Silica hydrogel composite and use thereof

Abstract

This invention relates to a silica hydrogel composite comprising inactive silica particles and solid particles of one or more active pharmaceutical ingredients. This silica hydrogel composite enables controlled and sustained delivery of the active pharmaceutical ingredient.

Description

Invention Field

[0001] This invention relates to silica hydrogel composites. More specifically, this invention relates to hydrogel composites comprising at least one active pharmaceutical ingredient as solid particles. The hydrogel composites enable controlled and sustained delivery of the active pharmaceutical ingredient. Background Technology

[0002] The low solubility of active pharmaceutical ingredients (APIs) is a common challenge in new drug development. One aspect relates to the water solubility of APIs in order to achieve desired concentrations in circulation or various bodily fluids, as well as good absorption and permeability. Another aspect involves the formulation and development of different dosage forms for controlled release, such as the solubility of APIs in water or other solvents / liquids used to prepare various types of medical biomaterials, such as silica or poly(lactic-co-glycolic acid) PLGA, which serve as matrix materials in controlled drug delivery. APIs are often incorporated, added to, encapsulated, or embedded in biomaterials used as matrix materials, or added in a soluble form to the process liquid of the matrix material to ensure uniform distribution throughout the system and in the final matrix material.

[0003] Conventionally, to develop different formulations, matrix materials, and dosage forms for controlled release, APIs are dissolved in water or other solvents / liquids such as ethanol, which are then used to prepare different types of matrix materials, such as silica. For example, when APIs are encapsulated in dosage forms based on sol-gel derived silica, it is preferable that the APIs can be dissolved in water, alcohol (e.g., in ethanol when using alkoxides such as tetraethyl orthosilicate (TEOS) as a silica precursor), or in a water-alcohol mixture, because the dissolved molecular form ensures a uniform distribution of the API in the reaction solution (e.g., in a silica sol), which also increases the likelihood of a uniform distribution of the API in the final matrix material, for example, when the API is encapsulated in silica microparticles prepared by spray drying a silica sol containing the dissolved API. However, the use of solvents must also be matched to the development of the matrix material properties during preparation. For example, if the API is insoluble in water, but dissolves in ethanol at a sufficiently high concentration, it is possible that the pH at which this dissolution occurs is unsuitable for developing silica species or silica microparticle properties during the process, and a suitable controlled-release matrix cannot be prepared.

[0004] When an API is dissolved in the processing fluid of a matrix material, it exists in molecular form and is uniformly distributed as molecules in the processing fluid of the matrix material. When the matrix material is further processed or transformed into a final dosage form for use as a controlled delivery device, such as a solid graft, solid particles, hydrogel, or some other material or dosage form, where the solid phase dominates the properties of the matrix material, the API may be in a solid phase, but the size of the solid phase is very small (because it is formed by molecular species of the active pharmaceutical ingredient uniformly distributed in 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 hydrogels for the hand, are often relatively loose structures due to their typically low solids content. The low solids content in hydrogels may be because the solid phase typically consists of cross-linked polymer networks or other polymer species, such as aggregated nanoparticles in the case of sol-gel derived silica. Due to the molecular or nanoscale size of the polymer network backbone or the nanoparticle aggregates, even low solids content is sufficient to achieve a solid phase distribution throughout the hydrogel structure. This means that in practice, hydrogels are porous structures where pores are filled with aqueous solutions. Controlled-release properties depend on the type of hydrogel and its final solids content. Some hydrogels are used as controlled-release matrices due to suitable pore size or due to pore expansion under fluid conditions. Some hydrogels, such as silica hydrogels, release encapsulated or embedded APIs primarily through the slow dissolution of the hydrogel's solid phase. While the typically low solids content in hydrogels is challenging from a controlled-release perspective, it is advantageous from another viewpoint, namely, that they can be used for minimally invasive fine-needle injections from syringes.

[0006] Jokinen et al. (WO 2014 / 207034) and Leino et al. (WO2017 / 068245) disclosed silica hydrogel composites. During spray drying, an API was first encapsulated or embedded in silica microparticles, and then these API-containing silica microparticles were further embedded in a loose silica hydrogel.

[0007] Liu et al. (US6303290) disclosed a method for encapsulating biologically important proteins into a transparent porous silica matrix using an alcohol-free, aqueous, colloidal sol-gel process. Specifically, Liu et al. stated that contact with alcohol was completely eliminated throughout the fabrication process of the porous silica matrix encapsulating the biopolymer, thus avoiding alcohol-induced denaturation (caused by chain unfolding or molecular aggregation) of many biopolymers commonly found in conventional encapsulation methods.

[0008] Purpose and content of the invention

[0009] The purpose of this invention is to minimize or even eliminate the drawbacks of the prior art.

[0010] One object of the present invention is to provide a silica hydrogel composite comprising an active pharmaceutical ingredient as solid particles.

[0011] A particular object of the present invention is to provide a silica hydrogel complex comprising solid particles of anagrelide or a pharmaceutically acceptable salt thereof for controlled release.

[0012] A further object of the present invention is to provide a silica hydrogel complex comprising at least one active pharmaceutical ingredient for medical use involving parenteral administration, such as via fine needle injection.

[0013] These objectives are achieved through the present invention, which has the features set forth in the characterizing portion of the independent claims below. Preferred embodiments of the invention are presented in the dependent claims.

[0014] The embodiments mentioned herein relate to all aspects of the invention where applicable, even if they are not always mentioned separately.

[0015] This invention provides a silica hydrogel complex comprising at least one active pharmaceutical ingredient, wherein the silica hydrogel complex is obtained by mixing the following:

[0016] a. Contains inactive silica particles with a diameter ≤100μm.

[0017] b. A silica sol, wherein the solid content in the silica sol is less than 3% by weight, and

[0018] c. Solid particles of at least one active pharmaceutical ingredient (API), said particles having a diameter preferably ≤300 μm.

[0019] The silica hydrogel composite comprises up to 75% by weight of the inactive silica particles, and the silica hydrogel composite is non-flowing and structurally stable when stored at rest, and is shear-thinned when shear stress is applied by injection. Attached Figure Description

[0020] Figure 1This study describes the in vitro cumulative precipitated silica dissolution and release rates of anagrelide from silica hydrogel complex reservoir formulation #29HG (comprising R300 silica hydrogel, micronized API powder, and inactive silica particles, pH 5.8) in 50 mM TRIS buffer (pH 7.4 at 37°C) with 0.5% SDS. The average values ​​of three analyses at each time point are given.

[0021] Figure 2 This describes the in vitro cumulative precipitation release rate (mg / h) of anagrelide from the silica hydrogel complex at a dose of 20 mg anagrelide hydrochloride. The silica hydrogel reservoir formulation #29HG is in 50 mM TRIS buffer (pH 7.4 at 37°C) with 0.5% SDS. The mean values ​​of three assays are given for each time point.

[0022] Figure 3 The rheological properties of the silica hydrogel complex including anagrelide, namely its stability at rest (e.g., in a syringe) and shear thinning under shear (e.g., after injection from a syringe), are described. The storage modulus (G') and tanδ (loss factor = G” / G') values ​​are also presented for the silica hydrogel complex reservoir formulation #29HG (comprising R300 silica hydrogel, micronized API (anagrelide hydrochloride) powder, and inactive silica particles, pH 5.8).

[0023] Figure 4 This study describes the mean plasma concentrations of anagrelide 12 hours after oral administration and subcutaneous injection of silica hydrogel complexes containing two different doses of anagrelide hydrochloride. The mean (average of 5 animals) plasma concentrations of anagrelide hydrochloride as a function of time were obtained in male SD rats 12 hours after oral (PO) administration of anagrelide hydrochloride and subcutaneous (SC) injection of silica hydrogel complex #29HG (reservoir) containing anagrelide hydrochloride (17.5 and 35 mg / kg).

[0024] Figure 5 This study describes the mean plasma concentrations of anagrelide in an in vivo pharmacokinetic study 10 days after subcutaneous injection of a silica hydrogel complex comprising two different doses of anagrelide hydrochloride. The mean (average of 5 animals) plasma concentrations of anagrelide hydrochloride as a function of time were obtained in male SD rats after subcutaneous injection (SC) of silica hydrogel complex #29HG (reservoir) comprising anagrelide hydrochloride (17.5 and 35 mg / kg).

[0025] Figure 6This study describes the mean plasma concentration of anagrelide in an in vivo pharmacokinetic study 28 days after subcutaneous injection of a silica hydrogel complex containing anagrelide hydrochloride. The mean (average of 5 animals) plasma concentration of anagrelide hydrochloride as a function of time was measured in male SD rats 28 days after subcutaneous (SC) injection (SC) of silica hydrogel complex #29HG (reservoir) containing anagrelide hydrochloride (35 mg / kg). Detailed Implementation

[0026] This invention relates to hydrogel complex formulations comprising at least one active pharmaceutical ingredient (API) as solid particles. The key point of this invention is that, although the solid particles of the API remain solid particles when encapsulated together with a large amount of inactive silica particles within a loose hydrogel portion of the hydrogel complex, both controlled and sustained release behavior and fine-needle injection properties are achieved.

[0027] the term

[0028] In this context, a gel should be understood as a homogeneous mixture of at least one solid phase and one liquid phase, i.e., a colloidal dispersion, wherein one or more solid phases, such as silica itself and / or partially or completely hydrolyzed silica, are continuous phases, and one or more liquids, such as water, ethanol, and residues of silica precursors, are homogeneously dispersed in the structure. Gels are viscoelastic, and elastic properties dominate at rest, as demonstrated by rheological measurements under small-angle oscillatory shear. When the loss coefficient (or loss tangent) tanδ = (G” / G’) is less than 1, elastic properties dominate, and the structure is non-flowing. The combined effect of the elastic modulus G’ and the viscous modulus G” can also be expressed in the form of a composite modulus (or composite shear modulus), G* = G’ + iG”.

[0029] The gel point, or gelation, should be understood as the point at which a flowing sol transforms into a non-flowing and viscoelastic gel, with elastic properties dominating. This is indicated by rheological measurements under small-angle oscillatory shear, where the elastic modulus G' is greater than the viscous modulus and the loss coefficient is less than 1. Viscoelastic properties are typically measured using a rheometer (a measuring device used to determine the correlation between deformation, shear stress, and time) via oscillatory shear, where the shear stress is small (small deformation angle). Measurements are performed by ensuring a sufficient signal for the specific measurement system; typically, strain scanning is performed at a constant frequency to find the appropriate signal and linear viscoelastic region for the rheometer system, and then actual measurements are taken at constant strain with varying frequencies. Different frequencies yield different elastic and viscous moduli, and the measurements indicate whether the solid or liquid phase is dominant. In the form of a sol, the liquid phase is dominant, but the system contains varying amounts of one or more solid phases, and the system is still flowing. A sharp increase in dynamic viscosity and elastic modulus is typically observed before the gel point, and it continues to increase after the gel point as the structure develops. In the context of this invention, the gel point of the complex of this invention has been reached before the injectable gel of this invention is obtained.

[0030] Inactive silica particles refer to silica particles themselves, i.e., they do not contain any encapsulating or embedding agents (except for possible residues derived from silica synthesis, such as water and ethanol), such as active pharmaceutical ingredients. Therefore, inactive silica particles do not contain any active pharmaceutical ingredients. Active silica particles refer to silica particles comprising 0.1 to 70% by weight, preferably 0.3 to 50% by weight, and most preferably 1 to 20% by weight of an active pharmaceutical ingredient. All material properties defined for inactive silica particles, such as the weight percentage of total solids in the silica hydrogel composite and particle size, are also applicable to active silica particles.

[0031] Non-flowing and structurally stable during static storage refers to a stable composite hydrogel structure composed of inactive silica particles and API particles within a silica hydrogel. Stability is indicated by rheological measurements under small-angle oscillating shear, using an elastic modulus G' greater than the viscous modulus and a loss coefficient less than 1. When the elastic modulus is greater than the viscous modulus and the loss coefficient is less than 1, the structure is non-flowing. The non-flowing structure ensures the stability of the composite hydrogel structure by preventing phase separation of the particles. In other words, the inactive silica particles and API particles are embedded within the silica hydrogel, and they do not, for example, precipitate or separate at the bottom of a container such as a syringe, where the hydrogel composite is typically stored at temperatures ≤25°C. Although the composite hydrogel structure is non-flowing when stored in a static state, for example, in a pre-filled, ready-to-use syringe, the structure is so loose that it is shear-thinned and therefore injectable through a fine needle, as shear stress is applied to the hydrogel composite during injection.

[0032] Hydrogels should be understood as gels in which the liquid phase is water or water-based and contains more than 50 wt% (wt%) of water. Preferably, the liquid phase of the hydrogel comprises >80 wt%, more preferably >90 wt%, and even more preferably >97 wt% of water. The liquid phase may additionally comprise other liquids, typically organic solvents such as ethanol. Typically, such solvents, such as ethanol, have a concentration of <10 wt%, more preferably <3 wt%, and even more preferably <1 wt%. In the context of this invention, the composites of this invention are considered hydrogels because they meet the basic criteria for hydrogels. Accordingly, when referring to the hydrogel composites of this invention, this reference is equivalent to the reference to the composites of this invention. In the context of this invention, the silica hydrogel composites of this invention preferably comprise 20 to 80 wt%, more preferably 30 to 70 wt%, and most preferably 40 to 60 wt% of water.

[0033] A sol should be understood as a homogeneous mixture of at least one liquid phase and one solid phase, i.e., a colloidal dispersion, wherein one or more liquid phases, such as water, ethanol, and residues of silica precursors, are continuous phases, and one or more solid phases, such as colloidal particles of silica and / or partially or completely hydrolyzed silica and / or aggregates of said particles, are uniformly dispersed in said liquid phase, characterized in that said sol has a defined flow property and the liquid phase is dominant.

[0034] In the context of this application, injectable gels or hydrogels or hydrogel complexes refer to the rheological properties of the composition. Prior to injection, for example, when stored in a syringe and / or aluminum foil at temperatures <37°C, such as room temperature (20-25°C) or refrigerator temperature (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 coefficient tanδ=(G” / G') is less than 1. Although the hydrogel complex structure is a gel-like structure, and the complex structure remains stable and non-flowing when stored at rest, the gel structure is so loose that it is shear-thinned when shear stress is applied, for example, by injection through a syringe needle, such as by using an 18-25G needle (outer / inner diameter of 1.27 / 0.84 mm to 0.50 / 0.26 mm).

[0035] In the context of this invention, injectable means that the drug can be administered via a surgical drug delivery device, such as a needle, catheter, or a combination thereof.

[0036] In the context of this application, shear thinning is a rheological property of a composition. Whenever the shear stress or shear rate of such a composition changes, the composition gradually shifts towards its new equilibrium state, and at lower shear rates, shear-thinned compositions are more viscous, while at higher shear rates, their viscosity is lower. Therefore, shear thinning refers to the effect of a fluid's viscosity, a measure of fluid flow resistance, decreasing with increasing shear stress.

[0037] Matrix material should be understood as a material in which an active pharmaceutical ingredient is incorporated, added, encapsulated, or embedded, such as silica microparticles or silica hydrogel complexes, and matrix materials that control the release rate of the active pharmaceutical ingredient due to their structure, such as porous structure, and / or due to their chemical composition, such as solubility in body fluids.

[0038] Dosage form should be understood as an injectable or implantable formulation that includes a matrix material and is used to administer the active pharmaceutical ingredient.

[0039] The reservoir formulations mentioned in this application are defined as drug (active pharmaceutical ingredient) formulations with sustained-action administration, which allow for slow release and gradual absorption, thereby enabling the active agent to act and be released in the body for a longer period of time, i.e., from days to months. Reservoir formulations are administered parenterally via subcutaneous, intramuscular, peritoneal, or intraocular injection or implantation.

[0040] The term silica refers to amorphous SiO2, preferably prepared via a sol-gel process. Sol-gel-derived silica refers to silica prepared via a sol-gel process, wherein silica is prepared from a liquid-phase precursor such as an alkoxide, alkyl alkoxide, amino alkoxide, or inorganic silicate solution, which forms a sol through hydrolysis and condensation reactions, and this sol transforms into a gel or forms a stable sol. Sol-gel-derived silica can also be prepared by simultaneously gelling, aging, drying, and shaping, for example by spray drying to microparticles, processing it into different morphologies.

[0041] The term silica sol refers to a suspension, i.e., a mixture of a liquid (continuous phase) and a solid (dispersed phase), wherein the solid phase consists of silica particles and / or aggregated silica particles, wherein the particle size of the silica particles and / or aggregates is typically less than 1 μm, preferably less than 100 nm, i.e., the silica particles and / or particle aggregates are colloidal. Silica sol is typically prepared from alkoxides or inorganic silicates, which are hydrolyzed to form partially hydrolyzed silica species or fully hydrolyzed silicic acid. The liquid phase typically consists of water and hydrolysis and condensation products such as ethanol. Subsequent condensation reactions of SiOH-containing species result in the formation of larger silica species with an increased amount of siloxane bonds. These species form nanoscale colloidal particles and / or particle aggregates. Depending on the conditions, silica sol remains a stable colloidal suspension or becomes a gel.

[0042] Active pharmaceutical ingredient (API) should be understood as a drug or other therapeutic and / or bioactive agent, preferably poorly soluble in water or completely insoluble in water. The solid particles of the API substantially comprise the API and are free of silica. Preferably, the solid particles of the API comprise at least 80% by weight, preferably 90% by weight, more preferably 95% by weight or 99% by weight, and sometimes even 99.5% by weight or more of the API.

[0043] Particle size or particle diameter refers to the maximum diameter of a particle when it is of any shape.

[0044] 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 for sol-gel derived silica and is also used in this invention. The R value can also be used to calculate the solid (silica) content of silica sol. For example, a molar ratio of water to TEOS of 200 (R200) ​​results in approximately 1.60% by weight of solid silica in the silica sol, R300 correspondingly results in approximately 1.08% by weight, and R400 correspondingly results in approximately 0.82% by weight.

[0045] In the context of this invention, micronization should be understood as any method for producing small solid particles, such as solid particles of active pharmaceutical ingredients, provided that the resulting solid material has a particle size of 300 micrometers or less. For example, solid particles of APIs can be produced by: 1) direct synthesis and / or precipitation, or 2) by any crystallization method or supercritical fluid technology for small particles, such as controlled expansion of supercritical solutions, or 3) by any dissolution-precipitation / crystallization cycle, or 4) by spraying or freeze-drying, or 5) by any mechanical method, such as grinding, impacting, and milling, for reducing the size of the solid material, such as grinding with a mortar and pestle, wet milling, pneumatic milling, or 6) by any granulation method starting from submicron particles.

[0046] Invention features

[0047] The inventors have discovered that a silica hydrogel composite comprising a hydrogel portion, inactive silica microparticles, and API as solid particles can achieve both the desired controlled-release properties and injection via a fine needle from a pre-filled syringe. API can be added as solid particles to the silica hydrogel portion, and because of their 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 includes inactive silica microparticles, i.e., silica microparticles without encapsulation or embedding of API. The inactive silica microparticles modulate the rheological properties of the hydrogel composite, but they also contribute to the overall controlled release of API by preventing the release of API solid particles embedded in the hydrogel portion of the hydrogel composite. Thus, the hydrogel portion and inactive silica microparticles together form a non-flowing but injectable silica hydrogel composite in which solid particles of API are incorporated and / or embedded. In this way, API is not released from the hydrogel composite while the solid phase of the hydrogel composite remains insoluble.

[0048] In this context, the term "hydrogel portion" refers to a portion of a hydrogel complex derived from silica sol.

[0049] This invention provides a silica hydrogel complex comprising at least one active pharmaceutical ingredient (API) as solid particles. In the manufacture of the silica hydrogel complex, the API is in the form of a dry powder or a suspension of solid particles before being encapsulated or incorporated into the silica hydrogel. As described above, a surprising finding of this invention is that although the solid particles of the API remain as solid particles after being encapsulated / incorporated into the loose hydrogel portion of the silica hydrogel complex, preferably having a diameter ≤300 μm, controlled and sustained release behavior is still achieved for the silica hydrogel complex both in vitro and in vivo, as well as injection from a syringe using a fine needle such as an 18G-25G needle.

[0050] The silica hydrogel complex comprises inactive silica particles and solid particles of at least one API in its hydrogel portion, both of which affect the controlled-release properties. Therefore, the controlled-release properties are influenced not only by the hydrogel portion of the complex and the inactive silica particles, but also by the particle size of the solid particles of the active pharmaceutical ingredient. Surprisingly, it has been found that active pharmaceutical ingredients that are practically insoluble or poorly soluble in water can be used as solid particles to prepare a homogeneous silica hydrogel complex for controlled release with fine-needle injection capability. The particle size of the API solid particles can be ≤300 μm, preferably 1 μm to 300 μm, and more preferably 1 μm to 200 μm.

[0051] Different gels, such as organic gels and hydrogels, have traditionally been used for controlled drug delivery, but many challenges exist for different types of active pharmaceutical ingredients. Hydrogels, generally speaking, typically have low solids content, and the majority of the gel structure is in liquid form. The solid portion or solid phase of a hydrogel includes 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 within the formed three-dimensional network. In practice, hydrogels are porous structures in which pores are filled with an aqueous liquid. The solids content of hydrogels is typically low, such as ≤3% by weight, and in many cases less than ≤1% by weight. At low solids contents, hydrogels readily become flowable and shear-thinning materials, which is advantageous in developing injectable dosage forms for controlled drug delivery. As the solids content of a hydrogel increases, the shear-thinning properties may be lost. Because the hydrogel structure is typically a very loose and open structure, incorporated, encapsulated, or embedded active pharmaceutical ingredients of varying sizes, such as small molecule drug molecules, proteins, peptides, and RNA, can diffuse relatively rapidly. If the release of the encapsulated API from the hydrogel depends on the dissolution rate of the solid phase, then the API size 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 used for fine-needle injection. Low solids content in the hydrogel, such as less than 3% by weight, is feasible for fine-needle injection, but may still be too loose for sustained delivery even for larger active pharmaceutical ingredients or therapeutic agents, such as solid API particles, fusion proteins, viral vectors, and vaccine antigens. In this invention, inactive silica particles are combined with silica hydrogel and solid API particles, resulting in a silica hydrogel complex in which both good injection capability with fine needles and sustained delivery are achieved.

[0052] In this invention, the silica hydrogel composite comprises inactive silica particles and solid particles of at least one API embedded in the silica hydrogel. The silica hydrogel composite is particularly suitable for the controlled release of APIs that are poorly or completely insoluble in water, because the main component of the liquid phase in the silica hydrogel is water. The silica hydrogel portion of the silica hydrogel composite is a loose hydrogel, with a solid content preferably ≤3% by weight, preferably ≤2% by weight, and most preferably 0.5–2% by weight.

[0053] The solid content in the silica hydrogel portion is typically less than 1.5% by weight of the total silica hydrogel composite.

[0054] In this invention, the silica hydrogel composite comprises inactive silica particles having a diameter ≤100 μm, or in the range of 1 μm to 100 μm, preferably 1 μm to 30 μm, more preferably 1 μm to 20 μm. Using inactive silica particles as part of the silica hydrogel composite increases the solids content of the hydrogel composite without sacrificing any fine needle injection capability, and the inactive silica particles also contribute to a sustained release rate of the API solids. The inactive silica particles can be spray-dried silica particles or silica fiber fragments. Alternatively, the inactive silica particles can be molded or cast silica monoliths, undisturbed or pulverized.

[0055] The silica hydrogel composite comprises up to 75% by weight of the aforementioned inactive silica particles, and according to one embodiment of the invention, 20-75% by weight of the total silica hydrogel composite is inactive silica microparticles. According to one embodiment, the silica hydrogel composite may further comprise active silica particles, and in this case, the total portion of the inactive and active particles is also 75% by weight. The general function of the inactive silica particles is to achieve good rheological properties of 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 such as 18-25G).

[0056] The silica hydrogel composite may have a total solids content of 20% to 80% by weight, preferably 30% to 60% by weight, and even more preferably 35% to 55% by weight.

[0057] The silica hydrogel composite includes at least one active pharmaceutical ingredient (API) as solid particles. The silica hydrogel composite may also include two or more different active pharmaceutical ingredients as solid particles. Preferably, the diameter of the API solid particles is ≤300 μm, more preferably in the size range of 1-200 μm. The solid particles of at least one API encapsulated in the hydrogel portion of the silica hydrogel composite result in an injectable dosage form, wherein sustained release is achieved despite the solid particles being encapsulated in a loose hydrogel portion of the hydrogel composite. The water solubility of the active pharmaceutical ingredient is preferably low or absent, and both low solubility and the size of the API solid particles contribute to the sustained and controlled release of the silica hydrogel composite of the present invention. The larger the size of the API solid particles, the greater the influence of particle size on the API release rate. However, the solid particles of the active pharmaceutical ingredient may also affect the final gelation and rheological properties of the silica hydrogel composite, and therefore, the optimal amount and particle size of the API solid particles are preferably determined on a case-by-case basis according to the API in question. According to one embodiment, 0.1-20% by weight, preferably 0.1-15% by weight, of the total silica hydrogel composite may be solid particles of the API. For example, if the API is anagrelide hydrochloride, the particle size of the API solid particles is 1-300 μm, preferably 1-200 μm, and / or the amount of API solid particles is 0.1-20% by weight, preferably 0.1-15% by weight, calculated from the total silica hydrogel composite.

[0058] Solid particles of at least one API, preferably ≤300 μm, more preferably 1-200 μm in diameter, can be readily added to a liquid system for forming a hydrogel, for example, to a silica sol for forming a silica hydrogel, or to a silica sol that will form a hydrogel portion in a silica hydrogel complex that also includes inactive silica particles. According to one embodiment of the invention, the particle size of the API solid particles can be 100-1000 nanometers. The API solid particles are embedded in the silica hydrogel portion without losing the good injectability of the formed hydrogel complex, an important property of minimally invasive dosage forms in controlled drug delivery. When the API solid particles are significantly larger than 1 micrometer, mixing must be used to ensure uniform particle distribution until the system transitions from a flowing form, for example, from a silica sol, to a non-flowing form, for example, to a silica hydrogel or silica hydrogel complex. API particle sizes from 1 to 300 μm can be prepared by any micronization method, such as direct synthesis and / or precipitation.

[0059] The excellent injectability of silica hydrogel composites, such as with 18-25G needles, and their controlled release in vitro and in vivo, are achieved through silica hydrogel composites comprising API solid particles with a size of 300 μm or smaller, or 1-200 μm. Despite the loose structure of the silica hydrogel portion with low solids content, controlled and sustained release properties are achieved through the solid particles of API embedded within the hydrogel portion of the silica hydrogel composite. This is due to the combined effect of the hydrogel portion, the large-sized API particles, and the inactive silica particles. The silica hydrogel portion and the inactive silica particles together form a structure in which the solid particles of API are trapped, preventing them from being released rapidly like particles, but rather releasing them slowly as the main solid component of the silica hydrogel composite, namely the inactive silica particles, dissolves. Silica itself is insoluble within the silica hydrogel composite due to its very low water solubility (e.g., 120-150 ppm (µg / ml) at 37°C and pH 7.4, and even lower at room temperature or 2-8°C). This means that most of the silica dissolves from the surface of the hydrogel composite when the in vitro dissolution medium is regenerated to maintain it under drain conditions (conditions ensuring free dissolution of silica) or when bodily fluids flow within the body. The fraction of inactive silica particles in the silica hydrogel composite is high, preferably up to 75% by weight, or 20-60% by weight, and the corresponding fraction of polymeric silica sol nanoparticles forming the solid phase in the hydrogel portion of the hydrogel composite is typically less than 3% by weight. The remainder consists of an aqueous solution of the active pharmaceutical ingredient and encapsulated solid particles (e.g., 0.1-20% by weight). Therefore, inactive 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 active pharmaceutical ingredients are combined in silica sol (which also includes aqueous solutions), they together form a silica hydrogel complex, wherein the solid particles of active pharmaceutical ingredients are encapsulated between silica particles (inactive silica particles and aggregated silica nanoparticles), and the aqueous solution is uniformly distributed over the entire mass of the hydrogel complex.

[0060] Poor or no solubility of API particles supports slow release, meaning their size does not decrease and they remain trapped within the hydrogel complex structure. According to a preferred embodiment, for solid particles of anagrelide hydrochloride with a solubility of 0.019 mg / ml in water, equivalent to 0.0019 wt%, a large-sized API solid particle was observed to contribute to good controlled-release performance. This means that at typical syringe doses of 0.05-1 ml administered parenterally, the API solid particles are virtually intact within the hydrogel portion of the complex. It can be assumed that dissolving less than 10 wt% of any API solid particles smaller than 300 micrometers in the aqueous phase of a single-dose silica hydrogel complex maintains its positive effect in both fine-needle injection and controlled-release properties. For API particles with a relatively large particle size distribution between 1 and 200 micrometers, i.e., an average size difference greater than 10% between the smaller half and the larger half, good sustained and controlled-release behavior as observed in this invention is observed. If 10% by weight is dissolved in the aqueous phase of the hydrogel phase, this means that virtually 90% by weight of the API particles remain intact, and since the dissolved form of the API is generally within the acceptable limits of controlled drug delivery, the initial release (burst) of 10% by weight of the API may be faster.

[0061] According to one embodiment of the invention, the composition may further comprise active silica particles containing 0.1 to 70% by weight, preferably 0.3 to 50% by weight, and most preferably 1 to 20% by weight of the active pharmaceutical ingredient. API can be encapsulated as nanoparticles with a particle size of 10-100 nm into active silica particles, for example, prepared by spray drying, and used in a silica hydrogel composite, thereby replacing inactive silica particles, or preferably in addition to inactive silica particles. If the silica hydrogel composite comprises both inactive and active silica particles, the total amount of silica particles (including both active and inactive) shall not exceed 75% by weight of the total mass of the silica hydrogel composite, as defined elsewhere in this application. If the API particles are sufficiently small, for example in the 10-100 nm range, compared to the size of the matrix material in the final dosage form, for example, compared to spray-dried silica particles typically with a size of 1-30 micrometers, they may be uniformly encapsulated into the silica particles and form active silica particles. The properties of the activated silica particles (the adjustable dissolution rate of silica) control the release properties of the API from the activated silica particles. The API encapsulated in the activated silica particles can be the same as or different from the API that exists as solid particles.

[0062] The size of the API-containing particles is one of the key parameters. Many matrix materials are used in drug delivery systems, and they come in a variety of forms, sizes, and shapes, such as monolithic grafts, fibers, particles in suspensions, hydrogels, etc. Microparticles are very common, and they can be used as active silica particles. In this case, the encapsulated or embedded API particles themselves should be small enough compared to the microparticles (typically ranging in size from about 1–30 micrometers), i.e., the API particles should be nanoparticles with a diameter of less than 100 nm. Excessively large API particles cannot be properly encapsulated in active silica particles, as this results in a heterogeneous structure and a loss of their controlled delivery properties. Furthermore, if the API particles are too large compared to the matrix particles, the API loading percentage in the matrix material may remain low. This also applies to different types of solid graft structures and fibrous materials, where large API particles can lead to heterogeneity and loss of controlled-release properties as well as mechanical properties.

[0063] The silica hydrogel composites of the present invention, comprising at least one active pharmaceutical ingredient as solid particles, offer advantages in developing novel matrix materials for controlled and sustained delivery. In addition to the previously proposed option of using relatively large solid particles of the active pharmaceutical ingredient in silica hydrogel composites for controlled delivery, the inventors have considered other options. For example, the active pharmaceutical ingredient may be pre-encapsulated in some other material (in the form of solid particles), which is not suitable for sustained release of the encapsulant, but makes it easier to encapsulate or embed the active pharmaceutical ingredient, which has low water solubility, into another material, such as a matrix material for controlling the release of the active pharmaceutical ingredient. Alternatively or additionally, pre-encapsulation may also relate to the protection of the active pharmaceutical ingredient, such as small molecule drugs or biopharmaceuticals (e.g., protein-based drugs, fusion proteins, peptides, RNA-based drugs, viral vectors, and vaccine antigens). Another possibility is to achieve more controlled and sustained delivery options for active pharmaceutical ingredients (independently, regardless of whether they are soluble in water or other processing fluids used for matrix materials), because the release rate profile of any matrix material will be different if the active pharmaceutical ingredient is dissolved in large solid particles, small particles, or in molecular form, or in different combinations of particles of different sizes and forms of dissolution.

[0064] Preferred Implementation

[0065] In the preferred storage formulation of the present invention, the silica hydrogel complex comprises at least one active pharmaceutical ingredient as solid particles having a diameter preferably ≤300 μm, and the silica hydrogel complex is non-flowing and structurally stable when stored at rest, and is shear-thinned when shear stress is applied by injection.

[0066] In the preferred reservoir formulation of the present invention, the silica hydrogel composite comprises up to 75% by weight of inactive silica particles.

[0067] In the preferred storage formulation of the present invention, the silica sol has a solid content of 0.5-3% by weight, preferably 0.5-2% by weight.

[0068] In the preferred reservoir 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, and more preferably 1 μm to 20 μm.

[0069] In the preferred storage formulation of the present invention, the silica sol comprises silica sol particles having a diameter of ≤100 nm, more preferably 5 to 100 nm.

[0070] In the preferred reservoir formulation of the present invention, the silica hydrogel composite has a solid content of 20% to 80% by weight, preferably 30% to 60% by weight, and even more preferably 35% to 55% by weight.

[0071] In the preferred reservoir formulation of the present invention, the silica hydrogel composite further comprises active silica particles containing 0.1 to 70% by weight, preferably 0.3 to 50% by weight, and most preferably 1 to 20% by weight of an active pharmaceutical agent.

[0072] In the preferred storage formulation of the present invention, the silica is alkoxysilane-derived silica, preferably tetraethoxysilane-derived silica.

[0073] In the preferred storage formulation 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, either as is or pulverized.

[0074] In the preferred reservoir formulation of the present invention, the solid particles of the active pharmaceutical ingredient are selected from the group consisting of particles prepared by means of: direct synthesis and / or precipitation; crystallization methods or supercritical fluid techniques for small particles, such as controlled expansion of supercritical solutions; dissolution-precipitation / crystallization cycles; spray drying or freeze drying; mechanical methods, such as grinding, impact and milling, for reducing the size of solid matter, such as grinding with mortar and pestle, wet grinding, pneumatic milling; and granulation methods starting from submicron particles.

[0075] In the preferred reservoir formulation of the present invention, the silica hydrogel complex is formed at least by: i) aggregated silica sol nanoparticles (which also include an aqueous solution) in a silica sol, 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 silica particles (inactive silica particles and aggregated silica nanoparticles), and the aqueous solution is uniformly distributed over the entire mass of the hydrogel complex.

[0076] The reservoir formulation of the present invention is typically used to administer active pharmaceutical ingredients.

[0077] The reservoir formulation of the present invention is used to administer anagrelide or any pharmaceutically acceptable salt thereof, including hydrochloride.

[0078] The reservoir formulation of the present invention is typically used for parenteral administration.

[0079] The reservoir formulation of the present invention is typically used for parenteral administration via injection.

[0080] The reservoir formulations of the present invention are typically used for the controlled delivery of active pharmaceutical ingredients.

[0081] Example

[0082] Some embodiments of the invention are described in the following non-limiting examples.

[0083] Example 1

[0084] Preparation of silica hydrogel complex containing anagrelide hydrochloride (API)

[0085] A silica sol was initially prepared for the production of inactive silica particles (ordinary silica microparticles) by hydrolyzing TEOS in water at pH 2 using 0.1 M HCl as a catalyst. The water-to-TEOS molar ratio (R value) of the silica sol was 2.5 (first R value). After hydrolysis, the R2.5 sol was cooled to 0–5 °C. The R2.5 sol was then diluted with ethanol to reduce the solids (silica) content, ultimately yielding a second R value of 50 (the volume of ethanol added corresponds to the volume of water required to achieve a water-to-TEOS molar ratio of 50). Finally, prior to spray drying, the pH of the diluted silica sol (R2.5-50) was adjusted to pH 4.9 with 0.1 M NaOH solution. Inactive silica particles were then prepared from the R2.5-50 silica sol by spray drying (using a Büchi B-290 spray dryer). The spray drying parameters are listed in Table 1.

[0086] Table 1. Spray Drying Parameters

[0087] Inlet temperature outlet temperature suction device pump Atomized airflow 120℃ 83–85℃ <![CDATA[35m 3 / h]]> 5.6 ml / min 670l / h

[0088] Since anagrelide hydrochloride is practically insoluble in water (0.019 mg / ml), and the basic form of anagrelide has even lower solubility than anagrelide hydrochloride, solid anagrelide hydrochloride powder was manually micronized in a mortar (to a particle size distribution of 1-200 micrometers) for about 10 minutes.

[0089] The next step was to prepare the hydrogel portion of the silica hydrogel composite using either R200 or R300 silica sol. Both R200-based and R300-based sols (R200 resulting in approximately 1.60 wt% solid silica in the silica sol, and R300 correspondingly 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. The mixture was prepared by suspending 920 mg of micronized API (anagrelide hydrochloride) and 6780 mg of inactive silica particles (R2.5-50) in 12.6 ml of R300 silica sol, followed by adjusting the pH of the mixture to pH 5.8 with the addition of 0.5 M NaOH (6.1 ml). This combined the inactive silica particles spray-dried from R2.5-50 sol, the micronized API powder (anagrelide hydrochloride), and the R300 silica sol. The mixture was transferred to a plastic syringe (Becton Dickinson Luer lock, needle-free 1 ml syringe) and slowly mixed in a vertically rotating mixer to stabilize the mixture (preventing sedimentation of the inactive silica particles and solid anagrelide hydrochloride particles). The mixture was allowed to gel at ambient temperature (approximately 25°C) for 2–3 days until gelation occurred, i.e., the mixture became a non-flowing silica hydrogel complex #29HG.

[0090] Example 2

[0091] Measurement of in vitro dissolution and release rates for inactive silica microparticles and silica hydrogel complexes including anagrelide hydrochloride (API).

[0092] In vitro degradation of silica and release of API (anagrelide hydrochloride) were measured in a 50 mM Tris buffer supplemented with SDS (0.5%, w / v) at pH 7.4 and 37 °C. Sample size analysis was performed for inactive silica particles at approximately 10–15 mg, and for silica hydrogel complex (reservoir) formulations at approximately 20–30 mg. Dissolution tests were conducted in a vibrating water bath at 37 °C (60 blows / min) for a maximum of 72 hours. In the dissolution medium, silica and API (anagrelide hydrochloride) concentrations were maintained under drain conditions (free dissolution of the silica matrix, i.e., silica concentration maintained below 20% of saturation). The dissolution medium was replaced with fresh medium at each sampling time point to maintain silica concentration below 30 ppm (under drain conditions). Quantitative analysis was performed to measure cumulative API release and silica dissolution. Three replicate samples were collected at each time point, and the average value is shown in the results. The concentration of silica was measured using a UV / VIS spectrophotometer, and the absorbance of the molybdenum blue complex at λ = 820 nm was analyzed. Anagrelide was analyzed using a 1100HPLC Agilent Technologies high-performance liquid chromatography (HPLC) system connected to a variable wavelength detector (λ = 250 nm). Chromatographic separations were obtained on a Waters XSelect HSS C18, 3.5 μm, 3.0 x 20 mm HPLC column, using a 1100HPLC Agilent Technologies G1314A variable wavelength detector, at a column temperature of 30 °C, with mobile phase A being water / formic acid 1000 / 1 (v / v) and mobile phase B being acetonitrile / formic acid 1000 / 1 (v / v).

[0093] The total silica and anagrelide hydrochloride content in the hydrogel composite were measured to accurately determine the dissolution and release rates. The total silica content of the sample material was measured by dissolving the sample in 0.5 M NaOH solution at 37 °C for 3 days. Correspondingly, the total API (anagrelide hydrochloride) content was measured by dissolving the sample in 50 mM glycine buffer at pH 9.6 supplemented with SDS (1.5% w / v) at 37 °C.

[0094] In vitro dissolution studies of inactive silica particles (R2.5-50, pH 4.9) were conducted under trough conditions for a maximum of 48 hours. The cumulative in vitro silica degradation (i.e., dissolution of the silica matrix) of the inactive silica particle formulation reached 100% (w / w) in approximately 24 hours, prior to which it was approximately 7% at 1 hour, approximately 32% at 2 hours, approximately 59% at 3 hours, approximately 68% at 4 hours, approximately 77% at 5 hours, approximately 83% at 6 hours, and approximately 95% at 9 hours.

[0095] The cumulative degradation (dissolution rate) of silica and the cumulative release of anagrelide from silica hydrogel complex reservoir formulation #29HG were observed. Figure 1 As shown in the figure. Dissolution studies were conducted under trough conditions for a maximum of three days. The silica dissolution rate of the silica hydrogel complex #29HG (including inactive silica particles R2.5-50, pH 4.9) was slower than that of the inactive silica microparticles (R2.5-50, pH 4.9). The same dissolution experiments of the silica hydrogel complex reservoir formulation #29HG were conducted in... Figure 2 As shown in the figure, but now calculated as mg / hour release corresponding to a 20 mg dose of anagrelide hydrochloride in the silica hydrogel complex.

[0096] Example 3

[0097] Rheological measurements and injection capability of silica hydrogel composites, and particle size analysis of inactive silica particles and anagrelide hydrochloride particles.

[0098] Rheological measurements were performed using a rotational rheometer (HaakeRheoStress 300, Germany) equipped with a parallel plate-plate (D = 20 mm) measuring geometry. Two distinct rheological characteristics were investigated: dynamic viscosity as a function of shear rate and viscoelasticity. The dynamic viscosity of the silica hydrogel composite was measured under a controlled shear rate (CR) rotational ramp program with a gap of 0.2 mm, and the shear rate ranged from 100 1 / s to 6000 1 / s at 25 °C. The viscoelastic properties of the samples were investigated via oscillatory measurements within the linear viscoelastic region (determined by amplitude scanning) using a measurement gap of 0.4 mm. The samples were studied under controlled deformation (γ < 0.002) within a frequency range of 0.01–10 Hz.

[0099] Injection capability was tested by injecting into the reservoir using plastic 1ml Luer-lock syringes (Becton Dickinson, needle-free 1ml syringes) connected to needles of different sizes. Injection volumes ranged from 200 to 300 μl.

[0100] Oscillation measurement ( Figure 3The study shows that the reservoir formulation #29HG exhibits a non-flowing gel-like structure at low frequencies, indicating that inactive silica particles and API particles do not deposit within the silica hydrogel composite (reservoir) when at rest (e.g., stored in a syringe). The loss coefficient (tanδ = G” / G”), which represents the relationship between the viscous (loss) modulus (G”), indicating the liquid-like properties of the viscoelastic material, and the elastic (storage) modulus (G’), indicating the solid-like properties of the viscoelastic material, clearly shows that the solid-like properties dominate at rest, i.e., it is a non-flowing material. G’ is approximately 10–20 times larger than G”, and G’ is approximately 415–440 kPa at the studied frequencies, indicating a relatively rigid silica hydrogel composite structure. However, dynamic viscosity measurements indicate that the reservoir formulation exhibits significant shear-thinning properties, predicting its injection capability through a fine needle (20G). The dynamic viscosity of the reservoir formulation #29HG decreased significantly from approximately 20 Pas at a shear rate of approximately 1 1 / s to approximately 48 mPas at a shear rate of approximately 1500 1 / s. The injectability of the reservoir formulation was further evaluated by performing a manual injection capability test, which showed that the reservoir formulation could be injected using a fine needle (20G).

[0101] For particle size distribution analysis, inactive silica particles (used in the silica hydrogel composite #29HG) were dispersed in ethanol and analyzed using a Sympatec HELOS H3973 laser diffractometer. The particle size distribution of the inactive silica particles is shown in Table 2 (D10, D50, and D90 refer to 10%, 50%, and 90% of the particles being equal to or smaller than the indicated particle size).

[0102] Table 2. Particle size distribution of inactive silica particles

[0103]

[0104] The particle size distribution of the micronized anagrelide hydrochloride particles (described in Example 1) was also analyzed using a Sympatec HELOS H3973 laser diffractometer. The particle size was mainly between 1 and 200 micrometers, with D10 being 16.6 micrometers, D50 being 80.4 micrometers, and D90 being 155 micrometers.

[0105] Example 4

[0106] In vivo pharmacokinetic studies of silica hydrogel complexes including anagrelide hydrochloride solid particles

[0107] The silica hydrogel complex #29HG was used as a reservoir for subcutaneous (SC + letter AE indicates different groups) administration of anagrelide to male SD (Sprague-Dawley) rats (5 animals / dose groups) and for oral (PO) administration. The oral dose was prepared by adding 18.00 mg of anagrelide hydrochloride to 31.520 ml of 10 w-% ethanol and vortexing and sonicating to obtain a suspension of anagrelide hydrochloride at a concentration of 0.5 mg / ml. The oral dose (5 mg / kg) was only provided in the 12-hour study and was prepared just before administration. Pharmacokinetic studies of the silica hydrogel complex were conducted at 12 hours and 10 days for two different doses of anagrelide hydrochloride (17.5 mg / kg and 35 mg / kg), and at 28 days for the 35 mg / kg dose only. Dosage, route of administration, and blood sampling time are shown in Table 3.

[0108] Table 3. Parameters of in vivo pharmacokinetic experiments with anagrelide hydrochloride treatment

[0109]

[0110] No abnormal clinical symptoms were observed in SD rats throughout the experiment. Bioanalysis was performed using LC-MS / MS. The desired series of working solution concentrations were obtained by diluting the stock solutions of the analytes with 50% acetonitrile aqueous solution. 5 μL of working solution (2, 5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng / mL) was added to 50 μL of male blank SD rat plasma to achieve a total volume of 55 μL of calibration standards ranging from 0.2 to 1000 ng / mL (0.2, 0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL). Independent of those used for calibration curves, four quality control samples for plasma were prepared at concentrations of 0.5 ng / mL, 1 ng / mL, 50 ng / mL, and 800 ng / mL. These QC samples were prepared on the day of analysis in the same manner as the calibration standards. 55 μL of standard, 55 μL of QC sample, and 55 μL of unknown sample (50 μL plasma and 5 μL blank solution) were added separately to 200 μL of IS mixture containing acetonitrile to precipitate proteins. The samples were then vortexed for 30 s. After centrifugation at 4700 rpm for 15 min at 4°C, 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 average plasma concentration of anagrelide hydrochloride in the 12-hour experiment was [missing value]. Figure 4 The results are shown in [the diagram], along with the corresponding results of the 10-day experiment. Figure 5 The results shown in the figure, as well as the corresponding results of the 28-day experiment, are in Figure 6 As shown in the image.

[0111] Plasma concentration results showed that sustained and controlled release was achieved when anagrelide hydrochloride was delivered as solid particles in the silica hydrogel complex.

[0112] Table 4. Summary of pharmacokinetic parameters of anagrelide hydrochloride at different doses

[0113]

Claims

1. A silica hydrogel composite comprising at least one active pharmaceutical ingredient, wherein the silica hydrogel composite is obtainable by mixing: a. non-active silica particles having a diameter < 100 pm, b. a silica sol having a solid content of 0.5 to 3 wt.%, and c. solid particles of at least one active pharmaceutical ingredient, wherein the solid particles of the active pharmaceutical ingredient have a diameter of < 300 pm, and wherein the active pharmaceutical ingredient is poorly water soluble or completely insoluble in water, wherein the silica hydrogel composite has a total solid content of 20 to 80 wt.%, the silica hydrogel composite comprises up to 75 wt.% of the non-active silica particles, and wherein the silica hydrogel composite is structurally stable and not flowing upon static storage, and shear-thinning when shear stress is applied by injection.

2. The silica hydrogel composite of claim 1, wherein, The silica sol has a solid content of 0.5 to 2 wt.%.

3. The silica hydrogel composite of claim 1, wherein, The non-active silica particles have a diameter in the range of 1 pm to 100 pm.

4. The silica hydrogel composite of claim 1, wherein, The non-active silica particles have a diameter in the range of 1 pm to 30 pm.

5. The silica hydrogel composite of claim 1, wherein, The non-active silica particles have a diameter in the range of 1 pm to 20 pm.

6. The silica hydrogel composite of claim 1, wherein, The silica sol comprises silica sol particles having a diameter < 100 nm.

7. The silica hydrogel composite of claim 1, wherein, The silica hydrogel composite has a total solid content of 30 to 60 wt.%.

8. The silica hydrogel composite of claim 1, wherein, The silica hydrogel composite has a total solid content of 35 to 55 wt.%.

9. The silica hydrogel composite of claim 1, wherein, The silica hydrogel composite further comprises active silica particles containing 0.1 to 70 wt.% of the active pharmaceutical agent.

10. The silica hydrogel composite of claim 1, wherein, The silica hydrogel composite further comprises active silica particles containing 0.3 to 50 wt.% of the active pharmaceutical agent.

11. The silica hydrogel composite of claim 1, wherein, The silica hydrogel composite further comprises active silica particles containing 1 to 20 wt.% of the active pharmaceutical agent.

12. The silica hydrogel composite of claim 1, wherein, The silica is an alkoxysilane derivatized silica.

13. The silica hydrogel composite of claim 1, wherein, The silica is a tetraethoxysilane derivatized silica.

14. 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 molded or cast silica monoliths, as-is or comminuted.

15. The silica hydrogel composite of claim 1, wherein, The solid particles of the active pharmaceutical ingredient are selected from the group consisting of particles prepared by: direct synthesis and / or precipitation; crystallization methods or supercritical fluid technology for small particles; dissolution-precipitation cycles or dissolution-crystallization cycles; spray-drying or freeze-drying; mechanical methods for reducing the size of solid substances; granulation methods starting from sub-micron particles.

16. The silica hydrogel composite of claim 1, wherein, The solid particles of the active pharmaceutical ingredient are particles prepared by controlled expansion of supercritical solutions.

17. The silica hydrogel composite of claim 1, wherein, The solid particles of the active pharmaceutical ingredient are selected from the group consisting of particles prepared by: grinding, impacting and milling.

18. The silica hydrogel composite of claim 1, wherein, The solid particles of the active pharmaceutical ingredient are selected from the group consisting of particles prepared by: grinding with a mortar and pestle, wet-milling, pneumatic milling.

19. The silica hydrogel composite of any one of claims 1-18, wherein, The silica hydrogel composite is formulated into a preparation for administration of an active pharmaceutical ingredient.

20. The silica hydrogel composite of claim 19, wherein, The active pharmaceutical ingredient is anagrelide or any pharmaceutically acceptable salt thereof.

21. The silica hydrogel composite of claim 20, wherein, The pharmaceutically acceptable salt of anagrelide is hydrochloride.

22. The silica hydrogel composite of claim 19, wherein, The preparation is formulated for parenteral administration.

23. The silica hydrogel composite of claim 22, wherein, The preparation is formulated for administration by injection.

24. The silica hydrogel composite of claim 1, wherein, The silica hydrogel composite comprises 0.1-20% by weight of solid particles of the active pharmaceutical ingredient.

25. Use of a silica hydrogel composite according to any one of claims 1-18 in the manufacture of a medicament for the controlled delivery of an active pharmaceutical ingredient.

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