoin 2-hydroxypropyl-β-cyclodextrin complex (1:1.2)] Phenytoin (DDL, 252 mg, 1 mmol) and 2-hydroxy-propyl-β-cyclodextrin (Biosynth Carbosynth, 1.752 g, 1.2 mmol) were volumetrically mixed in a mortar. Absolute alcohol (3 mL) was added and the mixture was stirred for 5 minutes and dried at 60° C. overnight. A white powder containing 12.6% (w / w) phenytoin was isolated.

[0202] [Intermediate 16 Amphotericin B γ-cyclodextrin (1:1.2)] Amphotericin B (DDL, 924 mg, 1 mmol) and gamma-cyclodextrin (Cavamax W8, 1.556 g, 1.2 mmol) were volumetrically mixed in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A yellow powder containing 37.3% (w / w) amphotericin B was isolated.

[0203] [Intermediate 17 Tetracycline hydrochloride methyl-β-cyclodextrin complex (1:1.5)] Tetracycline hydrochloride (DDL, 96 mg, 0.2 mmol) and methyl-β-cyclodextrin (Aldrich, 396 mg, 0.3 mmol) were volumetrically mixed in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60°C. A pale grey-green powder was isolated containing 19.5% (w / w) tetracycline hydrochloride.

[0204] [Intermediate 18 Cytarabine β-cyclodextrin complex (1:1.5)] Cytarabine (DDL, 243 mg, 1 mmol) and β-cyclodextrin (DDL, 2.003 g, 1.5 mmol) were volumetrically mixed in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60°C. A white powder containing 10.8% (w / w) cytarabine was isolated.

[0205] [Intermediate 19 Amoxicillin β-cyclodextrin complex (1:1.5)] Amoxicillin trihydrate (DDL, 420 mg, 1 mmol) and β-cyclodextrin (DDL, 2.003 g, 1.5 mmol) were mixed volumetrically in a mortar. Water was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60°C. A white powder was isolated containing approximately 17% (w / w) amoxicillin.

[0206] [Intermediate 20 Phenytoin 4-sulfobutyric acid-β-cyclodextrin complex (1:1.2)] Phenytoin (DDL, 232 mg, 1 mmol) and 4-sulfobutyric-β-cyclodextrin (Biosynth Carbosynth, 2.69 grams, 1.2 mmol) were mixed volumetrically in a mortar. Water / ethanol (1:1 (v / v)) was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 8.6% (w / w) phenytoin was isolated.

[0207] [Intermediate 21: Phenobarbital 4-sulfobutyric acid-β-cyclodextrin complex (1:1.2)] Phenobarbital (DDL, 252 mg, 1 mmol) and 4-sulfobutan-β-cyclodextrin (Biosynth Carbosynth, 2.69 grams, 1.2 mmol) were mixed volumetrically in a mortar. Water / ethanol (1:1 (v / v)) was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder was isolated containing 7.9% (w / w) phenobarbital.

[0208] [Intermediate 22 Griseofulvin 4-sulfobutyl-β-cyclodextrin complex (1:1.2)] Griseofulvin (Sigma Aldrich, 352 mg, 1 mmol) and 4-sulfobuyl-β-cyclodextrin (Biosynth Carbosynth, 2.69 grams, 1.2 mmol) were mixed volumetrically in a mortar. Water / ethanol (1:1 (v / v)) was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder containing 11.6% (w / w) griseofulvin was isolated.

[0209] [Intermediate 23 Prednisolone 4-sulfobutyl-β-cyclodextrin complex (1:1.2)] Prednisolone (Sigma Aldrich, 360 mg, 1 mmol) and 4-sulfobutyric-β-cyclodextrin (Biosynth Carbosynth, 2.69 grams, 1.2 mmol) were mixed volumetrically in a mortar. Water / ethanol (1:1 (v / v)) was added and a viscous paste was obtained using a mortar and pestle. The paste was mixed for 5 minutes and dried overnight at 60° C. A white powder was isolated containing 11.8% (w / w) prednisolone.

[0210] [Intermediate 24 Rapamycin β-cyclodextrin complex (1:2)] Rapamycin (MedChem express, 100 mg) and 2-hydroxypropyl-β-cyclodextrin (Aldrich, 320 mg) were mixed volumetrically in a mortar with a pestle for 5 minutes with the addition of a few drops of water to obtain a viscous paste. The paste was dried overnight under vacuum at room temperature. A white powder containing 23.8% (w / w) rapamycin was isolated.

[0211] [Intermediate 25: Preparation of aggregated amorphous cCVD-SP] The agglomerated amorphous cCVD-SP-like H18 particles are produced by CVD in a reactor, the reactor comprising a reactor body and a rotating device operably disposed in the reactor, the rotating device configured to rotate the reactor about an axis during production in accordance with WO2013048258. The preparation process of stable agglomerates such as particles type H18, which are not free non-agglomerated particles, involves the control of process parameters as described below. Silanes begin to decompose at about 400°C. The process is a stepwise process in which silanes decompose to form higher silanes, which in turn form rings and stacks. When the higher silanes start stacking into 3d structures, they are classified as nuclei that capture silanes and grow into larger particles. Depending on the growth rate, these particles can grow faster than they can release hydrogen, and thus they constitute both silicon and hydrogenated silicon, where the gradient of hydrogen content is greater toward the surface. The growth rate is high, but if the surface is kept cool, the hydrogenated silicon surface is sticky and collisions between particles lead to agglomeration. Therefore, to intentionally form aggregates, it is important to have a process that keeps the growth rate high, hydrogen release slow, and the number of particles per volume high, with a substantial residence time that allows many particle collisions before the process is stopped and the particles are collected.

[0212] [Example 1] Amorphous cCVD-SP containing atorvastatin calcium Atorvastatin β-cyclodextrin complex (intermediate 1, 500 mg) was dissolved in ethanol (10 mL). Silicon particles (batch R1F1, amorphous silicon mean diameter 554 nm, PDI 0.164, 50 mg) were suspended in 1 mL of ethanol solution containing atorvastatin β-cyclodextrin complex (intermediate 1) in a microcentrifuge vial. The mixture was sonicated for 10 min in a 70 °C sonicator bath, centrifuged (14 000X, 8 min) and dried at 60 °C until constant weight. The weight was 32 mg higher than the reference sample (same particles treated by pure water). The product contained about 39% atorvastatin β-cyclodextrin complex.

[0213] [Example 2 Amorphous cCVD-SP containing metformin hydrochloride] Metformin hydrochloride (European Pharmacopoeia, Weifa, 1.5 g) was dissolved in water (10 mL). Silicon particles (50 mg of batch R1F1, amorphous silicon, average diameter 554 nm, PDI 0.164) were suspended in 1 mL of an aqueous solution containing metformin hydrochloride in a microcentrifuge vial. The mixture was sonicated for 10 min in a sonicator bath at 70 °C, centrifuged (14 000X, 8 min) and dried at 60 °C until constant weight. The weight was 24 mg higher than the reference sample (same particles treated with pure water). The product contained about 32% metformin hydrochloride.

[0214] [Example 3 Amorphous cCVD-SP containing metformin losartan potassium] Losartan potassium (DDL, 1.5 g) was dissolved in water (10 mL). Silicon particles (batch R1F1, amorphous silicon, mean diameter 554 nm, PDI 0.164, 50 mg) were suspended in 1 mL of aqueous solution containing Losartan potassium in a microcentrifuge vial. The mixture was sonicated for 10 min in a 70 °C sonicator bath, centrifuged (14 000X, 8 min) and dried at 60 °C until constant weight. The weight was 16 mg higher than the reference sample (same particles treated by pure water). The product contained about 24% atorvastatin β-cyclodextrin complex.

[0215] [Example 4] Crystalline cCVD-SP containing atorvastatin calcium Atorvastatin-2-hydroxypropyl β-cyclodextrin complex (intermediate 1, 500 mg) was dissolved in ethanol (10 mL). Silicon particles (batch R4F1, crystalline silicon, average diameter 117 nm, PDI 0.277, 50 mg) were suspended in 1 mL of ethanol solution containing atorvastatin β-cyclodextrin complex in a microcentrifuge vial. The mixture was sonicated for 10 min in a 70 °C sonicator bath, centrifuged (14 000X, 8 min) and dried at 60 °C until constant weight. The weight was 10 mg higher than the reference sample (same particles treated by pure water). The product contained about 17% atorvastatin β-cyclodextrin complex.

[0216] [Example 5 Crystalline cCVD-SP containing metformin hydrochloride] Metformin hydrochloride (European Pharmacopoeia, Weifa, 1.5 g) was dissolved in water (10 mL). Silicon particles (batch R4F1, crystalline silicon, mean diameter 117 nm, PDI 0.277, 50 mg) were suspended in 1 mL of aqueous solution containing metformin hydrochloride in a microcentrifuge vial. The mixture was sonicated for 10 min in a 70 °C sonicator bath, centrifuged (14 000X, 8 min) and dried at 60 °C until constant weight. The weight was 12 mg higher than the reference sample (same particles treated by pure water). The product contained about 19% metformin hydrochloride.

[0217] [Example 6 Amorphous cCVD-SP containing Losartan Potassium] Losartan potassium (DDL, 1.5 g) was dissolved in water (10 mL). Porous silicon particles (batch R1F1, amorphous silicon, mean diameter 554 nm, PDI 0.164, 50 mg) were suspended in 1 mL of aqueous solution containing losartan potassium in a microcentrifuge vial. The mixture was sonicated for 10 min in a 70 °C sonicator bath, centrifuged (14 000X, 8 min) and dried at 60 °C until constant weight. The weight was 29 mg higher than the reference sample (same particles treated with pure water). The product contained 37% losartan potassium.

[0218] Example 7 Amorphous cCVD-SP Aggregates Containing Griseofulvin Griseofulvin (DDL, 50 mg) was dissolved in dimethylformamide (DMF) (0.5 mL). This solution was added dropwise to amorphous silicon particles (450 mg) in a mortar. The particles were in the form of stable aggregates (batch number H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried in a high vacuum oven at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w griseofulvin.

[0219] [Example 8 Amorphous cCVD-SP containing griseofulvin] Griseofulvin (DDL, 50 mg) was dissolved in dimethylformamide (DMF) (0.5 mL). This solution was added dropwise to amorphous silicon particles (batch number R8F2, 450 mg) in a mortar. The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried in a high vacuum oven at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w griseofulvin.

[0220] [Example 9] Amorphous cCVD-SP containing griseofulvin Griseofulvin (DDL, 50 mg) was dissolved in dimethylformamide (DMF) (0.5 mL). This solution was added dropwise to amorphous silicon particles (batch number F26F2, SEM size 200-400 nM, 450 mg) in a mortar. The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried in a high vacuum oven at 50 °C for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w griseofulvin.

[0221] [Example 10 Amorphous cCVD-SP containing erythromycin] Erythromycin (DDL, 100 mg) was dissolved in dimethylformamide (DMF) (1 mL). This solution was added dropwise to amorphous silicon particles (batch number R8F2, 900 mg) in a mortar. The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar with the pestle was dried in a high vacuum oven at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w erythromycin.

[0222] The release of erythromycin from the particles into water was studied over time using HPLC.

[0223] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01MK2HPO4, Flow rate: 1 mL / min, Injection volume 10 μL, Detection wavelength: 286 nm, Run time: 12 min.

[0224] The release of erythromycin from the particles at 2 hours was 290% compared to the release from free erythromycin powder.

[0225] [Example 11 Amorphous cCVD-SP containing erythromycin] Erythromycin (100 mg) was dissolved in dimethylformamide (DMF) (1 mL). The solution was added dropwise to amorphous silicon particles (batch number F26F2 SEM size 200-400 nM, 900 mg) in a mortar. The silicon particle size was 100-300 nm. The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar with the pestle was dried in a high vacuum oven at 50 °C for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w erythromycin.

[0226] (A new batch of silicon particles was prepared after cleaning the mortar and pestle in 2M sodium hydroxide and washing with water.)

[0227] The release of erythromycin from the particles into water was studied over time using HPLC.

[0228] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01MK2HPO4, Flow rate: 1 mL / min, Injection volume 10 μL, Detection wavelength: 286 nm, Run time: 12 min.

[0229] The release of erythromycin from the particles at 2 hours was 258% compared to the release from free erythromycin powder.

[0230] [Example 12 Amorphous cCVD-SP containing erythromycin] Erythromycin (300 mg) was dissolved in dimethylformamide (DMF) (1.5 mL). This solution was added dropwise to amorphous silicon particles (batch number F26F2, SEM size 200-400 nM, 900 mg) in a mortar. Silicon particle size was 100-300 nm. More DMF (3 mL) was added to the mixture to ensure good contact with the fluffy particles and stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar with the pestle was dried in a high vacuum oven at 50 °C for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w erythromycin.

[0231] The release of erythromycin from the particles into water was studied over time using HPLC.

[0232] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01MK2HPO4, Flow rate: 1 mL / min, Injection volume 10 μL, Detection wavelength: 286 nm, Run time: 12 min.

[0233] The release of erythromycin from the particles at 2 hours was 261% compared to the release from free erythromycin powder.

[0234] Example 13 Amorphous cCVD-SP Aggregates Containing Erythromycin Erythromycin (50 mg) was dissolved in dimethylformamide (DMF) (0.5 mL). This solution was added dropwise to amorphous silicon particles (450 mg) in a mortar. The particles were in the form of stable aggregates (batch number H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried in a high vacuum oven at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w erythromycin.

[0235] The release of erythromycin from the particles into water was studied over time using HPLC.

[0236] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01MK2HPO4, Flow rate: 1 mL / min, Injection volume 10 μL, Detection wavelength: 286 nm, Run time: 12 min.

[0237] The release of erythromycin from the particles at 2 hours was 219% compared to the release from free erythromycin powder.

[0238] Example 14 Amorphous cCVD-SP Aggregates Containing Griseofulvin-2-Hydroxypropyl-β-Cyclodextrin Griseofulvin-2-hydroxypropyl-β-cyclodextrin (Intermediate 2, 50 mg) was dissolved in dimethylformamide (DMF) (0.5 mL). This solution was added dropwise to the amorphous silicon particles (450 mg) in a mortar. The particles were in the form of stable aggregates (Batch no. H18). Average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried in a high vacuum oven at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 0.74% w / w griseofulvin.

[0239] [Example 15 Amorphous cCVS-SP Aggregates Containing Erythromycin-2-hydroxypropyl-β-cyclodextrion] Erythromycin-2-hydroxypropyl-β-cyclodextrin (Intermediate 10, 50 mg) was dissolved in absolute ethanol (0.5 mL). This solution was added dropwise to the amorphous silicon particles (450 mg) in a mortar. The particles were in the form of stable aggregates (Batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The pestle together with the pestle were dried at 60° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 0.74% w / w erythromycin.

[0240] Example 16 Amorphous cCVD-SP Aggregates Containing Griseofulvin-2-Hydroxypropyl-β-Cyclodextrin Griseofulvin-2-hydroxypropyl-β-cyclodextrin (Intermediate 11, 50 mg) was dissolved in absolute ethanol (1 mL) by heating. This solution was added dropwise to amorphous silicon particles (450 mg) in a mortar. The particles were in the form of aggregates (Batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried in a high vacuum oven at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 1.94% w / w griseofulvin.

[0241] The release of griseofulvin from the particles into water was studied over time using HPLC.

[0242] HPLC system: HP1100. Column: PLRP-S, 2.1×50 mm, 3 um, Mobile phase: 40% acetonitrile and 0.1% HCOOH, Flow rate: 0.2 mL / min, Injection volume: 2.4 μL, Detection wavelength: 286 nm, Run time: 8 min.

[0243] The release of griseofulvin from the particles at 2 hours was 99% compared to that from free griseofulvin powder.The release of griseofulvin from the particles at 2 hours was 96% compared to that from free griseofulvin-2-hydroxypropyl-β-cyclodextrin powder (Intermediate 11).

[0244] Example 17 Amorphous cCVD-SP Aggregates Containing Griseofulvin-2-Hydroxypropyl-β-Cyclodextrin Griseofulvin-2-hydroxypropyl-β-cyclodextrin (Intermediate 11, 50 mg) was dissolved in dimethylformamide (0.5 mL). This solution was added dropwise to the amorphous silicon particles (450 mg) in a mortar. The particles were in the form of stable aggregates (Batch no. H18 average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried in a high vacuum oven at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w griseofulvin-2-hydroxypropyl-β-cyclodextrin.

[0245] The release of griseofulvin from the particles into water was studied over time using HPLC.

[0246] HPLC system: HP1100. Column: PLRP-S, 2.1×50 mm, 3 um, Mobile phase: 40% acetonitrile and 0.1% HCOOH, Flow rate: 0.2 mL / min, Injection volume: 2.4 μL, Detection wavelength: 286 nm, Run time: 8 min.

[0247] The release of griseofulvin from the particles at 2 hours was 130% compared to the release from free griseofulvin powder.The release of griseofulvin from the particles at 2 hours was 125% compared to the release from free griseofulvin-2-hydroxypropyl-β-cyclodextrin powder (Intermediate 11).

[0248] Example 18 Amorphous cCVD-SP Aggregates Containing Griseofulvin Griseofulvin (SigmaAldrich, 50 mg) was dissolved in dimethylformamide (0.5 mL). This solution was added dropwise to amorphous silicon particles (450 mg) in a mortar. The particles were in the form of aggregates (batch no. H18 average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried in a high vacuum oven at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w griseofulvin.

[0249] The release of griseofulvin from the particles into water was studied over time using HPLC.

[0250] HPLC system: HP1100. Column: PLRP-S, 2.1×50 mm, 3 um, Mobile phase: 40% acetonitrile and 0.1% HCOOH, Flow rate: 0.2 mL / min, Injection volume: 2.4 μL, Detection wavelength: 286 nm, Run time: 8 min.

[0251] The release of griseofulvin from the particles at 2 hours was 109% compared to the release from free griseofulvin powder.

[0252] Example 19 Amorphous cCVD-SP Aggregates Containing Erythromycin-2-Hydroxypropyl-β-Cyclodextrin Erythromycin-2-hydroxypropyl-β-cyclodextrin (Intermediate 10, 100 mg) was dissolved in dimethylformamide (0.5 mL). The solution was added dropwise to the amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (Batch no. H18 average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar with the pestle was dried in a high vacuum oven at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 6.7% w / w erythromycin.

[0253] The release of erythromycin from the particles into water was studied over time using HPLC.

[0254] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01MK2HPO4, Flow rate: 1 mL / min, Injection volume 10 μL, Detection wavelength: 286 nm, Run time: 12 min.

[0255] The release of erythromycin from the particles at 2 hours was 291% compared to the release from free erythromycin powder.The release of erythromycin from the particles at 2 hours was 470% compared to the release from free erythromycin-2-hydroxypropyl-β-cyclodextrin (Intermediate 10).

[0256] Example 20 Amorphous cCVD-SP Aggregates Containing Cyclosporine and Additives Cyclosporine was extracted from the capsules together with pharmaceutical excipients (4 Sandumun Neooral 25 mg / Novartis). The capsules were opened and extracted with absolute alcohol (5 mL). The alcohol was evaporated and the final solution was dissolved in absolute alcohol (2 mL) and added dropwise to the amorphous silicon particles (400 mg) in the mortar. The particles were in the form of aggregates (batch number H18 average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mixture was dried together with the pestle at 60° C. for 24 hours. The granular material was scraped off from the mortar. The granular material contained about 25% w / w cyclosporine with some excipients from the Neooral formulation.

[0257] Example 21 Amorphous cCVD-SP Aggregates Containing Acyclovir-2-Hydroxypropyl-β-Cyclodextrin Acyclovir-2-hydroxypropyl-β-cyclodextrin (Intermediate 7, 100 mg) was dissolved in absolute ethanol (1.2 mL) by heating. The solution was added dropwise to the amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (Batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The pestle together with the pestle were dried at 60° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w of acyclovir-2-hydroxypropyl-β-cyclodextrin (1:1).

[0258] Example 22 Amorphous cCVD-SP Aggregates Containing Celecoxib Celecoxib (DDL, 100 mg) was dissolved in absolute ethanol (0.7 mL). This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (Batch no. H18 average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The pestle together with the pestle were dried at 60° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% celecoxib.

[0259] The release of celecoxib from the particles into water was studied over time using HPLC.

[0260] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250mm, 5um, Mobile phase: 80% methanol and 20% 0.01M K2HPO4, Flow rate: 1mL / min, Injection volume 5ul, Detection wavelength 250nm, Run time: 7min.

[0261] The release of celecoxib from the particles at 2 and 4 hours was 2.1-fold higher than the free celecoxib powder.

[0262] The release of celecoxib from the particles at 6 hours was 2.0-fold higher than the free celecoxib powder.

[0263] Example 23 Amorphous cCVD-SP Aggregates Containing Griseofulvin Griseofulvin (SigmaAldrich, 200 mg) was dissolved in dimethylformamide (0.7 mL). This solution was added dropwise to amorphous silicon particles (200 mg) in a mortar. The particles were in the form of aggregates (batch number H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 50% w / w griseofulvin.

[0264] The release of griseofulvin from the particles into water was studied over time using HPLC.

[0265] HPLC system: HP1100. Column: PLRP-S, 2.1×50 mm, 3 um, Mobile phase: 40% acetonitrile and 0.1% HCOOH, Flow rate: 0.2 mL / min, Injection volume: 2.4 μL, Detection wavelength: 286 nm, Run time: 8 min.

[0266] The release of griseofulvin from the particles at 2 hours was 70% compared to the release from free griseofulvin powder.

[0267] [Example 24 Amorphous cCVD-SP Aggregates Containing Atorvastatin-2-hydroxypropyl-β-cyclodextrin] Atorvastatin-2-hydroxypropyl-β-cyclodextrin (Intermediate 6, 100 mg) was dissolved in dimethylformamide (0.7 mL) by heating. The solution was added dropwise to the amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (Batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w of atorvastatin calcium-2-hydroxypropyl-β-cyclodextrin (1:1).

[0268] The release of atorvastatin from the particles into water was studied over time using HPLC.

[0269] HPLC system: HP1100. Column: PLRP-S, 2.1×50 mm, 3 um, Mobile phase: 40% acetonitrile and 0.1% HCOOH, Flow rate: 0.2 mL / min, Injection volume: 2.4 μL, Detection wavelength: 240 nm, Run time: 3 min.

[0270] The release of atorvastatin from the particles in 2 hours was 140% compared to the release from free atorvastatin powder.The release of atorvastatin from the particles in 2 hours was 140% compared to the release from free atorvastatin-2-hydroxypropyl-β-cyclodextrin (Intermediate 6).

[0271] Example 25 Amorphous cCVD-SP Aggregates Containing Nystatin-2-Hydroxypropyl-β-Cyclodextrin Nystatin-2-hydroxypropyl-β-cyclodextrin (Intermediate 8, 100 mg) was dissolved in dimethylformamide (0.6 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (Batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w nystatin-2-hydroxypropyl-β-cyclodextrin (1:1).

[0272] [Example 26 Amorphous cCVD-SP Aggregates Containing Losartan-2-Hydroxypropyl-β-Cyclodextrin] Losartan-2-hydroxypropyl-β-cyclodextrin (Intermediate 5, 100 mg) was dissolved in dimethylformamide (0.7 mL) by heating. The solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (Batch no. H18 average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w of Losartan potassium-2-hydroxypropyl-β-cyclodextrin (1:3).

[0273] The release of losartan from the particles into water was studied over time using HPLC.

[0274] HPLC system: HP1100. Column: PLRP-S, 2.1×50 mm, 3 um, Mobile phase: 40% acetonitrile and 0.1% HCOOH, Flow rate: 0.2 mL / min, Injection volume: 2.4 μL, Detection wavelength: 226 nm, Run time: 5 min.

[0275] The release of losartan from the particles at 2 hours was 56% compared to the release from free losartan potassium powder. The release of losartan from the particles at 2 hours was 70% compared to the release from free losartan-2-hydroxypropyl-β-cyclodextrin (intermediate 5) powder.

[0276] [Example 27 Amorphous cCVD-SP aggregates containing acyclovir] Acyclovir (DDL, 100 mg) was dissolved in dimethylsulfoxide (0.5 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w acyclovir.

[0277] [Example 28 Amorphous cCVD-SP Aggregates Containing Chloramphenicol] Chloramphenicol (SigmaAldrich, 100 mg) was dissolved in dimethylsulfoxide (0.5 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (batch number H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w chloramphenicol.

[0278] The release of chloramphenicol from the particles into water was studied over time using HPLC.

[0279] HPLC system: HP1100. Column: PLRP-S, 2.1×50 mm, 3 um, mobile phase: 40% acetonitrile and 0.1% HCOOH, flow rate: 0.2 mL / min, injection volume 2.4 μL, detection wavelength: 278 nm, run time: 12 min.

[0280] The release of chloramphenicol from the particles at 2 hours was 63% compared to the release from the free chloramphenicol powder. The release of chloramphenicol from the particles at 4 hours was 59% compared to the release from the free chloramphenicol powder. The release of chloramphenicol from the particles at 5 hours was 57% compared to the release from the free chloramphenicol powder.

[0281] [Example 29 Crystalline cCVD-SP containing chloramphenicol] Chloramphenicol (SigmaAldrich, 200 mg) was dissolved in dimenthyl sulfoxide (0.7 mL) by heating. This solution was added dropwise to crystalline silicon particles (800 mg, batch number R5F3, average particle size 2332 nM, PDI 0.407) in a mortar. The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w chloramphenicol.

[0282] The release of chloramphenicol from the particles into water was studied over time using HPLC.

[0283] HPLC system: HP1100. Column: PLRP-S, 2.1×50 mm, 3 um, Mobile phase: 40% acetonitrile and 0.1% HCOOH, Flow rate: 0.2 mL / min, Injection volume: 2.4 μL, Detection wavelength: 278 nm, Run time: 12 min.

[0284] The release of chloramphenicol from the particles at 2 hours was 85% compared to the release from the free chloramphenicol powder. The release of chloramphenicol from the particles at 4 hours was 98% compared to the release from the free chloramphenicol powder. The release of chloramphenicol from the particles at 5 hours was 100% compared to the release from the free chloramphenicol powder.

[0285] [Example 30 Crystalline cCVD-SP containing prednisolone] Prednisolone (SigmaAldrich, 200 mg) was dissolved in dimethylformamide (1.0 mL) by heating. This solution was added dropwise to crystalline silicon particles (800 mg, batch number R5F3, average particle size 2332 nm, PDI 0.407) in a mortar. The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w prednisolone.

[0286] [Example 31] Acyclovir-containing crystalline cCVD-SP Acyclovir (DDL, 200 mg) was dissolved in dimethyl sulfoxide (1.0 mL) by heating. This solution was added dropwise to crystalline silicon particles (800 mg, batch number R5F3, average particle size 2332 nm, PDI 0.407) in a mortar. The particle size was 100-300 nm. The mixture was stirred in the mortar with a pestle for 5 min to form a paste. The mortar together with the pestle was dried under high vacuum at 50 °C for 24 h. The dried particles were scraped off from the mortar. The particles contained 20% w / w acyclovir.

[0287] Example 32 Amorphous cCVD-SP Aggregates Containing Phenytoin Phenytoin (DDL, 100 mg) was dissolved in dimethylformamide (0.5 mL) by heating. This solution was added dropwise to amorphous silicon particles (900 mg) in a mortar. The particles were in the form of stable amorphous aggregates (batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w phenytoin.

[0288] The release of phenytoin from the particles into water was studied over time using HPLC.

[0289] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 50% acetonitrile, Flow rate: 1 mL / min, Injection 5 μL, Detection wavelengths: 210 and 200 nm, Run time: 6 min.

[0290] The release of phenytoin from the particles at 2 hours was 134% compared to the release from the free phenytoin powder.

[0291] [Example 33 Amorphous cCVD-SP Aggregates Containing Phenobarbital] Phenobarbital (DDL, 100 mg) was dissolved in dimethylformamide (0.7 mL) by heating. This solution was added dropwise to amorphous silicon particles (900 mg) in a mortar. The particles were in the form of stable aggregates (batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w phenobarbital.

[0292] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 50% acetonitrile, Flow rate: 1 mL / min, Injection 5 μL, Detection wavelengths: 210 and 200 nm, Run time: 6 min.

[0293] The release of phenobarbital from the particles at 2 hours was 174% compared to the release from free phenobarbital powder.

[0294] Example 34 Amorphous cCVD-SP Aggregates Containing Phenytoin 2-Hydroxypropyl-β-Cyclodextrin Complex Phenytoin 2-hydroxypropyl-β-cyclodextrin complex (Intermediate 15, 100 mg) was dissolved in dimethylformamide (0.6 mL) by heating. This solution was added dropwise to amorphous silicon particles (900 mg) in a mortar. The particles were in the form of stable aggregates (Batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 2.5% w / w phenytoin.

[0295] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 50% acetonitrile, Flow rate: 1 mL / min, Injection 5 μL, Detection wavelengths: 210 and 200 nm, Run time: 6 min.

[0296] The release of phenytoin from the particles at 2 hours was 206% compared to the release from the free phenytoin powder. The release of phenytoin from the particles at 2 hours was 100% compared to the release from the free 2-hydroxypropyl-β-cyclodextrin complex (Intermediate 15).

[0297] Example 35 Amorphous cCVD-SP Aggregates Containing Phenobarbital 2-Hydroxypropyl-β-Cyclodextrin Complex Phenobarbital 2-hydroxypropyl-β-cyclodextrin complex (intermediate 14, 100 mg) was dissolved in dimethylformamide (0.6 mL) by heating. This solution was added dropwise to amorphous silicon particles (900 mg) in a mortar. The particles were in the form of aggregates (batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 2.3% w / w phenobarbital.

[0298] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 50% acetonitrile, Flow rate: 1 mL / min, Injection 5 μL, Detection wavelengths: 210 and 200 nm, Run time: 6 min.

[0299] The release of phenobarbital from the particles at 2 hours was 290% compared to the release from free phenobarbital powder. The release of phenobarbital from the particles at 2 hours was 80% compared to the release from free phenobarbital 2-hydroxypropyl-β-cyclodextrin complex (Intermediate 14).

[0300] Example 36 Amorphous cCVD-SP Aggregates Containing Amphotericin B γ-Cyclodextrin Amphotericin B-gamma-cyclodextrin complex (intermediate 16, 100 mg) was dissolved in dimethylformamide (0.6 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of stable aggregates (batch number H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 7.5% amphotericin B.

[0301] Example 37 Amorphous cCVD-SP Aggregates Containing Tetracycline Hydrochloride Methyl-β-Cyclodextrin Complex Tetracycline-HCl-methyl-β-cyclodextrin complex (intermediate 17, 100 mg) was dissolved in dimethylformamide (1.0 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of stable aggregates (batch number H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 3.9% tetracycline HCl.

[0302] [Example 38 Amorphous cCVD-SP containing cytarabine β-cyclodextrin complex] Cytarabine β-cyclodextrin complex (intermediate 18, 100 mg) was dissolved in dimethylformamide (0.5 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of stable aggregates (batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 2.2% (w / w) cytarabine.

[0303] [Example 39 Amorphous cCVD-SP containing amoxicillin β-cyclodextrin complex] Amoxicillin β-cyclodextrin complex (intermediate 19, 100 mg) was dissolved in dimethylformamide (0.5 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of stable aggregates (batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 3.4% (w / w) amoxicillin.

[0304] Example 40 Amorphous cCVD-SP Aggregates Containing Phenytoin 4-Sulfopropyl-β-Cyclodextrin Complex Phenytoin 4-sulfobutanol-β-cyclodextrin complex (Intermediate 20, 100 mg) was dissolved in dimethyl sulfoxide (0.5 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of stable aggregates (Batch no. H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50° C. for 24 hours. The dried particles were scraped off from the mortar. The particles contained 1.7% (w / w) phenytoin.

[0305] [Example 41 Amorphous cCVD-SP Aggregates Containing Phenobarbital 4-Sulfobutyric-β-Cyclodextrin Complex] Phenobarbital 4-sulfobuyl-β-cyclodextrin complex (intermediate 21, 100 mg) was dissolved in dimethyl sulfoxide (0.5 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of stable aggregates (batch number H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50°C for 24 hours. The dried particles were scraped off from the mortar. The particles contained 1.6% phenobarbital.

[0306] [Example 42 Amorphous cCVD-SP containing griseofulvin 4-sulfobutyl-β-cyclodextrin complex] Griseofulvin 4-sulfobuyl-β-cyclodextrin complex (Intermediate 22, 100 mg) was dissolved in dimethyl sulfoxide (0.5 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (Batch No. H18). Average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50°C for 24 hours. The dried particles were scraped off from the mortar. The particles contained 2.3% griseofulvin.

[0307] [Example 43 Amorphous cCVD-SP containing prednisolone 4-sulfobutyl-β-cyclodextrin complex] Prednisolone-4-sulfobutyric-β-cyclodextrin complex (intermediate 23, 100 mg) was dissolved in dimethylformamide (0.5 mL) by heating. This solution was added dropwise to amorphous silicon particles (400 mg) in a mortar. The particles were in the form of aggregates (batch number H18, average aggregate diameter 210 nm, PDI 0.190). The mixture was stirred in the mortar with a pestle for 5 minutes to form a paste. The mortar together with the pestle was dried under high vacuum at 50°C for 24 hours. The dried particles were scraped off from the mortar. The particles contained 2.3% prednisolone.

[0308] Example 44 Amorphous cCVD-SP Aggregates Containing Amphotericin B γ-Cyclodextrin Coated with Polysorbate 80 Amorphous cCVD-SP aggregates containing amphotericin B γ-cyclodextrin (from Example 36, 50 mg) were suspended in an aqueous solution of polysorbate 80 (DDL, 0.2% w / w, 1 mL). The mixture was sonicated for 5 min and centrifuged (14×000 rpm) for 5 min. The supernatant was removed and the particles were dried at 50° C. for 12 h.

[0309] Example 45 Amorphous cCVD-SP Aggregates Containing Tetracycline Hydrochloride Methyl-β-Cyclodextrin Coated with Polysorbate 20 Amorphous cCVD-SP aggregates containing tetracycline hydrochloride methyl-β-cyclodextrin (from Example 37, 50 mg) were suspended in an aqueous solution of polysorbate 20 (DDL, 0.2% w / w, 1 mL). The mixture was sonicated for 5 min and centrifuged (14×000 rpm) for 5 min. The supernatant was removed and the particles were dried at 50° C. for 12 h.

[0310] Example 46: Cremophor EL-Coated Amorphous cCVD-SP Aggregates Containing Cytarabine β-Cyclodextrin Amorphous cCVD-SP aggregates containing cytarabine beta-cyclodextrin (from Example 38, 50 mg) were suspended in an aqueous solution of Cremophor EL (Sigma, 0.2% w / w, 1 mL). The mixture was sonicated for 5 min and centrifuged (14×000 rpm) for 5 min. The supernatant was removed and the particles were dried at 50° C. for 12 h.

[0311] Example 47 Amorphous cCVD-SP containing rapamycin (50% weight loading) Preparation of rapamycin-loaded particles: Amorphous agglomerated silicon particles (batch no. H18) with a hydrodynamic size of 210 nm and a PDI of 0.190 were first coated (adsorbed, non-covalent coating) with Pluronic F-127 (Sigma). A 0.5% (w / v) solution of Pluronic F-127 was added to 400 mg of H18, followed by sonication in a sonicator bath for 15 min, centrifugation, washing three times with water, and vacuum drying overnight after removing the supernatant. Rapamycin (MedChem express) and pluronic-coated H18 were weighed and dissolved in dimethylformamide. The dispersion was sonicated in a sonicator bath for 10 min before being pipetted into aliquots each containing 125 μg of rapamycin. The aliquots were dried overnight under vacuum.

[0312] Total weight of rapamycin: 5mg Total weight of Pluronic-coated H18: 5mg The particle product had a hydrodynamic size of 190.3 nm and a PDI of 0.362.

[0313] Release test: One aliquot vial containing 0.125 mg rapamycin in Si particles prepared above was selected for release test. The dried particle pellet was crushed with a spatula to a fine powder. 1 mL purified water was added and the suspension was sonicated for 1 min before being added to a round bottle with 50 mL of buffer solution. The suspension was stirred at 37 °C for 48 h. 1 mL samples were taken after 0.5, 1, 3, 6, 24, 30 and 48 h, centrifuged at 14 000 rpm for 6 min and the supernatant was dried overnight under vacuum (Speedvac concentrator). Reconstitution of the samples with 500 μl methanol followed by centrifugation (6 min, 14 000 rpm) to remove salts was performed prior to high performance liquid chromatography (HPLC, Surveyor Finnigan, Thermo) analysis. Quantification was performed by comparing the area under the chromatographic rapamycin peak with a chromatographic standard curve made from known concentrations of rapamycin in methanol solutions. HPLC conditions: PLRP-S reversed phase column (1x150mm, Agilent Technologies) set at 55 degrees Celsius, isocratic elution with a mobile phase of 70% acetonitrile with 0.1% formic acid and 30% purified water with 0.1% formic acid, flow rate 100μL / min, injection volume 20μL, UVPDA detection. 278nm was selected as the peak absorbance of rapamycin for quantification.

[0314] Buffer solution: Phosphate buffered saline (PBS) at pH 7.4.

[0315] Release experiments were performed in triplicate. The average rapamycin release was plotted against time (Figure 4). Control experiment: supersaturated solution of free rapamycin powder in PBS at pH 7.4 and 37°C (2 experiments).

[0316] Example 48 Amorphous cCVD-SP containing rapamycin (10% weight loading) Rapamycin loaded particles were prepared as described in Example 47 using 5 mg rapamycin and 45 mg pluronic coated H18 to obtain a 10% weight loading. The particle product had a hydrodynamic size of 177.7 nm and a PDI of 0.147.

[0317] Release studies were performed using PBS pH 7.4 and PBS pH 5.8 separately as described in Example 47. Three release experiments were performed with each buffer solution. The average rapamycin release was plotted against time (Figure 5).

[0318] Example 49 Amorphous cCVD-SP containing rapamycin (5% weight loading) Preparation of rapamycin loaded particles was carried out as described in Example 47, with 4 mg rapamycin weight and 71 wt. of Pluronic coated H18 used to obtain 5% weight loading. The particle product had a hydrodynamic size of 154.5 nm and a PDI of 0.143.

[0319] Release studies were performed using PBS pH 7.4 and PBS pH 5.8 separately as described in Example 47. Three release experiments were performed with each buffer solution. The average rapamycin release was plotted against time (Figure 6).

[0320] Example 50 Amorphous cCVD-SP containing rapamycin β-cyclodextrin complex (5% weight loading of rapamycin) Preparation of rapamycin-loaded particles was carried out as described in Example 47 using 16 mg of rapamycin-cyclodextrin complex (Intermediate 24) weight and 60 mg of Pluronic-coated H18 weight to obtain 5% rapamycin weight loading. The particle product had a hydrodynamic size of 165.7 nm and a PDI of 0.141.

[0321] Release studies were performed using PBS pH 7.4 as described in Example 47. Two release experiments were performed. The average rapamycin release was plotted against time (Figure 7). Control: rapamycin-cyclodextrin complex (Intermediate 2).

[0322] Example 51 Amorphous cCVD-SP containing rapamycin β-cyclodextrin complex (10% weight loading of rapamycin) Preparation of rapamycin-loaded particles was carried out as described in Example 47 using 16 mg weight of rapamycin-cyclodextrin complex (Intermediate 24) and 22 mg weight of Pluronic-coated H18 to obtain 10% rapamycin weight loading. The particle product had a hydrodynamic size of 168.3 and a PDI of 0.128.

[0323] Release studies were performed using PBS pH 7.4 as described in Example 47. Two release experiments were performed. The average rapamycin release was plotted against time (Figure 7). Control: rapamycin-cyclodextrin complex (Intermediate 24).

[0324] Example 52 Accelerated Stability Study of Amorphous cCVD-SP Containing Rapamycin (10% Weight Loading) Three vials containing particle samples (10% weight loading of rapamycin in Pluronic coated H18 particles) prepared as in Example 48 were used for product stability testing. The vials were placed with closed caps in a desiccator filled to the bottom with saturated salt solution (NaCl) placed in a heating cabinet at 40° C. creating an atmosphere of 75% relative humidity (RH). These conditions represent accelerated stability testing of drug products and are suggested by ICH guideline Q1A. One vial was used for zero point determination, one vial was analyzed after one month, and the third vial was analyzed after two months. Once the particle pellet was analyzed by crushing with a spatula, 1 mL of methanol was added and the vial was sonicated in a sonicator bath for 15 minutes. In this way, the loaded rapamycin was extracted from the particles. The dispersion was left on the bench for several hours before being centrifuged (6 minutes, 14 krpm) and the supernatant was collected for rapamycin quantification by HPLC analysis. The particle pellet was saved for measurement of hydrodynamic size by DLS.

[0325] The hydrodynamic size of the particle batches did not change significantly from 177.7 nm after 0 months, to 163.1 nm after 1 month, and to 173.8 nm after 2 months of storage at 40° C. and 75% RH. The PDI values ​​also did not change significantly, from 0.147 at 0 months, to 0.126 at 1 month, and to 0.169 at 2 months.

[0326] HPLC analysis for the identification of rapamycin at time 0 and after 1 month was performed using a Zorbax C18 column (1×150 mm, 3.5 μm, Agilent), isocratic elution with 80% methanol containing 0.1% trifluoroacetic acid, and a 5 μl injection volume (other conditions described in Example 47). HPLC analysis of samples after 2 months of storage was performed similarly to the release sample analysis described in Example 47.

[0327] The rapamycin peak is seen after 2.6-2.9 min (Figure 8). The absence of new peaks in the chromatogram indicates little degradation of rapamycin when the particle product was stored at 40°C and 75% RH after 1 and 2 months. This indicates the stability of the drug product during storage at refrigerated conditions.

[0328] Example 53 Amorphous cCVD particles for dual delivery (hydrogen + erythromycin) The particles (29 mg, NM014) prepared as in Example 13 were suspended in TRIS buffer (25 mL, pH 8.0) in a round bottle equipped with a tube with a needle for hydrogen outlet in an inverted measuring vial containing water. The inverted vial was placed in a water bath (standard laboratory setup for gas collection). The suspension was stirred at 37°C.

[0329] After 2 hours, 4 mL of hydrogen gas was generated (corresponding to 154 mL / g Si). From Example 13, 219% of erythromycin was released from the particles during 2 hours compared to free erythromycin powder. After 21 hours, 7 mL of hydrogen gas was generated (corresponding to 269 mL / g Si).

[0330] Example 54 Amorphous cCVD particles for dual delivery (hydrogen + erythromycin) Particles (31 mg, NM022) prepared as in Example 15 were tested for hydrogen evolution as in Example 53. After 2 hours, 8 mL of hydrogen gas was evolved (equivalent to 286 mL / g Si). After 21 hours, 23 mL of hydrogen gas was evolved (equivalent to 821 mL / g Si).

[0331] Example 55 Amorphous cCVD particles for dual delivery (hydrogen + griseofulvin) Particles (51 mg, NM025) prepared as in Example 18 were tested for hydrogen generation as in Example 53. From Example 18, 109% of the griseofulvin was released from the particles compared to the free griseofulvin powder over a 2 hour period. After 21 hours, 22 mL of hydrogen gas was generated (equivalent to 478 mL / g Si).

[0332] Example 56 Amorphous cCVD particles for dual delivery (hydrogen + griseofulvin) Particles (52 mg, NM023) prepared as in Example 16 were tested for hydrogen generation as in Example 53. After 2 hours, 13 mL of hydrogen gas was generated (equivalent to 277 mL / g Si). From Example 16, 99% of the griseofulvin was released from the particles compared to the free griseofulvin powder over a 2 hour period. After 21 hours, 47 mL of hydrogen gas was generated (equivalent to 1000 mL / g Si).

[0333] Example 57 Amorphous cCVD particles for dual delivery (hydrogen + celecoxib) Particles (52 mg, NM029) prepared as in Example 22 were tested for hydrogen evolution as in Example 53. After 2 hours, 7.5 mL of hydrogen gas was evolved (equivalent to 179 mL / g Si). From Example 22, 210% of the celecoxib was released from the particles compared to the free celecoxib powder over a 2 hour period. After 4 hours, 12 mL of hydrogen gas was evolved (equivalent to 286 mL / g Si).

[0334] Example 58 Amorphous cCVD particles for dual delivery (hydrogen + phenytoin) Particles (57 mg, NM041) prepared as in Example 32 were tested for hydrogen generation as in Example 53. After 2 hours, 13 mL of hydrogen gas was generated (equivalent to 253 mL / g Si). From Example 32, 134% of the phenytoin was released from the particles compared to the free phenytoin powder over a 2 hour period. After 16 hours, 34 mL of hydrogen gas was generated (equivalent to 663 mL / g Si).

[0335] Example 59 Amorphous cCVD particles for dual delivery (hydrogen + phenobarbital) Particles (54 mg, NM042) prepared as in Example 33 were tested for hydrogen generation as in Example 53. After 2 hours, 40 mL of hydrogen gas was generated (equivalent to 823 mL / g Si). From Example 33, 174% of the phenobarbital was released from the particles compared to the free phenobarbital powder over a 2 hour period. After 16 hours, 53 mL of hydrogen gas was generated (equivalent to 1090 mL / g Si).

[0336] Example 60: Amorphous cCVD particles for dual delivery (hydrogen + phenytoin) Particles (63 mg, NM044) prepared as in Example 34 were tested for hydrogen generation as in Example 53. After 2 hours, 5 mL of hydrogen gas was generated (equivalent to 99 mL / g Si). From Example 34, 206% of the phenytoin was released from the particles compared to the free phenytoin powder over a 2 hour period. After 16 hours, 40 mL of hydrogen gas was generated (equivalent to 794 mL / g Si).

[0337] Example 61 Amorphous cCVD particles for dual delivery (hydrogen + phenobarbital) Particles (64 mg, NM045) prepared as in Example 35 were tested for hydrogen generation as in Example 53. After 2 hours, 7 mL of hydrogen gas was generated (corresponding to 137 mL / g Si). From Example 35, 290% of the phenobarbital was released from the particles compared to the free phenobarbital powder over a 2 hour period. After 16 hours, 35 mL of hydrogen gas was generated (corresponding to 684 mL / g Si).

[0338] Example 62 Amorphous cCVD particles for dual delivery (hydrogen + griseofulvin) Particles (63 mg, NM024) prepared as in Example 17 were tested for hydrogen generation as in Example 53. After 2 hours, 7.5 mL of hydrogen gas was generated (equivalent to 149 mL / g Si). From Example 17, 130% of the griseofulvin was released from the particles compared to the free griseofulvin powder over a 2-hour period. After 3 days, 15 mL of hydrogen gas was generated (equivalent to 298 mL / g Si).

[0339] Example 63 Amorphous cCVD particles for dual delivery (hydrogen + griseofulvin) Particles (81 mg, NM030) prepared as in Example 23 were tested for hydrogen generation as in Example 53. After 2 hours, 3 mL of hydrogen gas was generated (equivalent to 74 mL / g Si). From Example 23, 70% of the griseofulvin was released from the particles compared to the free griseofulvin powder over a 2 hour period. After 16 hours, 22 mL of hydrogen gas was generated (equivalent to 544 mL / g Si).

[0340] Example 64 Amorphous cCVD particles for dual delivery (hydrogen + losartan) Particles (57 mg, NM033) prepared as in Example 26 were tested for hydrogen generation as in Example 53. After 2 hours, 5 mL of hydrogen gas was generated (equivalent to 97 mL / g Si). From Example 26, 56% of the losartan was released from the particles compared to the free losartan powder over a 2-hour period. After 3 days, 28 mL of hydrogen gas was generated (equivalent to 546 mL / g Si).

[0341] Example 65: Tablets containing amorphous cCVD-SP containing 5% rapamycin Each tablet contains: Amorphous cCVD-SP (from Example 49, 100 mg) containing rapamycin (5% weight loading) Microcrystalline cellulose 360mg Cross caramel rose (Na) (aCDiSO) 20mg Contains 20 mg of stearic acid.

[0342] Blend all ingredients. Compress tablets. Tablet diameter 10mm. Tablet weight: 500mg. Rapamycin content: 5mg.

[0343] Example 66: Injectable suspension containing amorphous cCVD-SP containing 5% rapamycin Amorphous cCVD-SP containing rapamycin (5% weight loading) is prepared from sterile cCVD-SP and sterile rapamycin similar to the procedure of Example 49 using a sterile manufacturing process.

[0344] Sterile particles (100 mg) are suspended in a sterile solution of isocratic glucose solution (50 mL, 5% w / v) by sonication for 10 min under aseptic conditions. The suspension is aseptically filled into injection vials (5 mL). Each vial contains 10 mg of particles.

[0345] [Example 67 Chemical-physical stability of aggregated amorphous cCVD-SP] Amorphous form of cCVD-SP (batch number H18) was suspended in different solutions at concentrations between 1 and 5 mg / mL. Samples were removed after 5 h and 4 days to evaluate the stability of the aggregated particles in the solutions by size measurements. Single particles have a size of 20-50 nm as seen from SEM images, whereas aggregated particles composed of smaller single particles have a size of around 200 nm as measured by DLS.

[0346] Chemical stability was tested in PBS buffer at pH 7.4, and physical stability was tested by shaking sample vials by hand, ultrasonic bath treatment for up to 15 min, exposure to elevated temperature (37°C) in a water bath, and vigorous magnetic stirring.

[0347] The aggregated particles in purified water gave a hydrodynamic size of 282 nm (PDI: 0.287) after shaking the vial and 209 nm (PDI: 0.189) after sonication. Thus, sonication readily disperses weakly bound large aggregates but does not separate particle aggregates into single particles. After immersion of amorphous aggregated cCVD-SP in PBS at room temperature for 5 h and 4 days, the hydrodynamic size (after 1 min sonication) was 264 nm (PDI: 0.352) and 323 nm (PDI: 0.479), respectively. In purified water and PBS at 37°C, the hydrodynamic size after 5 h (and 1 min sonication) was 249 nm (PDI: 0.238) and 344 nm (PDI: 0.463), respectively. Immersion in PBS at 37°C with vigorous magnetic stirring (followed by 1 min sonication) resulted in hydrodynamic sizes of 446 nm (PDI: 0.492) after 5 hours and 469 nm (PDI: 0.522) after 4 days. PBS, high temperature treatment and magnetic stirring do not break up stable aggregates but increase the formation of larger particles composed of weakly bound aggregates.

[0348] Example 68: Stability of aggregated amorphous cCVD-SP in the presence of surfactant and albumin The experiment was carried out as in Example 67. Amorphous aggregate particles (batch number H18) were immersed in purified water and PBS supplemented with 0.1% (w / v) Pluronic F-127 (Sigma) or polysorbate 80 (Apotekproduksjon), or 4% (w / v) albumin from human serum (≧96%, Sigma). All samples were treated in an ultrasonic bath for 1 min before measuring the hydrodynamic size.

[0349] Particles immersed in water supplemented with albumin, Pluronic F-127 and polysorbate 80 exhibited hydrodynamic sizes of 264 nm (PDI: 0.215), 221 nm (PDI: 0.168), 193 nm (PDI: 0.115) after 5 hours and 277 nm (PDI: 0.243), 292 nm (PDI: 0.269), 234 nm (PDI: 0.226) after 4 days. Particles immersed in PBS supplemented with albumin, Pluronic F-127 and polysorbate 80 exhibited hydrodynamic sizes of 266 nm (PDI: 0.192), 186 nm (PDI: 0.145), 185 nm (PDI: 0.122) after 5 hours and 291 nm (PDI: 0.244), 330 nm (PDI: 0.383), 193 nm (PDI: 0.139) after 4 days.

[0350] The aggregated particles are stable in that they do not break down into single particles. Aggregation in PBS is not as extensive after the addition of Pluronic F-127, Polysorbate 80, or albumin as it is without these additions. These substances likely form an adsorbed coating that stabilizes the particles in PBS solution.

[0351] Example 69: Stability of aggregated amorphous cCVD-SP in an artificial in vitro model of blood. The experiment was carried out similarly to Example 67. Amorphous aggregate particles (batch number H18) were immersed in an in vitro blood model containing PBS with 4% (w / v) albumin from human serum (≧96%, Sigma) kept in a 37° C. water bath.

[0352] The hydrodynamic size measured after 5 hours was 319 nm (PDI: 0.288) after manual shaking and 310 nm (PDI: 0.231) after 1 min of sonication. Some aggregation of particles is seen in the artificial blood compared to pure water.

Claims

1. 1. A process for preparing silicon particles containing at least one active pharmaceutical ingredient, said process comprising: a) preparing silicon particles by chemical vapor deposition (CVD); b) loading the silicon particles prepared in step a) with at least one active pharmaceutical ingredient.

2. 2. The process of claim 1, wherein the silicon particles are centrifugal chemical vapor deposition silicon particles (cCVD-SP), and the CVD in step a) is performed in a reactor comprising a reactor body and a rotation device operatively disposed in the reactor, the rotation device being configured to rotate the reactor about an axis during production.

3. The process of claim 1 , wherein step a) does not include grinding the particles.

4. The process of claim 1 , wherein the particles are unetched particles.

5. 2. The process of claim 1, wherein step b) comprises mixing the silicon particles prepared in step a) with at least one active pharmaceutical ingredient.

6. 2. The process of claim 1, wherein the silicon particles comprise at least 50% by weight crystalline silicon based on the total weight of silicon.

7. 2. The process of claim 1, wherein the silicon particles comprise at least 50% by weight amorphous silicon based on the total weight of silicon.

8. 2. The process of claim 1, wherein the silicon particles comprise at least 50% by weight elemental silicon based on the total weight of silicon.

9. 10. The process of claim 1, wherein the at least one active pharmaceutical ingredient is in the form of a cyclodextrin complex.

10. 2. The process of claim 1, wherein the at least one active pharmaceutical ingredient is selected from the group consisting of anti-cancer drugs, drugs having an effect on the immune system, anti-fungal drugs, antibiotics, anti-viral drugs, drugs for the treatment of CNS-related diseases, anti-diabetic drugs, drugs for the treatment of pain, and steroid drugs.

11. 2. The process of claim 1, wherein the at least one active pharmaceutical ingredient is selected from the group consisting of atorvastatin, simvastatin, losartan, valsartan, candesartan, enalapril, atenolol, propranolol, hydrochlorothiazide, cyclosporine, amphotericin B, diltiazem, phenoxymethylpenicillin, azithromycin, rapamycin, griseofulvin, chloramphenicol, erythromycin, acyclovir, nystatin, phenytoin, phenobarbital, ampicillin, celecoxib, prednisolone, and metformin.

12. Silicon particles containing at least one active pharmaceutical ingredient prepared according to the process of any one of claims 1 to 11.

13. 13. A pharmaceutical composition comprising silicon particles as defined in claim 12 and one or more pharma- ceutically acceptable carriers, diluents or excipients.

14. 14. The pharmaceutical composition of claim 13, formulated for oral administration.

15. 15. The pharmaceutical composition of claim 14 in the form of a tablet, capsule or suspension.

16. 14. The pharmaceutical composition of claim 13, formulated for subcutaneous administration.

17. 14. The pharmaceutical composition of claim 13, formulated for parenteral administration.

18. Silicon particles according to claim 12 for use in therapy.

19. 13. Silicon particles according to claim 12 for use in drug delivery.

20. A pharmaceutical composition according to claim 13 for use in treatment.

21. The pharmaceutical composition of claim 13 for use in drug delivery.

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