Silica hydrogel composites and uses thereof

Abstract

The present invention relates to silica hydrogel composites comprising inactive silica particles and solid particles of one or more active pharmaceutical ingredients, which are feasible for the controlled and sustained delivery of active pharmaceutical ingredients.

Description

[Technical Field]

[0001] The present invention relates to silica hydrogel composites. More specifically, the present invention relates to hydrogel composites containing at least one active pharmaceutical ingredient as solid particles. The hydrogel composites are suitable for controlled and sustained delivery of the active pharmaceutical ingredient. [Background technology]

[0002] Low solubility of active pharmaceutical ingredients (APIs) is a common challenge in the development of new drugs. One aspect relates to the water solubility and good absorption and permeability of APIs to achieve desired concentrations in the systemic circulation or various body fluids. Another aspect relates to the formulation and development of different dosage forms for controlled release, for example, depending on the solubility of the API in water or other solvents / liquids used in the manufacture of different types of medical biomaterials, such as silica or poly(lactic-co-glycolic acid) (PLGA), used as matrix materials in controlled drug delivery. The API is often incorporated, added, encapsulated, or embedded in the biomaterial used as the matrix material, or the API is added in a soluble state to the processing liquid of the matrix material to ensure homogeneous distribution throughout the system and in the final matrix material.

[0003] Traditionally, for the development of various formulations, matrix materials, and dosage forms for controlled release, APIs are dissolved in water or other solvents / liquids, such as ethanol, and then used to manufacture different types of matrix materials, such as silica. For example, when an API is encapsulated in a dosage form based on sol-gel-derived silica, it is preferable to dissolve the API in water, alcohol (e.g., ethanol when using an alkoxide such as tetraethyl orthosilicate (TEOS) as the silica precursor), or a water-alcohol mixture. This is because the dissolved molecular form ensures homogeneous dispersion of the API in the reaction solution (e.g., in the silica sol), which also increases the likelihood of homogeneous dispersion of the API in the final matrix material, for example, when the API is encapsulated in silica microparticles produced by spray drying a silica sol containing the dissolved API. However, the solvent used must also be compatible with the expression of the matrix material's properties during production. For example, if an API is insoluble in water but soluble in ethanol at a sufficiently high concentration, the pH at which this dissolution occurs may not be suitable for the expression of the silica species or silica microparticle properties during processing, making it impossible to produce a suitable controlled release matrix.

[0004] When the API is dissolved in the processing liquid of the matrix material, it is homogeneously dispersed in molecular form as molecules in the processing liquid for the matrix material. When the matrix material is further processed or converted into a final dosage form to be used as a controlled delivery device, such as a solid implant, solid particles, hydrogel, or some other material or dosage form, the API may be in a solid phase if the solid phase is dominant in the matrix material properties, but the size of the solid phase may be small (because the molecular species of the active pharmaceutical ingredient are formed uniformly distributed throughout the system), or the API may still be partially dissolved in molecular form (e.g., in the liquid phase of a hydrogel).

[0005] Different types of gels, such as hand hydrogels, are often relatively loosely structured due to their typically low solid content. Low solid content in hydrogels is possible because the solid phase of a hydrogel is generally composed of a crosslinked polymer network or other polymeric species, such as aggregated nanoparticles in silica obtained by sol-gel processing. Because the polymer network framework or nanoparticle aggregates are molecular or nanoscale in size, even low solid content is sufficient to distribute the solid phase throughout the hydrogel structure. In practice, hydrogels are porous structures whose pores are filled with an aqueous solution. Controlled release characteristics depend on the hydrogel type and its final solid content. Some hydrogels function as controlled-release matrices by appropriate pore size or by pore swelling in body fluid conditions. Some hydrogels, such as silica hydrogels, release encapsulated or embedded APIs primarily through the slow dissolution of the hydrogel's solid phase. The low solids content of hydrogels in general is a drawback from the perspective of controlled release, but is beneficial from another perspective, namely, they can be used in a minimally invasive manner in fine needle injection from a syringe.

[0006] Jokinen et al. (WO 2014 / 207304) and Leino et al. (WO 2017 / 068245) disclose silica hydrogel composites in which an API is first encapsulated or embedded in silica microparticles during spray drying, and then these API-containing silica microparticles are further embedded in a loose silica hydrogel.

[0007] Liu et al. (U.S. Patent No. 6,303,290) disclose a method for encapsulating biologically important proteins in a transparent porous silica matrix by an alcohol-free aqueous colloidal sol-gel process. In particular, Liu et al. state that contact with alcohol is completely eliminated throughout the manufacturing process of the porous silica matrix that encapsulates the biopolymer, thereby avoiding the alcohol-induced denaturation of many biopolymers (caused by chain unfolding or molecular aggregation) that is typically observed in conventional encapsulation methods. Summary of the Invention [Problem to be solved by the invention]

[0008] It is an object of the present invention to minimize or in some cases eliminate the drawbacks present in the prior art.

[0009] It is an object of the present invention to provide a silica hydrogel composite containing an active pharmaceutical ingredient as solid particles.

[0010] One particular object of the present invention is to provide a silica hydrogel composite containing solid particles of anagrelide or a pharmaceutically acceptable salt thereof for controlled release.

[0011] It is a further object of the present invention to provide a silica hydrogel composite containing at least one active pharmaceutical ingredient for medical use in parenteral administration, for example, by fine needle injection.

[0012] These objects are achieved by the invention with the features presented below in the characterizing part of the independent claims.Some preferred embodiments of the invention are presented in the dependent claims.

[0013] The embodiments mentioned in the associated text relate to all aspects of the invention, where applicable, even if this is not necessarily mentioned separately.

[0014] The present invention provides a silica hydrogel composite comprising at least one active pharmaceutical ingredient, the silica hydrogel composite comprising: a. Inactive silica particles with a diameter of 100 μm or less; b. a silica sol having a solids content of less than 3% by weight, and c. solid particles of at least one active pharmaceutical ingredient (API), preferably 300 μm or less in diameter and a silica hydrogel composite, wherein the silica hydrogel composite contains 75 wt. % or less of inactive silica particles, and the silica hydrogel composite is non-flowable and structurally stable when stored at rest, and shear-thinning when shear stress is applied by injection. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 shows the cumulative in vitro, in-sink silica dissolution rate and release rate of anagrelide from silica hydrogel composite depot formulation #29HG (containing R300 silica hydrogel, micronized API powder, and non-active silica particles, pH 5.8) in 50 mM TRIS buffer containing 0.5% SDS (pH 7.4, 37°C). Each time point is the average of three assays. [Figure 2] Figure 1 shows the cumulative in vitro, in-sink release rate profile (mg / hr) of anagrelide from silica hydrogel composites with a dose of 20 mg anagrelide HCl. Silica hydrogel depot formulation #29HG in 50 mM TRIS buffer containing 0.5% SDS (pH 7.4, 37°C). Each time point is the average of three assays. [Figure 3]Figure 1 shows the rheological properties of silica hydrogel composites containing anagrelide, i.e., stability at rest (as in a syringe) and shear thinning under shear (as in injection from a syringe). Storage modulus (G') and tan δ (loss factor = G" / G') values ​​for silica hydrogel composite depot formulation #29HG (containing R300 silica hydrogel, micronized API (anagrelide HCl) powder, and inactive silica particles, pH 5.8). [Figure 4] Figure 1 shows the mean plasma concentrations of anagrelide in a 12-hour pharmacokinetic in vivo study following oral administration and subcutaneous injection of silica hydrogel composites containing two different doses of anagrelide HCl. Mean (average of 5 animals) plasma concentrations of anagrelide HCl as a function of time over the 12-hour study following oral administration (PO) of anagrelide HCl and subcutaneous injection (SC) of silica hydrogel composite #29HG (depot) containing anagrelide HCl (17.5 and 35 mg / kg) in male SD rats. [Figure 5] Figure 1 shows the mean plasma concentrations of anagrelide in a 10-day pharmacokinetic in vivo study following subcutaneous injection of silica hydrogel composites containing two different doses of anagrelide HCl. Mean (average of 5 animals) plasma concentrations of anagrelide HCl as a function of time over the 10-day study following subcutaneous (SC) injection of silica hydrogel composite #29HG (depot) containing anagrelide HCl (17.5 and 35 mg / kg) in male SD rats. [Figure 6] Figure 1 shows the mean plasma concentrations of anagrelide in a 28-day pharmacokinetic in vivo study following subcutaneous injection of silica hydrogel composites containing anagrelide HCl. Mean (average of 5 animals) plasma concentrations of anagrelide HCl as a function of time over the 28-day study following subcutaneous (SC) injection of silica hydrogel composite #29HG (depot) containing anagrelide HCl (35 mg / kg) in male SD rats. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention relates to a hydrogel composite formulation containing at least one active pharmaceutical ingredient (API) as solid particles. The main gist of the present invention is that the solid particles of the API are encapsulated and maintained as solid particles in the loose hydrogel portion of the hydrogel composite together with a large amount of inactive silica particles, thereby achieving both controlled-release and sustained-release behavior, as well as fine-needle injection properties.

[0017] term In this context, a "gel" should be understood as a homogeneous mixture of at least one solid and one liquid phase, i.e., a colloidal dispersion, in which the solid phase, e.g., silica itself and / or partially or completely hydrolyzed silica, is the continuous phase, and the liquid phase, e.g., water, ethanol, and the remainder of the silica precursor, is homogeneously dispersed throughout the structure. Gels are viscoelastic at rest and predominantly elastic, as shown by rheological measurements under small-angle oscillatory shear. The structure is non-flowable when elasticity predominates and the loss factor (or loss tangent), tan δ = (G" / G'), is less than 1. The combined effect of the elastic modulus G' and the viscous modulus G" can also be expressed as the complex modulus (or complex shear coefficient), G* = G' + iG".

[0018] "Gel point" or "gelation" should be understood to mean the point at which a fluid sol transforms into a non-fluid, viscoelastic, and predominantly elastic gel, as indicated by a rheological measurement under small-angle oscillatory shear where the elastic modulus G' is greater than the viscous modulus and the loss factor is less than 1. Viscoelastic properties are generally measured using a rheometer (a measuring device for determining the relationship between strain, shear stress, and time) with oscillatory shear at low shear stresses (small strain angles). Measurements are performed by ensuring an appropriate signal for the specific measurement system; that is, a strain sweep is typically performed at a constant frequency to find the appropriate signal for the rheometer system and the linear viscoelastic region, after which the actual measurement is performed at a constant strain while varying the frequency. Variations in frequency result in variations in the elastic and viscous moduli, and the measurement indicates whether the solid or liquid phase is dominant. In the form of a sol, the liquid state predominates, but the system contains a variable amount of solid phase, and the system remains fluid. Prior to the gel point, a sharp increase in dynamic viscosity and modulus is typically observed, which continues to increase after the gel point as structure develops. In the context of the present invention, the gel point of the composite of the present invention is reached prior to obtaining the injectable gel of the present invention.

[0019] "Inactive silica particles" refer to silica particles that do not contain any encapsulated or embedded drugs, such as active pharmaceutical ingredients (other than residues that may result from the synthesis of silica, e.g., water and ethanol). Thus, inactive silica particles do not contain any active pharmaceutical ingredients. "Active silica particles" refer to silica particles that contain 0.1-70 wt. % active pharmaceutical ingredient, preferably 0.3-50 wt. % active pharmaceutical ingredient, and most preferably 1-20 wt. % active pharmaceutical ingredient. All material properties defined for inactive silica particles, such as particle size and weight percent of the total solids of the silica hydrogel composite, are also valid for active silica particles.

[0020] "Non-flowable and structurally stable when stored at rest" refers to a stable composite hydrogel structure containing non-active silica particles and API particles within a silica hydrogel. Stability is indicated by rheological measurements under small-angle oscillatory shear, with an elastic modulus G' greater than the viscous modulus and a loss factor less than 1. The structure is non-flowable when the elastic modulus is greater than the viscous modulus and the loss factor is less than 1. The non-flowable structure ensures the stability of the composite hydrogel structure by preventing particle phase separation. In other words, the non-active silica particles and API particles are embedded within the silica hydrogel and do not settle or separate on the bottom of the container, e.g., a syringe, in which the hydrogel composite is typically stored at temperatures below 25°C. Although the composite hydrogel structure is non-flowable when stored at rest, e.g., in a pre-filled, ready-to-use syringe, the structure is very loose and shear-thinning, and therefore injectable through a fine needle when the injection applies shear stress to the hydrogel composite.

[0021] The term "hydrogel" should be understood as a gel in which the liquid phase is water or an aqueous system in which the liquid phase contains more than 50 weight percent (wt%) of water. Preferably, the liquid phase of the hydrogel contains more than 80 wt%, more preferably more than 90 wt%, and even more preferably more than 97 wt% of water. The liquid phase may further contain other liquids, typically organic solvents such as ethanol. Typically, the concentration of such solvents, such as ethanol, is less than 10 wt%, more preferably less than 3 wt%, and even more preferably less than 1 wt%. In the context of the present invention, the composites of the present invention are considered hydrogels because they fulfill the basic criteria for a hydrogel. Therefore, when referring to the hydrogel composites of the present invention, this reference is equivalent to a reference to the composites of the present invention. In the context of the present invention, the silica hydrogel composites of the present invention preferably contain 20-80 wt%, more preferably 30-70 wt%, and most preferably 40-60 wt% of water.

[0022] A "sol" is to be understood as a homogeneous mixture of at least one liquid phase and one solid phase, i.e., a colloidal dispersion, in which the liquid phase, e.g., water, ethanol and residues of silica precursors, is the continuous phase, and the solid phase, e.g., colloidal particles of silica and / or partially or fully hydrolyzed silica and / or aggregates of these particles, is homogeneously dispersed in the aforementioned liquid phase, the sol being characterized by a clear fluidity and a predominance of the liquid phase.

[0023] In the context of this application, "injectable gel" or "hydrogel" or "hydrogel composite" refers to the rheological properties of the composition. Prior to injection, when stored in a syringe and / or aluminum foil at temperatures below 37°C, e.g., at room temperature (20-25°C) or in a refrigerator (2-8°C), the composition is a gel, i.e., the elastic modulus (measured under small-angle oscillatory shear) G' is greater than the viscous modulus G", and the loss factor tan δ = (G" / G') is less than 1. The structure of a hydrogel composite is a gel-like structure. While the structure of the composite remains stable and non-flowable when stored at rest, the gel structure is very loose and shear-thinning when subjected to shear stress in the form of injection through a syringe, e.g., using an 18-25G needle (1.27 / 0.84 mm to 0.50 / 0.26 mm outer diameter / inner diameter).

[0024] "Injectable" in the context of the present invention means capable of being administered via a surgical administration device such as a needle, a catheter or a combination thereof.

[0025] "Shear-thinning," in the context of this application, is a rheological property of a composition. Whenever the shear stress or shear rate of a composition is changed, the composition gradually moves toward its new equilibrium state; at low shear rates, a shear-thinning composition is more viscous, and at high shear rates, it is less viscous. Shear-thinning, therefore, refers to the effect whereby a fluid's viscosity, a measure of its resistance to flow, decreases with the rate of increase in shear stress.

[0026] A "matrix material" should be understood to be a material, such as silica microparticles or silica hydrogel composite, into which an active pharmaceutical ingredient is incorporated, loaded, encapsulated, or embedded, and which, due to its structure, such as pore structure, and / or chemical composition, such as dissolution in body fluids, controls the release rate of the active pharmaceutical ingredient.

[0027] A "dosage form" should be understood to be an injectable or implantable formulation that includes a matrix material used to administer the active pharmaceutical ingredient.

[0028] The "depot formulation" referred to in this application is defined as the administration of a sustained-action drug (active pharmaceutical ingredient) formulation that allows for sustained release and gradual absorption so that the active agent can act and be released in the body for a longer period, i.e., several days to several months. Depot formulations are administered parenterally, either by subcutaneous, intramuscular, peritoneal or ocular injection or implantation.

[0029] The term "silica" preferably refers to amorphous SiO2 produced by a sol-gel process. Sol-gel derived silica refers to silica produced by a sol-gel process, where the silica is produced from a liquid-phase precursor, such as an alkoxide, alkylalkoxide, aminoalkoxide, or inorganic silicate solution, which, by hydrolysis and condensation reactions, converts to a gel or forms a stable sol. Sol-gel derived silica can also be produced by processing into different morphologies by gelation, aging, drying, and shaping, for example, by spray drying into microparticles.

[0030] The term "silica sol" refers to a suspension, i.e., a mixture of a liquid (continuous phase) and a solid (dispersed phase), where the solid phase consists of silica particles and / or aggregates, typically less than 1 μm in size, preferably less than 100 nm, i.e., the silica particles and / or particle aggregates are colloidal. Silica sols are generally produced from alkoxides or inorganic silicates, which undergo hydrolysis to form either partially hydrolyzed silica species or fully hydrolyzed silicic acid. The liquid phase is typically composed of water and hydrolyzates and condensation products, such as ethanol. Subsequent condensation reactions of the SiOH-containing species result in the formation of larger silica species with increased siloxane bonds. These species form nano-sized colloidal particles and / or particle aggregates. Depending on the conditions, the silica sol either remains as a stable colloidal suspension or transforms into a gel.

[0031] An "active pharmaceutical ingredient (API)" should be understood to mean a drug or other therapeutically and / or biologically active agent, preferably one that is poorly water-soluble or completely water-insoluble. The solid particles of the API essentially comprise the API and are silica-free. Preferably, the solid particles of the API comprise at least 80% by weight, preferably 90% by weight, more preferably 95% or 99% by weight, and sometimes 99.5% by weight or more of the API.

[0032] "Particle size" or "particle size" refers to the largest diameter of a particle if the particle has any shape.

[0033] The "R value" refers to the molar ratio of water to tetraethyl orthosilicate (TEOS); for example, R300 corresponds to a molar ratio of water to tetraethyl orthosilicate of 300. TEOS is a common precursor to sol-gel-derived silica and is also used in the present invention. The R value can also be used to calculate the solid (silica) content of the silica sol. For example, a molar ratio of water to TEOS of 200 (R200) ​​results in about 1.60 wt.% solid silica in the silica sol, R300 corresponds to about 1.08 wt.%, and R400 corresponds to about 0.82 wt.%.

[0034] "Micronization," in the context of the present invention, should be understood as any method used to produce small solid particles, e.g., solid particles of an active pharmaceutical ingredient, so long as the particle size of the resulting solid material is 300 micrometers or less. For example, solid particles of an API can be produced by 1) direct synthesis and / or precipitation, or 2) any small particle crystallization method or supercritical fluid technology, such as controlled expansion of a supercritical solution, or 3) any solution-precipitation / crystallization cycle, or 4) spray- or freeze-drying, or 5) any mechanical method, e.g., grinding, mashing, and milling, used to reduce the size of solid materials, such as mortar and pestle grinding, wet milling, pneumatic milling, or 6) any granulation method starting with submicron particles.

[0035] Features of the invention The present inventors have discovered that a silica hydrogel composite comprising a hydrogel portion, non-active silica microparticles, and an API as solid particles can achieve both desirable controlled release characteristics and fine-needle injection from a prefilled syringe. The API can be added to the silica hydrogel portion as solid particles, and because of its very low solubility in water, the API particles also remain solid particles when present in the hydrogel portion of the composite. The hydrogel composite also contains non-active silica microparticles, i.e., silica microparticles without an encapsulated or embedded API. The non-active silica microparticles modify the rheological properties of the hydrogel composite but also contribute to the overall controlled release of the API by preventing the release of solid particles of the API embedded in the hydrogel portion of the hydrogel composite. Thus, the hydrogel portion and the non-active silica microparticles together form a non-flowable yet injectable silica hydrogel composite in which solid particles of the API are incorporated and / or embedded. In this way, the API will not be released from the hydrogel composite without dissolution of the solid phase of the hydrogel composite.

[0036] In the present context, the term "hydrogel portion" refers to the portion of the hydrogel composite that is derived from the silica sol.

[0037] The present invention provides a silica hydrogel composite containing at least one active pharmaceutical ingredient (API) as solid particles. In preparing the silica hydrogel composite, the API is in the form of a dry powder or exists as a solid particle suspension prior to encapsulation or incorporation into the silica hydrogel. As noted above, one surprising finding of the present invention is that the solid particles of the API preferably remain as solid particles of 300 μm or less in diameter, and after encapsulation / incorporation into the loose hydrogel portion of the silica hydrogel composite, both controlled-release and sustained-release behavior in vitro and in vivo, as well as injection through a syringe with a fine needle, such as an 18G to 25G needle, are still achieved for the silica hydrogel composite.

[0038] Silica hydrogel composites contain inactive silica particles and at least one solid API in the hydrogel portion of the composite, both of which affect the controlled-release characteristics. Therefore, the controlled-release characteristics are influenced not only by the hydrogel portion of the composite and the inactive silica particles, but also by the particle size of the solid particles of the active pharmaceutical ingredient. Surprisingly, it has been discovered that a substantially water-insoluble or poorly water-soluble active pharmaceutical ingredient can be used as the solid particles to produce a uniform silica hydrogel composite for controlled release that is suitable for fine needle injection. The particle size of the solid particles of the API can be 300 μm or less, preferably 1 μm to 300 μm, and more preferably 1 μm to 200 μm.

[0039] Various gels, such as organogels and hydrogels, have traditionally been used in controlled drug delivery, but many challenges remain for various types of active pharmaceutical ingredients. Hydrogels, generally as gels, typically have low solids content, with the majority of the gel structure being in liquid form. The solid portion or solid phase of a hydrogel contains polymer molecules or colloidal species, such as nanoparticles in a sol, which crosslink, agglomerate, or aggregate to form a three-dimensional network. The aqueous liquid is uniformly distributed throughout the resulting three-dimensional network. In practice, hydrogels have porous structures, with the pores filled with the aqueous liquid. The solids content of hydrogels is typically low, e.g., 3% by weight or less, and often 1% by weight or less. At low solids content, hydrogels can easily transform into flowable and shear-thinning materials, which is beneficial when developing injectable dosage forms for controlled drug delivery. As the solids content of a hydrogel increases, shear-thinning properties can be lost. Because hydrogel structures are typically very loose and open, incorporated, encapsulated, or embedded active pharmaceutical ingredients of different sizes, such as small drug molecules, proteins, peptides, and RNA, can diffuse relatively quickly. If the release of an encapsulated API from a hydrogel depends on the dissolution rate of the solid phase, the size of the API must be larger than the pores in the hydrogel network. However, the release rate also depends on the total solids content of the hydrogel, which is typically low, especially for typical dosage forms for fine-needle injection. Hydrogels with low solids content, such as less than 3 wt%, that are also suitable for fine-needle injection may be too loose to achieve sustained release of larger active pharmaceutical ingredients or therapeutic agents, such as solid API particles, fusion proteins, viral vectors, and vaccine antigens. In the present invention, inactive silica particles are combined with silica hydrogel and solid API particles, resulting in a silica hydrogel composite, which achieves both good fine-needle injectability and sustained release.

[0040] In the present invention, the silica hydrogel composite contains inactive silica particles and solid particles of at least one API embedded in the silica hydrogel. Because the liquid phase in the silica hydrogel is primarily water, the silica hydrogel composite is particularly suitable for the controlled release of APIs that are poorly soluble or completely insoluble in water. The silica hydrogel portion of the silica hydrogel composite is a loose hydrogel with a solid content of preferably 3 wt% or less, more preferably 2 wt% or less, and most preferably 0.5-2 wt%.

[0041] The solids content of the silica hydrogel portion is typically less than 1.5 wt % of the total silica hydrogel composite.

[0042] In the present invention, the silica hydrogel composite contains non-active silica particles having a diameter of 100 μm or less, or between 1 μm and 100 μm, preferably between 1 μm and 30 μm, and more preferably between 1 μm and 20 μm. The use of non-active silica particles as part of the silica hydrogel composite increases the solid content of the hydrogel composite without compromising fine needle injectability, and the non-active silica particles also contribute to a sustained release rate of the solid particles of the API. The non-active silica particles may be spray-dried silica particles or silica fiber fragments. Alternatively, the non-active silica particles may be molded or cast silica monoliths, or crushed silica monoliths.

[0043] The silica hydrogel composite contains up to 75 wt. % inactive silica particles, and according to one embodiment of the present invention, 20-75 wt. % of the total silica hydrogel composite is inactive silica microparticles. According to one embodiment, the silica hydrogel composite may also contain active silica particles, in which case the combined proportion of inactive and active particles is also 75 wt. The general role of the inactive silica particles is to achieve good rheological properties for the dosage form, i.e., a stable hydrogel composite structure at rest (e.g., in a syringe) and shear-thinning properties under shear (e.g., when the hydrogel composite is injected from a syringe through a needle, e.g., 18-25G).

[0044] The total solids content of the silica hydrogel composite can be 20% to 80% by weight, preferably 30% to 60% by weight, and even more preferably 35% to 55% by weight.

[0045] The silica hydrogel composite contains at least one active pharmaceutical ingredient (API) as solid particles. It is also possible for the silica hydrogel composite to contain two or several different active pharmaceutical ingredients as solid particles. Preferably, the diameter of the solid particles of the API is 300 μm or less, more preferably in the size range of 1 to 200 μm. Encapsulating at least one solid particle of the API in the hydrogel portion of the silica hydrogel composite results in an injectable dosage form in which sustained release is achieved despite the solid particles being encapsulated in the loose hydrogel portion of the hydrogel composite. The water solubility of the active pharmaceutical ingredient is preferably low or nonexistent, and both the low solubility and size of the solid particles of the API contribute to the sustained and controlled release achieved with the silica hydrogel composite of the present invention. The larger the size of the solid particles of the API, the greater the particle size affects the release rate of the API. However, solid particles of the active pharmaceutical ingredient may also affect the final gelation of the silica hydrogel composite and its rheological properties. Therefore, the optimal amount and particle size of the solid particles of the API are preferably determined case by case depending on the API in question. According to one embodiment, the solid particles of the API may account for 0.1 to 20 wt %, preferably 0.1 to 15 wt %, of the total silica hydrogel composite. For example, if the API is anagrelide HCl, the particle size of the solid particles of the API is 1 to 300 μm, preferably 1 to 200 μm, and / or the amount of the solid particles of the API is 0.1 to 20 wt %, preferably 0.1 to 15 wt %, calculated from the total silica hydrogel composite.

[0046] Solid particles of at least one API, preferably 300 μm or less in diameter, more preferably 1-200 μm, can be easily added to a liquid system forming a hydrogel, such as a silica sol used to form a silica hydrogel, or a silica sol forming the hydrogel portion in a silica hydrogel composite that also contains non-active silica particles. According to one embodiment of the present invention, the particle size of the solid API particles may be 100-1000 nanometers. The solid API particles are embedded in the silica hydrogel portion without impairing the injectability of the formed hydrogel composite, which is an important characteristic for minimally invasive dosage forms in controlled drug delivery. When the solid API particles are significantly larger than 1 micrometer, homogeneous dispersion of the particles must be ensured by mixing until the system transforms from a flowable form, such as a silica sol, to a non-flowable form, such as a silica hydrogel or silica hydrogel composite. API particles with a size of 1-300 μm can be produced by any micronization method, such as direct synthesis and / or precipitation.

[0047] For example, good injectability of silica hydrogel composites using 18-25G needles and controlled release both in vitro and in vivo have been achieved using silica hydrogel composites containing solid particles of API with sizes of 300 μm or less or 1-200 μm. The controlled, sustained release characteristics of the solid API particles embedded in the hydrogel portion of the silica hydrogel composite are achieved despite the low solid content of the silica hydrogel portion, which is a loose structure. This is due to the combined effect of the hydrogel portion, the large API particles, and the non-active silica particles. The silica hydrogel portion and the non-active silica particles together form a structure that prevents rapid release of the solid API particles, but entraps them for slow release as the main solid component of the silica hydrogel composite, i.e., the non-active silica particles, dissolves. Because silica itself has very low water solubility at 37°C and pH 7.4 (e.g., 120–150 ppm (micrograms / ml) and even lower at room temperature or 2–8°C), it does not dissolve inside the silica hydrogel composite. That is, silica dissolves mostly from the surface of the hydrogel composite when the in vitro dissolution medium is refreshed to maintain it under sink conditions (conditions that ensure free dissolution of silica) or when body fluids flow in vivo. The proportion of non-active silica microparticles in the silica hydrogel composite is high, preferably up to 75 wt%, or 20–60 wt%, while the corresponding portion of aggregated silica sol nanoparticles that form the solid phase in the hydrogel portion of the hydrogel composite is typically less than 3 wt%. The remainder is aqueous solution and encapsulated solid particles of the active ingredient (e.g., 0.1–20 wt%). Therefore, the non-active silica particles form the majority of the solid phase in the final hydrogel composite. When aggregated silica sol nanoparticles, inactive silica particles, and solid particles of an active pharmaceutical ingredient in a silica sol (including an aqueous solution) are combined, they together form a silica hydrogel composite, in which the solid particles of the active pharmaceutical ingredient are encapsulated between the silica particles (inactive silica particles and aggregated silica nanoparticles), and the aqueous solution is uniformly distributed throughout the entire mass of the hydrogel composite.

[0048] Slow release is supported by poor or no solubility of the API particles; i.e., their size does not decrease, and they remain trapped within the hydrogel composite structure. According to one preferred embodiment, the effect of the large size of the API solid particles on the well-controlled release characteristics was observed for solid particles of anagrelide HCl, which has a solubility of 0.019 mg / mL in water, corresponding to 0.0019 wt %. This means that the solid particles of the API remained virtually intact in the hydrogel portion of the mixture for a typical syringe dose of 0.05 to 1 mL for parenteral administration. It can be assumed that any solid particles of the API less than 300 micrometers in size, dissolving less than 10 wt % in the aqueous phase of a dose of silica hydrogel composite, will retain their favorable effect on both fine needle injection and controlled release characteristics. In the present invention, good sustained and controlled release behavior was observed for API particles with a relatively large particle size distribution of 1-200 micrometers, i.e., the difference between the mean particle size of the largest half of the particles and the mean particle size of the smallest half of the particles was greater than 10%. When 10 wt. % is dissolved in the aqueous phase of the hydrogel phase, this means that in practice 90 wt. % of the API particles are still intact, and a relatively fast initial release (burst) of 10 wt. % of the API may occur due to the dissolved API, which is generally within the acceptable range for controlled drug delivery.

[0049] According to one embodiment of the present invention, the composition can further comprise active silica particles containing 0.1-70 wt%, preferably 0.3-50 wt%, and most preferably 1-20 wt% of an active pharmaceutical ingredient. For example, active silica particles produced by spray drying can be used to encapsulate the API as nanoparticles with a particle size of 10-100 nm in active silica particles, and these can be used in place of, or preferably in addition to, non-active silica particles in a silica hydrogel composite. When a silica hydrogel composite contains both non-active and active silica particles, the total amount of silica particles, including both active and non-active, does not exceed a maximum weight percent of silica particles of 75 wt% of the total weight of the silica hydrogel composite, as defined elsewhere in this application. When API particles are sufficiently small, e.g., in the range of 10-100 nm compared to the size of the matrix material in the final dosage form, compared to spray-dried silica particles, which are typically 1-30 micrometers in size, they can be uniformly encapsulated within the silica particles to form active silica particles. The properties of the active silica particles (tunable dissolution rate of silica) control the release profile of the API from the active silica microparticles. The API encapsulated in the active silica microparticles may be the same as or different from the API present as the solid particles.

[0050] The size of the API, including particles, is one of the key parameters. Many matrix materials are used in drug delivery systems, and they come in many different forms, sizes, and shapes, including monolithic implants, fibers, particles in suspension, and hydrogels. Microparticles are very common and can be used as active silica particles. In this case, the encapsulated or embedded API particles themselves must be sufficiently small compared to microparticles (typical size range of approximately 1 to 30 micrometers); that is, the API particles must be nanoparticles with diameters of less than 100 nm. API particles that are too large cannot be properly encapsulated in active silica particles, resulting in a nonuniform structure and a loss of their controlled delivery properties. In addition, the loading percentage of the API in the matrix material may remain low if the API particles are too large compared to the matrix particles. The same applies to different types of solid implant structures and fiber materials; in this case, the API as large particles can cause nonuniformity and loss of controlled release and mechanical properties.

[0051] The silica hydrogel composites of the present invention, containing at least one active pharmaceutical ingredient (API) as solid particles, offer advantages in developing new matrix materials for controlled and sustained delivery. In addition to the previously proposed option of using relatively large solid particles for the active pharmaceutical ingredient (API) in the silica hydrogel composite for controlled delivery, other options are also contemplated by the inventors. For example, the active pharmaceutical ingredient (API) can be preencapsulated in some other material (in the form of solid particles) that is not suitable for sustained release of the encapsulated drug, but this makes it easier to encapsulate or embed an active pharmaceutical ingredient with low water solubility, for example, in a matrix material that controls the release of the active pharmaceutical ingredient. Alternatively, or in addition, preencapsulation can also be relevant for the protection of active pharmaceutical ingredients, such as small molecule drugs or biologics (e.g., protein-based drugs, fusion proteins, peptides, RNA-based drugs, viral vectors, and vaccine antigens). Yet another possibility is to achieve more options for controlled and sustained delivery of active pharmaceutical ingredients (whether they are sufficiently soluble in water or other processing liquid for the matrix material) since the release rate profile from any matrix material will be different if the active pharmaceutical ingredients are present as large solid particles, small particles, dissolved in molecular form, or in different combinations of particles of different sizes and dissolved forms.

[0052] Preferred Embodiments In preferred depot formulations of the present invention, the silica hydrogel composite comprises at least one active pharmaceutical ingredient as solid particles, preferably 300 μm or less in diameter, and the silica hydrogel composite is non-flowable and structurally stable when stored at rest, and shear-thinning when subjected to shear stress by injection.

[0053] In a preferred depot formulation of the present invention, the silica hydrogel composite contains up to 75% by weight of inactive silica particles.

[0054] In a preferred depot preparation of the present invention, the solid content of the silica sol is 0.5 to 3% by weight, preferably 0.5 to 2% by weight.

[0055] In a preferred depot formulation of the present invention, the inactive silica particles have a diameter in the range of 1 μm to 100 μm, preferably 1 μm to 30 μm, more preferably 1 μm to 20 μm.

[0056] In a preferred depot preparation of the present invention, the silica sol contains silica sol particles having a diameter of 100 nm or less, more preferably 5 to 100 nm.

[0057] In a preferred depot preparation of the present invention, the solid content of the silica hydrogel composite is 20% to 80% by weight, preferably 30% to 60% by weight, and even more preferably 35% to 55% by weight.

[0058] In a preferred depot formulation of the present invention, the silica hydrogel composite further comprises active silica particles containing 0.1-70 wt %, preferably 0.3-50 wt %, most preferably 1-20 wt % of an active pharmaceutical agent.

[0059] In a preferred depot formulation of the invention, the silica is an alkoxysilane-derivatized silica, preferably tetraethoxysilane-derivatized silica.

[0060] In preferred depot formulations of the present invention, the inactive silica particles are selected from the group consisting of spray-dried silica particles; silica fiber fragments; and molded or cast silica monoliths, whole or crushed.

[0061] In preferred depot formulations of the present invention, the solid particles of the active pharmaceutical ingredient are selected from the group consisting of particles produced by direct synthesis and / or precipitation; small particle crystallization methods or supercritical fluid techniques, such as controlled expansion of supercritical solutions; dissolution-precipitation / crystallization cycles; mechanical methods such as grinding, mashing, and milling used to reduce the size of solid materials, such as spray- or freeze-drying, mortar and pestle grinding, wet grinding, pneumatic grinding, etc.; and granulation methods starting with submicron particles.

[0062] In a preferred depot formulation of the present invention, a silica hydrogel composite is formed by at least i) aggregated silica sol nanoparticles in a silica sol (including an aqueous solution), ii) inactive silica particles, and iii) solid particles of an active pharmaceutical ingredient, wherein the solid particles of the active pharmaceutical ingredient are encapsulated between the silica particles (inactive silica particles and aggregated silica nanoparticles), and the aqueous solution is uniformly distributed throughout the entire mass of the hydrogel composite.

[0063] The pharmaceutical depots of the present invention are typically used to administer active pharmaceutical ingredients.

[0064] The pharmaceutical depot of the present invention is used for the administration of anagrelide or any of its pharmaceutically acceptable salts (including the hydrochloride salt).

[0065] The depot formulations of the present invention are typically used for parenteral administration.

[0066] The depot formulations of the present invention are typically used for parenteral administration by injection.

[0067] The pharmaceutical depots of the present invention are typically used for the controlled delivery of active pharmaceutical ingredients. [Example]

[0068] Some embodiments of the present invention are illustrated in the following non-limiting examples.

[0069] Example 1 Fabrication of silica hydrogel composites containing anagrelide HCl (API) Silica sol for producing non-activated silica particles (simple silica microparticles) was prepared by hydrolyzing TEOS in water using 0.1 M HCl as a catalyst at pH 2.0. The molar ratio of water to TEOS (=R value) of the silica sol was 2.5 (initial R value). After hydrolysis, the R sol was cooled to 0-5 °C. The R sol was then diluted with ethanol to reduce the solid (silica) content in the sol, finally reaching a second R value of 50 (the volume of ethanol added corresponds to the volume of water required to obtain a molar ratio of water to TEOS of 50). Finally, the pH of the diluted silica sol (R 2.5-50) was adjusted to pH 4.9 with 0.1 M NaOH solution before spray drying. Non-activated silica particles were then produced by spray drying the R 2.5-50 silica sol (using a Büchi B-290 spray dryer). The spray drying parameters are listed in Table 1.

[0070] [Table 1]

[0071] Since anagrelide HCl is practically insoluble in water (0.019 mg / ml) and the base form of anagrelide has even lower solubility than anagrelide HCl, the solid anagrelide HCl powder was manually pulverized in a mortar for approximately 10 minutes (to achieve a particle size distribution of 1-200 micrometers).

[0072] The next step was to prepare the hydrogel portion of the silica hydrogel composite from R200 or R300 silica sol. Both R200- and R300-based sols (a molar ratio of water to TEOS of 200 (R200) ​​yields approximately 1.60 wt% solid silica in the silica sol, while R300 corresponds to approximately 1.08 wt%) were successfully used to prepare injectable silica hydrogel composites. R300 silica sol was prepared by hydrolyzing TEOS in deionized water at pH 2 using 0.1 M HCl as a catalyst. Spray-dried non-active silica particles from the R2.5-50 sol, micronized API powder (anagrelide HCl), and R300 silica sol were combined by suspending 920 mg of micronized API (anagrelide HCl) and 6780 mg of non-active silica particles (R2.5-50) in 12.6 ml of R300 silica sol, followed by adding 6.1 ml of 0.5 M NaOH to adjust the pH of the mixture to 5.8. The mixture was transferred to a plastic syringe (Becton Dickinson luer-lock, needleless 1 ml syringe) and gently mixed in a vertical rotating mixer to keep the mixture stable (preventing settling of the non-active silica particles and solid anagrelide HCl particles). The mixture was allowed to gel at ambient temperature (approximately 25 °C) for 2-3 days until gelation occurred, i.e., the mixture transformed into a non-flowing silica hydrogel composite #29HG.

[0073] Example 2 In vitro dissolution and release rate measurements of silica hydrogel composites containing inactive silica microparticles and anagrelide HCl (API) In vitro silica degradation and API (anagrelide HCl) release were measured in 50 mM Tris buffer at pH 7.4 with the addition of SDS (0.5%, w / v) at 37°C. The analyzed sample size was approximately 10–15 mg for inactive silica particles and approximately 20–30 mg for silica hydrogel composite (depot) formulations. Dissolution tests were performed for up to 72 hours in a shaking water bath (60 strokes / min) at 37°C. Silica and API (anagrelide HCl) concentrations were maintained in the dissolution medium at sink conditions (i.e., free dissolution of the silica matrix, i.e., silica concentration maintained below 20% of the saturation concentration). To maintain silica concentrations below 30 ppm (sink condition), the dissolution medium was replaced with fresh medium at each sampling time. Quantitative analysis was used to measure cumulative API release and silica dissolution. Three replicate samples were collected at each time point, and the average values ​​are shown in the results. The silica concentration was determined by analyzing the absorbance of the molybdenum blue complex at λ = 820 nm using a UV / VIS spectrophotometer. Anagrelide was analyzed using a high-performance liquid chromatography (HPLC) 1100 HPLC Agilent Technologies connected to a variable wavelength detector (λ = 250 nm). Chromatographic separation was achieved using a Waters XSelect HSS C18, 3.5 μm, 3.0 x 20 mm HPLC column, Model G1314A variable wavelength detector, 1100 HPLC Agilent Technologies, column temperature 30 °C, and a mixture of water / formic acid 1000 / 1 (v / v) as mobile phase A and acetonitrile / formic acid 1000 / 1 (v / v) as mobile phase B.

[0074] The total silica and anagrelide HCl content in the hydrogel composites was measured to accurately determine dissolution and release rates. The total silica content of the sample materials was measured by dissolving the samples in 0.5 M NaOH solution at 37 °C for 3 days. Similarly, the total API (anagrelide HCl) content was measured by dissolving the samples in 50 mM glycine buffer, pH 9.6, supplemented with SDS (1.5% w / v) at 37 °C.

[0075] In vitro dissolution studies of non-activated silica particles (R 2.5-50, pH 4.9) were conducted under sink conditions for up to 48 hours. Cumulative in vitro silica degradation (i.e., dissolution of the silica matrix) from non-activated silica particle formulations reached 100% (w / w) in approximately 24 hours, followed by approximately 7% at 1 hour, 32% at 2 hours, 59% at 3 hours, 68% at 4 hours, 77% at 5 hours, 83% at 6 hours, and 95% at 9 hours.

[0076] The cumulative dissolution rate of silica and cumulative release of anagrelide from silica hydrogel composite depot formulation #29HG are shown in Figure 1. Dissolution studies were conducted under sink conditions for up to 3 days. The silica dissolution rate from silica hydrogel composite #29HG (containing inactive silica particles R2.5-50, pH 4.9) was slower than that from inactive silica microparticles (R2.5-50, pH 4.9). The same dissolution experiment for silica hydrogel composite depot formulation #29HG, calculated to correspond to mg / hour release for a dose of 20 mg of anagrelide HCl in the silica hydrogel composite, is shown in Figure 2.

[0077] Example 3 Rheological measurements and injectability of silica hydrogel composites and particle size analysis of inactive silica particles and anagrelide HCl particles Rheological measurements were performed using a rotational rheometer (Haake RheoStress 300, Germany) with a parallel-plate measurement geometry (D = 20 mm). Two different rheological properties were investigated: dynamic viscosity as a function of shear rate and viscoelasticity. The dynamic shear rate of the silica hydrogel composite was measured under a controlled shear rate (CR) rotation ramp program with a gap of 0.2 mm and shear rates ranging from 100 1 / s to 6000 1 / s at 25 °C. The viscoelasticity of the sample was investigated by oscillatory measurements within the linear viscoelastic region (measured by amplitude sweep measurements) with a measurement gap of 0.4 mm. The sample was examined under controlled strain (γ < 0.002) within the frequency range of 0.01 to 10 Hz.

[0078] Injectability was tested by injecting the depot using plastic 1 ml Luer-lock syringes (Becton Dickinson, needle-free 1 ml syringes) connected to different size needles, with injection volumes ranging from 200 to 300 μl.

[0079] Oscillatory measurements (Figure 3) show that depot formulation #29HG has a non-flowable gel-like structure at low frequencies, suggesting that the inactive silica particles and API particles do not settle within the silica hydrogel composite (depot) at rest (e.g., when stored in a syringe). The loss factor (tan δ = G" / G'), which is the relationship between the viscous (loss) modulus (G"), which indicates the liquid-like properties of a viscoelastic material, and the viscoelastic (storage) modulus (G'), which indicates the solid-like properties of a viscoelastic material, clearly indicates that the solid-like properties prevail at rest, i.e., it is a non-flowable material. G' was approximately 10-20 times larger than G", and G' was approximately 415-440 kPa at the investigated frequencies, indicating a relatively rigid silica hydrogel composite structure. However, dynamic viscosity measurements showed that the depot formulations possessed clear shear-thinning properties that predicted injectability through a fine needle (20G). The dynamic viscosity of depot formulation #29HG clearly decreased from approximately 20 Pas at a shear rate of approximately 1 l / s to approximately 48 mPas at a shear rate of approximately 1500 l / s. The injectability of the depot formulations was further evaluated by performing a manual injectability test, which showed that the depot formulations could be injected through a fine needle (20G).

[0080] For particle size distribution analysis, non-activated silica particles (used in silica hydrogel composite #29HG) were dispersed in ethanol, and the analysis was performed using a Sympatec HELOS H3973 laser diffraction instrument. The particle size distribution of the non-activated silica particles is shown in Table 2 (D10, D50, and D90 mean that 10%, 50%, and 90% of the particles are below the indicated particle size).

[0081] [Table 2]

[0082] Particle size distribution analysis for the micronized anagrelide HCl particles (described in Example 1) was also performed using a Sympatec HELOS H3973 laser diffraction instrument. Particle sizes were primarily between 1 and 200 micrometers, with a D10 of 16.6 micrometers, a D50 of 80.4 micrometers, and a D90 of 155 micrometers.

[0083] Example 4 In vivo pharmacokinetic studies of silica hydrogel composites containing solid particles of anagrelide hydrochloride Silica hydrogel composite #29HG was used as a depot for subcutaneous (SC + letters A–E denoting different groups) and oral (PO) administration of anagrelide to male Sprague Dawley rats (5 animals / treatment group). Oral doses were prepared by vortexing 18.00 mg of anagrelide hydrochloride into 31.520 ml of 10 wt% ethanol and sonicating to obtain a suspension containing anagrelide hydrochloride at a concentration of 0.5 mg / ml. Oral doses (5 mg / kg) were provided only in the 12-h study and were freshly prepared immediately before dosing. 12-h and 10-day pharmacokinetic studies were conducted on the silica hydrogel composite for two different anagrelide hydrochloride doses (17.5 mg / kg and 35 mg / kg), and a 28-day study was conducted for the 35 mg / kg dose only. The doses, administration routes, and blood collection times are shown in Table 3.

[0084] [Table 3]

[0085] No abnormal clinical symptoms were observed in the SD rats throughout the entire experimental period. Bioanalysis was performed using LC-MS / MS. The desired serial concentrations of the working solutions were achieved by diluting the analyte stock solution with 50% aqueous acetonitrile. 5 μL of diluted standard solution (2, 5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL) was added to 50 μL of male blank SD rat plasma to achieve calibration standards ranging from 0.2 to 1000 ng / mL (0.2, 0.5, 1, 2, 5, 10, 50, 100, 500, and 1000 ng / mL) in a total volume of 55 μL. Four quality control samples of plasma at 0.5 ng / mL, 1 ng / mL, 50 ng / mL, and 800 ng / mL were prepared independently from those used for the calibration curve. These QC samples were prepared on the day of analysis using the same method as the calibration standards. 55 μL of standard, 55 μL of QC sample, and 55 μL of unknown sample (5 μL of blank solution and 50 μL of plasma) were added to 200 μL of IS-containing acetonitrile mixture for protein precipitation, respectively. The samples were then vortexed for 30 seconds. After centrifugation at 4700 rpm at 4°C for 15 minutes, the supernatant was diluted three times with water, and 10 μL of the diluted supernatant was injected into the LC-MS / MS system for quantitative analysis. The mean plasma concentrations of anagrelide hydrochloride for the 12-hour experiment are shown in Figure 4, and the corresponding results for the 10-day experiment in Figure 5 and the 28-day experiment in Figure 6 are shown.

[0086] The plasma concentration results indicate that sustained and controlled release is achieved when anagrelide HC is delivered as solid particles in silica hydrogel composites.

[0087] [Table 4]

Claims

1. A silica hydrogel composite comprising at least one active pharmaceutical ingredient, said silica hydrogel composite comprising: a. Inactive silica particles with a diameter of 100 μm or less; b. a silica sol having a solids content of less than 3% by weight, and c. solid particles of at least one water-insoluble or poorly water-soluble active pharmaceutical ingredient (API) having a diameter of 300 μm or less; is a mixture of the silica hydrogel composite comprising 75 wt. % or less of the inactive silica particles, and The silica hydrogel composite is non-flowable and structurally stable when stored at rest, and shear-thinning when shear stress is applied by injection. Silica hydrogel composite.

2. 2. The silica hydrogel composite according to claim 1, wherein the solid content of said silica sol is 0.5-3 wt%, preferably 0.5-2 wt%.

3. 3. The silica hydrogel composite according to claim 1 or 2, wherein the diameter of said non-active silica particles is in the range of 1 μm to 100 μm, preferably 1 μm to 30 μm, more preferably 1 μm to 20 μm.

4. 4. The silica hydrogel composite of claim 1, 2 or 3, wherein the silica sol comprises silica sol particles having a diameter of 100 nm or less.

5. 5. The silica hydrogel composite according to any one of claims 1 to 4, wherein the solid content of the silica hydrogel composite is 20 wt% to 80 wt%, preferably 30 wt% to 60 wt%, and even more preferably 35 wt% to 55 wt%.

6. 6. The silica hydrogel composite according to any one of claims 1 to 5, further comprising active silica particles containing 0.1 to 70 wt%, preferably 0.3 to 50 wt%, most preferably 1 to 20 wt% of an active pharmaceutical agent.

7. 7. The silica hydrogel composite according to any one of claims 1 to 6, wherein the silica is an alkoxysilane-derived silica, preferably a tetraethoxysilane-derived silica.

8. 8. The silica hydrogel composite of claim 1, wherein the non-active silica particles are selected from the group consisting of spray-dried silica particles; silica fiber fragments; and whole or crushed molded or cast silica monoliths.

9. 9. A method for producing a silica hydrogel composite according to any one of claims 1 to 8, comprising the step of preparing the solid particles of the active pharmaceutical ingredient according to at least one of the following: direct synthesis and / or precipitation; small particle crystallization methods or supercritical fluid techniques, such as controlled expansion of supercritical solutions; dissolution-precipitation / crystallization cycles; mechanical methods such as grinding, mashing, and milling used for small particle size reduction of solid substances, such as spray drying or freeze drying, mortar and pestle grinding, wet milling, pneumatic milling, etc.; or granulation methods starting from submicron particles.

10. The silica hydrogel composite according to any one of claims 1 to 8, which is for administering an active pharmaceutical ingredient.

11. 11. The silica hydrogel composite of claim 10, wherein the active pharmaceutical ingredient is anagrelide or one of its pharmaceutically acceptable salts, wherein the salt comprises the hydrochloride salt.

12. The silica hydrogel composite of claim 10 or 11, wherein the administration is parenteral.

13. The silica hydrogel composite of claim 12, wherein the administration is by injection.

14. A silica hydrogel composite according to any one of claims 1 to 8 for controlled delivery of active pharmaceutical ingredients.

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