Silicon particles for hydrogen release

Abstract

The present invention relates to silicon particles for use in therapy, said silicon particles being prepared by Chemical Vapor Deposition (CVD).

Description

[Technical field]

[0001] The present invention relates to silicon particles for use in therapy, said silicon particles being prepared by Chemical Vapor Deposition (CVD).The present invention further relates to a pharmaceutical composition comprising said particles, and to a method for generating hydrogen using said particles. [Background technology]

[0002] Hydrogen gas has been reported for use in medicine since the 19th century, with deep sea divers using hydrogen to prevent decompression sickness. Currently, hydrogen has limited international use in therapy. However, during the last 15 years, there has been growing interest in hydrogen therapy with several clinical studies for various indications. Hydrogen has antioxidant, anti-inflammatory and anti-apoptotic properties and is therefore of interest for the treatment of several diseases, for example, in the cardiovascular system, central nervous system, lungs and kidneys. There are several reports in the fields of cancer, inflammatory diseases, sepsis and other infectious diseases. Recently, hydrogen gas has been evaluated for use in the treatment of Covid-19 infection.

[0003] Hydrogen gas is typically administered by inhalation, by oral administration of an aqueous solution containing hydrogen, or by injection of a solution containing hydrogen. The main challenge with inhalation of hydrogen is the risk of explosion. Hydrogen is highly explosive when mixed with oxygen or air, and with all electrical equipment used during treatment, this represents a fatal risk for the patient and others. The main challenge associated with oral administration and injection of water containing hydrogen is that hydrogen has a very low solubility in water. The solubility of hydrogen in pure water is approximately 18 mL of gas per liter of water.

[0004] An option to increase the amount of hydrogen in patients is to administer chemical compounds that generate hydrogen by themselves or through reaction with water. An interesting approach is the use of micro- or nanoparticles of various metal compounds as described in Zhou G, Goshi E, He Q: Micro / Nanomaterials-Augmented Hydrogen in Adv Healthc Mater. 2019 Aug;8(16). Some of the particles described include complex compounds with expensive metals such as palladium and gold.

[0005] An alternative to using these expensive materials is silicon. Silicon microparticles have been found to have hydrogen generating capabilities, especially when exposed to pH values ​​above 7. For example, WO2017130709 relates to a solid formulation containing silicon microparticles for generating hydrogen. The described particles are produced by the "bead mill method". WO2018037819 relates to hydrogen generating silicon particles or aggregates thereof.

[0006] The atomic silicon particles generate hydrogen in a redox process in which the silicon is oxidized and the hydrogen in the water is reduced, as shown below. Si+2H2O→SiO2+2H2

[0007] One mole of silicon will generate two moles of hydrogen gas. Since silicon weighs 28 grams / mole and has a molar volume of gas of approximately 22.4 liters, one gram of silicon will theoretically generate 1.6 liters of hydrogen gas.

[0008] The reported volume of hydrogen generated by state-of-the-art hydrogen-forming silicon particles is, as noted above, per gram of silicon: pH 7.0, 24 hours, approximately 50 mL of hydrogen (reference a), which is approximately a 3% yield. pH 8.3, 400 min (approximately 7 h), 600-700 mL of hydrogen (reference b), which is a yield of 38-44%. pH 8.3, 400 min (approximately 7 h), approximately 200 mL of hydrogen (reference c), this is a 13% yield. pH 8.3, 35 hours, 450 mL of hydrogen (reference c), which is a 28% yield. At pH 8.5, 24 hours, approximately 600 mL of hydrogen (reference a), which is a yield of approximately 30%. pH 9.0, 2 hours, approximately 350 mL of hydrogen (reference a), which is a yield of approximately 22%. pH 9.0, 15 hours, approximately 750 mL of hydrogen (reference a), which is approximately a 47% yield. ultrapure water, 350 min (approximately 6 h), 10 mL of hydrogen (ref. d), which is about a 0.6% yield. tap water, pH 7.1-7.4, 350 min, 45 mL of hydrogen (d). This is a yield of approximately 3%.

[0009] aYKobayashi, S.Fujie, K.Imamura, H.Kobayashi:Structure and hydrogen generation mechanism of Si-based agent in Applied Surface Science,536,15 January 2021,147398. bY Kobayashi, Y Kowada, T. Shirohata, T Kobayashi: Changes in structure and Surface properties of Si-based agent during hydrogen generation reaction in Applied surface science, 2021-01-01, Vol. 535, p. 147361. c. Kobayashi Y, Imamura R, Koyama Y, Kondo M, Kobayashi H, Nonomura N, Shimada S: Renoprotective and neuroprotective effects of enteric hydrogen generation from Si-based agent. Sci Rep. 2020 Apr 3;10(1):5859.doi:10.1038 / s41598-020-62755-9. dYKobayashi, S.Matsuda, K.Imamura, H.Kobayashi: Hydrogen generation by reaction of Si nanopowder with neutral water, J.Nanopart.Res.19(2017)176-1-9. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Zhou G,Goshi E,He Q:Micro / Nanomaterials-Augmented Hydrogen in Adv Healthc Mater.2019 Aug;8(16) [Non-Patent Document 2] Y.Kobayashi, S.Fujie, K.Imamura, H.Kobayashi:Structure and hydrogen generation mechanism of Si-based agent in Applied Surface Science,536,15 January 2021,147398 [Non-Patent Document 3] Y. Kobayashi, Y Kowada, T. Shirohata, T Kobayashi:Changes in structure and Surface properties of Si-based agent during hydrogen generation reaction in Applied surface science,2021-01-01,Vol.535,p.147361 [Non-Patent Document 4] Kobayashi Y, Imamura R, Koyama Y, Kondo M, Kobayashi H, Nonomura N, Shimada S: Renoprotective and neuroprotective effects of enteric hydrogen generation from Si-base [Non-Patent Document 5] Y.Kobayashi, S.Matsuda, K.Imamura, H.Kobayashi: Hydrogen generation by reaction of Si nanopowder with neutral water, J.Nanopart.Res.19(2017)176-1-9 Summary of the Invention [Problem to be solved by the invention]

[0011] Physiological pH is 7.4. This is generally the pH in human tissue. In the stomach, pH is 1-3, while pH in the intestine typically tends to be above 7.0. Thus, silicon particles provide the potential for valuable therapy in which hydrogen release in the intestine is especially useful for use in the treatment or prevention of conditions or injuries that can be treated by hydrogen. [Means for solving the problem]

[0012] [Summary of the Invention] The inventors have unexpectedly found that atomic silicon particles produced by a CVD process are much more efficient at producing hydrogen than atomic silicon particles produced by a milling process. In particular, the inventors have observed that the CVD produced particles are much more potent hydrogen-forming materials than milled particles previously described, especially near neutral and physiological pH values. The examples herein show that particles produced by the CVD method produce more hydrogen and produce hydrogen more quickly than the data reported for milled particles. Thus, these particles offer certain advantages for use in therapy.

[0013] During the growth of CVD silicon particles, both gas species and other nuclei are trapped. These other nuclei grow into nanospheres that preserve some degree of internal order during the trapping. If the growth is performed at a temperature higher than 650°C, the particles will be crystalline, and if the growth is performed at a lower temperature, the particles will be amorphous. Amorphous particles can also be crystallized after growth, but higher temperatures are required to crystallize the particles later. 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.

[0014] 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 trapping 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 observation with a transmission electron microscope. When the sample is crystalline, either grown crystalline or crystallized after growth, the domains are particularly clear. The purity, lack of internal oxidation and the spherical shape of the primary particles are all unique properties of particles grown by CVD.

[0015] The main difference between c-CVD and other CVD particles is the narrower size distribution, especially in combination with an amorphous structure. It is possible to achieve a narrow size distribution, for example, by using high energy supply by a laser or plasma torch growth zone and short growth times. However, by controlling the growth in this way, a crystalline structure with substantially larger crystals is always obtained.

[0016] The main difference between CVD particles and fractured particles is the spherical nature of the primary particles and the lack of sharp edges in CVD particles. CVD particles grow from gas in the process, but for clarity, they can be considered as growing hail. The spherical nature of hail is the result of the same primary growth mechanism, gas entrapment, and smaller solid domains that eventually form a complete hail sphere. The fractured silicon particles can be considered as the equivalent of breaking up ice cubes for clarity. Both CVD and fractured particles can contain crystalline domains, but for CVD particles, these domains are all small and of narrow size distribution, the particles are spherical, and the internal surfaces are not oxidized and are not contaminated. For fractured particles, internal crystalline domains may be present, but the size and distribution may vary. The fractured particles are formed by breaking up larger particles, and therefore, by definition, always have sharp edges. The internal surfaces, if any, are found to have atoms other than Si and H, and are therefore always more contaminated than direct electronics grade Si particles. Crushing is also difficult to do without causing substantial internal oxidation. The simplest analytical methods to distinguish between CVD and crushed particles are scanning or transmission electron microscopy, or by X-ray diffraction to identify a completely amorphous structure.

[0017] 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.

[0018] As discussed above, the two main differences between CVD-produced particles and crushed particles are structure and shape. CVD-produced particles can have an amorphous or nanocrystalline structure. Crushed particles are fractured silicon where the individual crystals of silicon are several orders of magnitude larger than their grain size. This description is valid for both fully monocrystalline and polycrystalline silicon wafers. Thus, for all practical purposes, each particle is monocrystalline and therefore consists of one crystal throughout the particle. In the case of CVD-formed particles, the particles grow from one or several nuclei, and the growth conditions describe whether the grown particles are amorphous, predominantly amorphous, or nanocrystalline with several crystallites within each particle. Our work has revealed that this amorphous or nanocrystalline structure has a deeper oxidation depth than monocrystalline particles and therefore can form substantially more hydrogen per weight of Si than crushed silicon particles.

[0019] X-Ray Diffraction (XRD) (sometimes referred to in the literature as Powder X-Ray Diffraction (PXD) when XRD is applied to particulate materials) gives different diffraction patterns for crystalline and amorphous materials. Crystalline materials tend to give sharp peaks, Bragg peaks, in XRD measurements due to the high degree of order and symmetry in their atomic structures. For crystalline silicon materials, XRD analysis typically gives sharp peaks at 28.4°, 47.4°, and 56.1° in the measured diffraction pattern. In comparison, amorphous materials, which lack the long-range order characteristic of crystalline molecular structures, typically give more broadened peaks that are significantly more "smudged" in the measured diffraction pattern. Amorphous silicon typically gives rounded peaks at 28° and 52°. These rounded peaks can be fitted with a Gaussian fit to reduce noise and obtain well-defined values ​​for the peak maxima and widths. Such fits can be performed by any skilled XRD operator.

[0020] Also, the "sharpness" of the peaks can be applied to distinguish between crystalline and amorphous materials. The typical full width at half maximum (FWHM) of the XRD peak of crystalline silicon is less than 2°, while the FWHM of amorphous silicon is typically greater than 5° when measured on a diffractometer applying non-monochromated CuKα radiation to reduce measurement noise and using a Gaussian fit. The full width at half maximum (FWHM) is the width of the peak curve measured between the points on the y-axis that are half the maximum amplitude of the peak curve (after subtraction of background signals and / or signals from the sample holder). Samples containing both amorphous and crystalline silicon obtain, in XRD analysis, diffraction patterns that show both sharp Bragg peaks typical of the crystalline phase and broader, more Gaussian peaks typical of the amorphous phase. The diffraction pattern can be applied to estimate the crystalline fraction of a sample from the ratio of the area under the Bragg peak and above the amorphous broad peak, and the total area of ​​the broad peak and the Bragg peak. The linear background should be subtracted from the calculation before calculation.

[0021] The angles and angle tolerances in XRD analysis applied herein refer to the use of a diffractometer applying non-monochromated CuKα radiation. This is because the radiation is high intensity and has a wavelength of 1.5406 Å, which corresponds well to the interatomic distance in crystalline solids, making the analysis sensitive to the presence of crystalline phases in silicon particles. For the same reason, XRD analysis applying a diffractometer using CuKα radiation is a natural choice, and therefore is the most widely used method in XRD analysis, well known and mastered by those skilled in the art. Other diffractometers applying radiation with other wavelengths may give different angles and angle tolerances. However, those skilled in the art will know how to convert these values ​​from one radiation source to another.

[0022] The particles described by the present invention are shown by X-ray diffraction (XRD) analysis to have either crystalline structure, amorphous structure, or a mixture.The diffraction pattern measured for the amorphous sample shows peaks at about 28° and 52°, and both peaks have FWHM of about 5° or greater than 5° when estimated using Gaussian peak fitting.The diffraction pattern measured for the crystalline sample shows sharp peaks at about 28°, 47°, and 56°, and all peaks have FWHM of about 2° or less when estimated using Gaussian peak fitting.

[0023] Amorphous materials have some internal structure that provides short range order on atomic length scales due to the nature of chemical bonds. This internal structure can be considered to be composed of interconnected building blocks. These blocks may or may not resemble the basic structural units found in the corresponding crystalline phase, i.e., may or may not provide the material with very small crystalline-like domains. Furthermore, for very small crystals, relaxation of surface and interface effects distorts the atomic positions and reduces structural order. Even the most advanced structural characterization techniques, such as X-ray diffraction and transmission electron microscopy, have difficulty distinguishing between amorphous and crystalline structures on these length scales. Therefore, since it is difficult to determine by structural characterization techniques whether the silicon material of the particles produced according to the first aspect of the present invention is completely amorphous or contains small crystalline domains on atomic length scales, the term "predominantly amorphous" as used herein encompasses silicon materials with 100% amorphous molecular structure to silicon materials containing very small crystalline domains on atomic length scales (which cannot actually be detected by XRD analysis). It is also reasonable to consider that the advantages of amorphous materials, and therefore oxidation depth, are maintained even when the material contains very small crystallites, typically less than 1 nm, such that atoms with nearest-neighbor distances distorted by grain boundaries constitute a similar mass fraction as atoms whose all nearest-neighbor atoms are in crystalline order.

[0024] Our research shows that both predominantly amorphous and crystalline particles generate more hydrogen than milled silicon particles. Differentiating between amorphous, nanocrystalline and single crystalline particles is most easily achieved by high-resolution Transmission Electron Microscopy (TEM) or a combination of TEM and XRD. Figures 1-9 show typical SEM, TEM and XRD images and data obtained for amorphous and crystalline silicon particles. [Brief description of the drawings]

[0025] [Figure 1] SEM image of CVD particles showing the morphology of the CVD grown particles. [Diagram 2] Amorphous silicon CVD particles in high-resolution TEM. [Diagram 3] Amorphous particles analyzed by TEM. [Figure 4] Nanocrystalline particles analyzed by TEM. [Diagram 5] SEM image of amorphous agglomerated cCVD Si particles. [Figure 6] XRD measurements of three samples of amorphous silicon. [Figure 7] XRD measurements of amorphous and crystalline silicon. [Figure 8] XRD measurements of amorphous and crystalline silicon. [Figure 9] XRD measurement of crystalline silicon. [Figure 10] Hydrogen release from cCVD silicon particles at pH 8.6 for Examples 1-3. [Figure 11] Hydrogen release from cCVD silicon particles at pH 8, pretreated at pH 2 and no pretreatment for Examples 4, 5 and 9. [Figure 12] Hydrogen release from cCVD silicon particles at pH 7.4, pretreated at pH 2 and no pretreatment for Examples 6-8. [Figure 13]Hydrogen release from cCVD silicon particles at pH 7.4 and pH 8, pretreated at pH 2 for Example 10. [Figure 14] Hydrogen release from cCVD silicon particles at pH 8 and pH 8 for Examples 11 and 12. [Figure 15] Hydrogen release from cCVD silicon particles at pH 7.4 and pH 7.4, pretreated at pH 2 for Examples 13 and 14. [Figure 16] Hydrogen release from cCVD silicon particles at pH 7.4 and pH 7.4, pretreated at pH 2 for Examples 15 and 16. [Figure 17] Hydrogen release from cCVD silicon particles at pH 7.4 and pH 7.4, pretreated at pH 2 for Examples 17 and 18. [Figure 18] TEM images of cCVD particles and elemental mapping of Si and O content for Examples 20 and 21. [Figure 19] TEM images and elemental mapping of Si and O content of cCVD particles after 50 min at pH 7.4 for Example 20. [Figure 20] TEM images and elemental mapping of Si and O content of cCVD particles after 200 min at pH 7.4 for Example 20. [Figure 21] TEM images and elemental mapping of Si and O content of cCVD particles after 200 min at pH 8 for Example 21. [Figure 22] Rapamycin release versus time for Example 68. [Figure 23] Rapamycin release versus time for Example 69. [Figure 24] Rapamycin release versus time for Example 70. [Diagram 25] Rapamycin release versus time for Examples 71 and 72. [Figure 26] HPLC analysis for the identification of rapamycin in Example 73. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] [Summary of the Invention] In a first aspect, the present invention provides silicon particles for use in therapy, wherein said silicon particles are prepared by chemical vapour deposition (CVD).

[0027] In a further aspect, the present invention provides a pharmaceutical composition comprising silicon particles and one or more pharma- ceutically acceptable carriers, diluents or excipients, wherein said silicon particles are as defined herein above.

[0028] In another aspect, the present invention provides a method for producing hydrogen (H2) using silicon particles, the method comprising: a) preparing silicon particles by chemical vapor deposition (CVD); b) exposing the silicon particles prepared in step a) to a pH of at least 7.0.

[0029] [Definition] The term "mesoporous" particles refers to particles that contain pores with diameters between 2 and 50 nm.

[0030] The term "microporous" particles refers to particles having pores less than 2 nm in diameter.

[0031] The term "macroporous" particles refers to particles having pores greater than 2 nm in diameter.

[0032] 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 marketed.

[0033] The term "drug product" refers to a composition comprising at least one drug substance intended for use and at least one excipient (ie, a pharmaceutical composition).

[0034] The term "pharmaceutical formulation" includes "drug product" and refers to a composition that includes at least one active pharmaceutical ingredient and at least one excipient.

[0035] The term "pharmaceutical acceptable" refers to chemical 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.

[0036] The term "excipient" refers to a chemical compound for use in a drug product that is not itself biologically active in the amounts present when the drug product is used in accordance with its intended or regulatory approval.

[0037] The term "complex" refers to a compound that includes at least two different molecules that are associated with each other by additional bonds other than the covalent bonds and classical ionic bonds in simple salts. One typical example is a cyclodextrin complex.

[0038] The term "cyclodextrin" refers to a compound of cyclic oligosaccharides consisting of a macrocyclic ring of glucose subunits connected by α-1,4 glycosidic bonds. α (alpha)-cyclodextrin is composed of six glucose subunits, β (beta)-cyclodextrin is composed of seven glucose subunits, and γ (gamma)-cyclodextrin is composed of 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.

[0039] The term "particles containing zero silicon" refers to particles in which at least 50% of the silicon of the present invention is at an oxidation level of 0, not 4 as in silica.

[0040] The term "small molecule compound" refers to a compound having a molecular weight of less than 3000 Daltons.

[0041] 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.

[0042] The term "food additive" refers to any food product in the market.

[0043] The term cCVD-SP is used to indicate "centrifugally deposited chemical vapor deposited silicon particles" and refers to silicon particles prepared by a centrifugation method. In particular, this term refers to silicon particles prepared by a CVD method in a reactor, the reactor comprising a reactor body and a rotating device operably arranged in the reactor, the rotating device being configured to rotate the reactor about an axis during the production of the silicon-containing particles described above.

[0044] The term PcCVD-SP is used to denote "porous centrifugation chemical vapor deposited silicon particles" and refers to silicon particles prepared by a centrifugation method followed by an etching process to prepare the porosity of the particles.

[0045] [Mode for carrying out the invention] The present invention relates to silicon particles for use in therapy, said silicon particles being prepared by chemical vapour deposition (CVD).

[0046] CVD process is a process in which gas is converted into a solid material, typically a film, under various conditions. Step a) of the process of the present invention preferably involves preparing silicon particles by CVD from a silicon-containing reactive gas, such as silane or trichlorosilane.

[0047] In a preferred embodiment of the present invention, the silicon particles are prepared by a CVD method that does not include a milling step.

[0048] In particular, the CVD process 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 the silicon-containing particles described above, hereinafter referred to as cCVD-SP (centrifuge chemical vapor deposition silicon particles).

[0049] In a further preferred embodiment of the present invention, the CVD process is carried out in a reactor, the reactor comprising a reactor body and a rotating device operatively arranged in the reactor, the rotating device being configured to rotate the reactor around an axis during the production of the above-mentioned 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 Particle).

[0050] One preferred embodiment of the present invention relates to porous, non-etched cCVD-SP particles. Such particles are typically formed by forming stable agglomerates of smaller particles.

[0051] Another preferred embodiment of the present invention relates to non-porous, non-etched cCVD-SP particles.

[0052] Yet another preferred embodiment of the present invention relates to porous amorphous non-etched cCVD-SP particles.

[0053] Yet another preferred embodiment of the present invention relates to non-porous, amorphous, non-etched cCVD-SP particles.

[0054] The etching process for producing PcCVD-SP from cCVD-SP is similar to other known etching processes for silicon particles described in the prior art, such as hydrofluoric acid-based methods. The particle surface may be modified to exhibit desired characteristics, including chemical or thermal oxidation or coating.

[0055] A particularly preferred method for preparing silicon particles is disclosed in WO 2013 / 048258 and is briefly described below.

[0056] In this preferred process, chemical vapor deposition is carried out in a reactor comprising a reactor body capable of rotating about an axis with the aid of a rotation device operably arranged in the reactor, at least one side wall surrounding the reactor body, at least one inlet for a reactant gas, at least one outlet for a residual gas, and at least one heating tool 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.

[0057] Therefore, the CVD process preferably comprises: - introducing particles for producing a particle layer from a silicon-containing reaction gas in a reactor or forming inner particles on the inner wall surface of the reactor; - introducing reactant gases for chemical vapor deposition; - Producing silicon by chemical vapor deposition on a layer of particles; loosening and removing the produced silicon from the particle bed and carrying out any preparation of the inner surface of the reactor before continuing the production of silicon by repeating the above-mentioned steps of the method.

[0058] 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.

[0059] In particles formed from the milling of electronics-grade silicon wafers, the average crystal size of the material is orders of magnitude larger than the grain size. For CVD-formed particles, the average crystal size is adjustable. It is possible to have one or a few crystals in each particle, to have many nanocrystallites in each particle, or to have a completely disordered amorphous structure. This is adjustable by the process, so that a particular crystallinity or average crystallite size can be selected for a particular application or according to further processing. For example, the etching rate depends on the crystallite size and orientation, as well as the defect distribution and frequency within each crystal.

[0060] The particle decomposition time depends to some extent on the number of crystal interfaces that reach the surface, in other words, how many oxidation channels there are through which oxidation can propagate down 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 the individual silicon atoms and oxidize them. Because 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 a crushed large crystal material given these properties. Especially in applications where rapid biodegradation is desired, CVD particles have substantial advantages over classical crushed crystal silicon.

[0061] As described above, the silicon particles of the present invention are capable of generating hydrogen.

[0062] In some embodiments, the silicon particles have the ability to generate greater than 900 mL (about 57%) of hydrogen per gram of silicon in less than 15 hours at a pH value of 9.0 or less.

[0063] In another embodiment, the silicon particles have the ability to generate greater than 100 mL (about 6.3%) of hydrogen per gram of silicon in less than 100 minutes at a pH value of 7.4 or less.

[0064] In a further embodiment, the silicon particles have the ability to generate greater than 200 mL (about 12.6%) of hydrogen per gram of silicon in less than 300 minutes at a pH value of 7.4 or less.

[0065] [Silicon] The silicon in the silicon particles of the present invention (preferably cCVD-SP and / or PcCVD-SP) is present as atomic silicon (silicon with oxidation number 0) at least 50% by weight based on the total weight of silicon. The more preferred form of silicon in the silicon particles of the present invention is at least 70% by weight based on the total weight of silicon, and even more preferably at least 80% by weight based on the total weight of silicon. Another preferred embodiment related to the form of silicon in the particles of the present invention is that the amount of atomic silicon and silicon dioxide is greater than 80% by weight based on the total weight of silicon, more preferably greater than 90%, and most preferably greater than 95%.

[0066] Silane and other silicon-containing gases used in the preparation of the present particles 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 particles of the present invention.Therefore, another preferred embodiment of the form of silicon in the particles of the present invention is that the amount of silicon-containing gas in particles is less than 10% by weight, more preferably less than 5% by weight, most preferably less than 2% by weight of the total silicon in particles.

[0067] The atomic silicon in the particles of the present invention can be in amorphous or crystalline form.The atomic silicon in the particles produced by CVD process is mainly in the form of amorphous atomic silicon at ambient temperature, but particles containing crystalline silicon can be directly prepared by CVD at high temperature (e.g., above 600°C) and longer reaction time.The particles containing crystalline silicon prepared by CVD method are typically in the form of polycrystalline material (crystal size about 1.5 nm), while the crushed crystalline particles are typically composed of one crystal of silicon.

[0068] Crystalline and amorphous forms of silicon can be routinely determined by X-ray diffraction analysis (XRD analysis). Amorphous forms of silicon can be converted to crystalline forms of silicon by heating to relatively high temperatures (e.g., above 500° C.).

[0069] Silicon particles produced by CVD processes typically contain some material that contains one or more silicon-hydrogen bonds, which may be available to form some hydrogen gas in a reaction with water.

[0070] In certain embodiments, the atomic silicon is present in crystalline form, and in some embodiments, typically greater than 50% by weight in crystalline form, in some embodiments, typically greater than 70% by weight in crystalline form, and finally, in some embodiments, typically greater than 90% by weight in crystalline form, based on the total weight of the atomic silicon.

[0071] In other embodiments, the silicon particles comprise atomic silicon in amorphous form, in some embodiments greater than 50% by weight, in some embodiments greater than 70% by weight, in some embodiments greater than 90% by weight, and ultimately in some embodiments greater than 95% by weight, based on the total weight of atomic silicon.

[0072] One preferred embodiment of this aspect of the invention is where the silicon particles are cCVD-SP or PcCVD-SP.

[0073] One of the most preferred embodiments of this aspect of the invention is a cCVD-SP in which the silicon particles comprise silicon in amorphous form, for example, greater than 50 wt. %, in some embodiments greater than 70 wt. %, in some embodiments greater than 90 wt. %, and ultimately in some embodiments greater than 95 wt. %, based on the total weight of atomic silicon.

[0074] 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 hydrofluoric acid (HydroFluoronic, HF) etching process, i.e., where the silicon particles are not etched.

[0075] The final form of the most preferred embodiments of this aspect of the invention is where the silicon particles comprise more than 50 wt. %, in some embodiments more than 70 wt. %, in some embodiments more than 90 wt. %, and ultimately in some embodiments more than 95 wt. % amorphous silicon based on the total weight of atomic silicon.

[0076] [Particle size] The process of the present invention allows the preparation of silicon particles with a "tailor-made" particle size. The typical median diameter of the silicon particles of the present 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 Zetasizer. The given particle size relates to the final silicon particles loaded with one or more drug substances and optionally excipients and coatings.

[0077] The polydispersity index can also vary from almost monodisperse particles to particles with a very broad particle size distribution.

[0078] The preferred particle size of silicon particles of the present invention generally varies depending on indication and route of administration.Particles for intravenous administration 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 ocular 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.

[0079] In one embodiment, the silicon particles preferably have an average diameter of less than 1 μm, more preferably less than 0.8 μm, even more preferably less than 0.6 μm, such as less than 0.5 μm.

[0080] [porosity] The silicon particles of the present invention can 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 that the particles are prepared by non-etching processes. The porous particles for hydrogen delivery and optional additional drug delivery can be prepared by forming stable aggregates of smaller particles (so-called stable particle clusters).

[0081] 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 50% porosity has a pore volume that is 50% of the total PcCVD-SP volume. The porosity of the PcCVD-SP may typically be between 20% and 90%. In certain embodiments, the porosity is greater than 40%, typically greater than 50%, greater than 60%, greater than 70%, greater than 80%, e.g., 90%. In other embodiments, the porosity is preferably about 50% or less.

[0082] The pore size of PcCVD-SP can vary from microporous through mesoporous 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.

[0083] In one 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, for example at least 50% by volume, based on the total pore volume.

[0084] 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.

[0085] In a further embodiment, the particles are macroporous, in which preferably at least 2% by volume of the pores are macroporous, more preferably at least 5% by volume, even more preferably at least 10% by volume, in particular at least 20% by volume, for example at least 50% by volume, based on the total pore volume.

[0086] [Particle Surface and Coating] The particle surface may typically be in the form of atomic silicon, or more preferably in the form of a layer of silicon oxide, where the atomic silicon on the particle surface undergoes a natural or chemical oxidation process.The surface may also be covered with a layer of drug molecules that are covalently or non-covalently bonded to the silicon-containing material.The surface may also be covered with a coating material that comprises 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.

[0087] The optional coating may have one or more different functions, such as: The coating may protect the silicon particles from degradation. Coatings can control the release profile of the drug substance. Coatings may affect the in vivo biodistribution of particles following administration. Coatings can improve the loading of API into silicon-containing particles. · The coating may form the basis for covalent bonding of the drug substance to the coating material.

[0088] 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. Positively charged particle surfaces at physiological pH. This can typically be achieved by the attachment of aliphatic amino groups to the particle surface. Negatively charging the particle surface at physiological pH. This can typically be achieved by the attachment of carboxylic acid 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).

[0089] 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 can be up to 1000 m per gram of particle. 2 may be also possible.

[0090] In a particularly preferred embodiment, the silicon particles do not comprise a coating or covering layer that does not dissolve in the stomach but dissolves in the small intestine and / or large intestine.

[0091] [drug substance] The silicon particles of the present invention optionally contain one or more active pharmaceutical ingredients. The silicon particles may contain only one active pharmaceutical ingredient, but it is also possible that there is more than one active pharmaceutical ingredient, such as two or three active pharmaceutical ingredients.

[0092] The invention further relates to a method for the preparation of a medicament comprising such particles comprising silicon produced by chemical vapor deposition (CVD) and, optionally, one or more drug substances, characterized in that the particles are mixed with the drug substance by mixing the silicon particles of the invention and the drug substance at ambient temperature in a solvent in which the particles are dispersed and in which the drug substance is at least partially soluble.

[0093] Drug substances for use in accordance with the present invention include any drug substance that is a regulatory agency approved drug substance, as well as any drug substance under development for prophylactic use and / or treatment of disease.

[0094] One preferred embodiment of the present invention relates to drugs 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, including anti-infectives and antiseptics for local oral treatment, corticosteroids for local oral treatment, and other drugs for local oral treatment.

[0095] Combinations for eradication of Helicobacter pylori, including prostaglandins, e.g., misoprostol and enprostil, proton pump inhibitors, e.g., omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole, dexlansoprazole, dexrabeprazole and vonoprazan, including drugs for peptic ulcer and Gastro-Oesophageal Reflux Disease (GORD), including H2 receptor antagonists, such as cimetidine, ranitidine, famotidine, nizatidine, niperotidine, roxatidine, ranitidine bismuth citrate and lafutidine, Other drugs for Acid Related Disorders, including other drugs for Glycosyltransferase (GORD), such as antacids, including carbenoxolone, sucralfate, pirenzepine, methiosulfonium chloride, bismuth subcitrate, proglumide, gefarnate, sulglycotide, acetoxolone, zolimidine, troxipide, bismuth subnitrate, arginic acid, rebamipide, carbenoxolone, and gefarnate.

[0096] Drug substances for the treatment of functional gastrointestinal disorders, including antispasmodics such as belladonna alkaloids and their derivatives.

[0097] 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, anti-constipation drug substances including laxatives, drug substances for the treatment of diarrhea, anti-obesity drug substances, and gastrointestinal additives including enzymes.

[0098] Drugs for the treatment of diabetes including insulin and analogues, including fast acting, injectable insulins and analogues such as, for example, insulin (human), insulin (bovine), insulin (porcine), insulin lispro, insulin aspart and insulin glulisine, including medium acting, injectable insulins and analogues such as, for example, insulin (human), insulin (bovine), insulin (porcine), insulin lispro, including medium or long acting, injectable insulins and analogues in combination with fast acting ones such as, for example, insulin (human), insulin (bovine), insulin (porcine), insulin lispro, insulin aspart, insulin degludec and insulin aspart, including insulin and analogues such as, for example, insulin (human), including long acting, injectable insulins and analogues such as, for example, insulin (bovine), insulin (porcine), insulin glargine, insulin detemir, insulin degludec, insulin glargine and lixisenatide and insulin degludec and liraglutide.biguanides such as, for example, phenformin, metformin and buformin; sulfonylureas such as, for example, glibenclamide, chlorpropamide, tolbutamide, glibornuride, tolazamide, carbutamide, glipizide, gliquidone, gliclazide, metahexamide, glisoxepide, glimepiride and acetohexamide; heterocyclic sulfonamides such as, for example, glymidine; alpha-glycosidase inhibitors such as, for example, acarbose, miglitol and voglibose; thiazolidinediones such as, for example, troglitazone, rosiglitazone, pioglitazone and lobeglitazone; for example, sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, gemigliptin. , including dipeptidyl peptidase 4 (DPP-4) inhibitors such as evogliptin and teneligliptin, including glucagon-like peptide-1 (GLP-1) analogues such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, veinaglutide, etc., other non-insulin blood glucose lowering drugs including sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, sotagliflozin, luseogliflozin, etc., and other diabetes related drug substances such as guar gum, repaglinide, nateglinide, pramlintide, benfluorex, mitiglinide and tolrestat.

[0099] Vitamins include any vitamin within the group: vitamin A, vitamin B, vitamin C, vitamin D, vitamin E and vitamin K.

[0100] 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 antithrombotic agents, including vitamin K antagonists such as warfarin, including dicoumarol, phenindione, and heparin, platelet aggregation inhibitors such as picotamide, clopidogrel, ticlopidine, acetylsalicylic acid, and dipyridamole, direct thrombin inhibitors such as desirudin, lepirudin, argatroban, melagatran, ximelagatran, bivalirudin, and dabigatran etexilate, direct factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and betrixaban, and other antithrombotic agents.

[0101] 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, including 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 regulators such as simvastatin, atorvastatin and ezetimibe.

[0102] Another preferred embodiment of the present invention relates to drugs for the preventive use and / or treatment of skin-related diseases, including dermatological agents. Such drug substances are typically included in ATC Group D.

[0103] Another preferred embodiment of the present invention relates to drugs for the preventive use and / or treatment of diseases related to the urogenital system, including sex hormones. Such drug substances are typically included in ATC group G. Such drug substances include 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.

[0104] 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, including pituitary and hypothalamic hormones, corticosteroids, and other hormones in clinical use.

[0105] 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.

[0106] Antibacterial agents include drug substances such as tetracyclines, chloramphenicol, beta-lactam antibiotics such as penicillins and cephalosporins, sulfonamides and trimethoprim, macrolides, lincosamides and streptogramins, aminoglycoside antibacterial agents, quinolone antibacterial agents, and the like.

[0107] Antifungal agents include, for example, substances such as imidazole derivatives, triazole derivatives, nystatin, and amphotericin B.

[0108] Antiviral agents include, for example, materials such as thiosemicarbazones, non-reverse transcriptase inhibitors nucleosides and nucleotides, cyclic amines, phosphonic acid derivatives, protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, neuraminidase inhibitors, integrase inhibitors, and antivirals for the treatment of HCV infection.

[0109] Another preferred embodiment of the present invention relates to anti-neoplastic drug substances and drugs for the prophylactic use and / or treatment of diseases associated with immunomodulators. Such drug substances are included in ATC Group L.

[0110] Antineoplastic drugs are included in ATC group L1. A preferred embodiment of the invention relates to drugs within ATC group L01.

[0111] Antineoplastic drugs include alkylating agents such as cyclophosphamide, chlorambucil, melphalan, mechlorethamine, ifosfamide, trofosfamide, prednimustine, bendamustine, busulfan, treosulfan, mannosulfan, thiotepa, triaziquone, carboquone, carmustine, lomustine, semustine, streptozocin, fotemustine, nimustine, ranimustine, uramustine, etoglucide, mitobronitol, pipobroman, temozolomide, and dacarbazine. antimetabolites such as methotrexate, raltitrexed, pemetrexed, pralatrexate, mercaptopurine, thioguanine, cladribine, fludarabine, clofarabine, nelarabine, cytarabine, fluorouracil, tegafur, carmofur, gemcitabine, capecitabine, azacitidine, decitabine, floxuridine, trifluridine, antimetabolites such as vinblastine, vincristine, vindesine, vinorelbine, vinflunine, vintafolide, etoposide, teniposide, demecolcine plant alkaloids and other natural products such as paclitaxel, docetaxel, paclitaxel poliglumex, cabazitaxel, topotecan, irinotecan, etirinotecan pegol, belotecan and trabectedin; cell-inflammatories such as dactinomycin, doxorubicin, daunorubicin, epirubicin, aclarubicin, zorubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, amrubicin, pixantrone, bleomycin, plicamycin mitomycin and ixabepilone; anti-inflammatory drugs and related substances, protein kinase inhibitors, e.g., BCR-ABL tyrosine kinase inhibitors such as imatinib, dasatinib, nilotinib, bosutinib and ponatinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, e.g., gefitinib, erlotinib, afatinib, osimertinib, rociletinib, olmutinib, dacomitinib and icotinib, B-Raf serine-threonine kinase inhibitors, e.g., vemurafenib, dabrafenib and encorafenib,BRAF (brain activating factor receptor (BRAF)) inhibitors, such as Anaplastic Lymphoma Kinase (ALK) inhibitors, such as crizotinib, ceritinib, alectinib, brigutinib, and lorlatinib; Mitogen-activated protein kinase (MEK) inhibitors, such as trametinib, cobimetinib, binimetinib, and 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 (HEG) inhibitors, such as lapatinib, naratinib, and tucatinib; 2, HER2 tyrosine kinase inhibitors, for example, Janus-Associated Kinase (JAK) inhibitors such as ruxolitinib and fedratinib, Vascular Endothelial Growth Factor Receptor (VEGFR) tyrosine kinase inhibitors such as axitinib, cediranib and tivozanib, Bruton's tyrosine kinase inhibitors such as ibrutinib, acalabrutinib and zanubrutinib,Kinase (BTK) inhibitors, for example, phosphatidylinositol-3-kinase (Pi3K) inhibitors such as idelalisib, copanlisib, alpelisib and duvelisib, for example, sunitinib, sorafenib, pazopanib, vandetanib, regorafenib, masitinib, cabozantinib, lenvatinib, nintedanib, midostaurin, quizartinib, larotrectinib, gilteritinib, entrectinib, pexidartinib, erdafitinib, capmatinib, other protein kinase inhibitors such as avapritinib, ripretinib, pemigatinib and tepotinib, other antineoplastic agents such as platinum compounds such as cisplatin, carboplatin, oxaliplatin, satraplatin and polyplatin, methylhydrazines such as procarbazine, e.g. edrecolomab, rituximab, trastuzumab, gemtuzumab ozogamicin, cetuximab, bevacizumab, panitumumab, catumaxomab, ofatumumab, ipilimumab, brentuximab vedotin, pertuzumab, trastuzumab Monoclonal antibodies such as bumetazin, obinutuzumab, dinutuximab beta, nivolumab, pembrolizumab, blinatumomab, ramucirumab, necitumumab, elotuzumab, daratumumab, mogamulizumab, inotuzumab ozogamicin, olaratumab, durvalumab, bermekimab, avelumab, atezolizumab, cemiplimab, moxetumomab pasudotox, tafasitamab, enfortumab vedotin, polatuzumab vedotin, isatuximab, belantamab mafodotin, dostarlimab, and trastuzumab deruxtecan; sensitizers used in photodynamic therapy / radiotherapy, such as porfimer sodium, methyl aminolevulinate, aminolevulinic acid, temoporfin, efaproxiral, padeliporfin, retinoids for cancer treatment, such as tretinoin, alitretinoin and bexarotene, proteasome inhibitors, such as bortezomib, carfizomib and ixazomib, histone deacetylase inhibitors, such as vorinostat, romidepsin, panobinostat, belinostat and entinostat,Deacetylase (HDAC) inhibitors, such as hedgehog pathway inhibitors such as vismodegib, sonidegib and glasdegib; poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, niraparib, rucaparib, talazoparib and veliparib; amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine, pentostatin, masoprocol, estramustine, mitoguazone, tiazofurin, mitotane, pegaspargase, arsenic trioxide, denileukin diftitox, celecoxib, anagrelide, oblimersen, sitimagene ceradenovec), omacetaxine mepesuxinate, eribulin, aflibercept, talimogene laherparepvec, venetoclax, vosaroxin, plitidepsin, epacadostat, enasidenib, ivosidenib, selinexor, tagraxofusp, lurbinectedin, axicabtagene ciloreucel, and tisagenlecleucel.

[0112] Drug substances for endocrine therapy, including hormones and antihormones. These drug substances are included in ATC group L02.

[0113] Immunostimulants are included in ATC group L03. A preferred embodiment of the present invention relates to drugs within ATC group L03.

[0114] Immunostimulants include colony stimulating factors, such as filgrastim, molgramostim, sargramostim, lenograstim, ancestim, pegfilgrastim, lipegfilgrastim, valgrastim, empegfilgrastim, and pegteograstim, such as interferon alpha natural, interferon beta natural, interferon gamma, interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon beta-1a, interferon beta-1b, interferon alfacon-1, peginterferon alpha-2b, peginterferon alpha-2a, including interferons such as albinterferon alfa-2b, peginterferon beta-1a, cepeginterferon alfa-2b, lopeginterferon alfa-2b, including interleukins such as aldesleukin and oprelvekin, for example, lentinan, rokinimex, BCG vaccine, pegademase, pidotimod, poly I:C, poly ICLC, thymopentin, immunocyanin, tasonermin, melanoma vaccine, glatiramer acetate, histamine, mifamurtide, plerixafor, sipuleucel-T, clidanimod, dasiprotimut-T, and elapeguademase.

[0115] Immunosuppressants are included in ATC group L04. A preferred embodiment of the present invention relates to drugs within ATC group L04.

[0116] Selective immunosuppressants such as muromonab-CD3, antilymphocyte immunoglobulin (horse), antilymphocyte immunoglobulin (rabbit), mycophenolate including mycophenolate mofetil, sirolimus, leflunomide, alefacept, everolimus, gusperimus, efalizumab, avetimus, natalizumab, abatacept, eculizumab, belimumab, fingolimod, beratidine, buprenorphine ... Tacept, Tofacitinib, Teriflunomide, Apremilast, Vedolizumab, Alemtuzumab, Begelomab, Ocrelizumab, Baricitinib, Ozanimod, Emapalumab, Cladribine, Imlifidase, Siponimod, Ravulizumab, Upadacitinib, Filgotinib, Itacitinib, Inebilizumab, e.g. Etanercept Infliximab, Afelimomab, Adalimumab Immunosuppressants including other immunosuppressants such as, for example, azathioprine, thalidomide, methotrexate, lenalidomide, pirfenidone, pomalidomide, dimethyl fumarate and dalvadostrocel; interleukin inhibitors including, for example, daclizumab, basiliximab, anakinra, rilonacept, ustekinumab, tocilizumab, canakinumab, briakinumab, secukinumab, siltuximab, brodalumab, ixekizumab, sarilumab, sirulumab, guselkumab, tildrakizumab, risankizumab and satralizumab; calcineurin inhibitors including, for example, cyclosporine, tacrolimus and voclosporin; tumor necrosis factor alpha (TNF-alpha) inhibitors such as certolizumab pegol, golimumab and opinercept.

[0117] 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 system, 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 system, including anti-inflammatory and anti-rheumatic compounds, such as non-steroidal anti-inflammatory compounds including indomethacin, diclofenac, ibuprofen and naproxen, and muscle relaxants.

[0118] Another preferred embodiment of the present invention relates to a drug 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 groups related to the nervous system include, for example, opium, such as natural opium alkaloids, e.g., morphine, codeine, and oxycodone; synthetic compounds, such as pethidine, ketobemidone, and fentanyl; antiepileptic drugs, e.g., barbiturates, hydantoin derivatives, oxazolidine derivatives, succinimide derivatives, benzodiazepine derivatives, carboxamide derivatives, and fatty acid derivatives; antiparkinson drugs, such as anticholinergics and dopaminergics; psycholeptic drugs, such as antipsychotics, anxiolytics, and hypnotics and sedatives; antidepressants, psychostimulants, drug substances used in ADHD, psychoenhancing drugs, such as nootropics, psycholeptics, and anti-dementia drugs.

[0119] 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.

[0120] Another preferred embodiment of the present invention relates to drugs for prophylactic and / or therapeutic use in the ear and eye. Such drug substances are included in ATC Group S.

[0121] In particularly preferred embodiments of the present invention, the at least one drug substance 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 steroidal drugs.

[0122] In a preferred embodiment, the at least one drug substance is selected from the group consisting of atorvastatin, simvastatin, losartan, valsartan, candesartan, enalapril, atenolol, propranolol, hydroclothiazide, cyclosporine, amphotericin B, diltiazem, phenoxymethylpenicillin, azithromycin, rapamycin, griseofulvin, chloramphenicol, erythromycin, acyclovir, nystatin, phenytoin, phenobarbital, ampicillin, celecoxib, prednisolone, and metformin.

[0123] A preferred embodiment of the present invention relates to silicon particles that can deliver both a clinically useful dose of hydrogen and one or more additional drugs. This dual drug delivery system based on silicon particles including CVD-SP, particularly cCVD-SP and PcCVD-SP, is a preferred embodiment of the present invention.

[0124] Such dual silicon-based drug delivery systems include drug delivery systems in which a clinically relevant dose of hydrogen is delivered together with a clinically relevant dose of another drug.This delivery can be in the form of a combined use or in the form of a combined product.In a combined use, hydrogen and one or more additional drugs can be administered in one or more separate dosage forms, for example in the form of one tablet, or for example in the form of two or more different tablets.In a combined product, hydrogen and one or more additional drug substances are present in the same dosage form, for example in the same tablet.

[0125] Optionally, one or more additional active pharmaceutical ingredients may be incorporated into silicon particles, or may be present in the drug product without being incorporated into silicon particles.A typical example for the first option is the amorphous cCVD particles containing erythromycin formulated in a capsule formulation for the treatment of bacterial infections based on the therapeutic effects of both hydrogen and erythromycin.A typical example for the similar product based on the second option is the simple amorphous cCVD particles formulated with erythromycin in a capsule formulation for the treatment of bacterial infections based on the therapeutic effects of both hydrogen and erythromycin.

[0126] The combination therapy and combination product options described in this patent document may provide additive therapeutic efficacy, including fully additive therapeutic effects, or even more preferably, a synergistic effect of molecular hydrogen with one or more additional pharmaceutical agents.

[0127] Several clinically relevant combination therapies and products include silicon-based products that form hydrogen gas in vivo and further release one or more active pharmaceutical ingredients.

[0128] Some examples of combination uses and combination products are silicon hydrogen forming products that contain additional drugs for the treatment of CNS disorders such as Parkinson's disease, ischemic cerebral disease and Alzheimer's disease.

[0129] A typical example of a combination product for the treatment of Parkinson's disease includes silicon particles for hydrogen delivery and one or more of the following drug substances: levotopa, preferably in combination with a dopamine decarboxylate inhibitor, such as benserazide or carbidopa, dopamine agonists, such as bromocriptine, pergolide, pramipexole, ropinirole and rotigotine, monoamine oxidase-B-inhibitors, such as selegiline and rasagiline, catechol-O-methyltransferase inhibitors, such as entacapone and opicapone.

[0130] A typical example of a combination product for the treatment of Alzheimer's disease includes silicon particles for hydrogen delivery and one or more of the following drug substances: cholinesterase inhibitors such as donepezil, rivastigmine and galantamine, glutamate modulators such as memantine, orexin receptor antagonists such as suvorexan, and disease modifying drugs such as aducanumab, a human antibody that targets the protein beta-amyloid and reduces amyloid plaques.

[0131] Some examples of combination uses and combination products are silicon hydrogen forming products that contain additional drugs for the treatment of cancer disorders.

[0132] A typical example of a combination product for the treatment of Alzheimer's disease would include silicon particles for hydrogen delivery and one or more of the following drug substances: Alkylating agents, antimetabolites, plant alkaloids and other natural products, cytotoxic antibiotics and related substances, protein kinase inhibitors, CD20 inhibitors, CD22 inhibitors, CD38 inhibitors, HER2 inhibitors, EGFR (Epidermal Growth Factor Receptor) inhibitors, PD-1 / PDL-1 (Programmed Cell Death Protein 1 / Death Ligand 1) inhibitors, monoclonal antibodies and antibody conjugates such as VEGF / VEGFR (Vascular Endothelial Growth Factor) inhibitors, other monoclonal antibodies and antibody drug conjugates, as well as platinum compounds, methylhydrazines, sensitizing drugs used in photodynamic therapy / radiotherapy, retinoids for cancer treatment, proteasome inhibitors and other antineoplastic agents such as histone deacetylase (HDAC) inhibitors and Hedgehog pathway inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors and other antineoplastic agents. Other drug classes include hormones and hormone antagonists for endocrine therapy.

[0133] Some examples of combination uses and combination products are silicon hydrogen forming products that include an additional drug for the treatment of immune related disorders.

[0134] Typical examples include immune stimulants such as colony stimulating factors, such as interferons and interleukins.

[0135] Typical examples include immunosuppressants such as muromonab-CD3, selective immunosuppressants such as antilymphocyte immunoglobulin (horse), antilymphocyte immunoglobulin (rabbit), mycophenolic acid and esters such as mycophenolate mofetil, sirolimus (rapamycin, leflunomide, alefacept, everolimus, gusperimus, efalizumab, avetimus, natalizumab, abatacept, eculizumab, belimumab, fingolimod, belatacept, tofacitinib, ozanimod, ez ... Tumor necrosis factor alpha (TNF)-alpha inhibitors, such as mapalumab, cladrizidin, imlifidase, siponimod, ravulizumab, upadacitinib, filgotinib, itacitinib, inebilizumab, belmosudil, peficitinib, ponesimod, anifrolumab, ofatumumab teprotunumab, pegcetacoplan, stimulimab and deuclavacitinib, tumor necrosis factor alpha (TNF) inhibitors, such as etanercept, infliximab, afelimomab, adalimumab, certolizumab pegol, golimumab and opinercept; Necrosis Factor alpha (TNF-α) inhibitors, interleukin inhibitors such as daclizumab, basiliximab, anakinra, rilonacept, ustekinumab, tocilizumab, canakinumab, briakinumab, secukinumab, siltuximab, brodalumab, ixekizumab, sarilumab, sirukumab, guselkumab, tildrakizumab, risankizumab, satralizumab, netakimab, bimekizumab and spesolimab, and calcineurin inhibitors such as cyclosporine, tacrolimus and voclosporin.

[0136] Some examples of combination uses and combination products are silicon hydrogen forming products that contain additional drugs for the treatment of kidney-related disorders.

[0137] Some examples of combination uses and combination products are silicon hydrogen forming products that contain additional drugs for the treatment of liver-related disorders.

[0138] Some examples of combination uses and combination products are silicon hydrogen forming products that contain additional drugs for the treatment of pancreatic related disorders and metabolic disorders such as diabetes.

[0139] Some examples of combination uses and combination products are silicon hydrogen forming products that include an additional drug for the treatment of gastrointestinal disorders, including intestinal disorders such as inflammatory bowel disease.

[0140] Some examples of combination uses and combination products are silicon hydrogen forming products that contain additional drugs for the treatment of cardiovascular disease, particularly heart disease.

[0141] Some examples of combination uses and combination products are silicon hydrogen forming products that contain additional drugs for the treatment of pulmonary diseases including asthma and COPD.

[0142] A highly preferred embodiment of the present invention relates to a cCVD-SP comprising an active pharmaceutical ingredient, said active pharmaceutical ingredient being poorly soluble in water.

[0143] In particularly preferred embodiments of the present invention, one or more of the active pharmaceutical ingredients is in the form of a complex with a cyclodextrin.

[0144] The most frequently used drug complex in clinical use is a complex with cyclodextrin. Cyclodextrin is a cyclic oligosaccharide containing 6 to 8 glucose subunits. α (alpha)-cyclodextrin is composed of 6 glucose subunits, β (beta)-cyclodextrin is composed of 7 glucose subunits, and γ (gamma)-cyclodextrin is composed of 8 glucose subunits. Any cyclodextrin or derivative thereof can be used in the present invention. The most preferred cyclodextrins are beta-cyclodextrin, 2.hydroxypropyl-β-cyclodextrin, and 4-sulfobutyl-β-cyclodextrin.

[0145] A preferred embodiment of the present invention relates to a cCVD-SP comprising one drug substance, said drug substance being in the form of a complex with cyclodextrin.

[0146] A more preferred embodiment of this aspect of the invention relates to a cCVD-SP comprising one drug substance, said drug substance being in the form of a complex with beta-cyclodextrin or a derivative thereof.

[0147] An even more preferred embodiment of this aspect of the invention relates to a PcCVD-SP which comprises one active pharmaceutical ingredient, which is in the form of a complex with cyclodextrin beta-cyclodextrin or a derivative thereof.

[0148] A preferred embodiment of the present invention relates to a cCVD-SP comprising two drug substances, at least one of said drug substances being in the form of a complex with cyclodextrin.

[0149] A more preferred embodiment of this aspect of the invention relates to a PcCVD-SP comprising two drug substances, at least one of said drug substances being in the form of a complex with beta-cyclodextrin or a derivative thereof.

[0150] A preferred embodiment of the present invention relates to a cCVD-SP comprising three or more drug substances, at least one of said drug substances being in the form of a complex with cyclodextrin.

[0151] A more preferred embodiment of this aspect of the invention relates to a PcCVD-SP comprising three or more drug substances, at least one of said drug substances being in the form of a complex with beta-cyclodextrin or a derivative thereof.

[0152] The present invention further relates to a process for the preparation of cCVD-SP or PcCVD-SP loaded with at least one drug cyclodextrin, characterized in that the cCVD-SP or PcCVD-SP and at least one drug cyclodextrin complex are mixed at ambient temperature in a solvent in which the particles are dispersed and in which the drug cyclodextrin complex is at least partially soluble.

[0153] Another preferred method for the preparation of cCVD-SP or PcCVD-SP loaded with at least one drug cyclodextrin complex is characterized by forming a drug cyclodextrin complex within the particles by mixing the cCVD-SP and PcCVD-SP with cyclodextrin at ambient temperature in a solvent in which the particles are dispersed and in which the drug cyclodextrin is at least partially soluble, optionally followed by isolation of the particles, followed 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 substance is at least partially soluble.

[0154] 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. If 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, if one or more of the drug substances are in the form of a cyclodextrin complex, the above weight % is a range based on the total weight of the cyclodextrin complex.

[0155] Composition and Use The present invention further relates to a pharmaceutical composition comprising the silicon particles defined above and one or more pharma- ceutically acceptable carriers, diluents or excipients, such carriers, diluents and excipients being well known in the art.

[0156] 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 and PcCVD-SP are typically selected from among sodium chloride or other physiologically acceptable salts, sugars, surfactants, antioxidants, flavors, sweeteners and pH adjusters.

[0157] Typically, oral capsules containing cCVD-SP and PcCVD-SP are capsules prepared from gelatin or hydroxypropyl methyl cellulose (HPMC). Typical excipients in such capsules include lactose, microcrystalline cellulose, and inorganic salts.

[0158] Typically, tablets containing cCVD-SP and 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.

[0159] The present invention relates to silicon particles as defined above for use in a therapy. Typically, said therapy involves hydrogen delivery, i.e. it involves the production and delivery of hydrogen to a subject.

[0160] In a further embodiment, the present invention relates to silicon particles 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 cancer, such as lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, skin cancer, testicular cancer, pancreatic cancer, colorectal cancer, renal cancer, cervical cancer, gastrointestinal cancer, and combinations thereof; pain-related disorders; diabetes; hypertension and immune-related disorders.

[0161] The particles 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 oral.

[0162] For oral administration, aqueous suspension, tablet and capsule are the most preferred formulations, and for dermal application, cream and ointment 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.The 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 suspension of particles.Ophthalmic products are typically sterile aqueous suspensions of particles, while the typical composition for nasal administration can be dry particles or aqueous suspensions.

[0163] 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.

[0164] 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.

[0165] 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 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 aforementioned effective daily amounts 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.

[0166] One embodiment of the present invention relates to a pharmaceutical composition comprising 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 injection 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.

[0167] In one embodiment, the pharmaceutical composition is formulated for parenteral administration, such as injection or infusion.

[0168] Furthermore, it is preferred if the pharmaceutical composition does not contain any organic acids.

[0169] It is also preferred if the silicon particles in the pharmaceutical composition do not comprise a coating or covering layer that does not dissolve in the stomach but dissolves in the small intestine and / or large intestine.

[0170] It is further preferred if the pharmaceutical composition further comprises an organic non-absorbable base. By "organic non-absorbable base" is meant a compound that does not contain sodium, potassium and other absorbable inorganic ions. The organic non-absorbable base is preferably selected from non-toxic and non-absorbable organic bases, such as amino sugars, e.g., N-methylglucamine, and water-soluble or water-insoluble polymeric materials.

[0171] One preferred embodiment of this aspect of the invention relates to a pharmaceutical composition comprising cCVD-SP or PcCVD-SP.

[0172] A 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 drug substance in the form of a free drug substance.

[0173] Another 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.

[0174] 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 beta-cyclodextrin complex.

[0175] 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.

[0176] 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 or a pharma- ceutically acceptable salt thereof.

[0177] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises at least one active ingredient in the form of a free active ingredient or a pharma- ceutically acceptable salt thereof, and wherein said silicon is in amorphous or crystalline form, comprising cCVD-SP or PcCVD-SP.

[0178] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises at least one active ingredient in the form of a free active ingredient or a pharma- ceutically acceptable salt thereof, and comprises cCVD-SP, wherein said silicon is in amorphous or crystalline form.

[0179] Another more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises at least one drug substance in the form of a free drug substance or a pharma- ceutically acceptable salt thereof, and comprises a non-etched cPCVD-SP, wherein said silicon is in amorphous or crystalline form.

[0180] 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.

[0181] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises at least one active pharmaceutical ingredient in the form of a cyclodextrin complex, and wherein the silicon is in amorphous or crystalline form, cCVD-SP or PcCVD-SP.

[0182] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises at least one active pharmaceutical ingredient in the form of a cyclodextrin complex and cCVD-SP, wherein the silicon is in amorphous or crystalline form as described above.

[0183] An even more preferred embodiment of this aspect of the invention is one in which the pharmaceutical composition comprises at least one active pharmaceutical ingredient in the form of a beta-cyclodextrin complex and the silicon as described above is in amorphous or crystalline form, comprising cCVD-SP or PcCVD-SP.

[0184] A further 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 an unsubstituted beta-cyclodextrin complex.

[0185] 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 beta-cyclodextrin complex.

[0186] Further preferred embodiments of this aspect of the invention are those in which the pharmaceutical composition comprises a cCVD-SP that comprises at least one active pharmaceutical ingredient in the form of an unsubstituted beta-cyclodextrin complex, a 2-hydroxypropyl-beta-cyclodextrin complex, or a 4-sulfobutyl-beta-cyclodextrin complex.

[0187] An even more 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 beta-cyclodextrin complex, a 2-hydroxypropyl-beta-cyclodextrin complex, or a 4-sulfobutyl-beta-cyclodextrin complex.

[0188] 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 beta-cyclodextrin complex, a 2-hydroxypropyl-beta-cyclodextrin complex, or a 4-sulfobutyl-beta-cyclodextrin complex.

[0189] The BCS (Biopharmaceutics 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, for example, Amidon GL, Lennernas 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.

[0190] A highly preferred embodiment of this aspect of the invention relates to a pharmaceutical composition of cCVD-SP comprising a drug substance, said drug substance being classified as BCS class II.

[0191] A further highly preferred embodiment of this aspect of the invention relates to a pharmaceutical composition of the non-etched PcCVD-SP comprising a drug substance, said drug substance being classified as a BCS class II drug substance.

[0192] The oral bioavailability of drug substances varies from nearly 0% to nearly 100%. The absolute bioavailability of some of the more frequently used drugs are: atorvastatin (bioavailability 12%), simvastatin (bioavailability less than 5%), losartan (bioavailability 33%), valsartan (bioavailability 25%), candesartan (bioavailability 40%), enalapril (bioavailability 60%), atenolol (bioavailability 40-50%), propranolol (bioavailability 26%), hydroclothiazide (bioavailability 70%), cyclosporine (bioavailability very low), amphotericin B (bioavailability very low), diltiazem (bioavailability 40%), phenoxymethylpenicillin (bioavailability 50%), azithromycin (bioavailability 40%), and metformin (bioavailability 50-60%).

[0193] In the context of formulating a pharmaceutical composition for oral administration, the following represent preferred embodiments.

[0194] Another highly preferred embodiment of the present invention relates to a pharmaceutical composition of cCVD-SP comprising a drug substance, said drug substance being itself a drug substance with low oral bioavailability.Typical low bioavailability is less than 50%, more preferably less than 30%, more preferably less than 20%, most preferably less than 10%.

[0195] A highly preferred embodiment of this aspect of the invention relates to a pharmaceutical composition of PcCVD-SP comprising a drug substance, said drug substance being itself a drug substance having low oral bioavailability.Typical low bioavailability is less than 50%, more preferably less than 30%, more preferably less than 20%, and most preferably less than 10%.

[0196] 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.

[0197] 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 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.

[0198] The list of drugs that are almost insoluble or have very low aqueous solubility is extensive. Some examples of these well-known drugs in clinical use around the world include, but are not limited to, simvastatin, lovastatin, celecoxib, naproxen, ibuprofen, estradiol, testosterone, finasteride, glipizide, ketoconazole, methylprednisolone, mometrasone, triamcinolone, griseofulvin, and amphotericin B.

[0199] Another highly preferred embodiment of the present invention relates to a pharmaceutical composition of cCVD-SP comprising a drug substance having a partition coefficient value (amount of a substance that dissolves in water relative to the organic phase, which is a measure of 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.

[0200] Another highly preferred embodiment of this aspect of the invention relates to a pharmaceutical composition of PcCVD-SP comprising a drug substance having a 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.

[0201] Some typical examples of well-known drugs in clinical use include the following drug substances known to have high logP values: Amiodarone (logP 7.81), amitriptyline (logP 4.41), amlodipine (logP 3.01), antazoline (logP 3.58), aripiprazole (logP 3.76), atomoxetine (logP 3.36), bacampicillin (logP 3.52), benzphentamine (logP 3.84), benztropine (logP 4.04), bitolterol (logP 4.16), bosentan (logP 4.36), bromodiphenhydramine (logP 4.03), brompheniramine (logP 3.24), bufuralol (logP 3.54), bupivacaine (logP 3.31), butacaine (logP 4.62), butaclamol (logP 3.81), butorphanol (logP 3.54), carbenoxolone (logP 6.63), carvedilol (logP 4.11), chlorcyclidine (logP 3.24), chlorpromazine (logP 5.35), chlorprothixene (logP 5.31), cinchonine (logP 3.69), citalopram (logP 3.47), clofibrate (logP 3.88), clopenthixol (log P3.91), clotrimazole (logP 4.92), clozapine (logP 3.94), cyclazocine (logP 3.52), cyclobenzaprine (logP 6.19), cyproheptadine (logP 4.92), darifenicin (logP 3.78), deserpidine (logP 4.95), desipramine (logP 3.97), desloratadine (logP 3.50), dextrobrompheniramine (logP 3.24), dextrofenfluramine (logP 3.55), dextromethorphan (logP 3.89), dibenzepin (logP 3.26), 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 (logP 4.73), dimethisoquine (logP 4.04), diperrodone (logP 4.65), diphenhydramine (logP 3.27), difenoxin (logP 3.97), diphenoxylate (logP 4.51), diphenylpyraline (logP 3.43), dipipanone (logP 5.10), dipyridamole (logP 3.35), donepezil (logP 3.91), doxepin (logP 3.85), droperidol (logP 3.10), duloxetine (logP 4.81), emetine (logP 3.82), enalapril (logP 3.25), enalaprilat (logP 3.63), entacapone (logP 3.02), ergotamine (logP 7.37), estrone (logP 3.62), ethopropazine (log 4.77), etidocaine (logP 3.57), etomidate (logP 3.05), fenclofenac (logP 4.59), fenfluramine (logP 3.55), fenoprofen (logP 3.72), fentanyl (logP 3.68), fesoterodine (logP 5.08), fexofenadine (logP 3.73), finasteride (logP 3.83), flurbiprofen (logP 3.66), flufenamic 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 3.08), haloperidol (logP 3.76), hexylcaine (logP 3.65), hycanthone (logP 3.81), ibuprofen (logP 3.50), imipramine (logP 4.35), indacaterol (logP 3.88), indomethacin (logP 4.25), iocetamic acid (logP 4.57), iodipamide (logP 5.10), iodoquinol (logP 4.10), iopanoic acid (logP 4.65), iprindole (logP 5.02), irbesartan (logP 5.25), ketamine (logP 3.01), ketoconazole (logP 4.04), levallorphan 8 (logP 3.85), levorphanol (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 (logP 3.93), methdilazine (logP 4.64), methotrimeprazine (logP 4.94), metolazone (logP 3.16), miconazole (logP 4.97), midazolam (logP 3.80), montelukast (logP 5.81), nabilone (logP 7.25), nebivolol (logP 4.08), nelfinavir (logP 7.28), nortriptyline (logP 3.97), novobiocin (logP 3.74), olanzapine (logP 3.08), orphenadrine (logP 3.33), oxybutynin (logP 5.05), oxyphenylbutazone (logP 3.28), pamaquine (logP 4.38), penbutolol (logP 4.02), pentazocine (logP 4.15), pergolide (logP 3.90), perphenazine (logP 3.94), perhexiline (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), and pivampicillin (logP 3.88), prasugrel (logP 4.31), prazepam (logP 3.70), prochlorperazine (logP 4.65), promazine (logP 4.69), promethazine (logP 4.89), proparacaine (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), thiopropazate (logP 4.76), thioridazine (logP 5.90), thiothixene (logP 3.72), L-tyrosine (logP 4.72), tiagabine (logP 4.03), ticrynfen (logP 3.05), toloteridine (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), vardenafil (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). .

[0202] As discussed herein, the silicon particles of the present invention are capable of generating hydrogen under certain conditions.

[0203] Thus, in a further aspect, the present invention relates to a method for generating hydrogen (H2) using silicon particles as defined herein above, the method comprising: a) preparing silicon particles by chemical vapor deposition (CVD); b) exposing the silicon particles prepared in step a) to a pH of at least 7.0.

[0204] Preferably, the method further comprises a step a1) of loading the silicon particles with at least one active pharmaceutical ingredient, such as a substance as defined hereinabove, wherein step a1) is performed between steps a) and b).

[0205] Step a) of this process involves preparing silicon particles by CVD. The silicon particles and CVD method may be as described above, and all preferred and optional aspects described above apply equally to this embodiment.

[0206] Step b) of this process can be carried out in vitro or in vivo. Preferably, step b) is carried out in vivo.

[0207] When step b) is carried out in vitro, the method may comprise administering the above-mentioned silicon particles in a composition formulated for administration to plants, including, for example, plants for the production of food and feed.

[0208] When step b) is carried out in vivo, this step preferably comprises administering to a subject silicon particles as described above, said particles being present in a pharmaceutical composition as defined hereinbefore. The subject may be a human or animal subject.

[0209] In this embodiment, it is particularly preferred if the pharmaceutical composition is formulated for oral administration.

[0210] Furthermore, it is preferred if the pharmaceutical composition does not contain any organic acids.

[0211] It is also preferred if the silicon particles do not comprise a coating or covering layer that does not dissolve in the stomach but dissolves in the small intestine and / or large intestine.

[0212] It is more preferred if the pharmaceutical composition further comprises an organic non-absorbable base. Alternatively, the organic non-absorbable base can be administered simultaneously, separately, or sequentially with the pharmaceutical composition. By "organic non-absorbable base" is meant a compound that does not contain sodium, potassium, and other absorbable inorganic ions. The organic non-absorbable base is preferably selected from non-toxic and non-absorbable organic bases, such as amino sugars, such as N-methylglucamine, and water-soluble or water-insoluble polymeric materials.

[0213] In embodiments of these methods, hydrogen is preferably evolved at a rate of at least 100 mL of hydrogen gas per gram of silicon over 24 hours at pH 7.4 and 37° C. Alternatively, hydrogen may be evolved at a rate of at least 500 mL of hydrogen gas per gram of silicon over 24 hours at pH 8.3 and 37° C.

[0214] [Brief description of the drawings] [Figure 1] SEM image of a CVD particle showing the shape of the CVD-grown particle. [Figure 2] Amorphous silicon CVD particles in a high-resolution TEM. [Figure 3] Amorphous particles analyzed by TEM. [Figure 4] Nanocrystalline particles analyzed by TEM. [Figure 5] SEM image of amorphous agglomerated cCVD Si particles. [Figure 6] XRD measurements of three samples of amorphous silicon. [Figure 7] XRD measurement of amorphous silicon and crystalline silicon. [Figure 8] XRD measurement of amorphous silicon and crystalline silicon. [Figure 9] XRD measurement of crystalline silicon. [Figure 10] Hydrogen release from cCVD silicon particles at pH 8.6 for Examples 1 to 3. [Figure 11] Hydrogen release from cCVD silicon particles at pH 8, pretreated at pH 2 and no pretreatment for Examples 4, 5 and 9. [Figure 12] Hydrogen release from cCVD silicon particles at pH 7.4, pretreated at pH 2 and not pretreated for Examples 6-8. [Figure 13] Hydrogen release from cCVD silicon particles at pH 7.4 and pH 8, pretreated at pH 2 for Example 10. [Figure 14] Hydrogen release from cCVD silicon particles at pH 8 and pH 8 for Examples 11 and 12. [Figure 15] Hydrogen release from cCVD silicon particles at pH 7.4 and pH 7.4, pretreated at pH 2 for Examples 13 and 14. [Figure 16] Hydrogen release from cCVD silicon particles at pH 7.4 and pH 7.4, pretreated at pH 2 for Examples 15 and 16. [Figure 17] Hydrogen release from cCVD silicon particles at pH 7.4 and pH 7.4, pretreated at pH 2 for Examples 17 and 18. [Figure 18] TEM images of cCVD particles and elemental mapping of Si and O content for Examples 20 and 21. [Figure 19] TEM images of cCVD particles after 50 min at pH 7.4 and elemental mapping of Si and O content for Example 20. [Figure 20] TEM images of cCVD particles after 200 min at pH 7.4 and elemental mapping of Si and O content for Example 20. [Figure 21] TEM images of cCVD particles after 200 min at pH 8 and elemental mapping of Si and O content for Example 21. [Figure 22] Rapamycin release versus time for Example 68. [Figure 23] Rapamycin release versus time for Example 69.

[0041] FIG. 24. Rapamycin release versus time for Example 70.

[0033] FIG. 25. Rapamycin release versus time for Examples 71 and 72. [Figure 26] HPLC analysis for identification of rapamycin in Example 73.

[0215] The invention will now be described with reference to the following non-limiting examples.

[0216] [Example] All silicon particles were produced by CVD in a reactor comprising a reactor body and a rotation device operably disposed in the reactor, the rotation device being configured to rotate the reactor about an axis during production in accordance with WO2013048258.

[0217] When used for the preparation of loaded silicon particles, the mortar and pestle were cleaned with 2M sodium hydroxide and washed with water before preparing a new batch of silicon particles.

[0218] All drug release experiments, except for the rapamycin experiments, were carried out with an excess of drug substance in purified water at room temperature with the samples rotating on a rotating table.

[0219] PDI is the polydispersity index.

[0220] Samples for HPLC analysis were centrifuged at 13000 rpm for 30 minutes prior to further sample preparation.

[0221] <Part 1: Hydrogen Release> [Example 1: Hydrogen release from cCVD silicon particles at pH 8.6] cCVD silicon particles (50 mg, batch R4-F1) were suspended in TRIS buffer (25 mL, pH 8.6) in an inverted weighing vial containing water, in a round bottle equipped with a tube with a needle for hydrogen outlet. The inverted vial was placed in a water bath (standard laboratory upside-down position for collecting gas). The suspension was stirred at 37° C. for 24 hours. The volume of gas was monitored over time.

[0222] The particles were partially crystalline silicon, atomic spherical silicon particles, with a hydrodynamic size of 309 nm and a polydispersity index of 0.162.

[0223] Hydrogen evolution was plotted versus time (Figure 10).

[0224] Hydrogen evolution started after 30 min and ceased after 150 min, the gas volume was 75 mL (this is a 94% yield).

[0225] [Example 2: Hydrogen release from cCVD silicon particles at pH 8.6] The experiment was carried out as in Example 1. Particle batch F20.

[0226] The particles were amorphous silicon, atomically spherical silicon particles, with sizes between 200 and 300 nm (SEM).

[0227] The average hydrogen release was plotted versus time (Figure 10).

[0228] Hydrogen evolution began almost immediately and ceased after 120 min. The gas volume was 69 mL, which is a yield of 86%.

[0229] Examples 1 and 2 show that particles produced by cCVD at pH 8.6 produce nearly 100% hydrogen within 2 hours.

[0230] [Example 3: Hydrogen release from cCVD silicon particles at pH 8.6] The experiment was carried out as in Example 1. Particle batch R8-F2.

[0231] The particles were amorphous silicon, atomically spherical silicon particles, with a hydrodynamic size of 279 nm and a polydispersity index of 0.137.

[0232] The average hydrogen release was plotted versus time (Figure 10).

[0233] Hydrogen evolution started after about 30 min and was complete after 250 min. The gas volume was 68 mL (this is a yield of 85%).

[0234] [Example 4: Hydrogen release from cCVD silicon particles at pH 8.0] The experiment was carried out as in Example 1. Buffer: TRIS buffer pH 8.0. Particle batch F20.

[0235] The particles were amorphous silicon, atomically spherical silicon particles, with sizes between 200 and 300 nm (SEM).

[0236] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 11).

[0237] Hydrogen evolution started after about 15 min and ceased after 100 min. The gas volume was 72 mL (this is a 90% yield).

[0238] [Example 5: Hydrogen release from cCVD silicon particles at pH 8.0] The experiment was carried out as in Example 1. Buffer: TRIS buffer pH 8.0. Particle batch R4-F1.

[0239] The particles were partially crystalline silicon, atomic spherical silicon particles, with a hydrodynamic size of 309 nm and a polydispersity index of 0.162.

[0240] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 11).

[0241] Hydrogen evolution began after about 15 min and ceased after 250 min. The gas volume was 65 mL (this is a yield of 81%).

[0242] [Example 6: Hydrogen release from cCVD silicon particles at pH 7.4] The experiment was carried out as in Example 1. Buffer: phosphate-buffered saline (PBS) pH 7.4. Particle batch F20.

[0243] The particles were amorphous silicon, atomically spherical silicon particles, with sizes between 200 and 300 nm (SEM).

[0244] The experiment was performed in duplicate and the average hydrogen release was plotted against time (Figure 12).

[0245] Hydrogen evolution started after about 15 min and ceased after 400 min. The gas volume was 48 mL (this is a 60% yield).

[0246] Example 7: Hydrogen release from cCVD silicon particles at pH 7.4, pretreated at pH 2 The particles were pretreated by stirring in aqueous HCl (pH 2) at 37° C. for 1 hour. The particles were collected, washed, and suspended in buffer. The rest of the experiment was carried out as in Example 1. Buffer: Phosphate buffered saline (PBS) at pH 7.4.

[0247] Particle batch: F20.

[0248] The particles were amorphous silicon, atomically spherical silicon particles, with sizes between 200 and 300 nm (SEM).

[0249] Control experiment: no pretreatment.

[0250] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 12).

[0251] Hydrogen evolution began after about 15 min and ended after 400 min. Hydrogen release was approximately the same for the pretreated particles compared to the non-pretreated particles.

[0252] Example 8: Hydrogen release from cCVD silicon particles at pH 8, pretreated at pH 2 The particles were pretreated by stirring in aqueous HCl (pH 2) for 1 hour at 37° C. The particles were collected, washed and suspended in buffer. The rest of the experiment was carried out as in Example 1. Buffer: TRIS buffer pH 8.0.

[0253] Particle batch: F20.

[0254] The particles were amorphous silicon, atomically spherical silicon particles, with sizes between 200 and 300 nm (SEM).

[0255] Control experiment: no pretreatment.

[0256] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 11).

[0257] Hydrogen evolution started after about 15 min and ended after 200 min. Hydrogen release was approximately the same for the pretreated particles compared to the non-pretreated particles.

[0258] Example 9: Hydrogen release from cCVD silicon particles at pH 7.4, pretreated at pH 2 The particles were pretreated by stirring in aqueous HCl (pH 2) at 37° C. for 1 hour. The particles were collected, washed, and suspended in buffer. The rest of the experiment was carried out as in Example 1. Buffer: Phosphate buffered saline (PBS) at pH 7.4.

[0259] Particle batch: H11A.

[0260] The particles were amorphous silicon, atomic silicon particles, with a hydrodynamic size of 721 nm and a polydispersity index of 0.343.

[0261] Control experiment: no pretreatment.

[0262] Hydrogen evolution was plotted versus time (Figure 13).

[0263] Hydrogen evolution began almost immediately and ceased after 200 min. Hydrogen release was approximately 50% higher for the pretreated particles compared to the non-pretreated particles.

[0264] Example 10: Hydrogen release from cCVD silicon particles at pH 8, pretreated at pH 2 The particles were pretreated by stirring in aqueous HCl (pH 2) for 1 hour at 37° C. The particles were collected, washed and suspended in buffer. The rest of the experiment was carried out as in Example 1. Buffer: TRIS buffer pH 8.0.

[0265] Particle batch: H11A.

[0266] The particles were amorphous silicon, atomic silicon particles, with a hydrodynamic size of 721 nm and a polydispersity index of 0.343.

[0267] Control experiment: no pretreatment.

[0268] Hydrogen evolution was plotted versus time (Figure 13).

[0269] Hydrogen evolution started almost immediately and ceased after 300 min. Hydrogen release was approximately 50% higher for the pretreated particles compared to the non-pretreated particles.

[0270] [Example 11: Hydrogen release from cCVD silicon particles at pH 8] The experiment was carried out as in Example 1. Buffer: TRIS buffer pH 8.0. Particle batch H12C.

[0271] The particles were crystalline silicon, atomic silicon particles, with a hydrodynamic size of 621 nm and a polydispersity index of 0.425.

[0272] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 14).

[0273] Hydrogen evolution began almost immediately and ceased after 200 min. The gas volume was 72 mL, which is a 90% yield.

[0274] [Example 12: Hydrogen release from cCVD silicon particles at pH 8] The experiment was carried out as in Example 1. Buffer: TRIS buffer pH 8.0. Particle batch H12A.

[0275] The particles were amorphous silicon, atomic silicon particles, with a hydrodynamic size of 247 nm and a polydispersity index of 0.248.

[0276] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 14).

[0277] Hydrogen evolution started almost immediately and ceased after 300 min. The gas volume was 56 mL (this is a 70% yield).

[0278] [Example 13: Hydrogen release from cCVD silicon particles at pH 7.4] The experiment was carried out as in Example 1. Buffer: Phosphate buffered saline (PBS) pH 7.4. Particle batch H11C.

[0279] The particles were crystalline silicon, atomic spherical silicon particles, with a hydrodynamic size of 716 nm and a polydispersity index of 0.481.

[0280] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 15).

[0281] Hydrogen evolution began almost immediately and ceased after 400 min. The gas volume was 66 mL, which is a yield of 83%.

[0282] Example 14: Hydrogen release from cCVD silicon particles at pH 7.4, pretreated at pH 2 The experiment was carried out as in Example 8. Buffer: Phosphate buffered saline (PBS) pH 7.4. Particle batch H11C.

[0283] The particles were crystalline silicon, atomic spherical silicon particles, with a hydrodynamic size of 716 nm and a polydispersity index of 0.481.

[0284] Control experiment: no pretreatment, pH 2 (less than 2 mL of hydrogen was produced).

[0285] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 15).

[0286] Hydrogen evolution started almost immediately and ceased after 200 min. The gas volume was 69 mL, which is a yield of 86%. Hydrogen evolution was slightly higher for the pretreated particles compared to the non-pretreated particles.

[0287] [Example 15: Hydrogen release from cCVD silicon particles at pH 7.4] The experiment was carried out as in Example 1. Buffer: Phosphate buffered saline (PBS) pH 7.4. Particle batch H18.

[0288] The particles were amorphous silicon, atomically spherical silicon particles, with a hydrodynamic size of 210 nm and a polydispersity index of 0.190.

[0289] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 16).

[0290] Hydrogen evolution began almost immediately and ceased after 400 min. The gas volume was 61 mL, which is a 76% yield.

[0291] Example 16: Hydrogen release from cCVD silicon particles at pH 7.4, pretreated at pH 2 The experiment was carried out as in Example 8. Buffer: Phosphate buffered saline (PBS) pH 7.4. Particle batch H18.

[0292] The particles were amorphous silicon, atomically spherical silicon particles, with a hydrodynamic size of 210 nm and a polydispersity index of 0.190.

[0293] Control experiment: no pretreatment, pH 2 (less than 2 mL of hydrogen was produced).

[0294] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 16).

[0295] Hydrogen evolution started almost immediately and ceased after 400 min. The gas volume was 66 mL, which is a yield of 83%. Hydrogen evolution was slightly higher for the pretreated particles compared to the non-pretreated particles.

[0296] [Example 17: Release of hydrogen from cCVD silicon particles at pH 7.4] The experiment was carried out as in Example 1. Buffer: Phosphate buffered saline (PBS) at pH 7.4. Particle batch R4-F1.

[0297] The particles were partially crystalline silicon, atomic spherical silicon particles, with a hydrodynamic size of 309 nm and a polydispersity index of 0.162.

[0298] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 17).

[0299] Hydrogen evolution began after approximately 150 min and ceased after 400 min. The gas volume was 27 mL (this is a 34% yield).

[0300] Example 18: Hydrogen release from cCVD silicon particles at pH 7.4, pretreated at pH 2 The experiment was carried out as in Example 8. Buffer: Phosphate buffered saline (PBS) pH 7.4. Particle batch: R4 F1.

[0301] The particles were partially crystalline silicon, atomic spherical silicon particles, with a hydrodynamic size of 309 nm and a polydispersity index of 0.162.

[0302] Control experiment: no pretreatment, pH 2 (less than 2 mL of hydrogen was produced).

[0303] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 17).

[0304] Hydrogen evolution started after about 150 min and ended after 500 min. The gas volume was 34 mL, which is a 43% yield. Hydrogen release was significantly higher for the pretreated particles compared to the non-pretreated particles.

[0305] [Example 19: Hydrogen release from cCVD silicon particles at pH 8] The experiment was carried out as in Example 1. Buffer: TRIS buffer pH 8.0. Particle batch H18.

[0306] The particles were amorphous silicon, atomic silicon particles, with a hydrodynamic size of 210 nm and a polydispersity index of 0.190.

[0307] The experiment was performed in triplicate and the average hydrogen release was plotted against time (Figure 14).

[0308] Hydrogen evolution began almost immediately and ceased after 100 min. The gas volume was 77 mL, which is a 96% yield.

[0309] Example 20: Oxidation of cCVD silicon particles after hydrogen release at pH 7.4 The experiment was carried out as in Example 15. Buffer solution: PBS pH 7.4. Particle batch: H18.

[0310] Samples were withdrawn from the hydrogen release experiment after 50 and 200 min. The samples were centrifuged, the supernatant was removed, and the particles were stored in ethanol until imaging by Transmission Electron Microscopy (TEM). After dilution in isopropanol and sonication for 5 min, a droplet of the particle sample was transferred to a Cu TEM grid. TEM was performed using a double spherical aberration corrected cooled FEG JEOL ARM 200FC operated at 200 kV. Atomic mapping for quantification of at% of Si and O, as well as the oxidation thickness, was performed by Energy Dispersive X-ray spectroscopy (EDS) and Electron Energy Loss Spectroscopy (EELS) analysis in the TEM instrument.

[0311] EDS and EELS TEM images (Figure 19) of the sample extracted at 50 min show that during hydrogen evolution, for the larger particles, a surface layer of SiO2 forms on a core of pure Si. The thickness of the SiO2 shell varies slightly from particle to particle, but is typically in the range of 2-6 nm. The smallest nanoparticles have developed into a pure SiO2 shell with no pure Si core.

[0312] TEM images (FIG. 20) with EDS and EELS of a sample withdrawn after 200 min show that the majority of the Si nanoparticles are hollow spheres, i.e., with nothing inside but a SiO2 shell. A few nanoparticles are still dense. However, a third type of nanoparticle is also observed. These particles consist of a dense core and an outer shell.

[0313] Control: unoxidized sample not treated in alkaline buffer. A thin, surface-grown oxide layer of only 1-2 nm surrounds the unoxidized zero-valent silicon (Figure 18).

[0314] Example 21: Oxidation of cCVD silicon particles after hydrogen evolution at pH 8 Hydrogen release experiments were carried out as in Example 19. Buffer solution: TRIS buffer pH 8.0. Particle batch: H18. Samples for TEM imaging with EDS and EELS elemental mapping were taken after 200 min and prepared as described in Example 20.

[0315] Near complete oxidation of the Si material was inferred from Example 19, which shows a 96% yield in hydrogen generation. TEM images show that the majority of the nanoparticles are hollow SiO2 spheres. The few nanoparticles are dense Si material (Figure 21). Elemental mapping shows that the hollow spheres consist of 72 at% Si and 28 at% O, while the dense spheres consist of 37 at% Si and 63 at% O.

[0316] Control: unoxidized sample not treated in alkaline buffer. A thin, surface-grown oxide layer of only 1-2 nm surrounds the unoxidized zero-valent silicon (Figure 18).

[0317] <Part 2: Hydrogen Release and Drug Delivery> [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 by volume 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.

[0318] [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 by volume 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 7.4% (w / w) griseofulvin.

[0319] [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 by volume 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.

[0320] [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 by volume 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 14.3% (w / w) erythromycin.

[0321] [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 mixed by volume 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 9.5% (w / w) losartan potassium.

[0322] [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 mixed by volume 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.

[0323] [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 by volume 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 13.4% (w / w) acyclovir.

[0324] [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 mixed by volume 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 32.4% (w / w) nystatin.

[0325] [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 mixed by volume 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 20.7% (w / w) celecoxib.

[0326] [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 by volume 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 33.4% (w / w) erythromycin.

[0327] [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 by volume 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 19.4% (w / w) griseofulvin.

[0328] [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 by volume 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.

[0329] [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 mixed by volume 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 12.6% (w / w) phenytoin.

[0330] [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 by volume 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.

[0331] [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 mixed by volume 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.

[0332] [Intermediate 16 Amphotericin B γ-cyclodextrin (1:1.2)] Amphotericin B (DDL, 924 mg, 1 mmol) and γ-cyclodextrin (Cavamax W8, 1.556 g, 1.2 mmol) were mixed by volume 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.

[0333] [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 mixed by volume 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 gray-green powder was isolated containing 19.5% (w / w) tetracycline hydrochloride.

[0334] [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 mixed by volume 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 10.8% (w / w) cytarabine.

[0335] [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 by volume 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.

[0336] [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 by volume 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 8.6% (w / w) phenytoin.

[0337] [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 by volume 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.

[0338] [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 by volume 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 11.6% (w / w) griseofulvin.

[0339] [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 by volume 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.

[0340] [Intermediate 24 Rapamycin β-cyclodextrin complex (1:2)] Rapamycin (MedChem express, 100 mg) and 2-hydroxypropyl-β-cyclodextrin (Aldrich, 320 mg) were mixed by volume 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 at room temperature under high vacuum. A white powder containing 23.8% (w / w) rapamycin was isolated.

[0341] [Intermediate 25: Preparation of aggregated amorphous cCVD-SP] Agglomerated amorphous cCVD-SP such as H18 particles were produced by CVD in a reactor comprising a reactor body and a rotating device operably disposed in the reactor, the rotating device being configured to rotate the reactor around an axis during production according to WO2013048258. The process for preparing stable aggregates such as particle type H18, rather than free non-agglomerated particles, involves the control of process parameters as described below.

[0342] Silanes start 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 therefore they constitute both silicon and silicon hydrides with a gradient of hydrogen content growing toward the surface. The growth rate is high, but if the surface is kept cool, the silicon hydride 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 particle counts per volume high, with substantial residence times that allow many particle collisions before the process is stopped and the particles are collected.

[0343] [Example 22 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 in a 70°C sonicator bath for 10 min, centrifuged (14000X, 8 min) and dried at 60°C until constant weight. The weight was 32 mg higher than the reference sample (same particles treated with pure water). The product contained approximately 39% Atorvastatin β-cyclodextrin complex.

[0344] [Example 23 Amorphous cCVD-SP containing metformin hydrochloride] Metformin hydrochloride (European Pharmacopoeia, Weifa, 1.5 g) was dissolved in water (10 mL). Silicon particles (batch R1F1, amorphous silicon, average diameter 554 nm, PDI 0.164 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 sonicator bath at 70° C., centrifuged (14000×, 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 approximately 32% metformin hydrochloride.

[0345] [Example 24 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 (14000×, 8 min), and dried at 60° C. until constant weight. The weight was 16 mg higher than the reference sample (same particles treated with pure water). The product contained approximately 24% Losartan potassium.

[0346] [Example 25] 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 in a 70°C sonicator bath for 10 min, centrifuged (14000X, 8 min), and dried at 60°C until constant weight. The weight was 10 mg higher than the reference sample (same particles treated with pure water). The product contained approximately 17% atorvastatin β-cyclodextrin complex.

[0347] [Example 26 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 the aqueous solution containing metformin hydrochloride in a microcentrifuge vial. The mixture was sonicated for 10 min in a sonicator bath at 70° C., centrifuged (14000×, 8 min) and dried at 60° C. until constant weight. The weight was 12 mg higher than the reference sample (same particles treated with pure water). The product contained approximately 19% metformin hydrochloride.

[0348] [Example 27 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, average 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 (14000X, 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.

[0349] Example 28 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.

[0350] [Example 29 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.

[0351] [Example 30 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.

[0352] [Example 31 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 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.

[0353] The release of erythromycoin from the particles into water was studied over time using HPLC.

[0354] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01M K2HPO4, Flow rate: 1 mL / min, Injection volume 10 ul, Detection wavelength 286 nm, Run time: 12 min.

[0355] The release of erythromycin from the particles at 2 hours was 290% compared to the release from free erythromycin powder.

[0356] [Example 32 Amorphous cCVD-SP containing erythromycin] Erythromycin (100 mg) was dissolved in dimethylformamide (DMF) (1 mL). This solution was added dropwise to amorphous silicon particles (batch number F26F2, SEM size 200-400 nM, 900 mg) in a mortar. The particle size of the silicon was 100-300 nm. 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.

[0357] (The mortar and pestle were cleaned with 2M sodium hydroxide and washed with water before preparing a new batch of silicon particles.)

[0358] The release of erythromycoin from the particles into water was studied over time using HPLC.

[0359] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01M K2HPO4, Flow rate: 1 mL / min, Injection volume 10 ul, Detection wavelength 286 nm, Run time: 12 min.

[0360] The release of erythromycin from the particles at 2 hours was 258% compared to the release from free erythromycin powder.

[0361] [Example 33 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. The 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.

[0362] The release of erythromycoin from the particles into water was studied over time using HPLC.

[0363] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01M K2HPO4, Flow rate: 1 mL / min, Injection volume 10 ul, Detection wavelength 286 nm, Run time: 12 min.

[0364] The release of erythromycin from the particles at 2 hours was 261% compared to the release from free erythromycin powder.

[0365] [Example 34 Amorphous cCVD-SP Aggregates Containing Erythromycin] Erythromycin (50 mg) was dissolved in dimethylformamide (DMF) (0.5 mL). The 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.

[0366] The release of erythromycin from the particles into water was examined over time using HPLC.

[0367] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01M K2HPO4, Flow rate: 1 mL / min, Injection volume 10 ul, Detection wavelength 286 nm, Run time: 12 min.

[0368] The release of erythromycin from the particles at 2 hours was 219% compared to the release from free erythromycin powder.

[0369] Example 35 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 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 0.74% w / w griseofulvin.

[0370] Example 36 Amorphous cCVS-SP Aggregates Containing Erythromycin-2-Hydroxypropyl-berta-Cyclodextrion Erythromycin-2-hydroxypropyl-β-cyclodextrin (Intermediate 10, 50 mg) was dissolved in absolute ethanol (0.5 mL). The solution was added dropwise to 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.

[0371] Example 37 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. The 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.

[0372] The release of griseofulvin from the particles into water was examined over time using HPLC.

[0373] 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 ul, Detection wavelength 286 nm, Run time: 8 min.

[0374] The release of griseofulvin from the particles in 2 hours was 99% compared to the release from free griseofulvin powder.The release of griseofulvin from the particles in 2 hours was 96% compared to the release from free griseofulvin-2-hydroxypropyl-β-cyclodextrin powder (Intermediate 11).

[0375] Example 38 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). The solution was added dropwise to 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 of griseofulvin-2-hydroxypropyl-β-cyclodextrin.

[0376] The release of griseofulvin from the particles into water was examined over time using HPLC.

[0377] 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 ul, Detection wavelength 286 nm, Run time: 8 min.

[0378] 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).

[0379] Example 39 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 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.

[0380] The release of griseofulvin from the particles into water was examined over time using HPLC.

[0381] 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 ul, Detection wavelength 286 nm, Run time: 8 min.

[0382] The release of griseofulvin from the particles at 2 hours was 109% compared to the release from free griseofulvin powder.

[0383] [Example 40 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 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 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.

[0384] The release of erythromycin from the particles into water was examined over time using HPLC.

[0385] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01M K2HPO4, Flow rate: 1 mL / min, Injection volume 10 ul, Detection wavelength 286 nm, Run time: 12 min.

[0386] 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).

[0387] Example 41 Amorphous cCVD-SP Aggregates Containing Cyclosporine and Additives Cyclosporine was extracted from capsules (4 Sandimmun Neooral 25mg / Novartis) together with pharmaceutical excipients. The capsules were opened and extracted with absolute alcohol (5mL). The alcohol was evaporated and the final solution was dissolved in absolute alcohol (2mL) and added dropwise to amorphous silicon particles (400mg) in a mortar. The particles were in the form of aggregates (batch number H18, average aggregate diameter 210nm, PDI 0.190). The mixture was stirred in a 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 particulate material was scraped off from the mortar. The particulate material contained about 25% w / w cyclosporine with some excipients from the Neooral formulation.

[0388] [Example 42 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 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).

[0389] [Example 43 Amorphous cCVD-SP aggregates containing celecoxib] Celecoxib (DDL, 100 mg) was dissolved in absolute ethanol (0.7 mL). The 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 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.

[0390] The release of celecoxib from the particles into water was studied over time using HPLC.

[0391] HPLC system: HP1100. Column: Zorbax Extend C-18, 4.6×250 mm, 5 um, Mobile phase: 80% methanol and 20% 0.01M K2HPO4, Flow rate: 1 mL / min, Injection volume 5ul, Detection wavelength 250 nm, Run time: 7 min.

[0392] The release of celecoxib from the particles at 2 and 4 hours was 2.1-fold higher than the free celecoxib powder.

[0393] The release of celecoxib from the particles at 6 hours was 2.0-fold higher than the free celecoxib powder.

[0394] Example 44 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.

[0395] The release of griseofulvin from the particles into water was examined over time using HPLC.

[0396] 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 ul, Detection wavelength 286 nm, Run time: 8 min.

[0397] The release of griseofulvin from the particles at 2 hours was 70% compared to the release from free griseofulvin powder.

[0398] [Example 45 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 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 at 50° C. under high vacuum 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).

[0399] The release of atorvastatin from the particles into water was studied over time using HPLC.

[0400] 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 ul, Detection wavelength 240 nm, Run time: 3 min.

[0401] 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).

[0402] [Example 46 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 at 50° C. under high vacuum 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).

[0403] [Example 47 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 with the pestle was dried at 50° C. under high vacuum 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).

[0404] The release of losartan from the particles into water was studied over time using HPLC.

[0405] 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 ul. Detection wavelength 226 nm. Run time: 5 min.

[0406] 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.

[0407] [Example 48 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 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 acyclovir.

[0408] [Example 49 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 at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w chloramphenicol.

[0409] The release of chloramphenicol from the particles into water was studied over time using HPLC.

[0410] 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 ul, detection wavelength 278 nm, run time: 12 min.

[0411] 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.

[0412] [Example 50 Crystalline cCVD-SP containing chloramphenicol] Chloramphenicol (SigmaAldrich, 200 mg) was dissolved in dimenthylsulfoxide (0.7 mL) by heating. This solution was added dropwise to crystalline silicon particles (800 mg, batch number R5F3, average particle diameter 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 with the pestle was dried at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w chloramphenicol.

[0413] The release of chloramphenicol from the particles into water was studied over time using HPLC.

[0414] 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 ul, Detection wavelength 278 nm, Run time: 12 min.

[0415] 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.

[0416] [Example 51 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 diameter 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 with the pestle was dried at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w prednisolone.

[0417] [Example 52] Crystalline cCVD-SP containing acyclovir 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 diameter 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 minutes to form a paste. The mortar with the pestle was dried at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 20% w / w acyclovir.

[0418] Example 53 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 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 10% w / w phenytoin.

[0419] The release of phenytoin from the particles into water was studied over time using HPLC.

[0420] 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 ul, Detection wavelengths 210 and 200 nm, Run time: 6 min.

[0421] The release of phenytoin from the particles at 2 hours was 134% compared to the release from the free phenytoin powder.

[0422] [Example 54 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 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 at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 10% w / w phenobarbital.

[0423] 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 ul, Detection wavelengths 210 and 200 nm, Run time: 6 min.

[0424] The release of phenobarbital from the particles at 2 hours was 174% compared to the release from free phenobarbital powder.

[0425] Example 55 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.

[0426] 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 ul, Detection wavelengths 210 and 200 nm, Run time: 6 min.

[0427] The release of phenytoin from the particles at 2 hours was 206% compared to the release from free phenytoin powder. The release of phenytoin from the particles at 2 hours was 100% compared to the release from free 2-hydroxypropyl-β-cyclodextrin complex (Intermediate 15).

[0428] Example 56 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 at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 2.3% w / w phenobarbital.

[0429] 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 ul, Detection wavelengths 210 and 200 nm, Run time: 6 min.

[0430] 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).

[0431] Example 57 Amorphous cCVD-SP Aggregates with Amphotericin B β-Cyclodextrin Amphotericin B-γ-cyclodextrin complex (Intermediate 16, 100 mg) was dissolved in dimethylformamide (0.6 mL) by heating. The 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 at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 7.5% amphotericin B.

[0432] Example 58 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 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 at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 3.9% tetracycline HCl.

[0433] [Example 59 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 at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 2.2% (w / w) cytarabine.

[0434] [Example 60 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 at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 3.4% (w / w) amoxicillin.

[0435] Example 61 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. The 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 at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 1.7% (w / w) phenytoin.

[0436] [Example 62 Amorphous cCVD-SP aggregates containing phenobarbital 4-sulfobutyl-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.

[0437] [Example 63 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. 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 2.3% griseofulvin.

[0438] [Example 64 Amorphous cCVD-SP containing prednisolone 4-sulfobutyric-β-cyclodextrin complex] Prednisolone-4-sulfobutanyl-β-cyclodextrin complex (Intermediate 23, 100 mg) was dissolved in dimethylformamide (0.5 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 at 50° C. under high vacuum for 24 hours. The dried particles were scraped off from the mortar. The particles contained 2.3% prednisolone.

[0439] Example 65 Polysorbate 80-Coated Amorphous cCVD-SP Aggregates Containing Amphotericin B γ-Cyclodextrin 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 (14000 rpm) for 5 min. The supernatant was removed and the particles were dried at 50° C. for 12 h.

[0440] Example 66 Polysorbate 20-Coated Amorphous cCVD-SP Aggregates Containing Tetracycline Hydrochloride Methyl-β-Cyclodextrin 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 (14000 rpm) for 5 min. The supernatant was removed and the particles were dried at 50° C. for 12 h.

[0441] Example 67: Cremophor EL-Coated Amorphous cCVD-SP Aggregates Containing Cytarabine β-Cyclodextrin Amorphous cCVD-SP aggregates containing cytarabine β-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 (14000 rpm) for 5 min. The supernatant was removed and the particles were dried at 50° C. for 12 h.

[0442] Example 68 Amorphous cCVD-SP containing rapamycin (50 wt. % loading) Preparation of rapamycin-loaded particles: Amorphous aggregated silicon particles (batch number H18) with a hydrodynamic size of 210 nm and a PDI of 0.190 were first coated with Pluronic F-127 (Sigma) (adsorption, non-covalent coating). A 0.5% (w / v) solution of Pluronic F-127 was added to 400 mg of H18, followed by sonication in an ultrasonic bath for 15 minutes, centrifugation, washing with water three times, and drying overnight under high vacuum after removing the supernatant. Rapamycin (MedChem express) and Pluronic-coated H18 were weighed and dissolved in dimethylformamide. The dispersion was sonicated in an ultrasonic bath for 10 minutes and then pipetted into aliquots each containing 125 μg of rapamycin. The aliquots were dried overnight under high vacuum.

[0443] Total weight of rapamycin: 5 mg.

[0444] Total weight of Pluronic-coated H18: 5mg.

[0445] The particle product had a hydrodynamic size of 190.3 nm and a PDI of 0.362.

[0446] 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. After 0.5, 1, 3, 6, 24, 30 and 48 h, 1 mL samples were withdrawn and centrifuged at 14000 rpm for 6 min and the supernatant was dried overnight under high vacuum (Speedvac concentrator). Prior to high performance liquid chromatography (HPLC, Surveyor Finnigan, Thermo) analysis, the samples were reconstituted with 500 μl methanol followed by centrifugation (6 min, 14000 rpm) for salt removal. Quantification was performed by comparing the area under the chromatographic rapamycin peak to a chromatographic standard curve made from rapamycin in methanol solutions of known concentrations. HPLC conditions: PLRP-S reversed-phase column (1×150 mm, Agilent Technologies) set to 55° C., isocratic elution with a mobile phase of 70% acetonitrile with 0.1% formic acid and 30% purified water with 0.1% formic acid, a flow rate of 100 μl / min, an injection volume of 20 μl, and UV PDA detection. 278 nm was selected as the peak absorbance of rapamycin for quantification.

[0447] Buffer solution: Phosphate buffered saline (PBS) at pH 7.4.

[0448] Release experiments were performed in triplicate. The average rapamycin release was plotted against time (Figure 22). Control experiment: supersaturated solution of free rapamycin powder in PBS pH 7.4 at 37°C (2 experiments).

[0449] Example 69 Amorphous cCVD-SP containing rapamycin (10 wt. % loading) Preparation of rapamycin loaded particles was performed as described in Example 68, using 5 mg rapamycin weight and 45 mg Pluronic coated H18 weight to obtain 10 wt% loading. The particle product had a hydrodynamic size of 177.7 nm and a PDI of 0.147.

[0450] Release studies were performed using PBS pH 7.4 and PBS pH 5.8 separately as described in Example 68. Three release experiments were performed with each buffer solution. The average rapamycin release was plotted against time (Figure 23).

[0451] Example 70 Amorphous cCVD-SP containing rapamycin (5 wt. % loading) Preparation of rapamycin loaded particles was performed as described in Example 68, using 4 mg rapamycin weight and 71 pluronic coated H18 weight to obtain 5 wt% loading. The particle product had a hydrodynamic size of 154.5 nm and a PDI of 0.143.

[0452] Release studies were performed using PBS pH 7.4 and PBS pH 5.8 separately as described in Example 68. Three release experiments were performed with each buffer solution. The average rapamycin release was plotted against time (Figure 24).

[0453] Example 71 Amorphous cCVD-SP containing rapamycin β-cyclodextrin complex (5 wt% rapamycin loading) Preparation of rapamycin-loaded particles was carried out as described in Example 68, using 16 mg of rapamycin-cyclodextrin complex (Intermediate 24) by weight and 60 mg of Pluronic-coated H18 by weight to obtain a 5 wt% rapamycin loading. The particle product had a hydrodynamic size of 165.7 nm and a PDI of 0.141.

[0454] Release studies were performed using PBS pH 7.4 as described in Example 68. Two release experiments were performed. The average rapamycin release was plotted against time (Figure 25). Control: rapamycin-cyclodextrin complex (Intermediate 2).

[0455] Example 72 Amorphous cCVD-SP containing rapamycin β-cyclodextrin complex (10 wt% rapamycin loading) Preparation of rapamycin-loaded particles was carried out as described in Example 68, using 16 mg of rapamycin-cyclodextrin complex (Intermediate 24) by weight and 22 mg of Pluronic-coated H18 by weight to obtain a rapamycin loading of 10 wt.%. The particle product had a hydrodynamic size of 168.3 and a PDI of 0.128.

[0456] Release studies were performed using PBS pH 7.4 as described in Example 68. Two release experiments were performed. The average rapamycin release was plotted against time (Figure 25). Control: rapamycin-cyclodextrin complex (Intermediate 24).

[0457] Example 73 Accelerated stability study of amorphous cCVD-SP containing rapamycin (10 wt% loading) Three vials containing particle samples (10 wt% loading of rapamycin in Pluronic-coated H18 particles) prepared as in Example 69 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 pellets were broken up with a spatula and analyzed, 1 mL of methanol was added and the vials were sonicated in an ultrasonic 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, then centrifuged (6 minutes, 14 krpm) and the supernatant was withdrawn for rapamycin quantification by HPLC analysis. The particle pellet was saved for measurement of hydrodynamic size by DLS.

[0458] 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.

[0459] 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 an injection volume of 5 μl (other conditions as described in Example 68). HPLC analysis of samples after 2 months of storage was performed similarly to the release sample analysis described in Example 68.

[0460] The rapamycin peak is seen after 2.6-2.9 minutes (Figure 26). The absence of new peaks in the chromatogram indicates that there is little degradation of rapamycin after 1 and 2 months when the particle product is stored under 40°C and 75% RH. This indicates the stability of the drug product during storage under refrigerated conditions.

[0461] Example 74 Amorphous cCVD particles for dual delivery (hydrogen and erythromycin) The particles (29 mg, NM014) prepared as in Example 34 were suspended in TRIS buffer (25 mL, pH 8.0) in an inverted weighing vial containing water, in a round bottle equipped with a tube with a needle for hydrogen outlet. The inverted vial was placed in a water bath (standard laboratory upside-down position for collecting gas). The suspension was stirred at 37°C.

[0462] After 2 hours, 4 mL of hydrogen gas was generated (corresponding to 154 mL / g of Si). From Example 13, 219% of erythromycin was released from the above particles during 2 hours compared to free erythromycin powder. After 21 hours, 7 mL of hydrogen gas was generated (corresponding to 269 mL / g of Si).

[0463] Example 75 Amorphous cCVD particles for dual delivery (hydrogen and erythromycin) Particles (31 mg, NM022) prepared as in Example 36 were tested for hydrogen evolution as in Example 70. After 2 hours, 8 mL of hydrogen gas was evolved (equivalent to 286 mL / g of Si). After 21 hours, 23 mL of hydrogen gas was evolved (equivalent to 821 mL / g of Si).

[0464] Example 76 Amorphous cCVD particles for dual delivery (hydrogen + griseofulvin) Particles (51 mg, NM025) prepared as in Example 39 were tested for hydrogen generation as in Example 70. From Example 39, 109% of the griseofulvin was released from the particles in 2 hours compared to free griseofulvin powder. After 21 hours, 22 mL of hydrogen gas was generated (equivalent to 478 mL / g of Si).

[0465] Example 77 Amorphous cCVD particles for dual delivery (hydrogen + griseofulvin) Particles (52 mg, NM023) prepared as in Example 37 were tested for hydrogen generation as in Example 74. After 2 hours, 13 mL of hydrogen gas was generated (equivalent to 277 mL / g of Si). From Example 34, 99% of the griseofulvin was released from the above particles in 2 hours compared to free griseofulvin powder. After 21 hours, 47 mL of hydrogen gas was generated (equivalent to 1000 mL / g of Si).

[0466] Example 78 Amorphous cCVD particles for dual delivery (hydrogen + celecoxib) Particles (52 mg, NM029) prepared as in Example 43 were tested for hydrogen evolution as in Example 74. After 2 hours, 7.5 mL of hydrogen gas was evolved (equivalent to 179 mL / g of Si). From Example 40, 210% of celecoxib was released from the above particles over a 2 hour period compared to free celecoxib powder. After 4 hours, 12 mL of hydrogen gas was evolved (equivalent to 286 mL / g of Si).

[0467] Example 79 Amorphous cCVD particles for dual delivery (hydrogen + phenytoin) Particles (57 mg, NM041) prepared as in Example 53 were tested for hydrogen generation as in Example 74. After 2 hours, 13 mL of hydrogen gas was generated (equivalent to 253 mL / g of Si). From Example 50, 134% of phenytoin was released from the above particles in 2 hours compared to free phenytoin powder. After 16 hours, 34 mL of hydrogen gas was generated (equivalent to 663 mL / g of Si).

[0468] Example 80: Amorphous cCVD particles for dual delivery (hydrogen + phenobarbital) Particles (54 mg, NM042) prepared as in Example 54 were tested for hydrogen generation as in Example 74. After 2 hours, 40 mL of hydrogen gas was generated (equivalent to 823 mL / g of Si). From Example 51, 174% of phenobarbital was released from the above particles in 2 hours compared to free phenobarbital powder. After 16 hours, 53 mL of hydrogen gas was generated (equivalent to 1090 mL / g of Si).

[0469] Example 81 Amorphous cCVD particles for dual delivery (hydrogen + phenytoin) Particles (63 mg, NM044) prepared as in Example 55 were tested for hydrogen generation as in Example 70. After 2 hours, 5 mL of hydrogen gas was generated (equivalent to 99 mL / g of Si). From Example 52, 206% of phenytoin was released from the above particles in 2 hours compared to free phenytoin powder. After 16 hours, 40 mL of hydrogen gas was generated (equivalent to 794 mL / g of Si).

[0470] Example 82 Amorphous cCVD particles for dual delivery (hydrogen + phenobarbital) Particles (64 mg, NM045) prepared as in Example 56 were tested for hydrogen generation as in Example 70. After 2 hours, 7 mL of hydrogen gas was generated (equivalent to 137 mL / g of Si). From Example 53, 290% of phenobarbital was released from the above particles in 2 hours compared to free phenobarbital powder. After 16 hours, 35 mL of hydrogen gas was generated (equivalent to 684 mL / g of Si).

[0471] Example 83 Amorphous cCVD particles for dual delivery (hydrogen + griseofulvin) Particles (63 mg, NM024) prepared as in Example 38 were tested for hydrogen generation as in Example 70. After 2 hours, 7.5 mL of hydrogen gas was generated (equivalent to 149 mL / g of Si). From Example 17, 130% of griseofulvin was released from the above particles in 2 hours compared to free griseofulvin powder. After 3 days, 15 mL of hydrogen gas was generated (equivalent to 298 mL / g of Si).

[0472] Example 84 Amorphous cCVD particles for dual delivery (hydrogen + griseofulvin) Particles (81 mg, NM030) prepared as in Example 44 were tested for hydrogen generation as in Example 70. After 2 hours, 3 mL of hydrogen gas was generated (equivalent to 74 mL / g of Si). From Example 23, 70% of the griseofulvin was released from the above particles in 2 hours compared to free griseofulvin powder. After 16 hours, 22 mL of hydrogen gas was generated (equivalent to 544 mL / g of Si).

[0473] Example 85 Amorphous cCVD particles for dual delivery (hydrogen + losartan) Particles (57 mg, NM033) prepared as in Example 47 were tested for hydrogen generation as in Example 70. After 2 hours, 5 mL of hydrogen gas was generated (equivalent to 97 mL / g of Si). From Example 26, 56% of losartan was released from the above particles in 2 hours compared to free losartan powder. After 3 days, 28 mL of hydrogen gas was generated (equivalent to 546 mL / g of Si).

[0474] Example 86: Tablets containing amorphous cCVD-SP containing 5% rapamycin Each tablet contains: Amorphous cCVD-SP containing rapamycin (5 wt% loading) (from Example 70, 100 mg) Microcrystalline cellulose 360mg Crosscaramellose (Na) (AcDiSoI) 20mg Stearic acid 20mg Blend all ingredients. Compress tablets. Tablet diameter 10mm. Tablet weight: 500mg. Rapamycin content: 5mg.

[0475] Example 87 Injectable suspension containing amorphous cCVD-SP containing 5% rapamycin Amorphous cCVD-SP containing rapamycin (5% loading by weight) is prepared from sterile cCVD-SP and sterile rapamycin similar to the procedure of Example 70 using a sterile manufacturing process.

[0476] Sterile particles (100 mg) are suspended in a sterile solution of isotonic glucose solution (50 mL, 5% w / v) under aseptic conditions by sonication for 10 minutes. The suspension is aseptically filled into injection vials (5 mL). Each vial contains 10 mg of particles.

[0477] [Example 88 Chemical and 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 withdrawn after 5 hours 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 about 200 nm as measured by DLS.

[0478] 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.

[0479] 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 large, weakly bound aggregates, but does not separate the particle aggregates into single particles. After immersion of amorphous aggregated cCVD-SP in PBS at room temperature for 5 hours and 4 days, the hydrodynamic size (after 1 min sonication) was 264 nm (PDI: 0.352) and 323 nm (PDI: 0.479), respectively. After 5 hours (and 1 min sonication) in purified water and PBS at 37°C, the hydrodynamic size 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.

[0480] [Example 89] Stability of aggregated amorphous cCVD-SP in the presence of surfactant and albumin. The experiment was carried out similarly to Example 88. 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.

[0481] Particles immersed in water supplemented with albumin, Pluronic F-127 and polysorbate 80 gave 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 gave 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.

[0482] 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 the PBS solution.

[0483] Example 90: Stability of aggregated amorphous cCVD-SP in an artificial in vitro model of blood. The experiment was carried out similarly to Example 88. 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.

[0484] 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 observed in the artificial blood compared to pure water.

Claims

1. 1. Silicon particles for use in therapy, said silicon particles being prepared by Chemical Vapor Deposition (CVD).

2. The silicon particles for use according to claim 1, wherein the CVD is carried out in a reactor comprising a reactor body and a rotating device operably disposed in the reactor, the rotating device being configured to rotate the reactor around an axis during production.

3. 2. The silicon particles for use according to claim 1, wherein the CVD does not include milling the particles.

4. 2. The silicon particles for use according to claim 1, wherein the particles are non-etched particles.

5. 2. The silicon particles for use according to claim 1, wherein the silicon particles comprise at least 50% by weight of crystalline silicon, based on the total weight of silicon.

6. 2. The silicon particles for use according to claim 1, wherein the silicon particles comprise at least 50% by weight of amorphous silicon, based on the total weight of silicon.

7. 2. The silicon particles for use according to claim 1, wherein the silicon particles comprise at least 50% by weight of atomic silicon based on the total weight of silicon.

8. 2. The silicon particles for use according to claim 1, wherein said particles further comprise at least one active pharmaceutical ingredient.

9. 9. The silicon particles for use according to claim 8, wherein the active pharmaceutical ingredient is in the form of a cyclodextrin complex.

10. 2. Silicon particles for use according to claim 1, wherein the particles are not coated with an organic acid, are not coated with a coating layer that does not dissolve in the stomach and dissolves in the small intestine and / or large intestine.

11. Silicon particles for use according to any one of claims 1 to 10, wherein the therapy comprises hydrogen delivery.

12. A pharmaceutical composition comprising silicon particles and one or more pharma- ceutically acceptable carriers, diluents or excipients, said silicon particles being as defined in any one of claims 1 to 10.

13. The pharmaceutical composition of claim 12, wherein the composition is formulated for oral administration.

14. 14. The pharmaceutical composition of claim 13, wherein the composition is in the form of a tablet, capsule or suspension.

15. The pharmaceutical composition of claim 12, wherein the composition is formulated for parenteral administration.

16. 13. The pharmaceutical composition of claim 12, further comprising an organic non-absorbable base.

17. Using silicon particles, hydrogen (H 2 5. A method for generating a stoichiometric amount of stoichiometric stoichiometry, the method comprising: a) preparing silicon particles by chemical vapor deposition (CVD); b) exposing the silicon particles prepared in step a) to a pH of at least 7.

0.

18. 18. The method according to claim 17, further comprising between steps a) and b) a step a1) of loading the silicon particles prepared in step a) with at least one active pharmaceutical ingredient.

19. The method according to claim 17, wherein the silicon particles are as defined in any one of claims 1 to 10.

20. The method of claim 17, wherein step b) is performed in vivo.

21. 21. The method of claim 20, wherein step b) comprises administering to a subject said silicon particles, said silicon particles being present in a pharmaceutical composition according to claim 12.

22. 18. The method of claim 17, wherein the hydrogen is evolved at a rate of at least 100 mL of hydrogen gas per gram of silicon over a 24 hour period at pH 7.4 and 37°C.

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