Delivery system comprising silicon-containing material

Abstract

The present application provides a delivery system comprising a silicon-containing material. Also provided is a method for promoting controlled binding and release of a bioactive agent or agent from a composition comprising silicon nanoparticles wherein the silicon nanoparticles comprise at least 50 wt% silicon, the method comprising treating the surface of the silicon nanoparticles with at least one lipid, and treating the surface of the silicon nanoparticles with at least one amino acid, wherein the ratio of lipid to silicon is from 1: 1 to 15: 1. The invention also relates to a composition and a method.

Description

[0001] This application is a divisional application of a patent application with an application date of March 30, 2020, application number 202080025659.6, and invention name “Delivery system comprising silicon-containing materials”. Technical Field

[0002] The present invention relates to delivery agents for cosmetics, skin care and pharmaceuticals. More particularly, but not exclusively, the present invention relates to the use of silicon nanoparticles as controlled-release agents. The present invention also relates to related compositions. Background Art

[0003] Achieving improved methods for the effective delivery of active ingredients to desired target sites remains a goal of the cosmetic, skin care, and pharmaceutical industries.

[0004] Numerous methods have been developed for delivering pharmaceutical active ingredients in a controlled or sustained-release manner. However, little attention has been paid to the fate of carrier materials once they have fulfilled their function of delivering and releasing the active ingredient. The present invention seeks to provide a novel delivery system for delivering pharmaceutical active ingredients in a controlled and / or sustained-release manner, and also to provide a delivery system that converts silicon-based carrier materials into biobeneficial substances after administration.

[0005] Topical delivery of active agents presents particular challenges due to the poor stability of most biological compounds and the inability of active agents to penetrate deeper skin layers due to their molecular size. Active agent delivery also faces challenges with hydrophobicity and poor biocompatibility of topical formulations, which can lead to health issues for patients.

[0006] In order to enable the topical delivery of a wider range of active ingredients, a great deal of research has focused on developing strategies to temporarily disrupt the stratum corneum barrier in a controlled manner, allowing the drug to penetrate in sufficient and predictable amounts, thereby achieving therapeutic levels. Although some techniques, such as iontophoresis and ultrasound, have been explored as skin absorption enhancers, most efforts have focused on identifying non-toxic chemical penetration enhancers that can reversibly interact with the stratum corneum to allow larger amounts of drugs to penetrate the skin. Early attempts to disrupt the barrier used simple solvents or solvent mixtures, surfactants, and fatty acids. Although these materials can enhance the penetration of molecules into the skin, they are often associated with undesirable side effects, such as causing irritation or inflammatory responses.

[0007] The use of delivery systems has also been studied. Commonly used delivery systems include relatively viscous fluids such as lotions, creams, and gels that can be rubbed into the skin, providing direct contact with the target area. These vehicles have been successfully used for cosmetic and pharmaceutical compounds. However, due to the relatively short residence time on the skin, these vehicles are generally not suitable for delivering active compounds over long periods of time.

[0008] In order to create controlled release topical delivery systems, other vehicles have been used. Particularly commonly used topical delivery systems utilize lipid-based carriers, such as liposomes. However, these carrier systems have many disadvantages, such as an unstable central core and a limited loading capacity for hydrophobic compounds. Such carriers are also not suitable for delivering substances that are too large or disruptive to the phospholipid vesicles of skin cells. Liposomes are also expensive to produce and have a short shelf life, which in certain applications requires them to be prepared immediately before use. There is also a continuing need for improved delivery systems for topically applied active agents that can stabilize easily degradable active agents, such as plant extracts, ecdysis enzymes, RNA, etc., especially hydrophilic active agents, and deliver such agents in active form to the skin or other body surfaces, while being suitable for formulation into a vehicle.

[0009] silicon

[0010] Silicon is an essential trace element in plants and animals. Silicon plays a structural role as a component of the protein-glycosaminoglycan complex found in the connective tissue matrix of mammals, as well as a metabolic role in growth and osteogenesis (silicon facilitates the mineralization process of bone). Therefore, silicon is crucial for the normal development of bone and connective tissue. Silicon is also known to play an important role in skin health, acting as a collagen and elastin promoter, and participating in the body's antioxidant processes. It is involved in the production of glycosaminoglycans, and silicon-dependent enzymes enhance the benefits of natural tissue-building processes.

[0011] For medical applications, silicon can be produced as micro- or nanoparticles, which facilitate drug delivery via a variety of routes, such as topical administration, oral administration, injection, or implantation. Biodegradable silicon-based particles have also been used for drug targeting.

[0012] Silicon as part of a delivery system

[0013] Elemental silicon (Si) dissolves in an aqueous environment to form silicic acid, which represents a family of oxygen-containing acid compounds of the elements O, H, and Si, with the general formula [SiO x (OH) 4-2x ] n .

[0014] The first reaction in this process results in the formation of orthosilicic acid:

[0015] Silicon + 2H2O + O2 → Si(OH)4

[0016] Orthosilicic acid (OSA), also known as monosilicic acid, is the simplest soluble form of silica. When the concentration of OSA is kept below the solubility limit in the amorphous phase (less than 2 mM), OSA is a weakly acidic molecule with a Pk of a1The SiO2O3O4O4O5O5O6O6O7O8 ...

[0017] Dimerization: 2Si(OH)4→(HO)3Si-O-Si(OH)3+H2O

[0018] At concentrations above 2 mM, OSA undergoes extensive condensation reactions to reduce the concentration of OSA in solution. OSA condensation reactions form small oligomers ranging from linear or monocyclic trimers and tetramers to prismatic octamers and decamers.

[0019] Linear polysilicic acid: n Si(OH)4→HO-[Si(OH)2-O] n -H+(n-1)H2O

[0020] Monocyclic polysilicic acid: n Si(OH)4→-[Si(OH)2-O] n -+n H2O

[0021] Prismatic polysilicic acid: 2n Si(OH)4→-[Si2(OH)2-O3] n -+3n H2O

[0022] At concentrations greater than 2 mM, small oligomers serve as nuclei for the formation of small colloidal species that eventually aggregate to form gels or aggregates of amorphous "polysilicic acid" (polySA) precipitates. Silicon dioxide [SiO2] represents the endpoint of complete polycondensation of OSA, which reduces its solubility and, therefore, its bioavailability, biodegradability, and safety.

[0023] Si(OH)4←→SiO2+2H2O

[0024] The formation of silica is a reversible process, so the reverse reaction from silica to OSA is theoretically possible. However, it is thermodynamically unfavorable under physiological conditions because the reaction requires strongly alkaline conditions (pH above 13) and high temperatures.

[0025] OSA polymerization is catalyzed under acidic and alkaline conditions, the mechanism of which is described below.

[0026] Basic catalysis mechanism

[0027] Si(OH)4+HO - →(HO)3Si-O - +H2O

[0028] (HO)3Si-O -+Si(OH)4→(HO)3Si-O-Si(OH)3+HO -

[0029] Acidic catalyst mechanism

[0030] Si(OH)4+H3O+→(HO)3Si-OH2 + +H2O

[0031] (HO)3Si-OH2 + +Si(OH)4→(HO)3Si-O-Si(OH)3+H3O +

[0032] The dimerization of OSA occurs via a condensation reaction between silicic acid molecules and protonated or deprotonated silicic acid in solution. The condensation rate has a minimum at pH ≈ 3 and increases at pH values ​​above or below ≈ 3. At pH 6, the dimerization rate is two orders of magnitude faster than at pH 4. When the pH of OSA is ≡ pK a1 (=9.8), the polymerization rate reaches a maximum because the concentrations of neutral OSA species and the deprotonated form of OSA are the same in solution, allowing more dimerization events to occur.

[0033] The overall solubility of silicon species in water is influenced by the solution's pH. OSA and its oligomers dissociate into various soluble silicates in alkaline solutions, particularly at pH > 8. Silicic acid oligomers are stronger acids than OSA and therefore dissociate preferentially. The higher acidity of OSA oligomers and their tendency to dissociate offset the reduced solubility of silicon-containing species due to the formation of larger oligomers / polymers of OSA. At pH > 9, the solubility of silicic acid increases with increasing pH due to the increased rate of dissociation of larger molecules back into OSA and the resulting formation of soluble poly-SA. In fact, silicate solubility reaches its lowest point between pH 7 and 7.5.

[0034] Therefore, prerequisites for the use of silicon-based formulations as delivery systems for pharmaceutical and bioactive agents are (a) water solubility of the silicon-containing material and (b) its subsequent reactivity towards biomolecules.

[0035] The water solubility of silicon depends on the ratio of free silanol (Si-OH) functional groups to the silicon backbone. Increasing the complexity of silicates means decreasing the ratio of silanol groups to silicon, resulting in larger molecules with poorer solubility and reactivity compared to smaller analogs. Therefore, the efficacy of such formulations is influenced by the ability of silicon to degrade to form OSA, the most bioactive and therefore beneficial type of silicic acid. The type of silicic acid produced by a formulation is primarily determined by the total concentration of these compounds and the pH of the medium in which dissolution occurs. Therefore, to ensure controlled release of OSA in vivo, the concentration of silicic acid must be carefully controlled.

[0036] When generated from silicon-based formulations, OSA is the only significant species in solution, allowing for its gradual, slow release without locally reaching a threshold concentration (2 mM) at which OSA condenses significantly into dimers and polymers. At higher concentrations, OSA polymerization can be improved, for example, by additives, formulation methods, or chemical or physical modifications of the silicon material.

[0037] The pH-dependent stability of OSA can be improved by adding biocompatible buffer systems (e.g., phosphate, citrate, ascorbate, etc.) to maintain the local aqueous environment at a slightly acidic pH (i.e., 5-6). Nevertheless, the pH in vivo is physiologically regulated and should not be altered.

[0038] As a more feasible alternative, the dissolution rate can be modulated by particle size and surface chemistry prior to in vivo use. To slow the dissolution of silicon particles, providing an oxide layer of suitable thickness can be used to create a hysteresis in the dissolution curve. This hysteresis is caused by the time it takes for the oxide layer to dissolve. The thickness of the oxide layer determines the length of the lag period before the silicon core becomes accessible to water.

[0039] Manipulation of the silicon surface requires careful consideration. This is because the binding of drug molecules to the silicon surface is highly dependent on surface energy. Surface hydroxylation will reduce the surface contact angle, favoring the binding of polar molecules. Alternatively, the growth of surface oxides will increase the surface contact angle, favoring the binding of hydrophobic molecules. Therefore, a combined strategy of size and surface chemistry should be considered to control drug loading and dissolution rate levels.

[0040] While some studies have considered the potential use of microparticles of silicon-based materials as delivery vehicles for beneficial compounds, achieving high and controlled levels of silicon degradation products—particularly the bioactive form of OSA—after decomposition of such carrier systems remains difficult. Previously proposed silicon-based drug delivery systems do not produce and release OSA in a controlled manner, and the extent to which these formulations retain silicic acid in the form of OSA has not been previously determined. Because many formulations decompose rapidly, high OSA concentrations are generated, which can lead to the formation of polysilicic acid.

[0041] While silicates and silicon-based formulations have been used as carrier systems for several applications, aggregation remains a major safety concern. Previously disclosed delivery systems using all forms of silicon, whether porous, fine silica, nanosilica, or silica particles, are said to dissolve to form silicic acid as the particles degrade. However, a major problem with known silicon-based delivery systems is the uncontrolled generation and release of OSA, which leads to OSA aggregation. The particle size distribution of the precipitated silicon is not uniform, and the silicate structure consists of aggregates and agglomerates. The primary particles of silicon or silicate bind to each other via hydrogen bonds to form primary agglomerates, which, in a further stage, combine to form a spatial structure of secondary aggregates. The lack of uniformity and particle size growth of unmodified silicon can be a significant safety concern if the particles remain in the body as silicate particles or polysilicic acid during the release of the active compound.

[0042] Another approach is to use stabilized OSA to ensure that silicon degrades to OSA in vivo. Skin care, cosmetic, pharmaceutical, and cosmeceutical compositions containing stabilized OSA are well known in the art, but they are not suitable for use as drug delivery systems. Therefore, there remains a need for silicon-based delivery systems in which silicon-containing carrier materials reliably degrade to OSA and in which polymerization of OSA can be prevented.

[0043] Silicon and its derivatives have also been used in drug discovery as drug or bioactive carriers. However, these carriers cannot control the release of loaded drugs without further modification. This is attributed to the open-porous matrix of these solid materials, which, without coatings, suffer from dose dumping and premature release of the active substance.

[0044] Australian Patent AU 774668 B2 describes a complex comprising bioassimilable orthosilicic acid in solid form stabilized by complexation with a polypeptide. This complex is prepared by hydrolyzing a precursor of hydrosilicic acid, such as tetraalkoxysilane, in the presence of an aqueous solution of the polypeptide, followed by evaporation of the water to form the solid complex. Suitable polypeptide stabilizers capable of stabilizing orthosilicic acid described in AU 774668 B2 include protein hydrolysates and collagen hydrolysates. While this complex can deliver OSA in a bioassimilable form that is stable at neutral and physiological pH levels, it does not provide a system for delivering other beneficial compounds, such as therapeutically active agents.

[0045] U.S. Patent No. 5,922,360 describes stable forms of OSA and biological preparations comprising stable OSA. In particular, US 5,922,360 describes the stability of the use of a stabilizer containing a nitrogen atom with a free electron pair that forms a complex with the silanol groups of OSA. Suitable stabilizers are quaternary ammonium compounds, such as tetraalkyl compounds, each of which contains, for example, 1-5 carbon atoms, particularly methyl and ethyl groups, and trialkylhydroxyalkyl compounds, wherein the hydroxyl group is preferably methanol or ethanol. Choline, for example in the form of choline hydrochloride, is described as being particularly suitable, as well as amino acids, such as proline and serine, which enhance absorption in the stomach and provide additional stability. Stable OSA is prepared by hydrolyzing a silicon-containing compound in water in the presence of a stabilizer, such that OSA is complexed with the stabilizer during production. International patent application WO 2004 / 016551 A1 similarly discloses a process for producing silicic acid-containing extrudates, wherein a silicon compound is hydrolyzed to OSA in the presence of a stabilizer selected from quaternary ammonium compounds, amino acids or amino acid sources.

[0046] The present inventors have developed a method for promoting the controlled release of OSA upon degradation of a composition containing silicon-containing nanoparticles, see WO 2011 / 012867 A. This method has been shown to successfully stabilize the degradation of silicon into bioavailable OSA in vivo. The present inventors have also developed a method for promoting the controlled release of OSA and a pharmaceutical or bioactive agent upon degradation of a composition containing silicon-containing nanoparticles, see EP 2459156.

[0047] While the work outlined in WO 2011 / 012867 and EP 2459156 provides for the use of lipids to control silica particle degradation and control OSA concentration, the present invention is based on the discovery that treating silicon particles with lipids provided at a certain level in combination with one or more amino acids results in particles having a greatly improved ability to bind compounds such as pharmaceutical or bioactive agents. By carefully selecting the lipids used and the optional other compounds used to treat the silicon particles, a combination of effective binding of the active agent and its release as the silicon-containing particles hydrolyze at a controlled rate can be achieved. Summary of the Invention

[0048] According to a first aspect of the present invention, there is provided a method for promoting the controlled binding and release of active pharmaceutical and cosmetic agents from a composition comprising silicon nanoparticles, wherein the silicon nanoparticles comprise at least 50 wt% silicon, the method comprising treating the surface of the silicon nanoparticles with at least one lipid, and treating the surface of the silicon nanoparticles with at least one amino acid, wherein the ratio of lipid to silicon is from 1:1 to 15:1.

[0049] Advantageously, by treating the surface of the silicon nanoparticles with lipids, the hydrolysis rate of silicon can be controlled, such that the silicon nanoparticles are hydrolyzed into bioavailable OSA degradation products. The present inventors have discovered that treating the surface of the silicon nanoparticles with at least one lipid also stabilizes the pharmaceutical or bioactive agent delivered by the silicon nanoparticles and controls its release rate at the target site.

[0050] The method further comprises the step of treating the surface of the nanoparticles with at least one amino acid. Advantageously, it has been found that the addition of amino acids to the surface of the nanoparticles affects the release rate of the pharmaceutical or bioactive agent delivered by the silicon nanoparticles over time.

[0051] According to a second aspect of the present invention, there is provided a composition comprising silicon nanoparticles prepared according to the first aspect of the present invention and one or more additional ingredients.

[0052] According to a third aspect of the present invention, there are provided silicon nanoparticles prepared according to the first aspect of the present invention and a composition for use as a medicament according to the second aspect of the present invention.

[0053] According to a fourth aspect of the present invention, there is provided a method for treating a medical condition, the method comprising administering to a subject in need thereof an effective dose of one or more active pharmaceutical ingredients (API), wherein the API is administered as a pharmaceutical composition according to an embodiment of the second aspect of the present invention.

[0054] According to a fifth aspect of the present invention, there is provided a method of providing a cosmetic benefit to a subject, the method comprising administering to the subject a composition according to an embodiment of the second aspect of the present invention.

[0055] It will of course be appreciated that features described in relation to one aspect of the invention may be incorporated into other aspects of the invention. For example, the method of the invention may incorporate any features described with reference to the apparatus of the invention, and vice versa. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 Graph showing oil-containing compositions and skin penetration using the Franz cell assay.

[0057] Figures 2 to 10 The zeta potential distribution of various samples is shown according to the following table:

[0058] picture preparation sample 2 1 Unloaded nanoparticles 3 2 Unloaded nanoparticles 4 3 Unloaded nanoparticles 5 4 Unloaded nanoparticles 6 5 Unloaded nanoparticles 7 2 siRNA-loaded nanoparticles 8 3 siRNA-loaded nanoparticles 9 4 siRNA-loaded nanoparticles 10 5 siRNA-loaded nanoparticles

[0059] Figure 11 Figure 2 is a graph comparing the zeta potential of formulations 1 to 5 (labeled F1 to F5) loaded (first in each pair of bars) and siRNA loaded (second in each pair of bars). Statistical analysis of differences was performed by t-test using GraphPad software.

[0060] Figure 12 Fluorescence micrographs of HCE-s cells transfected with formulations 2 to 5 (labeled F2 to F5) loaded with siGlow green fluorescent label are shown. Cell nuclei were stained with DAPI (blue, first column) and FAM (green, second column), and images were captured 24 hours later.

[0061] Figure 13 for Figure 12 It shows fluorescence micrographs of unloaded HCE-s cells transfected with formulations 2 to 5 (labeled F2 to F5). Cell nuclei were stained with DAPI (blue, first column) and FAM (green, second column), and images were captured 24 hours later.

[0062] Figure 14 Relative luciferase activity obtained from a dual-luciferase assay using HCE-S cells treated with siRNA-loaded formulations (nonspecific NSC4-loaded (first bar of three), specific LUC2P-loaded (middle bar of three), or empty formulation (last bar of three)) and a positive liposome control is shown. Measurements were taken 72 hours after treatment. The y-axis represents the ratio of firefly to Renilla luciferase, expressed as a percentage of the NSC4 control. Asterisks indicate statistical significance for knockdown: **p<0.01, ***p<0.001 when compared to the nonspecific NSC4 control.

[0063] Figure 15 Shown is a comparison of the zeta potential of silicon nanoparticles loaded with two different ratios of phosphatidylcholine (PC), stearylamine (SA), phosphatidylethanolamine (PE) and phosphatidylcholine (75 μg Si: 200 μg lipid and 150 μg Si: 200 μg lipid). Statistically significant differences between samples (by one-way analysis of variance (ANOVA) and Tukey post hoc analysis) are presented in the table below:

[0064] Figure 16 Shown is a comparison of the zeta potential measured in phosphatidylcholine (PC)-treated silicon nanoparticles with various arginine contents.

[0065]

[0066] Figure 17 Shown is a comparison of the zeta potential measured in stearylamine (SA)-treated silicon nanoparticles with various arginine contents.

[0067] Figure 18 Shown is a comparison of the zeta potential measured in phosphatidylethanolamine (PE)-treated silicon nanoparticles with various arginine contents.

[0068] Figure 19 Shown is a comparison of the zeta potential measured in lecithin-treated silicon nanoparticles with various arginine contents.

[0069] exist Figures 16 to 19 In the Figures, asterisks indicate the statistical significance of the differences between samples containing arginine and control (no arginine) samples (*p<0.05, **p<0.01, ***p<0.001), which were assessed by ANOVA followed by Tukey's post hoc analysis.

[0070] Figures 20 to 23 The changes in the zeta potential of formulations 1 to 38 (labeled F01 to F38) treated after loading siRNA are shown. The same amount of siRNA was added to each sample, mixed and incubated at room temperature for at least one hour before measurement. Statistical analysis was performed using GraphPad software by t-test, and asterisks indicate the statistical significance of the difference between the samples without and with siRNA loading (*p<0.05, **p<0.01, ***p<0.001). Figure 20 Data from formulations treated with phosphatidylcholine (PC) are shown. Figure 21 Data are shown for formulations treated with phosphatidylethanolamine (PE), Figure 22 Data are shown for formulations treated with stearylamine (SA), Figure 23 Data are shown for formulations treated with lecithin.

[0071] Figure 24 Fluorescence evaluation of HCE-S cells transfected with formulations 11, 12, 14, 15, 17, or 18 (F11, F12, F14, F15, F17, F18) loaded with siGlo (labeled with a green fluorescent tag, second column) is shown. Cell nuclei were stained with DAPI (blue, first column). Images were taken 24 hours after treatment.

[0072] Figure 25 Fluorescence evaluation of HCE-S cells transfected with unloaded formulations 11, 12, 14, 15, 17, or 18 (F11, F12, F14, F15, F17, F18) is shown. Cell nuclei were stained with DAPI (blue, first column). Images were taken 24 hours after treatment.

[0073] Figure 26Relative luciferase activity obtained from a dual-luciferase assay using HCE-S cells treated with formulations 11, 12, 14, 15, 17, or 18 (nonspecific NSC4-loaded (first bar of three), specific LUC2P-loaded (middle bar of three), or empty formulation (last bar of three)) and a positive liposome control is shown. Measurements were taken 72 hours after treatment. The y-axis represents the ratio of firefly to Renilla luciferase, expressed as a percentage of the NSC4 control (according to Table 4). Asterisks indicate statistical significance of knockdown: *p<0.05, **p<0.01 when compared to the nonspecific NSC4 control. DETAILED DESCRIPTION

[0074] definition

[0075] According to the present disclosure, a derivative of a compound may be a compound having substantially the same structure but having one or more substituents. For example, one or more chemical groups may be added, deleted, or substituted for another group. In certain preferred embodiments, the derivative retains at least some of the pharmaceutical or cosmetic activity of the compound from which it is derived, for example, at least 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the activity of the compound from which it is derived. In some embodiments, the derivative may exhibit increased pharmaceutical or cosmetic activity compared to the compound from which it is derived.

[0076] For example, in the context of peptides, peptide derivatives may encompass peptides in which one or more amino acid residues have been added, deleted or substituted for another amino acid residue. In the case of substitutions, the substitutions may be non-conservative substitutions or conservative substitutions, preferably conservative substitutions.

[0077] According to a first aspect of the present invention, there is provided a method for controlling the controlled binding and release of an active pharmaceutical agent (also referred to as an API - for example, the API may be a hydrophobic API; the API may be an immunosuppressant such as cyclosporin, in particular cyclosporin A, or a derivative thereof) or an active cosmetic agent (also referred to as an ACI - for example, the ACI may be an anti-aging agent such as an anti-aging lipopeptide, or a derivative thereof) from a composition comprising silicon nanoparticles, wherein the silicon nanoparticles comprise at least 50% by weight silicon, the method comprising treating the surface of the nanoparticles with at least one lipid (for example, one or more phospholipids and / or one or more additional charged lipids, for example, one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, lecithin and any derivatives thereof) and at least one amino acid (for example, one or more cationic amino acids, or a combination of amino acids, wherein the one or more amino acids are cationic, such as one or more of arginine and glycine), wherein the ratio of lipid to silicon is from 1:1 to 15:1.

[0078] Silicon nanoparticles

[0079] According to all aspects of the present invention, the composition comprises silicon nanoparticles. Their nominal diameter is between 5 and 400 nm, for example, 20 to 400 nm, for example, 50 to 350 nm, for example, 80 to 310 nm, for example, 100 to 250 nm, for example, 120 to 240 nm, for example, 150 to 220 nm, for example, about 200 nm. They are made of pure silicon or a hydrolyzable silicon-containing material. They are preferably porous. The nominal diameter mentioned above may refer to the average diameter, and at least 90% of the total particles in a sample of silicon nanoparticles may fall within the specified size range. They are made of pure silicon or a hydrolyzable silicon-containing material. The silicon nanoparticles can be made porous by standard techniques, such as contacting the particles with a hydrofluoric acid (HF) / ethanol mixture and applying an electric current. By varying the HF concentration and current density and exposure time, the density and size of the pores can be controlled and can be monitored by scanning electron microscopy and / or nitrogen adsorption-desorption volume isothermal measurements.

[0080] The silicon nanoparticles may be pure silicon or another hydrolyzable silicon-containing material. If they are not pure silicon, the silicon nanoparticles comprise at least 50% by weight silicon. They preferably comprise at least 60%, 70%, 80%, 90% or 95% silicon and preferably exhibit a hydrolysis rate (e.g., in PBS buffer at room temperature) of at least 10% of the hydrolysis rate of pure silicon particles of the same dimension. Determination of the hydrolysis of silicon-containing materials is well known in the art, for example, WO 2011 / 001456. It should be understood that silicon dioxide (SiO2) nanoparticles that do not comprise 50% by weight elemental silicon do not fall within the definition of silicon nanoparticles. Silica nanoparticles are also not hydrolyzable because hydrolysis of silicon dioxide is thermodynamically unfavorable under the conditions present in vivo.

[0081] Nanoparticles according to all aspects of the present invention are preferably porous. For example, their porosity can increase their surface area by at least 1.5, 2, 2.5, 3, 3.5, or 4 times that of a non-porous material of equivalent size. In some embodiments, their total surface area preferably increases by at least 50% or at least 100% due to their porosity compared to the surface area of ​​corresponding non-porous particles. In many cases, porous silicon nanoparticles will actually have a greater increase in total surface area due to their porosity.

[0082] Preferably, the average diameter of the silicon nanoparticles is between 20-300 nm, for example between 20-290 nm, between 20-280 nm, between 20-270 nm, between 20-260 nm, between 20-250 nm, between 20-240 nm, between 20-230 nm, between 20-220 nm, between 20-210 nm, in particular between 20-200 nm.

[0083] Advantageously, silica nanoparticles of this size are well suited for topical skin delivery because they are too small to block the sebaceous glands or sweat ducts (pores) of the hair follicles, but their small size enables the particles to actively penetrate to the base of the hair follicles rather than simply acting as a surface drug reservoir (e.g., when the active pharmaceutical or cosmetic agent is a hydrophobic agent for topical skin delivery, such as a hydrophobic peptide or lipopeptide, such as cyclosporin A or a derivative thereof, or an anti-aging lipopeptide or a derivative thereof).

[0084] lipids

[0085] According to all aspects of the present invention, the silicon nanoparticles are surface-treated with at least one lipid (e.g., one or more phospholipids and / or one or more additional charged lipids, such as one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof). Surface treatment of the silicon nanoparticles with lipids has been found to help control the release rate of an active agent (e.g., the active agent can be a hydrophobic active agent; the active agent can be an immunosuppressant such as cyclosporin, particularly cyclosporin A, or a derivative thereof, or alternatively an anti-aging agent such as an anti-aging lipopeptide, or a derivative thereof). The type of lipid used to treat the nanoparticle surface (e.g., one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof) influences the release rate of the active agent or cosmetic agent (e.g., an immunosuppressant such as cyclosporin A or a derivative thereof, or an anti-aging agent such as an anti-aging lipopeptide, or a derivative thereof).

[0086] Silicon to lipid ratio

[0087] The ratio of lipid (e.g., one or more phospholipids and / or additional charged lipids, e.g., one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, lecithin, and any derivatives thereof) to silicon is between 1:1 and 15:1, e.g., between 1:1 and 13:1, between 1:1 and 12:1, between 1:1 and 11:1, between 1:1 and 10:1, between 1:1 and 9:1, between 1:1 and 8:1, between 1:1 and 13:1, between 2:1 and 12:1, between 2:1 and 11:1, between 2:1 and 10:1, between 2:1 and 9:1, between 2:1 and 8:1, e.g., between 1:1 and 7:1, between 2:1 and 7:1, between 3:1 and 8:1, between 4:1 and 5:1. Preferably, the ratio of lipid to silicon is between 1: 1 and 3: 1, more preferably between 1: 1 and 8: 3. Advantageously, this ratio of lipid to silicon provides for the controlled release and stabilization of the pharmaceutical or bioactive agent (e.g., a hydrophobic agent; the agent may be an immunosuppressant such as cyclosporin, particularly cyclosporin A or a derivative thereof, or alternatively an anti-aging agent such as an anti-aging lipopeptide or a derivative thereof) delivered by the silicon nanoparticles, and for the controlled release of OSA, a bioavailable degradation product of silicon.

[0088] Advantageously, lipid compounds (e.g., one or more phospholipids and / or additional charged lipids, such as one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof) can have a significant effect on the surface charge of silicon nanoparticles. Silicon nanoparticles treated with phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylcholine exhibited a negative surface charge (ranging from -60 to -20 mV, with a Si: lipid ratio ranging from 1:1 to 1:3) when subjected to zeta potential analysis. Silicon nanoparticle surfaces treated with stearylamine exhibited a positive zeta potential (ranging from 0 to 40 mV, with a Si: lipid ratio ranging from 1:1 to 1:3) compared to glycine and histidine.

[0089] In the method of the first aspect of the invention, the ratio of lipid to silicon is 1:1 to 15:1. In one embodiment, the method of the first aspect of the invention comprises treating the surface of the silicon nanoparticles with at least 30 wt%, typically at least 50 wt%, of lipid, based on the total weight of the coated nanoparticles. It has been found that a molar ratio of lipid to silicon of between 1:1 and 3:1 is particularly advantageous, such as between 1:1 and 8:3, for example 1:1, 1.5:1, 2:1 or 2.5:1.

[0090] In certain embodiments, the method of the first aspect of the invention comprises treating the surface of the silicon nanoparticles with at least 5% by weight of a phospholipid (e.g., one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, and any derivatives thereof), for example, at least 20% by weight, typically at least 30% by weight, and in particular at least 50% by weight of a phospholipid, based on the total weight of the coated nanoparticles. It has been found that a molar or weight ratio of lipid to silicon of between 1:1 and 3:1 is particularly advantageous, such as between 1:1 and 8:3, for example, 1:1, 1.5:1, 2:1, or 2.5:1.

[0091] In one embodiment, the number average molecular weight of phospholipid (for example, one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine and any derivative thereof) is in the range of 500 to 1000. Particularly suitable phospholipid is glycerophospholipid. Particularly suitable phospholipid is those in which polar head group is connected with quaternary ammonium moiety, such as phosphatidylcholine (PC) or hydrogenated phosphatidylcholine. The type of phospholipid can be selected according to the properties of preparation, wherein neutral or negatively charged lipid is preferably used for aprotic preparations, and positive charge and little CH3 chain lipid are preferably used for proton preparations. Preferably, side chain is the aliphatic side chain with 15 or more carbon atoms or the ether side chain with 6 or more repeating ether units, such as polyethylene glycol or polypropylene glycol chain.

[0092] In certain embodiments of the present invention where transient release of an agent from a formulation is desired, the surface of the silicon nanoparticles can be treated with phosphatidylcholine and other phosphatidylcholine derivatives, such as didecanoylphosphatidylcholine or mirystoil phosphatidylcholine. This is particularly advantageous when the pharmaceutical or bioactive agent in question is a cationic substance.

[0093] Preferably, the lipid is selected from the group consisting of dioleoylphosphatidylethanolamine (DOPE), phosphatidylcholine, phosphatidylethanolamine (PE), stearylamine (SA), and phosphatidylcholine (PC), or any combination thereof. Most preferably, the lipid comprises phosphatidylcholine. Preferably, the phosphatidylcholine is present in a weight ratio to silicon of 1:1 to 3:1, most advantageously 1:1 to 2:1.

[0094] In another embodiment where extended drug release over a prolonged period of time is desired, treating the surface of the silicon nanoparticles with lecithin will allow for a high percentage release of the agent.

[0095] In another embodiment, where the active pharmaceutical agent (API) or cosmetic agent (ACI) is anionic, such as short interfering RNA or messenger RNA, the surface of the silicon nanoparticles may be treated with phosphatidylcholine (PC) and / or phosphatidylcholine.

[0096] Lipid to API / ACI ratio

[0097] Preferably, the ratio of lipid (e.g., one or more phospholipids and / or other charged lipids, such as one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine and any derivatives thereof) to API / ACI (e.g., a hydrophobic API or ACI; the API may be an immunosuppressant, such as cyclosporin, particularly cyclosporin A or a derivative thereof, or the ACI may be an anti-aging agent, such as an anti-aging lipopeptide or a derivative thereof) is between 1:0.1 and 15:1, for example, between 1:1 and 13:1. Preferably, the lipid to API / ACI ratio is between 1:1 and 4:1, particularly between 1:1 and 3:1. Advantageously, this ratio of lipid to API / ACI provides a structured multilamellar vesicle system that allows for control of the specific secondary and tertiary structures of the API associated with the silicon nanoparticles, particularly when the API / ACI is a lipopeptide (e.g., an anti-aging agent, such as an anti-aging lipopeptide or a derivative thereof) or an API capable of self-assembly. Alternatively, a specific ratio can be advantageously used to stabilize the interaction between the lipid (e.g., one or more phospholipids and / or other charged lipids, such as phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof) and the API / ACI (e.g., a hydrophobic API or ACI; the API can be an immunosuppressant, such as cyclosporin, particularly cyclosporin A or a derivative thereof; the ACI can be an anti-aging agent, such as an anti-aging lipopeptide or a derivative thereof) absorbed onto the surface of the silicon nanoparticles. This ratio can indeed provide further control over the release and stabilization of the pharmaceutical or bioactive agent delivered by the silicon nanoparticles, as well as controlling the release of OSA, a bioavailable degradation product of the silicon.

[0098] amino acids

[0099] According to all aspects of the present invention, lipid-treated silicon nanoparticles (e.g., silicon nanoparticles treated with one or more phospholipids and / or other charged lipids, such as phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof) are further treated with an amino acid (e.g., one or more of arginine and glycine). In the broadest sense, the term "amino acid" encompasses any artificial or naturally occurring organic compound containing an amine (-NH2) and a carboxyl (-COOH) functional group. It includes α, β, γ, and δ amino acids. It includes amino acids of any chiral configuration. According to some embodiments, it is preferably a naturally occurring amino acid (e.g., one or more of arginine and glycine). It can be a proteinogenic amino acid or a non-proteinogenic amino acid (e.g., carnitine, levothyroxine, hydroxyproline, ornithine, or citrulline). In a particularly preferred embodiment, it is arginine, histidine, or glycine, or a mixture of arginine and glycine, most preferably one or more of arginine and glycine.

[0100] Thus, preferred pharmaceutically or cosmetically compatible compositions of the present invention associate surface-treated nanoparticles (e.g., nanoparticles treated with one or more phospholipids and / or other charged lipids, such as phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, lecithin, and any derivatives thereof) with active pharmaceutical or cosmetic agents ("API," e.g., a hydrophobic API; the API can be an immunosuppressant, such as a cyclosporin, such as cyclosporin A or a derivative thereof; and "ACI," e.g., a hydrophobic ACI; the ACI can be an anti-aging agent, such as an anti-aging lipopeptide or a derivative thereof) and amino acids (preferably selected from arginine, glycine, histidine, and mixtures thereof, most preferably arginine and glycine, and in some embodiments, arginine).

[0101] According to a preferred embodiment, at least 80% by weight, such as at least 90% by weight, of the API (e.g., a hydrophobic API; the API may be an immunosuppressant, such as a cyclosporin, such as cyclosporin A or a derivative thereof) or ACI (e.g., a hydrophobic ACI; the ACI may be an anti-aging agent, such as an anti-aging lipopeptide or a derivative thereof) present in the product of all aspects of the invention is associated with the surface-treated nanoparticles (e.g., surface-treated nanoparticles wherein the lipid is selected from one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, lecithin and any derivatives thereof, and the amino acid is selected from one or more of arginine and glycine).

[0102] Molecular association between the API or ACI (e.g., a hydrophobic API or ACI, such as cyclosporin A) and lipid-treated silicon nanoparticles (e.g., silicon nanoparticles treated with one or more phospholipids and / or other charged lipids, such as phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, lecithin, and any derivatives thereof) advantageously ensures that the API or ACI becomes bioavailable as the surface-treated silicon nanoparticles degrade. The degradation rate of the composition is controlled by the hydrolysis of the silicon nanoparticles. Because this rate can be controlled, the rate at which the API or ACI becomes bioavailable can also be controlled to avoid dose dumping and / or ensure that the nanoparticles are released only when they find their way to a location away from the skin surface (e.g., a basal location).

[0103] Treatment of lipid-treated silicon nanoparticles with amino acids (e.g., one or more cationic amino acids, or one or more of a combination of amino acids in which one or more amino acids are cationic, such as one or more of glycine and arginine) has been found to provide a beneficial stabilizing effect on the pharmaceutical or bioactive agent loaded onto the silicon nanoparticles. In particular, treatment of lipid-treated silicon nanoparticles (e.g., nanoparticles treated with one or more phospholipids and / or other charged lipids, such as phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, lecithin, and any derivatives thereof) with amino acids (e.g., one or more cationic amino acids, or one or more of a combination of amino acids in which one or more amino acids are cationic, such as one or more of glycine and arginine) has been shown to stabilize pharmaceutical or bioactive agents in biological fluids.

[0104] According to certain embodiments of all aspects of the present invention, lipid-treated silicon nanoparticles (e.g., nanoparticles treated with one or more phospholipids and / or other charged lipids, such as phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof) are further treated with arginine. Surface treatment of silicon nanoparticles with arginine loaded with an API (e.g., a hydrophobic API, such as a hydrophobic peptide, such as cyclosporin A or a derivative thereof) shows better stability of the API in biological fluids.

[0105] Amino acid to silicon ratio

[0106] Preferably, the ratio of amino acid (e.g., one or more cationic amino acids, or one or more of a combination of amino acids in which one or more amino acids are cationic, such as one or more of glycine and arginine) to silicon is between 0.05:1 and 2:1, e.g., between 0.05:1 and 1.8:1, between 0.05:1 and 1.6:1, between 0.05:1 and 1.4:1, between 0.05:1 and 1.2:1, and 0.05:1 and 1.3:1. 1 and 0.8: 1, in particular between 0.3: 1 and 0.7: 1. Advantageously, this ratio of amino acid to silicon further influences and stabilizes the release rate of pharmaceutical and bioactive agents delivered by lipid-treated silicon nanoparticles (e.g., nanoparticles treated with one or more phospholipids and / or other charged lipids, for example, phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, lecithin, and any derivatives thereof).

[0107] According to other embodiments of all aspects of the present invention, the silicon nanoparticles are treated with a lipid (e.g., one or more phospholipids and / or other charged lipids, such as phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof) and an amino acid (e.g., one or more cationic amino acids, or one or more of a combination of amino acids in which one or more amino acids are cationic, such as one or more of glycine and arginine). The amino acid may be any amino acid. Preferably, the amino acid is arginine or glycine or a combination of glycine and arginine. The lipid may be any lipid (e.g., one or more phospholipids and / or other charged lipids, such as one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof). Preferably, the lipid is a phospholipid, more preferably PC or hydrogenated PC. Preferably, the ratio of amino acid to silicon is between 0.05:1 and 0.4:1, such as between 0.08:1 and 0.35:1, and in particular between 0.09:1 and 0.32:1. In some embodiments, the amino acids are a combination of arginine and glycine, wherein the ratio of Arg:Gly is between 1:0.6 and 3:1, such as between 1:0.8 and 2.5:1, such as between 1:1 and 2:1.

[0108] According to other embodiments of all aspects of the present invention, the lipid-treated silicon nanoparticles are treated with arginine. The lipid can be any lipid (e.g., one or more phospholipids and / or other charged lipids, such as one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof). Preferably, the lipid is a phospholipid, such as PC or hydrogenated PC. Preferably, the ratio of arginine to silicon is between 0.05:1 and 0.4:1, such as between 0.08:1 and 0.35:1, and in particular between 0.09:1 and 0.32:1. Advantageously, it has been found that such ratios provide a high rate of release of an API (e.g., a hydrophobic API; the API can be an immunosuppressant, such as a cyclosporin, such as cyclosporin A, or a derivative thereof) and an ACI (e.g., an anti-aging agent, such as an anti-aging lipopeptide, or a derivative thereof).

[0109] In some embodiments, preferred formulations comprising PC and arginine have a silicon to PC ratio between 1:1 and 3:1, and a silicon to arginine ratio between 4:1 and 8:1.

[0110] Arginine present in a ratio below 0.2:1 (Arg:Si) does not effectively increase the release of the API. However, even at these low amounts, arginine contributes to the stability of the API (e.g., the stability of a hydrophobic API; the API may be an immunosuppressant such as a cyclosporin, e.g., cyclosporin A, or a derivative thereof). In addition, the presence of small amounts of arginine further improves the stability of the released OSA. When larger amounts of arginine are used, the excess amino acid contributes to the formation of transiently soluble peptide aggregates. This is particularly true if the peptide is formed from charged and polar amino acids, such as arginine. The effect of forming such peptide aggregates is a reduction in the amount of active substance released. Similarly, the formation of such peptides also inhibits the release of OSA.

[0111] According to certain embodiments of all aspects of the present invention, the lipid-treated nanoparticles (e.g., nanoparticles treated with one or more phospholipids and / or other charged lipids, such as phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof) are further treated with histidine. Advantageously, when histidine is used in combination with any lipid, improved API stability (e.g., stability of a hydrophobic API; the API may be an immunosuppressant, such as a cyclosporin, such as cyclosporin A, or a derivative thereof) is observed. This can be attributed to the better buffering effect of the resulting composition in the range of pH 5.12 to pH 7.12. Preferably, the ratio of histidine to silicon is between 0.05:1 and 0.4:1, such as between 0.08:1 and 0.5:1, and in particular between 0.35:1 and 0.45:1. Advantageously, this ratio allows for a high rate of release of the API (e.g., a hydrophobic API, such as a cyclosporin, such as cyclosporin A, or a derivative thereof). Preferably, the lipid used in combination with histidine is PC, hydrogenated PC or lecithin.

[0112] According to certain embodiments of all aspects of the present invention, the lipid-treated nanoparticles (e.g., nanoparticles treated with one or more phospholipids and / or other charged lipids, such as phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, phosphatidylcholine, and any derivatives thereof) are further treated with glycine. Advantageously, glycine promotes cytoplasmic penetration of the silicon nanoparticles within animal or human cells. A high ratio of glycine to silicon is beneficial for increasing the release rate of the API (e.g., the release of a hydrophobic API, such as a cyclosporin, e.g., cyclosporin A or a derivative thereof).

[0113] According to other embodiments of all aspects of the present invention, the silicon nanoparticles are surface-treated with hydrogenated PC and glycine. Advantageously, such compositions enable the release of an API (e.g., a hydrophobic API, such as a cyclosporin, e.g., cyclosporin A or a derivative thereof) to reach a plateau over time. In particular, controlled release of the drug was observed over a 12-hour period.

[0114] In some embodiments of the second aspect of the invention, a composition is provided comprising silicon nanoparticles surface-treated with at least one lipid (e.g., one or more phospholipids and / or other charged lipids, such as one or more of phosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, stearylamine, lecithin, and any derivatives thereof) and at least one amino acid for use as a delivery system for prolonged drug release over time.

[0115] Oil

[0116] In certain embodiments of all aspects of the present invention, the composition further comprises at least one oil. Advantageously, the inclusion of oil in the composition of the present invention has the beneficial effect of masking odor, and has been observed to increase the skin penetration / permeability of the API (e.g., when the API is a hydrophobic API; the API can be an immunosuppressant such as a cyclosporin, for example, cyclosporin A or a derivative thereof) or ACI (e.g., when the ACI is an anti-aging agent such as an anti-aging lipopeptide or a derivative thereof) and form an amphiphilic interface capable of overcoming precipitation due to poor solubility at the oil / water interface.

[0117] In a preferred embodiment, the oil is selected from limonene, coconut oil, oregano oil, sesame oil, or a combination thereof.

[0118] In certain embodiments, the oil is selected from limonene, coconut oil, or a combination thereof. Advantageously, the use of such oils has been shown to be effective in masking odors, such as fish oils (eg, omega-3 fish oils).

[0119] In certain embodiments, the oil is selected from limonene, oregano oil, sesame oil, or a combination thereof. Preferably, the composition comprises oregano oil and sesame oil. Advantageously, these oils have been shown to aid in the loading, vehiculating, and delivery of APIs to provide fish vaccines. In certain embodiments, the ratio of silicon nanoparticles:oregano oil:sesame oil is 1.6:4.5:3.8.

[0120] In another embodiment of all aspects of the invention, the oil is limonene. Advantageously, the inclusion of limonene in compositions has been shown to increase the skin penetration rate of an API (e.g., when the API is a hydrophobic API; the API can be an immunosuppressant such as a cyclosporin, e.g., cyclosporin A or a derivative thereof) or an ACI (e.g., a hydrophobic ACI; the ACI can be an anti-aging agent such as an anti-aging lipopeptide or a derivative thereof) loaded onto the silicon nanoparticles, when compared to silicon nanoparticles without the additional oil component. In particular, embodiments of the second aspect of the invention that also include an oil have been found to improve the amphiphilic nature of the nanoparticles to overcome the poor water-in-oil distribution of the API-loaded silicon nanoparticles. This is particularly true when the API or ACI is a hydrophobic peptide or lipopeptide (e.g., when the API is a hydrophobic peptide such as cyclosporin A or a derivative thereof, or when the ACI is a lipopeptide such as an anti-aging lipopeptide or a derivative thereof).

[0121] According to certain embodiments of the invention (eg, when the API is a hydrophobic API), the at least one oil is present in the composition at between 1000 and 10, such as between 500 and 50, especially between 250 and 80 wt%.

[0122] Table 1. Weights and ratios of materials used in the protocol for preparing Sample 1: silicon nanoparticles containing 20 mg of API.

[0123]

[0124] Additional components

[0125] In certain embodiments of all aspects of the invention, the composition further comprises silicon nanoparticles loaded with a charged API or ACI (e.g., a charged lipopeptide or derivative thereof). In certain embodiments of all aspects of the invention, the silicon nanoparticles are loaded with a cationic API or ACI. In another aspect of all embodiments of the invention, the silicon nanoparticles are loaded with an anionic API or ACI.

[0126] The compositions of the present invention preferably also comprise one or more active pharmaceutical ingredients (e.g., a hydrophobic API; the API may be an immunosuppressant, such as a cyclosporin, for example, cyclosporin A or a derivative thereof). For example, each API may be present at up to 0.1%, 0.5%, 1%, 2%, 4%, 6%, 8% or 10% by weight of the total composition.

[0127] The API is preferably associated with the silicon nanoparticles.

[0128] The API may advantageously be hydrophobic, such as a hydrophobic peptide or a hydrophobic lipopeptide. For example, the API may be a hydrophobic peptide, such as cyclosporin A or a derivative thereof.

[0129] According to certain embodiments, the API may be selected from:

[0130] Nonsteroidal anti-inflammatory drugs, such as but not limited to aceclofenac, diclofenac, celecoxib, choline and magnesium salicylate, ibuprofen, naproxen, and piroxicam (NSAIDs);

[0131] anti-inflammatory and immunosuppressive agents, such as, but not limited to, cyclosporins, e.g., cyclosporin A or its derivatives, hydrocortisone and related derivatives, and corticosteroids, e.g., prednisone and dexamethasone; and steroids;

[0132] Analgesics and antipyretics, such as, but not limited to, acetaminophen and acetylsalicylic acid;

[0133] antifungal active substances, such as, but not limited to, griseofulvin, miconazole, fluconazole, itraconazole, oxiconazole, econazole, bifonazole as free bases and the relevant salts, e.g. as nitrates (antifungal category);

[0134] Antiviral and antiparasitic drugs, such as but not limited to acyclovir, ganciclovir, valacyclovir, metronidazole and tinidazole, and amphotericin (antiviral / antiparasitic);

[0135] Antibiotics, such as but not limited to gentamicin, nystatin, and clindamycin;

[0136] Anticancer drugs and / or adjuvants used in anticancer treatment, such as but not limited to paclitaxel, methotrexate, curcumin, and aloe-emodin;

[0137] Anesthetic (in liquid form);

[0138] Non-depolarizing muscle relaxants;

[0139] Opioid painkillers;

[0140] Benzodiazepines;

[0141] Antiepileptic drugs;

[0142] Peptides and / or amino acids;

[0143] ·hormone;

[0144] mRNA;

[0145] siRNA;

[0146] Other nucleic acids.

[0147] In other embodiments, the compositions of the present invention preferably further comprise one or more active cosmetic ingredients (ACIs, such as anti-aging agents, such as anti-aging lipopeptides, or derivatives thereof), for example, each API may be present at up to 0.1%, 0.5%, 1%, 2%, 4%, 6%, 8% or 10% by weight of the total composition.

[0148] ACI (such as an anti-aging agent, such as an anti-aging lipopeptide or a derivative thereof) is preferably located in association with the silicon nanoparticles. In certain embodiments, the composition of the second aspect of the invention further comprises an API and an ACI located substantially in association with the silicon nanoparticles.

[0149] The ACI may be hydrophobic. Advantageously, the ACI may comprise one or more hydrophobic and / or hydrophilic portions.

[0150] ACI can be a peptide or a lipopeptide. When ACI is a lipopeptide, such as an anti-aging lipopeptide, the peptide portion can be hydrophilic and the lipid portion can be hydrophobic. For example, when ACI is an anti-aging lipopeptide, ACI can be a 5-mer peptide lipidated at the N-terminus.

[0151] According to certain embodiments, the ACI may be selected from:

[0152] Glycyrrhizic acid (also known as licorice extract), kojic acid, or more generally, whitening agents used in skin products;

[0153] Antioxidants (such as plant extracts, for example, lupin (Lupinus albus) extract)

[0154] and vitamins;

[0155] Peptides;

[0156] Copper peptide (6-amino-2-[[2-[(2-aminoacetyl)amino]-3-(1H-imidazol-5-yl)propionyl]

[0157] amino]caproic acid, with or without copper ions);

[0158] Alpha-hydroxy acids;

[0159] Beta-hydroxy acids;

[0160] Hydroquinone;

[0161] Retinol

[0162] L-ascorbic acid;

[0163] Hyaluronic acid;

[0164] • Anti-aging agents (eg, anti-aging lipopeptides).

[0165] While the compositions of the present invention can be administered alone, preferably the compositions are present in a pharmaceutical or cosmetic composition.

[0166] Thus, a second aspect of the present invention provides a composition of the present invention and one or more additional ingredients.While those additional ingredients will typically include one or more excipients, they may also optionally include one or more additional active agents.

[0167] Compositions according to the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), inhalation (including fine particle dusts or mists which may be generated by various types of metered dose pressurized aerosols, nebulizers, or insufflators), rectal and topical (including dermal, transdermal, transmucosal, buccal, sublingual and intraocular) administration, although the most appropriate route may depend, for example, on the condition and disorder of the recipient.

[0168] The compositions are conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical formulation art. All methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more auxiliary ingredients. Generally, the compositions are prepared by uniformly and intimately associating the silicon nanoparticles with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product into the desired formulation.

[0169] Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste. Various pharmaceutically acceptable carriers and their formulations are described in standard formulation treatises, such as Remington's Pharmaceutical Sciences by EW Martin. See also Wang, YJ and Hanson, MA, Journal of Parenteral Science and Technology, Technical Report No. 10, Supplement 42:2S, 1988, the contents of which are incorporated herein by reference.

[0170] Tablets can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as a powder or granules in a suitable machine, optionally mixed with a binding agent, lubricant, inert diluent, lubricant, surfactant or dispersant. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide slow or controlled release of the active ingredient therein.

[0171] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for increasing volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavorings such as those known in the art; and immediate-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents, and lubricants such as those known in the art. Molded tablets, compressed tablets, or freeze-dried tablets are exemplary forms that may be used. Exemplary compositions include those in which the compounds of the present invention are formulated with rapidly dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrins. Such formulations may also include high molecular weight excipients such as cellulose (microcrystalline cellulose) or polyethylene glycol (PEG). Such formulations may also include excipients to aid mucoadhesion, such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and agents to control release, such as polyacrylic acid copolymers (e.g., Carbopol 934). Lubricants, glidants, flavorings, colorants, and stabilizers may also be added for ease of manufacture and use.

[0172] Compositions for parenteral administration include aqueous and non-aqueous sterile injections, which may contain antioxidants, buffers, bacteriostats, and solutes that make the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The composition may be present in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, immediately before use. Exemplary compositions for parenteral administration include injectable suspensions of the compositions of the present invention, which may also contain, for example, a suitable non-toxic, parenterally acceptable diluent or solvent, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersants or wetting agents and suspending agents, including synthetic monoglycerides or diglycerides, and fatty acids, including oleic acid or Cremaphor. The aqueous carrier can be, for example, an isotonic buffer solution having a pH of about 3.0 to about 8.0, preferably a pH of about 3.5 to about 7.4, for example 3.5 to 6.0, for example 3.5 to about 5.0. Useful buffers include sodium citrate-citric acid and sodium phosphate-phosphoric acid, as well as sodium acetate / acetic acid buffers. The composition preferably does not include oxidizing agents and other compounds known to be harmful to any active ingredient. Excipients that may be included are, for example, proteins, such as human serum albumin or plasma preparations. If desired, the composition may also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, preservatives, and pH buffers, such as sodium acetate or sorbitol monolaurate.

[0173] Exemplary compositions for nasal aerosol or inhalation administration include saline solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, and / or other solubilizing agents or dispersants, such as those known in the art. Conveniently, compositions of the present invention may be delivered in suitable powder inhalers for nasal aerosol or inhalation administration. Capsules and cartridges of, for example, gelatin for such inhalers may be formulated into a powder mixture containing compound and a suitable powder matrix such as lactose or starch. Compositions for rectal administration may be provided as retention enemas or suppositories with conventional carriers such as cocoa butter, synthetic glycerides or polyethylene glycol. Such carriers are typically solid at room temperature, but liquefy and / or dissolve in the rectal cavity to release the drug.

[0174] The compositions of the present invention may be suitable for topical administration. For example, the compositions of the present invention may be suitable for topical application to the skin. When the compositions of the present invention comprise a hydrophobic API, the compositions of the present invention may be topically administered. When the compositions of the present invention comprise an immunosuppressant, such as a cyclosporin, such as cyclosporin A or a derivative thereof, the compositions of the present invention may be topically administered. When the compositions of the present invention comprise an ACI that is an anti-aging agent, such as an anti-aging lipopeptide or a derivative thereof, the compositions of the present invention may be topically administered.

[0175] Compositions for topical administration in the mouth, e.g., buccal or sublingual, include lozenges containing the active ingredient in a flavored base, such as sucrose and acacia or tragacanth, and lozenges containing the active ingredient in a base, such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier, such as a composite ointment base (Plastibase) of liquid paraffin and polyethylene (mineral oil gelled with polyethylene).

[0176] According to some embodiments, the pharmaceutical composition of the present invention is a unit dose composition comprising a single effective dose or an appropriate fraction thereof of the API.

[0177] It should be understood that in addition to the ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents.

[0178] The compositions of the present invention may also be suitably administered as a sustained-release system. Suitable examples of sustained-release systems of the present invention include suitable polymeric materials, such as semipermeable polymer matrices in the form of shaped articles, such as films or microcapsules; suitable hydrophobic materials, such as emulsions in acceptable oils; or ion exchange resins; and sparingly soluble derivatives of the compounds of the present invention, such as sparingly soluble salts. The sustained-release system may be administered orally; rectally; parenterally; intracisternal; intravaginally; intraperitoneally; topically, for example, as a powder, ointment, gel, drops, or transdermal patch; buccally; sublingually, or as an oral or nasal spray.

[0179] A therapeutically effective amount of the API or a cosmetically effective amount of the ACI can be administered as a single pulse dose, as a bolus dose, or as pulse doses administered over time, for example, over the course of a day, over the course of a week, or over the course of a month.

[0180] In many preferred embodiments, the composition of the present invention is a topical cream or gel. For example, it can comprise a pharmaceutically or cosmetically compatible cream or gel suitable for topical application to the skin or other body surface, including a cream base in which the composition of the present invention is suspended. For example, when the API or ACI is a hydrophobic API or ACI, such as cyclosporin A or a derivative thereof, or an anti-aging lipopeptide or a derivative thereof, the composition of the present invention can be a topical cream or gel.

[0181] Pharmaceutically or cosmetically compatible creams comprise a cream base. Cream bases are typically water-in-oil or oil-in-water emulsions. Preferably, they are oil-in-water emulsions in which the oil phase comprises a mixture of lipids, sterols, and emollients. For example, when the API or ACI is cyclosporin A or a derivative thereof, or an anti-aging lipopeptide or a derivative thereof, the composition of the present invention may be in a pharmaceutically or cosmetically compatible cream comprising a cream base.

[0182] The pharmaceutically or cosmetically compatible gel comprises the composition of the present invention dispersed in the liquid phase of the gel. The gel is preferably a hydrogel (colloidal gel) comprising a cross-linked polymer such as polyethylene oxide, polyacrylamide or agarose, methylcellulose, hyaluronic acid, elastin-like polypeptide, carbomer (polyacrylic acid), gelatin, or collagen. For example, when the API or ACI is cyclosporin A or a derivative thereof, or an anti-aging lipopeptide or a derivative thereof, the composition of the present invention can be dispersed in the liquid phase of the pharmaceutically or cosmetically compatible gel.

[0183] The composition of the present invention may be in the form of an adhesive patch comprising a backing layer and an adhesive film, wherein the adhesive film comprises the composition according to the present invention or a cream or gel comprising the composition according to the present invention. For example, when the API or ACI is cyclosporin A or a derivative thereof, or an anti-aging lipopeptide or a derivative thereof, the composition of the present invention may be in the form of such an adhesive patch.

[0184] Patches according to the present invention are typically transdermal patches and consist of a backing layer, which may be a fabric, polymer, or paper and protects the patch from the external environment; an optional diaphragm, such as a polymeric diaphragm to prevent migration of fluorouracil through the backing layer; and an adhesive. The composition of the present invention may be provided in an adhesive layer or a reservoir of the patch, or the gel may serve as a reservoir within the patch product (a so-called "integrated" device).

[0185] Patches can be used to ensure the correct dosage is given to a subject by reducing the likelihood of careless or inappropriate use by the end user. Additionally, patches will confine the treatment area, preventing inadvertent application to other areas.

[0186] According to a third aspect of the present invention, there is provided a composition of the present invention for use as a medicament.

[0187] Optionally, the medicament can be used to treat a subject in need of an API (eg, a hydrophobic API; the API can be an immunosuppressant, such as a cyclosporin, eg, cyclosporin A or a derivative) included in the composition of the invention.

[0188] For example, if a composition of the invention includes an anti-inflammatory drug, the drug can be used to treat or prevent inflammation, injury, or pain.

[0189] If the composition of the present invention includes an immunosuppressant (e.g., cyclosporin A or a derivative thereof), the medicament can be used to treat or prevent psoriasis, atopic dermatitis, allergies, allergic reactions, transplant rejection, hay fever, pet allergies, allergic rhinitis or urticaria, in particular psoriasis or atopic dermatitis.

[0190] If the composition of the present invention includes an analgesic or antipyretic, the medicament may be used to treat or prevent pain or fever.

[0191] If the composition of the invention includes an antifungal agent, the medicament may be used to treat or prevent fungal infections such as candidiasis, cryptococcal meningitis, tinea pedis, tinea cruris, or fungal nail infections.

[0192] If the composition of the invention includes an antiviral compound, the medicament may be used to treat or prevent viral infections.

[0193] If the composition of the invention includes an antiparasitic compound, the medicament may be used to treat or prevent a parasitic infection or infestation.

[0194] If the composition of the invention includes an antibacterial compound, such as an antibiotic, the medicament may be used to treat or prevent a bacterial infection.

[0195] If the composition of the invention includes an anti-tumor compound, the medicament may be used to treat or prevent a neoplastic condition, such as cancer. In particular, it may be used to treat cancer of the skin or other body surface to which the product of the invention may be applied topically.

[0196] If the composition of the present invention includes an anesthetic agent, the drug may be used to induce or maintain an anesthetized state in a subject.

[0197] If the composition of the invention includes a muscle relaxant, the medicament can be used to provide muscle relaxation in a subject, for example, as a treatment for a spastic condition, a condition characterized by spasticity, or as a premedication prior to surgery.

[0198] If the composition of the present invention includes an antihypertensive agent, the medicament may be used to treat or prevent hypertension.

[0199] If the composition of the present invention includes an anxiolytic agent, the medicament may be used to treat or prevent anxiety.

[0200] If the composition of the invention includes a hormone, the medicament can be used to treat or prevent conditions caused by hormone deficiency, such as menopausal disorders or diabetes, growth disorders, hypogonadism, thyroid disease or osteoporosis.

[0201] If the composition of the present invention includes a contraceptive agent, the medicament may be used to prevent pregnancy.

[0202] If the composition of the present invention includes an antidepressant drug, the drug can be used to treat or prevent depression.

[0203] If the composition of the present invention includes an anti-epileptic agent, the medicament may be used to treat or prevent epilepsy.

[0204] If the composition of the present invention includes a hypnotic agent, the medicament may be used to treat or prevent insomnia.

[0205] If the composition of the present invention includes an antiemetic, the medicament may be used to treat or prevent nausea and / or vomiting.

[0206] If the composition of the invention includes an antipsychotic compound, the medicament may be used to treat or prevent psychosis.

[0207] If the composition of the present invention includes a spermicidal compound, the drug may be used as a spermicide, optionally in combination with a barrier contraceptive device.

[0208] If the composition of the present invention includes an erectile dysfunction (ED) drug, the drug can be used to treat or prevent erectile dysfunction and / or male impotence.

[0209] In compositions of the present invention including an ocular lubricant, the medicament can be used to treat or prevent dry eye.

[0210] If the composition of the present invention includes a laxative, the medicament may be used to treat or prevent constipation.

[0211] If the composition of the invention includes a bile acid sequestrant or a bowel bulking agent or a serotonin agonist, the medicament may be used to treat or prevent diarrhea.

[0212] If the composition of the present invention includes an appetite suppressant, the medicament may be used to treat or prevent obesity.

[0213] According to a fourth aspect of the present invention, there is provided a method for treating a medical condition, the method comprising administering to a subject in need thereof an effective dose of one or more active pharmaceutical ingredients (API, such as one or more hydrophobic APIs, such as cyclosporin A or a derivative thereof), wherein the API is administered as a pharmaceutical composition according to an embodiment of the second aspect of the present invention.

[0214] According to certain preferred embodiments of the fourth aspect of the present invention, the medical condition is one of the medical conditions mentioned above in relation to the fourth aspect of the present invention, and the API is optionally one of the pharmaceutical active agents mentioned above in the context of treating or preventing a specific condition (e.g., cyclosporin A or a derivative thereof).

[0215] According to a fifth aspect of the present invention, there is provided a method of providing a cosmetic benefit to a subject, the method comprising administering to the subject a composition prepared according to the first aspect of the present invention or a composition according to the second aspect of the present invention.

[0216] According to a preferred embodiment, the composition includes one or more ACIs, such as one or more of the ACIs listed herein, such as a hydrophobic ACI; the ACI may be an anti-aging agent, such as an anti-aging lipopeptide or a derivative thereof.

[0217] The method according to the fifth aspect of the invention may optionally provide a cosmetic benefit selected from the group consisting of: skin hydration, skin softening, reduced signs of skin aging, reduced appearance of age-related skin spots, reduced uneven skin tone, skin brightening, reduced appearance of bumps or scars, reduced redness, and reduced appearance of capillaries on the skin surface. Such methods preferably comprise administering to the skin a topical composition (e.g., a composition comprising an anti-aging agent, such as a composition comprising an anti-aging lipopeptide or derivative thereof).

[0218] The methods of the fifth aspect of the present invention also include methods for providing cosmetic benefits to hair, nails, and eyelashes. Such methods may optionally include administering to a subject a composition that is a shampoo or conditioner or tonic; a nail polish or cream; or a mascara.

[0219] In the foregoing description, when referring to integers or elements with known, obvious or foreseeable equivalents, such equivalents are incorporated herein as if separately set forth. The true scope of the present invention should be determined with reference to the claims, which should be interpreted as encompassing any such equivalents. The reader will also understand that the entirety or features of the present invention described as preferred, advantageous, convenient, etc. are optional and do not limit the scope of the independent claims. In addition, it should be understood that such optional integers or features, although they may be beneficial in some embodiments of the present invention, may be undesirable in other embodiments and therefore may not exist.

[0220] Preparation of silicon nanoparticles

[0221] Silicon nanoparticles relevant to the present invention can be easily prepared by conventional techniques in the art, for example, by grinding processes or by other known techniques for reducing particle size. Silicon-containing nanoparticles are made from sodium silicate particles, colloidal silicon dioxide, or silicon wafer materials. Large or micro-sized particles are ground in a ball mill, planetary ball mill, plasma or laser ablation method, or other size reduction mechanism. The resulting particles can be air-sorted to reclaim the nanoparticles. Plasma methods and laser ablation can also be used to produce nanoparticles.

[0222] Porous particles can be prepared by conventional methods in the art, including those described herein.

[0223] Preparation of creams and gels

[0224] Creams and gels can be formulated simply by dispersing (i.e., mixing) the organosilicon nanoparticles of the present invention with a cream or gel base. For example, the silicon nanoparticles can be stirred into a pharmaceutical cream base. For gels, the powder can be stirred into the gel base in powder form and then the gel can be hydrated, or stirred into a pre-hydrated gel.

[0225] Preparation of patches

[0226] Patches can be formulated by any suitable method, for example, patches can be produced comprising a mucoadhesive hydrophilic gel, the silica nanoparticles of the invention being prepared and dispersed therein, and the gel optionally dried by gentle water evaporation to a film having the desired adhesive properties.

[0227] Silicon nanoparticle preparation example

[0228] Weights and ratios of materials used in the exemplary scheme:

[0229]

[0230] method:

[0231] Part 1. Loading of silicon nanoparticles

[0232] A. Preparation of Caffeine Stock Solution

[0233] 1. Weigh 10 mg of caffeine and dissolve the contents in 10 ml of distilled water into a test tube, sonicating if necessary.

[0234] 2. The clear solution is 1 mg / mL of caffeine.

[0235] B. Preparation of Hydrogenated Phosphatidylcholine Stock Solution (PC)

[0236] 1. Dissolve 10 mg of PC in 10 mL of ethanol. The final concentration is 1 mg / mL of phosphatidylcholine.

[0237] C. Preparation of Glycine (Gly200) Stock Solution

[0238] 1. Dissolve 10 mg of arginine in 10 mL of distilled water and sonicate if necessary. The final concentration is 1 mg / mL.

[0239] D. Stock Suspension of Silicon Nanoparticles

[0240] 1. Transfer 8 mL of Si-NP stock solution to a test tube. The concentration of Si-NP filter particles is equal to 1 mg / mL.

[0241] E. Buffer pH 7.4

[0242] 1. Transfer 1 tablet of phosphate buffered saline (Sigma Aldrich) to a beaker and dissolve it in 200 mL of distilled water. The final solution is PBS at pH 7.4.

[0243] Part II: Sample Preparation and Analysis

[0244] A- Preparation of Caffeine-Loaded Nanoparticles - Sample PC1 (Caffeine + Si-NP + PC4 + Gly100)

[0245] 1- Transfer 1 mL of PC solution (B) to the small round flask.

[0246] 2- Evaporate the solvent using a rotary evaporation system to form a PC film.

[0247] 3- In a separate test tube, mix 1 ml of caffeine solution (A) to 2 ml of filtered Si-NPs (D) and 200 μL of glycine solution (C), then gently stir the solution.

[0248] 4- Rehydrate the PC membrane using the above SiNP-caffeine solution mixture.

[0249] 5- Wash the walls of the flask with 0.5 ml of distilled water.

[0250] 6- Mix the components using a vortex for a few minutes.

[0251] 7- Keep in refrigerator for 2 hours and then move to freezer for 2-3 hours.

[0252] 8- Connect the tubes to a freeze drying system and dry overnight.

[0253] 9- The dried powder is silicon nanoparticles loaded with caffeine at a ratio of 2:1.

[0254] Other examples

[0255] Franz Cell Research

[0256] In another example, the Franz cell study was used as an in vitro method to test the release of an API from a semisolid formulation. When the API was formulated without the silicon nanoparticles of the present invention, more than 99% of the sample was lost and not detected in the Franz cell study. Figure 1 When formulated according to the details given in the table above, formulations F1, F2, F6, F2 and F5 shown resulted in detection of the API in the receptor compartment of treated tissues and Franz cells compared to controls (bars A and B, not visible in the figure).

[0257] Cyclosporin A-loaded silica nanoparticles formulated with phosphatidylcholine

[0258] In yet another example, the API cyclosporin A (CyA) was formulated with the silicon nanoparticles (SiNPs) of the present invention and the lipid phosphatidylcholine (PC). Different ratios of lipid to silicon and lipid to API were used, as shown in Table 3 below.

[0259] The average particle size and zeta potential of CyA, PC3-Si, and PC3-CyA-Si were recorded using a Malvern zeta particle sizer (Malvern Instrument Ltd., Malvern, UK). All batches were vortexed to obtain a homogeneous suspension (1 mg / ml) in deionized water and then diluted 1:10 with water for analysis. FT-IR analysis was performed on: CyA; SiNPs (30 nm); SiNPs before CyA loading; and CyA-loaded SiNPs.

[0260] Zeta potential analysis (see Table 2) showed that the zeta potential of the CyA-loaded SiNPs was -17.8 mV. The corresponding unloaded SiNPs showed a surface charge of -22.2 mV. Since the zeta potentials of the CyA alone, unloaded SiNPs, and CyA-loaded SiNPs were similar, this finding indicates that CyA has been successfully embedded in the SiNPs and therefore does not generate a surface charge. In addition, the zeta potential of each lipid formulation was higher than -30 mV, indicating that these lipid formulations are stable under aqueous conditions.

[0261] Dynamic light scattering measurements showed a significant increase in diameter from empty SiNPs (377.9 nm) to CyA-loaded SiNPs (1334 nm). This increase in diameter indicated successful loading of the SiNPs with CyA.

[0262] Table 2

[0263] sample Size (nm) Zeta potential (mV) CyA -- -31.2 SiNP -- -22.5 Empty PC3-Si (without CyA) 377.9 -22.2 PC3-CyA-Si (loaded with CyA) 1334 -17.8

[0264] CyA is a lipophilic peptide, which means that if CyA is loaded onto PC-Si nanoparticles, it is expected to be carried out within the lipid (PC) bilayer, where CyA aggregation is reduced. FT-IR analysis was used to determine the extent of any CyA β-sheet ordering, which would indicate CyA aggregation. FT-IR analysis of free CyA (before loading) showed a β-sheet at 1624 cm 1 The peak at β-sheets is indicative of β-sheet ordering. As the free CyA concentration increases, an increase in signal is observed, indicating that CyA aggregation is concentration-dependent. The FT-IR spectrum of CyA-loaded PC (without SiNPs) shows that as the PC content increases, the β-sheet ordering decreases, indicating that the CyA loading within the PC bilayer increases with increasing PC content. A similar pattern is observed for CyA-loaded SiNPs formulated with PC, indicating that CyA is loaded within the PC lipid bilayer of the loaded nanoparticles.

[0265] To test the recovery of CyA from silicon nanoparticles, a method was developed for digesting the formulations in Table 2 using methanol and sonication over a 1-hour period. Each lyophilized formulation was suspended in methanol to provide a theoretical CyA concentration of 0.05 mg / ml. Sonication was performed for 30 minutes prior to analysis by HPLC. The results are shown in Table 3.

[0266] Table 3

[0267]

[0268] As shown in Table 3, under sufficiently high lipid and silicon nanoparticle mass ratios, the recovery of the API reaches a plateau and then declines. Therefore, the inventors have found that the recovery of the API depends on the lipid and silicon nanoparticle ratio. However, the API recovery does not simply increase with the increase of this ratio. On the contrary, there is an optimal range of lipid and silicon nanoparticle ratios (and the corresponding optimal range of lipid and API ratios) for delivering the API. It was further found that the particles have a clinically safe orthosilicic acid (OSA) release curve.

[0269] Cyclosporine (CyA) is considered the gold standard for treating moderate to severe psoriasis and atopic dermatitis. Topical administration of CyA is preferred for treating these conditions. However, a number of physicochemical issues are associated with CyA. The drug has a high molecular weight (1202 Da), high hydrophobicity (LogP approximately 3), poor water solubility (2 to 6 μg / ml), and a fragile structure. Topical delivery of CyA is limited by the molecule's inability to cross the stratum corneum, resulting in insufficient penetration of CyA into the skin.

[0270] The novel delivery system of the present invention has been shown to absorb and release CyA in a controlled and sustained manner, facilitating the topical delivery of CyA. Liposomal delivery systems, such as the liposome delivery system of the present invention, are considered promising vehicles for topical drug delivery because they can penetrate the skin through skin pores. Topical delivery of CyA using the delivery system of the present invention can result in drug deposition within the stratum corneum, enabling drug delivery to the site of psoriatic lesions. Furthermore, the orthosilicic acid released by the SiNPs themselves can help restore dermal fibroblasts damaged by psoriatic inflammation.

[0271] Lipopeptide-loaded silica nanoparticles formulated with phosphatidylcholine

[0272] In another example, a 5-mer peptide lipidated at the N-terminus was selected as the API and formulated with the silicon nanoparticles (SiNPs) of the present invention and the lipid phosphatidylcholine (PC). This API is a lipopeptide comprising a hydrophilic head group (comprising the peptide) and a hydrophobic tail group (comprising the lipid chain).

[0273] Different lipid to silica and lipid to API ratios were used as shown in Table 5 below.

[0274] Dynamic light scattering was performed to determine the overall size of the nanoparticles with and without the API. Changes in nanoparticle size can indicate whether the API has been loaded. Similarly, changes in surface charge or zeta potential (ZP) can indicate whether the API has been loaded. A Malvern Zeta Sizer (Malvern Instruments, Malvern, UK) was used to perform these measurements. The results are shown in Table 4.

[0275] It was observed that the zeta potential of empty PC-Si (nanoparticles without API) was negative. In contrast, PC-API-Si (nanoparticles loaded with API) reported a positive zeta potential. This increase in surface charge with API indicates that the API has been incorporated into the PC bilayer. It appears that the lipid chains of the API (which is a lipopeptide) have been incorporated into the PC lipid bilayer, while the peptide head group modifies the surface of the nanoparticles. This head group contains two lysine residues, which are positively charged, resulting in the API-loaded nanoparticles having a positive zeta potential value. In addition, the concomitant increase in nanoparticle size indicates that the nanoparticles are successfully loaded with API.

[0276] Table 4

[0277] sample Size (nm) Zeta potential (mV) Empty PC-Si (no API) 1954 -4.49 PC-API-Si (loaded with API) 2574 10.9

[0278] The protocol used to test API recovery corresponded to the protocol used to test CyA recovery described above. The API recovery results are shown in Table 5.

[0279] Table 5

[0280]

[0281] As shown in Table 5, at sufficiently high lipid to silicon nanoparticle mass ratios, the recovery of the API reached a plateau and then declined. Therefore, there exists an optimal range of lipid to silicon nanoparticle ratios for delivering the API.

[0282] Lipopeptides are commonly used to promote collagen production in anti-wrinkle formulations. However, topical administration of lipopeptides has been found to be problematic due to the inability of the API to be delivered through the stratum corneum. To improve the penetration of the API into the skin, the nanoparticles of the present invention can be used to deliver the lipopeptide, which penetrates the skin through the skin pores.

Claims

1. A method for promoting controlled binding and release of a bioactive agent or pharmaceutical agent from a composition comprising silicon nanoparticles, wherein the silicon nanoparticles comprise at least 50% silicon by weight, the method comprising treating the surface of the silicon nanoparticles with at least one lipid, and treating the surface of the silicon nanoparticles with at least one amino acid, wherein the ratio of lipid to silicon is from 1:1 to 15:

1.

2. The method of claim 1, wherein the ratio of lipid to silicon is 1:1 to 8:

3.

3. A method according to claim 1 or claim 2, wherein the ratio of amino acid to silicon is from 0.05:1 to 2:1, preferably from 0.25:1 to 0.7:1, and / or wherein the ratio of the lipid to the bioactive agent or pharmaceutical agent is from 1:1 to 15:1, preferably from 1:1 to 3:

1.

4. The method according to any one of the preceding claims, wherein the silicon nanoparticles have an average diameter between 20 and 100 nm, and / or wherein the silicon nanoparticles are porous.

5. The method of any one of the preceding claims, wherein the lipid is phosphatidylcholine and the amino acid is arginine.

6. A method according to any one of the preceding claims, wherein the method comprises loading the treated silicon nanoparticles with a pharmaceutical or bioactive agent.

7. The method of claim 6, wherein the pharmaceutical or bioactive agent is cyclosporin A or an anti-aging lipopeptide; or wherein the pharmaceutical or bioactive agent is an anionic molecule, such as a nucleic acid; or wherein the pharmaceutical or bioactive agent is a peptide or polypeptide associated with the silicon nanoparticles, and the ratio of lipid to API associated with the silicon nanoparticles is from 15:1 to 1:

1.

8. A method according to any one of the preceding claims, wherein the method comprises treating the surface of the silicon nanoparticles with oil.

9. The method of any one of the preceding claims, wherein the at least one lipid is chosen from phosphatidylcholine, hydrogenated phosphatidylcholine, a phosphatidylcholine derivative, didecanoylphosphatidylcholine, mirystoil phosphatidylcholine, lecithin, phosphatidylethanolamine, stearylamine, dioleoylphosphatidylethanolamine, or a combination thereof, and / or wherein the at least one amino acid is chosen from aspartic acid, glutamic acid, tyrosine, glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, histidine, threonine, asparagine, arginine, or glutamine.

10. A composition for the controlled release of a pharmaceutical or bioactive agent, the composition comprising silicon nanoparticles, at least one lipid, and at least one amino acid, wherein the ratio of lipid to silicon is from 1:1 to 15:1, preferably from 1:1 to 8:3, and wherein the silicon nanoparticles comprise at least 50% by weight silicon.

11. A composition according to claim 10, wherein the ratio of amino acid to silicon is from 0.1:1 to 2:1, preferably from 0.25:1 to 0.7:1, and / or wherein the lipid is phosphatidylcholine and the amino acid is arginine, and / or wherein the average diameter of the silicon nanoparticles is between 20-100 nm, and / or wherein the silicon nanoparticles are porous.

12. The composition of claim 10 or claim 11, wherein the treated silicon nanoparticles are loaded with a pharmaceutical or bioactive agent, optionally wherein the pharmaceutical or bioactive agent is an anionic molecule, a cationic molecule, cyclosporin A, or an anti-aging lipopeptide.

13. The composition according to any one of claims 10 to 12, further comprising an oil, and / or wherein the composition is for use in cosmetics, or for treating scars, acne or dry skin.

14. The composition of any one of claims 10 to 13, wherein the at least one lipid is chosen from phosphatidylcholine, hydrogenated phosphatidylcholine, a phosphatidylcholine derivative, didecanoylphosphatidylcholine, mirystoil phosphatidylcholine, lecithin, phosphatidylethanolamine, stearylamine, dioleoylphosphatidylethanolamine, or a combination thereof, and / or wherein the at least one amino acid is chosen from aspartic acid, glutamic acid, tyrosine, glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, histidine, threonine, asparagine, arginine, or glutamine.

15. The composition according to any one of claims 10 to 14, wherein the ratio of the lipid to the pharmaceutical or bioactive agent is from 1:1 to 15:1, preferably from 1:1 to 3:1.

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