Silica hydrogel composite with a water soluble additive

Abstract

The present invention relates to a silica hydrogel composite, which is shear-thinning. The silica hydrogel composite comprises up to 85 weight-% of silica microparticles having a maximum diameter of ≤ 1 000 µm, combined with a silica sol which has a solid content of ≤5 weight-%. According to the invention, at least one water soluble additive having a solubility in water of at least 3 mg / ml, at pH 7, at 25 °C, is encapsulated in at least some of the silica microparticles.

Description

[0001] SILICA HYDROGEL COMPOSITE WITH A WATER SOLUBLE ADDITIVE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a silica hydrogel composite according to the preambles of the enclosed independent claims.

[0004] BACKGROUND OF THE INVENTION

[0005] Injectable delivery systems for active pharmaceutical ingredients (API) utilizing thin needles are an attractive option for controlled drug delivery. This is true especially for active pharmaceutical ingredients relying on sustained or long-acting release, e.g. small-molecule drugs, peptides, proteins, polypeptides, fusion proteins, mRNA, RNA aptamers, vaccine antigens, viral vectors, vaccine adjuvants, lipid nanoparticle-API combinations, and many more. Silica hydrogel composites have shown to be a platform technology that provides minimally invasive, injectable, controlled release and long-acting release material matrix. Silica hydrogel composites are applicable for many parenteral administration routes, e.g., subcutaneous, intramuscular, intra-articular, intravitreal and other intraocular routes, but also for topical administration, e.g., as eye drops or eye gels.

[0006] When dealing with a platform technology that can be applied for many different types of APIs, it is common that the APIs may affect the properties of material matrix in many ways, and different APIs, as well as varying API concentrations, can provide different effects when combined into the material matrix. Injectable silica hydrogel composites comprise silica microparticles of amorphous silica. When an API is encapsulated in the silica microparticle, the release rate of the API is mainly controlled by dissolution rate of the silica microparticle. APIs and their varying concentrations may influence the properties of the silica microparticle and consequently the properties of silica hydrogel composites comprising such microparticles. Just mere presence of the API in the silica microparticle structure may change the structure of the silica microparticle, for example by making it more heterogeneous. The API and / or its concentration may also influence the surface properties of the silica microparticle. For example, the API may be directly present at the outer surface of the silica microparticle, or the API may have changed the surface roughness of the silica microparticle at the nanoscale. Thus, the surface charge, zeta potential and hydrophobicity / hydrophilicity of the silica microparticles may vary depending on the API encapsulated in the silica microparticle and / or its concentration.

[0007] The changes in surface properties of the silica microparticles may change the properties, which are important for the silica hydrogel composites, their manufacture and their properties, such as injectability. For example, the rheological properties of the silica hydrogel composite and its injectability through thin needles are strongly dependent on the surface properties of the silica microparticles present in the silica hydrogel composite. The varying surface properties of the silica microparticles may increase or decrease viscosity of the silica hydrogel, affect its storage stability, as well as storage modulus, loss modulus and gel stability. The surface properties of the silica microparticles may also affect the formation of the gel structure of the silica hydrogel composite, disturb it or even obstruct the hydrogel formation.

[0008] Consequently, there is a need to control and / or adjust the dissolution rate of the silica microparticles and the silica hydrogel composites comprising silica microparticles. Furthermore, there is a need to improve the compatibility of the silica microparticles with diverse active pharmaceutical ingredients. PCT / FI2024 / 050316 discloses an injectable composite depot, where at least one pharmaceutically nonactive additive encapsulated in the silica microparticles and / or present in the silica sol. The document discloses specifically a second additive selected from citric acid and its salts, which can be encapsulated in the silica microparticles.

[0009] WO 2014 / 207304 by Jokinen et al. discloses shear-thinning combined hydrogel compositions formed from spray-dried silica microparticles with encapsulated agents and silica sols. The specific challenges of APIs or their different concentrations, and their effects on the properties of the injectable silica hydrogel composites, or use of specific additives are not addressed.

[0010] OBJECT AND SUMMARY OF THE INVENTION An object of this invention is to minimise or possibly even eliminate the disadvantages existing in the prior art.

[0011] One object of the present invention is a silica microparticle with adjustable and / or controllable dissolution rate.

[0012] A further object of the present invention is to provide a silica hydrogel composite with improved and / or controllable release properties, enabling incorporation various active pharmaceutical ingredients and / or biologically active agents in the silica hydrogel composite.

[0013] These objects are attained with the invention having the characteristics presented below in the characterising parts of the independent claims.

[0014] Some preferred embodiments of the invention are presented in the dependent claims.

[0015] The embodiments mentioned in this text relate, where applicable, to all aspects of the invention, even if this is not always separately mentioned. Especially, all features, advantages and embodiments fully apply both to the silica microparticle as well as to the silica hydrogel composite, if not explicitly stated otherwise.

[0016] A typical silica microparticle has

[0017] - a maximum diameter of <1000 pm, and

[0018] - a solid structure of amorphous silica, wherein at least one water soluble additive having a solubility in water of at least 3 mg / ml, at pH 7, at 25 °C, is encapsulated into the solid structure of the silica microparticle.

[0019] A typical silica hydrogel composite according to the present invention is shearthinning and comprises a) up to 85 weight-% of silica microparticles having a maximum diameter of < 1 000 pm, combined with b) a silica sol which has a solid content of <5 weight-%, wherein at least one water soluble additive having a solubility in water of at least 3 mg / ml, at pH 7, at 25 °C, is encapsulated in at least some of the silica microparticles.

[0020] A typical use of the silica hydrogel composite according to the present invention is for an injectable formulation.

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 illustrates the dissolution rate of silica from the silica microparticles comprising both tirzepatide and trehalose in different concentrations.

[0023] Figure 2 illustrates the release rate of tirzepatide from the silica microparticles comprising both tirzepatide and trehalose in different concentrations.

[0024] Figure 3 illustrates the dissolution rate of silica from the silica microparticles comprising tirzepatide in different concentrations.

[0025] Figure 4 illustrates the release rate of tirzepatide from the silica microparticles comprising tirzepatide in different concentrations.

[0026] Figure 5 illustrates the dissolution rate of silica from the injectable silica hydrogel composites comprising the silica microparticles with different tirzepatide and trehalose concentrations.

[0027] Figure 6 illustrates the release rate of tirzepatide from the injectable silica hydrogel composites comprising the silica microparticles with different tirzepatide and trehalose concentrations.

[0028] Figure 7 illustrates the measured injection force of injectable silica hydrogel composites comprising tirzepatide with or without 5% load of water soluble additives. Figure 8 illustrates the measured injection force of injectable silica hydrogel composites comprising tirzepatide with or without 2% load of water soluble additives.

[0029] Figure 9 illustrates the measured injection force of injectable silica hydrogel composites comprising tirzepatide (20% load or 30% load) with or without 5% load of arginine.

[0030] Figure 10 illustrates in vitro daily release of both tirzepatide and silica in flow-through dissolution from injectable silica hydrogel composite comprising tirzepatide without water soluble additive.

[0031] Figure 11 illustrates in vitro daily release of both tirzepatide and silica in flow-through dissolution from injectable silica hydrogel composite comprising tirzepatide and methionine.

[0032] Figure 12 illustrates in vitro daily release of both tirzepatide and silica in flow-through dissolution from injectable silica hydrogel composites comprising tirzepatide and trehalose in separate microparticles.

[0033] Figure 13 illustrates dose adjusted pharmacokinetic profile of Formulation 6-1 (Silica-Tirzepatide 30%), Formulation 6-4 (Silica-Tirzepatide 30%-Asp 1 %), Formulation 6-6 (Silica-Tirzepatide 30%-Met 2%), Formulation 6-8 (Silica- Tirzepatide 30%-His 2%) and intravenous 1 mg / kg tirzepatide (Tirzepatide 1 mg / kg i.v.).

[0034] DETAILED DESCRIPTION OF THE INVENTION

[0035] Now it has been surprisingly found that a silica microparticle has significantly improved properties, especially when it forms a part of silica hydrogel composite, when it has an additive with relatively high or high water solubility encapsulated into its structure. Citric acid and its salts are preferably excluded from water soluble additives. When the silica microparticle comprises at least one water soluble additive which has a higher solubility in water, and preferably also in body fluids, than the amorphous silica, the surface properties of the silica microparticle and its dissolution behaviour are changed in a manner that could not earlier envisioned. It is assumed, without wishing to be bound by a theory, that the water soluble additive changes the structure of the silica microparticle, leading inter alia to an increase in the dissolution rate of the silica microparticle. In case the silica microparticle comprises also an active pharmaceutical ingredient (API), its release rate is simultaneously affected, because the API release is mainly dependent on the dissolution rate of silica. This means that the encapsulation of the water soluble additive to the silica microparticle structure provides simple and unexpectedly effective way to tailor-made the dissolution properties of the silica microparticle. Further, when a silica hydrogel composite comprises such silica microparticles, the dissolution properties of the silica hydrogel composite can be surprisingly controlled and / or adjusted, as explained below, especially in vivo. The present invention may even facilitate the use of silica microparticles not only in silica hydrogel composites, but also in suspensions, non-silica based hydrogels or composites comprising two or more solid phases, such as implants.

[0036] According to the present invention, when the silica microparticles comprising at least one water soluble additive are encapsulated into a silica hydrogel composite, it possible not only to adjust the dissolution rate of the silica and the release rate of the possible active pharmaceutical ingredient, but also control and adjust the rheological properties, injectability and / or gel formation of the silica hydrogel composite. This may enable incorporation or encapsulation of completely new active pharmaceutical ingredients into the silica hydrogel composite or use of new encapsulation levels of active pharmaceutical ingredients, either higher or lower than previously imagined.

[0037] Definitions and Terms

[0038] In the present context, the viscoelastic properties of the materials, such as sols and gels, are defined and measured with a rheometer by the oscillatory shear, where shear stresses are small (small angles of deformation). Any rheometer capable of determining the correlation between deformation, shear stress and time can be used. The total resistance in small oscillatory shear is described by the complex modulus (G*). The complex modulus G* contains two components:

[0039] 1 ) elastic modulus, also called storage modulus, G’ that describes that material has some elastic properties that are characteristic for a solid material, i.e., the gel system will gain energy from the oscillatory motion as long as the motion does not disrupt the gel structure. This energy is stored in the sample and is described by elastic modulus; and

[0040] 2) viscous modulus, also called loss modulus, G” that describes flow properties, i.e., a system, e.g. a silica sol, that will in an oscillatory shear create motion between the ingredients of the sol describing the part of the energy, which is lost as viscous dissipation.

[0041] When G*=G’ the material is called elastic and when G*=G” the material is called viscous. When G’>G”, the material is called semi-solid, i.e. non-flowing at rest, and correspondingly when G”>G’, the material is called semi-liquid. The magnitude of the elastic modulus and viscous modulus depends on the shear stress, which depends on the applied strain (small angle deformation) and frequency (of the oscillatory shear). The measurements are conducted by ensuring an adequate signal for a specific measuring system, i.e., a strain sweep is commonly done at constant frequencies to find a proper signal and a linear viscoelastic region for the rheometer and then the actual measurements are done at constant strain with varying frequency. The varying frequencies give varying elastic and viscous modulus and the measurement shows whether the solid or liquid phase dominates.

[0042] In the present context, the term linear viscoelastic region refers to a measurement which is carried out employing small oscillatory shear selecting the strain (deformation) so that the material is not at all, or only minimally, disrupted. To determine the linear viscoelastic region, a strain sweep test at constant frequency is done by increasing the amplitude incrementally. The maximum strain to be used in the oscillatory measurements conducted within the linear viscoelastic region is preferably selected so that the elastic modulus G’ decreases less than 5 % compared with the elastic modulus G’ at the lowest amplitude in the sweep. Gel should be understood in the present context to be a homogeneous mixture of at least one solid phase and at least one liquid phase, preferably one liquid phase, where solid phase forms the continuous phase and the liquid phase is homogeneously dispersed in the continuous phase. The gel is viscoelastic and the elastic properties dominate, which is indicated by rheological measurements under small angle oscillatory shear when the elastic modulus, G’ is greater than the viscous modulus, G”. In the present context, typically G’ is <210 x G”; and often G’ is >5 - 100 x G”. In the context of the present invention, the gel denotes hydrogel (see below), where the continuous phase comprises silica as such, silica as partly hydrolysed and / or silica as fully hydrolysed. Silica as such, silica as partly hydrolysed and / or silica as fully hydrolysed is the major component of the continuous solid phase.

[0043] The hydrogel should be understood to be a gel, where the liquid phase is water or where the liquid phase is water-based. The liquid phase of the hydrogel comprises more than 50 weight-% of water, calculated from the total weight of the liquid phase. Preferably the liquid phase of the hydrogel comprises >65 weight-% or >80 weight- %, more preferably >90 weight-% and even more preferably >97 weight-% of water. The liquid phase can additionally comprise small amounts of other liquids, typically organic solvents, such as ethanol. Typically the concentration of organic solvents, e.g. ethanol, is <10 weight-%, more preferably <3 weight-% and even more preferably <1 weight-%, calculated from the total weight of the liquid phase. In the present context the silica hydrogel composite is considered to be a hydrogel since it fulfils the basic criteria of a hydrogel. The silica hydrogel composite may comprise 25 - 90 weight-% or 25 - 80 weight-%, preferably 40 - 70 weight-%, more preferably 45 - 60 weight-% of water.

[0044] Shear-thinning in the present context denotes a rheological property of the silica hydrogel composite. The silica hydrogel composite of the present invention is shearthinning. Whenever the shear stress or shear rate of such a silica hydrogel composite is altered, the silica hydrogel composite will gradually move towards its new equilibrium state. At lower share rates the shear-thinning silica hydrogel composite is having a higher viscosity, and at higher shear rates the viscosity is lower. Thus shear-thinning refers to an effect where the viscosity of the silica hydrogel composite, i.e. the measure of its resistance to flow, decreases with an increasing rate of shear stress and shear rate. For example, shear-thinning indicates clearly decreasing dynamic viscosity with increasing shear rate, e.g. 10-500-fold decrease or 10-100-fold decrease in dynamic viscosity with 100-fold increase in the shear rate. When the shear stress ends, e.g. after injection with the thin needle, the injectable silica hydrogel composite becomes again a gel, non-flowing and the elastic modulus G’ is larger than the viscous modulus G”.

[0045] Injectable Gel in the present context describes a rheological property of the silica hydrogel composite. The silica hydrogel composite of the invention is an injectable gel. Before injection, e.g. as stored in a syringe or in an autoinjector, or as the syringe or autoinjector is further placed in an aluminium foil, at temperatures <37 °C, e.g., at room temperature of 20 - 25 °C, or at refrigerator temperature of at 4 - 8 °C, the silica hydrogel composite is a gel, i.e., the elastic modulus G’ (measured under small angle oscillatory shear) is greater than the viscous modulus G”. Preferably G’ is <10x G”. For example, G’ is <1500 kPa, typically <1200 kPa or <1000 kPa, more typically <800 kPa, sometimes even <700 kPa or <100 kPa. When a shear stress is applied on the injectable silica hydrogel composite, e.g. by injecting from a syringe through a thin needle, e.g., 18-30G (the outer diameter of 30G is 0.312 mm, the inner diameter varies, it is usually <0.159 mm; the outer diameter of 18G is 1.27 mm, the inner diameter varies, it is usually <0.84 mm), it turns into a flowing form, which is indicated in a shear-thinning behaviour in rotational measurements with a rheometer.

[0046] The sol should be understood to be a homogeneous mixture of at least one liquid phase and at least one solid phase, i.e., a colloidal dispersion, or a colloidal suspension, where the liquid phase is the continuous phase, and the solid phase(s) are homogenously dispersed in the said liquid phase. Sol has clear flow properties and the liquid phase is dominating. In a silica sol, the liquid phase comprises mainly water, and optionally small amounts of ethanol and residuals of silica precursors. The solid phase(s) in a silica sol comprise colloidal nanoparticles of silica, partly or fully hydrolysed silica, nanoaggregates and / or nanoagglomerates of said nanoparticles and any combinations thereof. Nanoaggregates or nanoagglomerates of silica nanoparticles may comprise two, three, four or more silica nanoparticles associated together to form a cluster. The term so / refers to a colloidal dispersion where the solid particles, solid nanoaggregates and / or solid nanoagglomerates typically have a particle size <200 nm, quite often <100 nm or <50 nm.

[0047] The term suspension in the present context refers to a dispersion, where a liquid phase is the continuous phase and the solid particles are homogeneously dispersed in the said liquid phase, wherein the solid particles have a particle size >1 pm.

[0048] When R-value is defined or given in the present context, especially in the examples, it indicates the water-to-alkoxide molar ratio of the recipe for a silica composition. Silica compositions may also be expressed with 2 R-values, e.g., R6-50, where the number 6 indicates the initial molar ratio (“first R value”) that is used, and the number 50 (“second R-value”) indicates the total molar water-to-alkoxide ratio after addition of extra water (or other liquid, such as ethanol or water-ethanol mixture in the same volume that would correspond to the volume of water needed for water-to-alkoxide ratio 50) during some stage of the preparation. The R-value is usually between 1 and 500. R-values between 2 and 250 are typical first and second R-values when preparing silica microparticles from primary silica sols. Higher R-values, such as R- values between 300 and 400 are typical, when the silica sol is mixed with the readymade silica microparticles to form a silica hydrogel composite. The ready-made silica microparticles, e.g. as a suspension or as a dry powder, can also be mixed with the silica sol in portions in a number of successive steps. For example, one portion of silica microparticles at time is mixed with the silica sol until the final desired silica microparticle amount is achieved. The silica sol may initially have a lower R- value, and it can be increased to the final value, e.g., to R400 in the end. For example, the molar water-to-tetraethyl orthosilicate, TEOS (also called tetraethoxy silane or silicon tetraethoxide) ratio of 400 (R400) corresponds to ca. 0.82 weight- % of silica in the resulting silica sol.

[0049] The term sol-gel transfer in the present context refers to a process where a sol turns to a gel. A typical example on a preparation process comprising a sol-gel transfer is when silica or other corresponding materials, such as TiO2 and ZrO2, are synthesised from liquid phase precursors, for example alkoxides, such as tetraethyl orthosilicate (i.e. tetraethoxy silane / silicon tetraethoxide); alkylalkoxides; aminoalkoxides; or inorganic precursors, such as silicate solutions, e.g., sodium silicates. The liquid phase precursors form after hydrolysis and condensation first particles, which turn the system to a sol, after which the particles aggregate, agglomerate and / or grow in size, and the sol turns into a gel either spontaneously (usually in acidic sols) or by induced changes, such as pH change or salt addition (usually in alkaline sols). Alternatively, the sol-gel transfer may occur for ready-made silica powders or other ceramic powders, such as oxide powders, e.g. SiC>2, TiO2, ZrO2, AI2O3. The powders may have been prepared by any method; also mined powders can be used as such or as modified, e.g. as ground and washed. The solgel transfer for the ready-made powders is possible especially for colloidal powders of particles with diameter ca. 5 pm or less, for example with a diameter of 1 - 5 pm or even smaller. When the colloidal powder is mixed with a liquid, e.g. water, it can form a stable suspension, i.e., a sol and it may spontaneously form a gel as the particles are hydrolysed in water and at least partial condensation of hydroxyl groups and / or particle aggregation occur(s), or the suspension can be further flocculated / coagulated to a gel, e.g. by adjusting pH and / or adding salt and / or other substances that affect the stability, such as other liquids or an additional silica sol.

[0050] Gel point shall be understood to mean the time point when a sol or a suspension that is flowing turns to a gel that is viscoelastic and where the elastic properties dominate, as defined above. At the gel point, the elastic modulus G’ becomes larger than the viscous modulus G”. The elastic modulus may increase fast after the gel point when the surrounding conditions are not significantly changed, e.g. 100-700 fold increase in elastic modulus G’ within few minutes after the gel point may be seen for gels formed from acidic sols near room temperature, e.g. for a R15 sol at pH=2 that turns to a gel, or when a mixture of a silica sol and silica microparticles turns into a gel, e.g. at pH 5 - 7. For larger R-values, such as R150 and R400, the elastic modulus G’ remains on a low level even after the gel point and increase of elastic modulus G’ is not fast, which makes it possible to have gel structures that remain injectable with thin needles. Before the gel point a steep increase in dynamic viscosity and elastic modulus may be observed, which continues after the gel point as the structure is developing. The gel point of the silica hydrogel composite has been reached prior to obtaining the injectable silica hydrogel composite.

[0051] Injectable means, in the present context, parenteral administration via a surgical administration apparatus, e.g., syringe or autoinjector with a needle, a catheter, or a combination of these.

[0052] Silica microparticles refer in the present context to particles of silica prepared by spray drying or by liquid phase synthesis, by chopping spun or drawn silica fibres, by moulding or casting silica monoliths and, when necessary for obtaining defined particle size, by crushing moulded or cast silica monoliths. In the present context liquid phase synthesis refers to e.g. emulsion polymerisation, sol-gel transfer or molecular self-assembly. Preferably silica microparticles comprise or consist of solgel derived silica.

[0053] The term sol-gel derived silica refers to silica prepared by the sol-gel process wherein the silica is prepared from liquid phase precursors, such as alkoxides, alkylalkoxides, aminoalkoxides or inorganic silicate solutions, which by hydrolysis and condensation reactions form a sol that turns to a gel or forms a stable sol. The liquids in the stable silica sol can be evaporated, which results in the formation of a powder consisting typically of colloidal silica microparticles. The resulting gels / particles can be optionally aged, dried and heat-treated and if heat-treated, preferably below 700 °C. The sol-gel derived silica prepared below 700 °C is commonly amorphous. The sols can be let to gel in a mould for form-giving. The solgel derived silica can also be prepared by processing to different morphologies by simultaneous gelling, aging, drying and form-giving, e.g. by spray-drying to silica microparticles, by dip / drain / spin-coating to films, by extrusion to monolithic structures or by spinning to fibres.

[0054] Silica refers in the present context to amorphous silica as such, amorphous silica which contains water, fully or partly hydrolysed amorphous silica, silica in water- dissolved form, such as silicic acid, or any mixtures of these. Active pharmaceutical ingredient, API, refers to any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body. In the present context the terms “active pharmaceutical ingredient” and “pharmaceutically active agent” are used synonymously and they are wholly interchangeable with each other.

[0055] Biologically active agent in the present context refers to any organic or inorganic agent that is biologically active, i.e. induces a statistically significant biological response in a living tissue, organ or organism. The biologically active agent can be selected from medicines, small-molecule drugs, proteins, fusion proteins, peptides, peptidomimetic molecules, and polynucleotides, e.g. DNA and RNA. The biologically active agent can be in a free acid or base form, a salt or a neutral compound. A biologically active agent can be for treatment of diseases in therapeutic areas like alimentary / metabolic, blood and clotting, cardiovascular, dermatological, genitourinary, hormonal, immunological, infection, cancer, musculoskeletal, neurological, parasitic, ophthalmic, respiratory and sensory. A biologically active agent can further be for treatment of diseases like osteoporosis, epilepsy, Parkinson’s disease, pain and cognitive dysfunction. A biologically active agent can be for the treatment of hormonal dysfunction diseases or for hormonal treatment e.g. for contraception, hormonal replacement therapy or treatment with steroidal hormones. A biologically active agent can further be an antibiotic or antiviral, anti-inflammatory, neuroprotective, prophylactic vaccine, memory enhancer, analgesic (or analgesic combination), immunosuppressant or antidiabetic. A biologically active agent can be an antiasthmatic, anticonvulsant, antidepressant, antidiabetic, or antineoplastic. A biologically active agent can be an antipsychotic, antispasmodic, anticholinergic, sympathomimetic, antiarrhythmic, antihypertensive, or diuretics. A biologically active agent can be for pain relief or sedation. A biologically active agent can be a tranquilliser or a drug for cognitive dysfunction. Encapsulated agents should be understood to be drugs, active pharmaceutical ingredients (APIs) or other therapeutically and / or biologically active agents, or delivery device, which is / are encapsulated into the silica microparticles of the silica hydrogel composite or which is / are incorporated in the structure of the silica microparticles, i.e. present inside the silica microparticle and on the surface of the silica microparticle. In the present context, the terms “encapsulated” and “incorporated” are used synonymously and they are fully interchangeable.

[0056] The burst, initial burst or burst release should be understood to be the amount of the encapsulated agent as defined above released (in / into tissue, tissue / body fluids, simulated body / physiological / tissue fluids) in the beginning of the release. Depending on the context, i.e. whether release continues for minutes, hours, days, weeks, months or years, burst can be considered to occur during minutes (or even less), hours, weeks or even up to a few weeks. Release of the encapsulated agent is typically considered burst release if the release is 10 % or more of the total release within a time period of 3 % or less, preferably 1 % or less, of the time period of the total release.

[0057] Water soluble additive in the present context refers to any functional, pharmaceutically non-active, ingredient, which improves, adjusts or controls the in vivo release rate of an active pharmaceutical ingredient (API) or other therapeutic or biologically active agent, when encapsulated or incorporated in the silica microparticle. Citric acid and its salts are preferably excluded from water soluble additives. The water soluble additive is non-silica based or non-silica containing substance, compound or ingredient. The water soluble additive does not preferably show, exhibit or demonstrate pharmaceutical or therapeutical activity against any medical condition. The water soluble additive is encapsulated in the silica microparticle, i.e. incorporated into the structure of the silica microparticle, which means that it is present inside the silica microparticle and on the surface of the silica microparticle. Water soluble additive has a solubility in water of at least 3 mg / ml, at pH 7, at 25 °C. Saccharide in the present context denote any carbohydrate comprising one monosaccharide unit or two or more monosaccharide units linked together. Saccharides comprise monosaccharide, disaccharides, oligosaccharides and polysaccharides, as well as any of their derivatives. Saccharides can be linear or branched.

[0058] Dissolution rate in the present context refers to a rate or speed at which a substance, such as amorphous silica, a water soluble additive or an active pharmaceutical ingredient, dissolves in a surrounding medium. The surrounding medium may be a human body fluid or a buffer that simulates typical human body fluid temperature and pH. The buffer simulating the human body fluid may also comprise typical human body fluid salts in typical human body fluid concentrations. The dissolution rate may also be measured in sink conditions, where the substance can freely dissolve, i.e., the dissolution product of the dissolving substance does not retard the dissolution rate. The in sink conditions may be achieved by refreshing the surrounding medium regularly or by using a flowing system for the surrounding medium. There may also be additives in the buffer simulating the human body fluid, such as surfactants, which ensure free dissolution of rate of the substance, e.g., of an active pharmaceutical ingredient, in sink conditions. The dissolution rate may also be called release rate, especially when referring to active pharmaceutical ingredients.

[0059] In the present context solid content refers to the proportion of non-volatile material contained after the volatile solvent(s) has vaporized. More particularly it can refer to the solid content of the silica sol used to obtain the silica hydrogel composite or solid content of the silica hydrogel composite comprising at least silica microparticles and silica sol.

[0060] In the present context, when the silica hydrogel composite comprises a particular weight per cent (weight-%) of silica microparticles, then the weight-% is calculated from the total weight of the silica hydrogel composite, i.e. from the amount of silica microparticles and silica sol used to obtain the silica hydrogel composite. Thus, if e.g. 100 g of silica microparticles is mixed with 900 g of silica sol, then the weight- % of silica microparticles in the silica hydrogel composition is 10 weight-%. If the silica hydrogel composite is obtained by first preparing a suspension of the silica microparticles, then the percentage is calculated from the original weight of the silica microparticles in comparison to the final total weight of the silica hydrogel composite, which is then the weight of the silica microparticles + the weight of liquid used to make a suspension of the silica microparticles + the weight of the silica sol.

[0061] Features of the Invention

[0062] The gist of the present invention is that when a water soluble additive is encapsulated in the silica microparticle, it becomes possible to adjust or fine-tune one or several properties of the said silica microparticle as well as the properties of the injectable silica hydrogel composites comprising the said silica microparticles. It is assumed, without wishing to be bound by any theory, that the water soluble additive may influence the structure, such as shape and size, of the nanoparticles or nanoagglomerates of the primary sol from which the silica microparticle is formed. This may influence the Si-OH groups of the silica microparticle, especially the Si- OH groups on the surface of the silica microparticle. The water soluble additive may thus influence the surface properties of the silica microparticle, such as hydrophobicity and / or change the zeta potential of the silica microparticle. The water soluble additive may also increase the heterogeneity of the structure of the silica microparticle. It is assumed that the water soluble additive thus influences the degree and speed of dissolution of the silica microparticle, and even control or adjust the release rate of a possible API from the silica microparticle and consequently from the silica hydrogel composite. The water soluble additive can even improve the storage stability of the silica microparticles, for example by minimising the changes in dissolution rate. For example, in manufacture of silica hydrogel composites, the silica microparticles are an intermediate product, which might be stored for at least some weeks before it is used in the preparation of the silica hydrogel composite. It has been observed that the presence of at least one water soluble additive encapsulated in the silica microparticle is able to decrease the change in the dissolution rate during storage and also to decrease the batch-to-batch variation. The water-soluble additive thus enables better control of the aging of the particles. This makes the manufacturing process more reproducible i.e. reduces variation between drug product batches and / or reduces variation between drug products within batch.

[0063] The silica microparticle has a solid structure formed of amorphous silica. The amorphous silica has a solubility in water about 100 - 150 ppm, at pH 7, at 25 °C, as well as in the body fluid conditions (pH 5 - 8, at 37 °C). The silica microparticles may be selected from the group consisting of spray dried silica microparticles, silica fibre fragments, and moulded or casted silica monoliths as such or as crushed. The silica microparticles are preferably spray dried silica microparticles, prepared by spray drying of a primary silica sol. The solid phase of the primary silica sol used for the spray-drying comprises silica nanoparticles and silica nanoparticle agglomerates. The water soluble additive is dissolved in the primary silica sol before spray-drying and thus becomes encapsulated in the formed silica microparticle. When the silica microparticle comprises an active pharmaceutical ingredient, the active pharmaceutical ingredient is also mixed as small particles into the primary silica sol or dissolved into the primary silica sol before spray drying. The concentration of the water soluble additive and the possible at least one API can be selected according to the need, such as desired silica microparticle properties, the potency of the used API, and / or due to the desired dissolution / release time.

[0064] The silica microparticles are preferably spherical, ellipsoidal, oblate spheroidic or prolate spheroidic in shape. The silica microparticles have a maximum diameter of <1000 pm, preferably <700 pm, more preferably <500 pm, even more preferably <300 pm or <100 pm. The silica microparticles may have the maximum diameter in a range of 1 - 300 pm, preferably 1 - 100 pm, more preferably 1.5 - 30 pm even more preferably 1.5 - 20 pm. The silica hydrogel composite comprises silica microparticles. The silica hydrogel composite comprises at least 90 weight-%, preferably at least 95 weight-%, sometimes at least 97 weight-% or at least 99 weight-%, of the silica microparticles having the maximum diameter in a range of 1 - 300 pm, preferably 1 - 100 pm, more preferably 1 .5 - 30 pm even more preferably 1.5 - 20 pm. Particle size can be measured by using laser diffraction. Maximum diameter describes the maximum length of a straight line drawn from outer surface to outer surface that goes through the geometrical centre of the silica microparticle. The solid structure of the silica microparticles is typically dense, i.e. the silica microparticles have a specific surface area <10 m2 / g, preferably <7 m2 / g, more preferably <5 m2 / g. The specific surface area of the silica microparticles may be in a range of 1 - 10 m2 / g, preferably 1.5 - 7 m2 / g, more preferably 2 - 5 m2 / g. The solid structure of the silica microparticles may comprise pores, and the pore size is typically <2 nm, even <1 nm. The specific surface area is measured by gas sorption using nitrogen and krypton, i.e., gas adsorption and desorption isotherms have been used to measure the specific surface area (by BET method) and the pore size distribution according to methods described in ISO 15901 -2:2022. The small specific surface area and small pore size means that the silica microparticles have a dense structure, where the measured specific surface area mainly correlates with the outer surface of the silica microparticle. For the dense silica microparticles, the release rate of possible encapsulated active pharmaceutical ingredients is primarily dependent on the dissolution rate of the silica at the outer surface of the silica microparticle, and is not primarily dependent on pore size of the silica microparticle.

[0065] According to the present invention the silica microparticle comprises at least one water soluble additive having a water solubility of at least 3 mg / ml, at pH 7, at 25 °C, encapsulated in the silica microparticle. Preferably the water soluble additive having the solubility in water of at least 5 mg / ml, more preferably at least 30 mg / ml, even more preferably at least 50 mg / ml, at pH 7, at 25 °C, is used. The at least one water soluble additive may have a very high solubility in water, for example, at least 100 mg / ml, or at least 500 mg / ml, even at least 1000 mg / ml or at least 2000 mg / ml, at pH 7, at 25 °C. In principle, the water soluble additive can have as high solubility as possible. Often the solubility may be in a range of 3 - 3000 mg / ml, or 30 - 2500 mg / ml, or 50 - 2000 mg / ml, at pH 7, at 25 °C. The incorporation of the water soluble additive into the dense silica microparticle affects properties of the silica microparticle, especially its surface properties, as well as the properties of the silica hydrogel composite comprising the said silica microparticles, such as rheology and injectability. More precisely, the water soluble additive is selected so that it can provide a long-acting, controlled release dosage form. According to one preferable embodiment the silica microparticles comprising at least one water soluble additive are combined, i.e. mixed, with a silica sol to form a silica hydrogel composite, which is shear-thinning. The silica hydrogel composite comprises up to 85 weight-%, preferably up to 80 weight-%, more preferably up to 75 weight-%, of the silica microparticles, calculated from the total weight of the silica hydrogel composite. According to one preferable embodiment the silica hydrogel composite may comprise 10 - 85 weight-% or 20 - 85 weight-%, preferably 25 - 80 weight-%, more preferably 30 - 75 weight-% or 40 - 70 weight-%, of the silica microparticles, calculated from the total weight of the silica hydrogel composite. At least some, alternatively all, of the silica microparticles of the silica hydrogel composite comprise the water soluble additive.

[0066] Now it has been surprisingly found that the presence of the silica microparticles with at least one encapsulated water-soluble additive in the silica hydrogel composite enable the adjustment of the properties of the silica hydrogel composite in an unexpected manner. The silica microparticles with the water soluble additive can enhance the proper gel formation as well as the rheological properties of the silica hydrogel composite, even in the presence of active pharmaceutical ingredient(s). The proper gel formation is important with the respect of the stability and homogeneity of the silica hydrogel composite at rest (e.g., in storage). The rheological properties of the silica hydrogel composite preferably allow the injection through thin needles, which means that the silica hydrogel composite is shearthinning under shear, such as injection from a syringe or autoinjector through a thin needle, but non-flowing at rest, and has appropriate storage modulus and loss modulus. The water soluble additive encapsulated in the silica microparticles may adjust the shear-thinning properties of the hydrogel in a desired manner, make the gel formation easier, and / or increase or decrease the viscosity, storage modulus and / or loss modulus, of the silica hydrogel composite. This is advantageous especially when at least some of the silica microparticles comprise an active pharmaceutical ingredient having an unwanted effect on silica hydrogel formation or properties. For example, some active pharmaceutical ingredients or their concentrations may change the surface properties of the silica microparticles so much that the formation of the silica hydrogel composite becomes impossible or difficult, or the formed silica hydrogel composite is too loose or too stiff. Now the water soluble additive, encapsulated in the silica microparticle, can be used to compensate these adversary effects of the active pharmaceutical ingredient.

[0067] The silica hydrogel composite can be prepared by combining, i.e. mixing, the silica microparticles, as a suspension or as a dry powder, preferably as dry powder, with a silica sol with a solids content of <5 weight-%, preferably <3 weight-%, more preferably <1 weight-%. The solids content of the silica sol may be 0.6 - 5 weight- %, preferably 0.7 - 3 weight-%, more preferably 0.8 - 1 weight-%. The silica sol comprises mainly water and <5 weight-%, preferably <3 weight-%, more preferably <1 weight-%, of silica nanoparticles and nanoagglomerates of silica nanoparticles. For example, silica sol may comprise 0.6 - 5 weight-%, preferably 0.7 - 3 weight- %, more preferably 0.8 - 1 weight-% of silica nanoparticles and nanoagglomerates of silica nanoparticles, calculated from the total weight of the silica sol. The solid content of the silica sol thus essentially consists of silica nanoparticles and nanoagglomerates of silica nanoparticles. According to one embodiment, the silica sol may comprise silica nanoparticles and nanoagglomerates having a diameter in a range of 5 - 995 nm, preferably 50 - 900 nm, more preferably 50 - 800 nm or 55 - 800 nm.

[0068] According to one embodiment, the silica hydrogel composite can be prepared by combining, i.e. mixing, the silica microparticles, as a suspension or as a dry powder, with a silica sol in two or more portions in successive steps. For example, one portion of silica microparticles at time is mixed with the silica sol until the final desired silica microparticle amount is achieved. The silica sol may initially have a lower Revalue, and it can be increased to the final value, e.g., to R400 in the end.

[0069] The silica sol mixed with the silica microparticles for preparing the silica hydrogel composite is different from the primary silica sol, which is used for preparing the silica microparticles by spray-drying.

[0070] After mixing of the silica sol and the silica microparticles, the silica nanoparticles and nanoparticle agglomerates of the silica sol merge to the surface of the silica microparticles. This causes silica microparticles to create a network with each other, a continuous network, which leads to a formation of a silica hydrogel structure. This continuous network of the silica microparticles thus forms the continuous solid phase of the silica hydrogel composite. The continuous solid phase of the silica hydrogel composite comprises or consists of mainly of silica microparticles of amorphous silica. The liquid phase of the silica hydrogel composite comprises or consists of mainly water. The silica hydrogel composite may have a solid content in a range of 10 - 75 weight-% or 20 - 75 weight-%, preferably 30 - 60 weight-%, more preferably 40 - 55 weight-%.

[0071] The silica hydrogel composite is preferably injectable gel, as defined above. The silica hydrogel composite can be injected with thin needles from syringes or autoinjectors or it can be applied trough a catheter or hoses / tubings. The silica hydrogel composite is injectable, flowing and / or extrudable under shear, because it is shear-thinning. Thus, the viscosity of the silica hydrogel composite is substantially decreased due to shear stress during injection, and after injection when the silica hydrogel composite is no more exposed to shear stress, the non-flowing structure of the silica hydrogel composite is restored. According to one embodiment the silica hydrogel composite may have an elastic modulus measured under small angle oscillatory shear in a linear viscoelastic region <1500 kPa, typically <1200 kPa or <1000 kPa.

[0072] At least one water soluble additive having a solubility in water of at least 3 mg / l, at pH 7, at 25 °C, is encapsulated in at least some of the silica microparticles. Citric acid and its salts are preferably excluded from the water soluble additives of the present invention. For example, at least one water soluble additive may be encapsulated in at least 20 weight-%, preferably at least 40 weight-%, more preferably at least 60 weight-% or at least 80 weight-% of the silica microparticles of the silica hydrogel composite, calculated from the total weight of the silica microparticles in the silica hydrogel composite. The amount of silica microparticles comprising at least one water soluble additive may be in a range of 20 - 100 weight- %, or 40 - 99 weight-%, or 60 - 97 weight-%, or 80 - 95 weight-%, calculated from the total weight of the silica microparticles in the silica hydrogel composite. According to one embodiment the silica hydrogel composite may comprise at least one water soluble additive, encapsulated in the silica microparticles, in amount of <30 weight-% or <20 weight-%, preferably <15 weight-% or <10 weight-%, sometimes <5 weight-%, calculated from the total weight of silica in the silica hydrogel composite. For example, the silica hydrogel composite may comprise at least one water soluble additive, encapsulated in the silica microparticles, in amount of in range of 0.01 - 50 weight-% or 0.01 - 30 weight-%, preferably 0.03 - 20 weight- %, more preferably 0.05 - 15 weight-% or 0.07 - 10 weight-%, sometimes 0.1 - 5 weight-% or 0.1 - 3 weight-%, calculated from the total weight of the silica in the silica hydrogel composite.

[0073] The water soluble additive encapsulated in the silica microparticles is preferably pharmaceutically non-active additive.

[0074] According to one preferable embodiment of the present invention, the at least one water soluble additive, encapsulated in the silica microparticle, may be a saccharide selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, their salts and derivatives, and any mixtures thereof. For example, the at least one water soluble additive, encapsulated in the silica microparticle, may be a saccharide derivative selected from polyols, such as sorbitol. Preferably the salts and derivatives of the saccharides are pharmaceutically acceptable. The saccharides and especially their salts are preferable additives due to their good solubility in water, which makes them easy to encapsulate into the silica microparticles. The saccharides can be used as the water soluble additive for effectively adjust the surface properties of the silica microparticles, and especially the in vivo release rate and release profile of the silica hydrogel composites comprising the silica microparticles. The above-listed saccharides can also be used to adjust the gel formation, rheological properties and injectability of the silica hydrogel composite. Suitable monosaccharides may be selected, for example, from glucose, fructose, dextrose, galactose, or their mixtures. Suitable disaccharides may be selected from sucrose, trehalose, maltose, lactose, or their mixtures. Suitable oligosaccharides may be selected from melezitose, raffinose, or different broken down forms of polysaccharides, or any of their mixtures. Suitable polysaccharides may be selected from starch, cyclodextrin, hyaluronic acid, glycogen, chitin, chitosan, dextran with different molecular weights, cellulose, cellulose derivatives, or their mixtures. One example of possible polysaccharide is starch, modified starches, starch derivatives and any mixtures thereof. Starches, modified starches, and starch derivatives often have good solubility in cold water, which can be utilised in encapsulation into the silica microparticles.

[0075] The saccharide encapsulated into the silica microparticle may have a solubility in water at least 3 mg / ml or at least 5 mg / ml, preferably at least 10 mg / ml, more preferably at least 30 mg / ml, at pH 7, at 25 °C. The saccharide may have a solubility in water, which be in a range of 3 - 2500 or 5 - 2500 mg / ml, preferably 10 - 2000 mg / ml, more preferably 30 - 1500 mg / ml, at pH 7, at 25 °C. The monosaccharides and disaccharides have generally lower solubility than oligosaccharides and polysaccharides, but still significantly higher than the amorphous silica (about 0.13 mg / ml). For example, for some monosaccharides and disaccharides, the solubility in water may be 5 - 2000 mg / ml, or 10 - 1500 mg / ml, or 20 - 1000 mg / ml, or 30 - 700 ml / mg, at pH 7, at 25 °C. For some oligosaccharides and polysaccharides the solubility in water may be 500 - 2500 mg / ml, or 750 - 2000 mg / ml, or 800 - 1500 mg / ml, at pH 7, at 25 °C.

[0076] According to one preferable embodiment of the invention the at least one water soluble additive, encapsulated in the silica microparticle, may be selected from trehalose, cyclodextrin, hyaluronic acid, alginate, their salts and derivatives, and any of their mixtures. Even more preferably, the at least one water soluble additive, encapsulated in the silica microparticle, is trehalose. The amount of trehalose encapsulated in the silica microparticle may be 0.1 - 30 weight-%, preferably 0.2 - 20 weight-%, more preferably 0.5 - 10 weight-%, calculated from the total weight of silica in the silica microparticle.

[0077] According to one embodiment of the invention, the at least one water soluble additive, encapsulated in the silica microparticle, may be selected from B vitamins, C vitamin (ascorbic acid), their derivatives, salts and hydroxides, and any mixtures thereof. B vitamins and C vitamin have a water solubility which is at least 3 mg / ml or at least 5 mg / ml, at pH 7, at 25 °C. This means that B vitamins and C vitamins have a higher water solubility than amorphous silica, which forms the structure of the silica microparticle and solid phase of the silica hydrogel composite. This makes these vitamins capable of adjusting the dissolution properties and surface properties of the silica microparticle. B vitamins and C vitamin can also provide protection for active pharmaceutical ingredient, optionally incorporated in the silica microparticle. These vitamins have antioxidant properties, and can protect sensitive pharmaceutical ingredients from degradation. They may also prevent aggregation of biological drugs. When the silica microparticle forms a part of silica hydrogel composite, an additive selected from B vitamins and C vitamin can also adjust the in vivo release of the silica hydrogel composite in a tissue. Through modified surface properties of the silica microparticle, they can also improve the gel formation, rheological properties and injectability of the silica hydrogel composite.

[0078] According to one preferable embodiment, the water soluble additive may be selected from B vitamins. Any of the B vitamins, namely Vitamin Bi (thiamine); Vitamin B2 (riboflavin); Vitamins B3 including niacin (nicotinic acid), niacinamide and nicotinamide riboside; Vitamin Bs (pantothenic acid); Vitamins Be including pyridoxine, pyridoxal and pyridoxamine; Vitamin B7 (biotin), Vitamin B9 (folate), Vitamin B12 (cobalamins), can be used as the water soluble additive encapsulated in the silica microparticle. B vitamins having a solubility in water at least 10 mg / ml or more, preferably at least 12 mg / ml or more, preferably at least 25 mg / ml or more, are preferred. The solubility in water may be in a range of 10 - 200 mg / ml or 12 - 150 mg / ml, preferably 25 - 100 mg / ml, at pH 7, at 25 °C. For example, the solubility in water may be 15 - 50 mg / ml, at pH 7, at 25 °C.

[0079] According to one preferable embodiment, the at least one water soluble additive is selected from natural or synthetic B12 vitamin, their salts, hydroxide and any combinations thereof. The water soluble additive may thus be cobalamin or cyanocobalamin. According to one embodiment, the at least one water soluble additive is C vitamin (ascorbic acid), its salt, hydroxide or any combination thereof. The solubility of C vitamin, its salt, or hydroxide in water may be in a range of 250 - 500 mg / ml, or 300 - 400 mg / ml, at pH 7, at 25 °C. For example, the solubility in water may be 330 - 350 mg / ml, at pH 7, at 25 °C.

[0080] According to one embodiment, the at least one water soluble additive encapsulated in the silica microparticle may be selected from amino acids, such as arginine, aspartic acid, glutamic acid, lysine, proline, glycine, histidine, and methionine. Suitable amino acids may have a solubility in water at least 3 mg / ml or at least 5 mg / ml or at least 10 mg / ml or more, preferably at least 50 mg / ml or more. The solubility in water may be in a range of 5 - 2000 mg / ml or 10 - 2000 mg / ml, preferably 50 - 1500 mg / ml, at pH 7, at 25 °C. For example, the solubility in water may be 5 - 370 mg / ml or 13 - 370 mg / ml, at pH 7, at 25 °C. According to one embodiment, amino acids which are zwitterionic close to neutral conditions, i.e. at pH 5.5 - 7.5, are particularly suitable as the water soluble additive. Especially those amino acids having their isoelectric point pl in a pH range of 5.5 - 7.5 can be used to adjust the dissolution and surface properties of the silica microparticles. When the silica microparticles are then incorporated into silica hydrogel composite, the encapsulated amino acids then enhance the gel formation, rheological properties and the injectability of the silica hydrogel composite, as the hydrogel structure of the silica hydrogel composite is often formed at pH 5.5 - 7.5. Pharmaceutically acceptable amino acids are preferred.

[0081] According to one preferable embodiment of the invention at least one active pharmaceutical ingredient may be encapsulated in the silica microparticle, especially when the silica microparticle is used for the silica hydrogel composite. In the silica hydrogel composite at least one active pharmaceutical ingredient may be encapsulated at least some of the silica microparticles, or all of the silica microparticles. It is known that different active pharmaceutical ingredients have different effect on the properties of the silica microparticles. The properties of the silica microparticles can also be dependent on the concentration of the active pharmaceutical ingredient. For example, if the active pharmaceutical ingredient introduces chemical groups at the outer surface of the silica microparticle, the rheological properties may be different for the prepared silica hydrogel composite, or the active pharmaceutical ingredient may even disturb or prevent the gel formation. Now it has been surprisingly found that the encapsulation of a water soluble additive into the structure of the silica microparticle makes it possible to adjust, control or fine-tune the release rate of active pharmaceutical ingredient, in vitro and in vivo, through control of the dissolution rate of silica microparticles. When the silica hydrogel composite is injected into a tissue, the silica hydrogel composite takes usually a three-dimensional form, which is often nearly spherical or slightly ellipsoidal. Often the silica hydrogel composite has a three-dimensional form, which is spherical, ellipsoidal, oblate spheroidic or prolate spheroidic. The silica hydrogel composite dissolves mainly from the surface, and thus its geometrical form affects the dissolution of silica and release of the active pharmaceutical ingredient. When the silica hydrogel composite having a spherical or ellipsoidal form dissolves, the dissolution rate and the release rate of active pharmaceutical ingredient decreases when the three-dimensional structure becomes smaller. By incorporating water soluble additives in the silica microparticles, which form the continuous solid network of the silica hydrogel composite, it is possible to increase the permeability of the structure of the silica hydrogel composite. The dissolution of the water soluble additive may also affect how the physical form of the silica hydrogel composite is transformed during the dissolution process, as explained below. This increases the dissolution and release rates especially in vivo. The water soluble additives thus improve the properties needed for the long-acting, controlled release dosage forms.

[0082] According to one preferable embodiment both a water soluble additive and an active pharmaceutical ingredient may be encapsulated in the same silica microparticle.

[0083] When the silica hydrogel composite is injected into tissues, e.g., to subcutaneous tissue, intramuscular tissue or into the vitreous, it typically takes a nearly spherical or slightly ellipsoidal form, as noted above. The injected volume of the silica hydrogel composite may be in a range of 0.01 - 1.5 ml or 0.05 - 1.5 ml, preferably 0.07 - 1.25 ml, more preferably 0.1 - 1 ml. The in situ formed implant-like structure of silica hydrogel composite mainly dissolves from its surface or close to the surface only, although the structure is porous, due to the low solubility of amorphous silica. The pores and voids of injected silica hydrogel composite structure are mainly filled with water which is saturated with dissolution products of silica microparticles. Thus, silica cannot dissolve from silica microparticles located in the inner parts of injected silica hydrogel composite structure. Conventionally, the original nearly spherical or slightly ellipsoidal shape of the injected silica hydrogel composite structure is retained during the dissolution of the silica hydrogel composite, which means that the injected structure only decreases in size but does not change its shape. The continuous flow of body fluids in tissue around the injected structure is the main driving force for the dissolution of silica and for the release of the active pharmaceutical ingredient, and the flow proceeds easier at the surface of the injected silica hydrogel composite structure than through its structure. When the spherical, nearly spherical or slightly ellipsoidal three-dimensional injected structure dissolves from the surface, it has been observed that the rate of silica dissolution and release rate of the active pharmaceutical ingredient slows down as a function of time. This problem may now be solved, however, by encapsulation of a water soluble additive into at least some of the silica microparticle of the silica hydrogel composite. It is assumed that in tissue the water soluble additive is also able to dissolve from the inner parts of the injected silica hydrogel composite structure. When the water soluble additive is dissolving, it fractures the injected silica hydrogel structure effectively, and increases the possibility for the body fluids to permeate and flow through the injected silica hydrogel composite structure. The dissolution of the water soluble additive may also turn the nearly spherical or slightly ellipsoidal form to a flatter structure, which dissolves faster from the surface than a spherical structure. The water soluble additive may also affect the release profile, such as the geometry-dependent decrease in the dissolution.

[0084] In a silica hydrogel composite at least one active pharmaceutical ingredient may be encapsulated in at least some of the silica microparticles of the silica hydrogel composite. At least one active pharmaceutical ingredient may be encapsulated in at least 20 weight-%, preferably at least 40 weight-%, more preferably at least 60 weight-% or at least 80 weight-% of the silica microparticles of the silica hydrogel composite, calculated from the total weight of the silica microparticles in the silica hydrogel composite. The amount of silica microparticles having at least one active pharmaceutical ingredient encapsulated may be in a range of 20 - 100 weight-%, or 40 - 99 weight-%, or 60 - 97 weight-%, or 80 - 95 weight-%, calculated from the total weight of the silica microparticles in the silica hydrogel composite.

[0085] Alternatively, or in addition, the active pharmaceutical ingredient may be incorporated to the silica sol used for preparing the silica hydrogel composite.

[0086] At least one active pharmaceutical ingredient may be encapsulated in the silica microparticles in amount of 0.001 - 70 weight-% or 0.01 - 70 weight-%, preferably 0.1 - 50 weight-% or 0.3 -50 weight-%, more preferably 1 - 30 weight-%, calculated from the total weight of silica microparticle. In certain embodiments, the active pharmaceutical ingredient may be encapsulated in the silica microparticles in amount of 0.00001 - 15 weight-% or 0.00002 - 10 weight-%, preferably 0.0001 - 5 weight-% or 0.0003 - 3 weight-%, even 0.0005 - 0.9999 weight-%, calculated from the total weight of silica microparticle. The amount of the active pharmaceutical ingredient can be adjusted depending on the type, desired dosage and desired release period. Preferably, the amount of the active pharmaceutical ingredient encapsulated in the silica microparticle may be <50 weight-%, calculated from the total weight of silica microparticle. In higher concentrations, the silica microparticle structure may sometimes become heterogeneous and controllability of the release of the active pharmaceutical ingredient may become more difficult. In general, the concentration of the active pharmaceutical ingredient can vary from ingredient to ingredient, because the differences in the potency of the different active pharmaceutical ingredients. For example, some active pharmaceutical ingredients may provide desired long-acting release, such as 1 - 6 months release, already at concentration of 0.001 weight-%, calculated from the total weight of silica microparticles in the silica hydrogel composite, when the silica hydrogel composite comprises 20 - 50 weight-% of the silica microparticles. With another active pharmaceutical ingredients, the needed concentration in the same silica hydrogel composite formulation may be 40 - 50 weight-%, calculated from the total weight of silica microparticles in the silica hydrogel composite. The active pharmaceutical ingredient may be selected from a GLP-1 receptor agonist, a dual GIP / GLP-1 receptor agonist, a triple GIP / GLP-1 / GCG receptor agonist, and their pharmaceutically accepted salts. For example, the active pharmaceutical ingredient may be selected from a GLP-1 receptor agonist comprising liraglutide, semaglutide and their pharmaceutically accepted salts; a dual GIP / GLP-1 receptor agonist comprising tirzepatide and its pharmaceutically accepted salts; and a triple GIP / GLP-1 / GCG receptor agonist comprising retatrutide and its pharmaceutically accepted salts. According to one embodiment, the active pharmaceutical ingredient may be the dual GIP / GLP-1 receptor agonist, such as tirzepatide.

[0087] The active pharmaceutical ingredient may be selected from peptides, proteins, fusion proteins, vaccine antigens, mRNA-based drugs and small-molecule drug molecules having molecular weight of <1000 Da. Typically the molecular weight of the small-molecule drug molecule is 100 - 1000 Da. The active pharmaceutical ingredient may be a small-molecule drug molecule selected from ropivacaine, meloxicam, cariprazine, octreotide, or the active pharmaceutical ingredient may be protein or fusion protein, such as adalimumab. Further, it is possible that the active pharmaceutical ingredient may be selected from mRNA-based drugs or vaccine antigens, such as protein-based antigens or viral vectors. The silica microparticles may also comprise nanoparticles, such as lipid nanoparticles, which comprise the active pharmaceutical ingredient in the nanoparticle. The silica microparticles release the nanoparticles comprising the active pharmaceutical ingredient in a long- acting and / or controlled manner, and after their release the nanoparticles then releases the active pharmaceutical ingredient.

[0088] Silica hydrogel composite may comprise silica microparticles with an encapsulated water soluble additive and silica microparticles without an encapsulated water soluble additive. Alternatively, the silica hydrogel composite may consist of silica microparticles with an encapsulated water soluble additive. Furthermore, the silica hydrogel composite may comprise silica microparticles with an encapsulated active pharmaceutical ingredient and silica microparticles without an encapsulated active pharmaceutical ingredient. All combinations of these are also possible. The silica hydrogel composite may comprise silica microparticles with an encapsulated water soluble additive and an encapsulated active pharmaceutical ingredient as well as silica microparticles without an encapsulated water soluble additive and / or an active pharmaceutical ingredient. This versatility increases the possibilities to control and adjust the properties of the silica hydrogel composites.

[0089] The silica hydrogel composite may further comprise first silica microparticles with a first water soluble additive, second silica microparticles with a second water soluble additive, and any successive silica microparticles with any successive water soluble additives, wherein the first, the second and any successive water soluble additives are different from each other and / or present in different concentrations in the first, the second and any successive silica microparticles. This enables effective optimisation of the dissolution of silica microparticles and release of the active pharmaceutical ingredient and control of other properties of the silica hydrogel composite, e.g. rheology.

[0090] The silica hydrogel composite may further comprise first silica microparticles with a first active pharmaceutical ingredient, second silica microparticles with a second active pharmaceutical ingredient, and any successive silica microparticles with any successive active pharmaceutical ingredient, wherein the first, the second and any successive active pharmaceutical ingredients are different from each other and / or present in different concentrations in the first, the second and any successive silica microparticles.

[0091] Silica hydrogel composite may comprise silica microparticles without water soluble additive, as long as a water soluble additive is encapsulated in some of the silica microparticles of the silica hydrogel composite.

[0092] The water soluble additive, encapsulated in the silica microparticle, can also be used to the fine-tuning of the release profile of the silica hydrogel composite, especially in the later parts or near the end of the dissolution. This is important for a long-acting active pharmaceutical ingredients, especially in the repeated dose medication. When injections of the silica hydrogel composite comprising long-acting active pharmaceutical ingredient are repeated with a certain time intervals, it is not desired that excess residuals of the previous injection exist, when the next injection will be administered.

[0093] The water soluble additive encapsulated in the silica microparticle may even reduce the initial high release (initial burst) of the active pharmaceutical ingredient at the start of the in vitro or in vivo dissolution. The initial burst may be reduced to produce an even release profile or to provide a delayed release with little to no release of the active pharmaceutical ingredient directly after injection of the silica hydrogel composite. It is assumed that the reduction of the initial burst might follow two principles. First, the encapsulation of the water soluble additive in the silica microparticle can affect how much active pharmaceutical ingredient is encapsulated in the interior of the silica microparticles and how much remains on the surface. The active pharmaceutical ingredient encapsulated in the interior of the silica microparticle is released slower than the active pharmaceutical ingredient encapsulated or incorporated on the surface of the silica microparticle. Secondly, the heterogeneity of the silica microparticles, induced by the water soluble additive, might cause some of the silica to be more accessible to the dissolution medium, which could lead that the surroundings of the silica microparticle become saturated with silica, preventing the release of the active pharmaceutical ingredient. Heterogeneity of the silica microparticles can be controlled by controlling the amount of water soluble additive in the silica microparticles, or by incorporating into the silica hydrogel composite different silica microparticles with different amounts of water soluble additive(s). For example, the silica hydrogel composite may comprise first silica microparticles with a first amount of a water soluble additive and second silica microparticles with encapsulated active pharmaceutical ingredient and a second amount of the water soluble additive, which is lower than the first amount. The silica is dissolved faster from the first silica microparticles, which lead to saturation of the surrounding medium and prevents the dissolution from the second silica microparticles, as explained above. Initial burst of the silica hydrogel composite can be thus controlled by for example controlling the amount and / or type of the silica microparticles with encapsulated water soluble additive. Alternatively, the water soluble additive encapsulated in the silica microparticle might increase the release rate of the active pharmaceutical ingredient directly after the injection of the silica hydrogel composite, i.e. at the start of the treatment. This could be achieved by silica hydrogel composite where a first group of the silica microparticles comprise encapsulated water soluble additive, which significantly increases the dissolution rate of the active pharmaceutical ingredient from those microparticles. This guarantees high release of the active pharmaceutical ingredient at the start of the dissolution without changing the release profile of active pharmaceutical ingredient from a second group of silica microparticles without encapsulated water soluble additive, also comprised in the silica hydrogel composite.

[0094] The present invention may enable even combination of delayed release and enhanced release at the start of the release period. This can be achieved with a silica hydrogel composite comprising fast dissolving silica microparticles without encapsulated active pharmaceutical ingredient and with a higher amount of encapsulated water soluble additive; moderately dissolving silica microparticles with an encapsulated active pharmaceutical ingredient and with a lower amount of encapsulated water soluble additive; and silica microparticles with encapsulated active pharmaceutical ingredient but without an encapsulated water soluble additive. It is assumed that this leads to a small release of the active pharmaceutical ingredient at start of the release period after which the release of the API begins with high release rate already at the start of the release period.

[0095] The silica hydrogel composite of the present invention is for administering an active pharmaceutical agent. According to one embodiment the administration is parenteral. According to a preferable embodiment the administration may be parenteral and selected from the group consisting of intravenous, intraarterial, intracardiac, topical, transdermal, intradermal, subcutaneous, intramuscular, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intraosseous, intraarticular, intraocular, intravitreal, subconjunctival, intrasternal, intravesical and intracavernosal. Preferred embodiments

[0096] The present invention includes following numbered embodiments in any order and / or in any combination:

[0097] 1 . A silica microparticle having

[0098] - a maximum diameter of <1000 pm, and

[0099] - a solid structure of amorphous silica, wherein at least one water soluble additive having a solubility in water of at least 3 mg / ml, at pH 7, at 25 °C, is encapsulated into the solid structure of the silica microparticle.

[0100] 2. The silica microparticle according to the preceding embodiment 1 , wherein the silica microparticle is prepared by spray-drying of a primary silica sol.

[0101] 3. The silica microparticle according to the preceding embodiments 1 or 2, wherein the silica microparticle is spherical, ellipsoidal, oblate spheroidic or prolate spheroidic in shape.

[0102] 4. The silica microparticle according to any of the preceding embodiments 1 , 2 or 3, wherein the silica microparticle has a maximum diameter of <1000 pm, preferably <700 pm, more preferably <500 pm, even more preferably <300 pm or <100 pm.

[0103] 5. The silica microparticle according to any of preceding embodiments 1 - 4, wherein the silica microparticle has a specific surface area <10 m2 / g, preferably <7 m2 / g, preferably <5 m2 / g, measured by gas sorption using nitrogen and krypton.

[0104] 6. A silica hydrogel composite, which is shear-thinning and comprises a) up to 85 weight-% of silica microparticles having a maximum diameter of < 1 000 pm, combined with b) a silica sol which has a solid content of <5 weight-%, wherein at least some of the silica microparticles are according to any of the preceding embodiments 1 - 5. 7. A silica hydrogel composite, which is shear-thinning and comprises a) up to 85 weight-% of silica microparticles having a maximum diameter of < 1 000 pm, combined with b) a silica sol which has a solid content of <5 weight-%, wherein at least one water soluble additive having a solubility in water of at least 3 mg / ml, at pH 7, at 25 °C, is encapsulated in at least some of the silica microparticles.

[0105] 8. The silica hydrogel composite according to preceding embodiment 6 or 7, wherein the at least one water soluble additive has the solubility in water at least 5 mg / ml, more preferably at least 30 mg / ml, even more preferably at least 50 mg / ml, at pH 7, at 25 °C.

[0106] 9. The silica hydrogel composite according to any of preceding embodiments 6 - 8, wherein the silica hydrogel composite comprises at least one water soluble additive in amount in a range of 0.01 - 50 weight-% or 0.01 - 30 weight-%, preferably 0.03 - 20 weight-%, more preferably 0.05 - 15 weight-% or 0.07 - 10 weight-%, calculated from a total weight of the silica in the silica hydrogel composite.

[0107] 10. The silica hydrogel composite according to preceding embodiments 6 - 9, wherein the at least one water soluble additive is a saccharide, selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, their salts and derivatives, and any mixtures thereof.

[0108] 11 . The silica hydrogel composite according to any of preceding embodiments 6 - 10, wherein the saccharide is selected from trehalose, cyclodextrin, hyaluronic acid, alginate, their salts and derivatives, and any mixtures thereof, preferably trehalose.

[0109] 12. The silica hydrogel composite according to any of preceding embodiments 6 - 11 , wherein the at least one water soluble additive is selected from B vitamins, C vitamin, their derivatives, salts and hydroxides, and any mixtures thereof. 13. The silica hydrogel composite of according to any of preceding embodiments 6 - 12, wherein the at least one water soluble additive is selected from natural or synthetic B12 vitamin, their salts, hydroxides and any mixtures thereof.

[0110] 14. The silica hydrogel composite according to any of preceding embodiments 6 -

[0111] 13, wherein the at least one water soluble additive is selected from amino acids, such as arginine, aspartic acid, glutamic acid, lysine, proline, glycine, histidine, and methionine.

[0112] 15. The silica hydrogel composite according to any of preceding embodiments 6 -

[0113] 14, wherein at least one active pharmaceutical ingredient is encapsulated in at least some of the silica microparticles.

[0114] 16. The silica hydrogel composites according to any of preceding embodiments 6 -

[0115] 15, wherein the at least one active pharmaceutical ingredient is selected from a GLP-1 receptor agonists, a dual GIP / GLP-1 receptor agonists, or a triple GIP / GLP- 1 / GCG receptor agonists, or their pharmaceutically accepted salts.

[0116] 17. The silica hydrogel composites according to any of preceding embodiments 6 - 15, wherein the at least one active pharmaceutical ingredient is selected from peptides, proteins, fusion proteins, vaccine antigens, mRNA-based drugs and smallmolecule drugs having molecular weight of <1000 Da.

[0117] 18. The silica hydrogel composite according to any of preceding embodiments 6 - 17, wherein at least one active pharmaceutical ingredient is encapsulated in the silica microparticle in amount of 0.001 - 70 weight-%, preferably 0.1 - 50 weight-%, more preferably 1 - 30 weight-%, calculated from the total weight of silica microparticle.

[0118] 19. The silica hydrogel composite according to any of preceding embodiments 6 - 18, wherein at least one active pharmaceutical ingredient is encapsulated in the silica microparticle in amount of 0.00001 - 15 weight-% or 0.00002 - 10 weight-%, preferably 0.0001 - 5 weight-% or 0.0003 - 3 weight-%, even 0.0005 - 0.9999 weight-%, calculated from the total weight of silica microparticle.

[0119] 20. The silica hydrogel composite according to any of preceding embodiments 6 -

[0120] 19, wherein at least 90 weight-% of the silica microparticles have the diameter in a range of 1 - 300 pm, preferably 1 - 100 pm, more preferably 1.5 - 30 pm, even more preferably 1 .5 - 20 pm.

[0121] 21. The silica hydrogel composite according to any of preceding embodiments 6 -

[0122] 20, wherein the silica hydrogel composite comprises 10 - 85 weight-% or 20 - 85 weight-%, preferably 25 - 80 weight-%, more preferably 30 - 75 weight-% of the silica microparticles, calculated from the total weight of the silica hydrogel composite.

[0123] 22. The silica hydrogel composite according to any of preceding embodiments 6 -

[0124] 21 , wherein the silica hydrogel composite has a solid content in a range of 10 - 75 weight-% or 20 - 75 weight-%, preferably 30 - 60 weight-%, more preferably 40 - 55 weight-%.

[0125] 23. The silica hydrogel composite according to any of preceding embodiments 6 -

[0126] 22, wherein the silica sol has the solids content of <3 weight-%, preferably <1 weight-%.

[0127] 24. The silica hydrogel composite according to any of preceding embodiments 6 -

[0128] 23, wherein the silica sol comprises silica nanoparticles and agglomerates having a diameter in a range of 5 - 995 nm, preferably 50 - 900 nm, more preferably 50 - 800 nm.

[0129] 25. The silica hydrogel composite according to any of preceding embodiments 6 -

[0130] 24, wherein the silica hydrogel composite has an elastic modulus measured under small angle oscillatory shear in a linear viscoelastic region <1500 kPa, typically <1200 kPa. 26. The silica hydrogel composite according to any of preceding embodiments 6 - 25, wherein the silica microparticles are selected from the group consisting of spray dried silica microparticles, silica fibre fragments and moulded or casted silica monoliths as such or as crushed.

[0131] 27. Use of the silica hydrogel composite according to any of preceding embodiments 6 to 26 for an injectable formulation.

[0132] 28. The silica hydrogel composite of any of preceding embodiments 6 to 27 for administering an active pharmaceutical agent.

[0133] 29. The silica hydrogel composite of any of preceding embodiments 6 - 28, wherein in that administration is parenteral.

[0134] 30. The silica hydrogel composite of any of preceding embodiments 6 - 11 , wherein the administration is parenteral and selected from the group consisting of intravenous, intraarterial, intracardiac, topical, transdermal, intradermal, subcutaneous, intramuscular, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intraosseous, intraarticular, intraocular, intravitreal, subconjunctival, intrasternal, intravesical and intracavernosal.

[0135] EXAMPLES

[0136] Some embodiments of the present invention are described in the following nonlimiting examples.

[0137] Example 1

[0138] Preparation and Analysis of Silica Microparticles Comprising Tirzepatide and Both Trehalose and Tirzepatide

[0139] In Example 1 trehalose was used as water soluble additive encapsulated in the silica microparticles. The active pharmaceutical ingredient was tirzepatide, encapsulated in the silica microparticles. The reference silica microparticles contained only tirzepatide, the silica microparticles according to the present invention comprised both tirzepatide and trehalose.

[0140] For silica microparticles comprising both trehalose and tirzepatide, four identical silica sols were first prepared by hydrolysing tetraethyl orthosilicate (TEOS by Merck) in water. The molar water-to-TEOS ratio for the silica sols was 5 (i.e. , the Revalue is 5, “R5”). The pH for the hydrolysis of TEOS was adjusted to pH 2.0 using 0.1 M HCI (Merck), and after the formation of the silica sol, the temperature was cooled down to ca. 0 °C in an ice-bath. The pH of the silica sols was further adjusted to pH 4.1 prior to mixing them with the solution of an active pharmaceutical ingredient, tirzepatide and a water soluble additive, trehalose.

[0141] Tirzepatide stock solution in the concentration of 9 mg / ml and trehalose stock solution in the concentration of 200 mg / ml in water were further mixed with water. This resulted in solutions with two different tirzepatide concentrations, 7.02 mg / ml in one of the solutions, and 1 .75 mg / ml in three of the solutions, and in four different trehalose concentrations, 3.50 mg / ml, 1.75 mg / ml, 0.35 mg / ml and 0.035 mg / ml. These solutions comprising tirzepatide and trehalose were mixed with the R5 silica sols, and the total amount of water in the mixtures increased the molar water-to- TEOS ratio to 100. The mixtures were spray-dried (Buechi S-300) to silica microparticles comprising tirzepatide in payloads of 5 weight-% (in 3 silica microparticle batches) and 20 weight-% (in one silica microparticle batch), and in trehalose payloads of 0.1 weight-%, 1.0 weight-%, 5.0 weight-% and 10 weight-%.

[0142] Three identical silica sols were prepared by hydrolysing tetraethyl orthosilicate (TEOS by Merck) in water. The molar water-to-TEOS ratio for the three identical silica sols was 5 (i.e., the R-value is 5). The pH of each silica sol was adjusted to pH 2.1 using 0.1 M HCI (Merck). After the hydrolysis, the three identical R5 silica sols were cooled down to ca. 0 °C in an ice-bath.

[0143] For the formulations comprising tirzepatide only, tirzepatide was dissolved in three different concentrations in water, 1.75 mg / ml, 3.51 mg / ml, and 7.02 mg / ml. The pH of the resulting tirzepatide solutions was 6.35. The three tirzepatide solutions were then combined with the three identical R5 silica sols for the spray-drying. The pH of the R5 silica sols was adjusted to pH 4 just before the mixing with the tirzepatide solutions, and the final pH of the mixtures was then further adjusted to pH 5.6 by using 0.1 M NaOH. The volume of water in the tirzepatide solutions increased the molar water-to-TEOS ratio from the silica sol’s 5 to 100 in the silica sol-tirzepatide mixture (i.e., R5-100). The silica sol-tirzepatide mixtures were pumped into the Buechi S-300 spray-dryer and the resulting silica microparticles comprised tirzepatide in the payloads of ca. 5 weight-%, 10 weight-% and 20 weight-% in relation to the silica amount.

[0144] In the spray-drying of the silica microparticles (both with trehalose and without trehalose) with Buechi S-300 spray-dryer, the inlet temperature was 100 °C, outlet temperature 51 - 55 °C, aspirator at 20 m3 / h, pump at ca. 6 ml / min and the atomization air flow was at 670 l / h.

[0145] The silica microparticle formulations are summarized in Table 1 .

[0146] Table 1 Compositions of the silica microparticles comprising tirzepatide

[0147] (reference) and the silica microparticles comprising tirzepatide and trehalose.

[0148] Calculated from the total weight of silica in the silica microparticle

[0149] The resulting particle size distributions of the silica microparticles comprising tirzepatide and trehalose and only trehalose were measured by laser diffraction (HELOS 2370, Sympatec) and the results are shown in Tables 2 and 3. The measured mean values D10, D50 and D90 indicate the percentage (10 %, 50 %, and 90 %) of particles below a certain size. Table 2 Particle size distributions of the silica microparticles comprising tirzepatide and trehalose.

[0150] Table 3 Particle size distributions of the silica microparticles comprising tirzepatide (reference).

[0151] It can be seen from Tables 2 and 3 that the differences between the particle sizes are relatively small independently whether they contain both trehalose and tirzepatide or only tirzepatide. The payloads, i.e. , the concentrations of trehalose and tirzepatide in the silica microparticles, did not either affect significantly the particle sizes.

[0152] The in vitro in sink (ensuring free dissolution of silica and API) dissolution rates at pH 7.4, at 37 °C, of silica and release rates of tirzepatide are shown in Figures 1 - 4. It is clear that trehalose affects both the dissolution rate of silica and the release rate of tirzepatide. The dissolution and release rates in Figure 1 and 2 for the silica microparticles comprising 5 weight-% of tirzepatide and 0.1 or 1.0 weight-% of trehalose are quite similar, and even a bit faster for the silica microparticles comprising 0.1 weight-% of trehalose, but the difference is within the error bars in the parallel measurements. When comparing the silica microparticles comprising 5 weight-% of tirzepatide and 0.1 or 1.0 weight-% of trehalose to the silica microparticles comprising 5 weight-% of tirzepatide only, the silica dissolution rates and tirzepatide release rates are clearly faster for the silica microparticles comprising 0.1 weight-% or 1.0 weight-% of trehalose. Even greater difference in the dissolution and release rates is seen for the silica microparticles comprising 5 weight-% of tirzepatide and 10 weight-% of trehalose. The dissolved amount of silica at 48 h is about 3.87 times larger and released amount of tirzepatide ca. 2.2 times larger for the silica microparticles comprising 5 weight-% of tirzepatide and 10 weight-% of trehalose than for the silica microparticles comprising 5 weight-% of tirzepatide only. The results for the silica microparticles comprising 5 weight-% of tirzepatide and 10 weight-% of trehalose are very similar to those of the silica microparticles comprising 20 weight-% of tirzepatide and 5 weight-% of trehalose. The smaller total payload, 15 weight-% giving practically the same results as 25 weight-% suggests that trehalose is quite effective in adjusting the dissolution and release rate at a large scale. It was also shown that the spray-drying produced very similar silica microparticle size distributions, and because the particles size distributions were very similar, the trehalose had the greatest effect on the dissolution and release rates.

[0153] Example 2

[0154] Injectable Silica Hydrogel Composite Comprising 1) Silica Microparticles with Encapsulated Tirzepatide and 2) Silica Microparticles with Tirzepatide and Trehalose

[0155] Three injectable silica hydrogel composite depots were prepared by using the batches of the silica microparticles comprising tirzepatide only and silica microparticles comprising both tirzepatide and trehalose, described in Example 1. The silica hydrogel composites were prepared by mixing the silica microparticles into silica sols (a R400 silica sol, which corresponds to ca. 0.82 weight-% of silica nanoparticles) at pH 6.1. The silica sol (R400) was made by hydrolysing TEOS in molar water-to-TEOS ratio of 400 at pH 2, and after the hydrolysis, the pH was adjusted to pH 6.1 The silica microparticles comprising tirzepatide or both tirzepatide and trehalose were mixed with the R400 silica sol in 1 :1 ratio (weight-to- volume), and the resulting mixtures were transferred into syringes, and the syringes were attached into a roller mixer at room temperature (25 °C) for 72 hours to ensure formation of a non-flowing hydrogel composite structure. For the injectable silica hydrogel composites, which are used for controlled and long- acting release of the active pharmaceutical ingredients, both the dissolution and release rates, and the rheological properties are important. The important rheological properties are the shear-thinning viscosity which predicts good injectability through thin needles, and the stability of the gel structure, i.e., they should remain non-flowing at rest and at low shear stresses, such as vibrations during handling and transportation. Dissolution and release rates of the active pharmaceutical ingredients, as well as the rheological properties of the silica hydrogel composites are strongly dependent on the type of the active pharmaceutical ingredient and the active pharmaceutical ingredient concentration which is encapsulated in the silica microparticles. Hence, it is important to be able to adjust all the said properties, and here the same water soluble additive in the silica microparticles can be used to adjust all the said properties.

[0156] The rheological results of the injectable silica hydrogel composites are summarized in Table 4. All silica hydrogel composites clearly shear-thinning under shear in the viscosity measurements, and non-flowing gel structures at rest according to the oscillatory measurements in the linear viscoelastic region.

[0157] Table 4 Rheological results for the silica hydrogel composites of Example 2.

[0158] *LVR=linear viscoelastic region, where the amplitude in the oscillatory measurements is so low that it does not affect the moduli, i.e., it simulates the properties of a material at rest. The results in Table 4 show that trehalose in the silica microparticles influences the rheology of the injectable silica hydrogel composites, and that the different concentrations of trehalose encapsulated together with tirzepatide in the silica microparticles also change the rheological properties. As the silica microparticles comprise 5 weight-% of tirzepatide, the effect of the co-encapsulated trehalose concentration (0.1 , 1.0 and 10 weight-%) is not big. The loss factors show that all those silica hydrogel composites have a stable gel structure, and there is also a slight trend that viscosities are slightly higher, when trehalose concentration increases.

[0159] When comparing the injectable silica hydrogel composites comprising the silica microparticles with 5 weight-% of tirzepatide only, and the ones comprising both 5 weight-% of tirzepatide and trehalose (0.1 , 1 .0 and 10 weight-%), it is seen that the rheological properties are different. According to the loss factors, the stability of the gel structure is quite similar in all the studied materials. The viscosity is shearthinning for all, but trehalose seems to affect viscosity levels, i.e., it predicts that trehalose can be used to adjust the injectability of the silica hydrogel composites through thin needles, e.g., with the tirzepatide concentration of 20 weight-% in the silica microparticles. In the cases with 5 weight-% of the tirzepatide, coencapsulated trehalose affects less the viscosity, but there is a trend in the storage modulus when the tirzepatide concentration is 5 weight-%. The storage modulus increases with the increasing concentration of trehalose, i.e., the gel structure is a bit looser with lower trehalose concentration, and the lowest in the silica hydrogel composite with 5 weight-% tirzepatide only. The storage modulus also affects the injectability. If the material has a lower storage modulus, there is a bigger chance that the particles as a solid network in a hydrogel (as is the case in the silica hydrogel composite) form separate larger clusters under high shear, which may clog the needle. The results also show that trehalose affects the rheological properties a bit differently with different tirzepatide concentrations, e.g., the loosest gel structure is achieved with tirzepatide payload of 20 weight-% and with 5 weight-% of trehalose, and the gel structure with 20 weight-% of tirzepatide only is tougher. These differences show that it is possible to affect the rheological properties to different directions, and to find proper concentrations to optimise the rheological properties. The dissolution rate of silica and release rate of tirzepatide for the silica hydrogel composites comprising the silica microparticles with tirzepatide and trehalose are shown in Figures 5 and 6. The corresponding results for the silica hydrogel composites comprising the silica microparticles with tirzepatide only are summarised in Table 5. The dissolution and release rates for the silica hydrogel composites follow quite well the corresponding silica microparticle results, because major part of the solid content of the silica hydrogel composites, i.e. , 50 weight-% is based on the same silica microparticles of which results were shown in Example 1 . The rest of the silica hydrogel composite is water and ca. 0.82 weight-% of silica nanoparticles agglomerates, which are merged to the surface of the silica microparticles.

[0160] Table 5 Released amounts of tirzepatide and dissolved amount of silica from the silica hydrogel composites comprising silica microparticles with 10 and 20 weight-% of tirzepatide only (reference).

[0161] The dissolution and release rates of silica hydrogel composites comprising silica microparticles with 5 weight-% of tirzepatide and 10 weight-% of trehalose, and 20 weight-% of tirzepatide and 5 weight-% of trehalose are almost identical, as they were also for the silica microparticles as such in Example 1 . It is also seen that the difference between the silica hydrogel composites comprising the silica microparticles with 5 weight-% of tirzepatide and 0.1 weight-% or 1 .0 weight-% are small, as it was for the corresponding silica microparticles as such. Also, the cumulative amounts are close to each other at different time points. When comparing the results, where 5 weight-% of trehalose is co-encapsulated with 20 weight-% of tirzepatide to the results in Table 5, where the silica microparticles comprise 20 % tirzepatide only, the difference is clear. The silica hydrogel composite, where the silica microparticles also comprise trehalose silica dissolves clearly faster and also the release rate of trehalose is higher. However, the differences between the dissolution and release rates of the silica hydrogel composites comprising only tirzepatide 10 weight-% and 20 weight-% in the silica microparticles are quite small although the payload is doubled. The results of Example 2 show that trehalose encapsulated together with tirzepatide in the silica microparticles can be simultaneously used to the adjust several properties of the silica hydrogel composites, i.e., the rheological properties, the dissolution rate of silica and release rate of tirzepatide.

[0162] Example 3

[0163] Preparation of Silica Microparticles Comprising Dexamethasone Phosphate and both Trehalose and Dexamethasone phosphate

[0164] Six silica microparticle batches were prepared comprising dexamethasone phosphate. Four of the batches comprised trehalose encapsulated also in the silica microparticles. Microparticles were prepared by combining and spray drying three different solutions, as described below.

[0165] First solution was silica sol which was prepared by hydrolysing tetraethyl orthosilicate (TEOS by Merck) in water. The molar water-to-TEOS ratio for the silica sols was 5 (i.e., the R-value is 5, “R5”). The pH for the hydrolysis of TEOS was adjusted to pH 2.0 using 0.1 M HCI (Merck), and after the formation of the silica sol, the temperature was cooled down to ca. 0 °C in an ice-bath.

[0166] Second solution comprised dexamethasone phosphate and optionally trehalose mixed with water. Dexamethasone phosphate and trehalose concentrations were adjusted to reach the desired microparticle load-%, described in Table 6. Load indicates the weight-% of substance in relation to silica amount, for example if microparticle has 7 weight-% of substance and 70 weight-% silica then the load-% is 10 %. Dexamethasone phosphate concentration ranged from 3.5 mg / ml to 7.0 mg / ml and trehalose concentration ranged from 0 to 7 mg / ml.

[0167] Third solution was 0.0015 M sodium hydroxide in water. The three solutions were pumped and combined in tube which mixed them together. Time all three solutions spent in tube together was 2 seconds for first two formulations and 2 minutes for rest of the formulations until they reached the end of the spray dryer nozzle. Time the mixed solution spent in the tube was dictated by tube length. Pump rates for different solutions were first solution: 0.84 ml / min, second solution: 2.56 ml / min and third solution: 2.60 ml / min.

[0168] In the spray-drying of the silica microparticles with Buechi B-290 spray-dryer, the inlet temperature was 100 °C, outlet temperature 61 -70 °C, aspirator at 35 m3 / h, and the atomization air flow was at 670 l / h.

[0169] Table 6 Compositions of the silica microparticles of Example 3.

[0170] The resulting particle size distributions of the silica microparticles comprising dexamethasone phosphate were measured by laser diffraction (HELOS 2370, Sympatec) and the results are shown in Table 7. The measured mean values D10, D50 and D90 indicate the volume percentage (10 %, 50 %, and 90 %) of particles below a certain size (e.g. D50 2.5 pm means that half of the total volume of the sample is in particles higher 2.5 pm in size). Table 7 Particle size distributions of the silica microparticles comprising dexamethasone phosphate or both dexamethasone phosphate and trehalose.

[0171] It can be seen from Table 7 that the differences between the particle sizes are relatively small independently whether they contain both trehalose and dexamethasone phosphate or only dexamethasone phosphate. The payloads, i.e. , the concentrations of trehalose and dexamethasone phosphate in the silica microparticles did not either affect significantly the particle sizes.

[0172] The measurements for dissolution rate of silica and release rate of dexamethasone phosphate were conducted in 50 mM TRIS buffer pH 7.4 at 37 °C. The dissolution conditions were kept in sink conditions, i.e. below ca. 20 % of the solubility of silica and dexamethasone phosphate to ensure free dissolution and no decrease of dissolution or release rate due to dissolution products. The in vitro in sink dissolution rates of silica and the release rates of dexamethasone phosphate from the silica microparticles are summarized in Tables 8 and 9. Release% in Table 8 and 9 indicates the total amount of silica or dexamethasone phosphate dissolved in specific time points compared to the total amount of silica or dexamethasone phosphate in sample. Noteworthy information from the dissolution is that from formulations numbers 1 -1 and 1 -2, where all solutions were together only 2 seconds prior to spray drying, dexamethasone phosphate releases faster than silica. This may indicate that the silica microparticles are more heterogeneous and there is more dexamethasone phosphate closer to the surface of the microparticle than in the core, and therefore also more dexamethasone phosphate at the surface. Silica microparticles having more dexamethasone phosphate at the surface affects the surface chemistry of the silica microparticles. Therefore, also the gel formation is expected to be different when the silica microparticles are combined with silica sol during manufacturing of injectable silica hydrogel composite.

[0173] Table 8 The in sink dissolution rates of silica and the release rates of dexamethasone phosphate from the silica microparticles for formulation numbers 1 -

[0174] 1 , 1 -2 and 1 -3.

[0175] Table 9 The in sink dissolution rates of silica and the release rates of dexamethasone phosphate from the silica microparticles for formulation numbers 1- 4, 1 -5 and 1 -6.

[0176] Non-encapsulated dexamethasone phosphate, i.e. dexamethasone phosphate that is outside of the silica microparticles, was measured by mixing the microparticles with ethanol. Ethanol dissolves dexamethasone phosphate but not silica and since encapsulated dexamethasone phosphate does not dissolve unless silica is dissolved, only non-encapsulated dexamethasone phosphate is dissolved in ethanol. When the dissolved dexamethasone phosphate content is measured from ethanol and compared to the total amount of dexamethasone in the silica microparticles the relative content of non-encapsulated dexamethasone phosphate can be calculated. Relative contents of non-encapsulated dexamethasone phosphate in formulations are in Table 10. From Table 10 it can be seen that addition of trehalose to the formulation does not increase the amount of nonencapsulated dexamethasone phosphate amounts in large amounts. Also, when comparing formulations numbers 1 -5 and 1 -6 it can be seen that addition of dexamethasone phosphate to the formulation increases the non-encapsulated dexamethasone phosphate amount more than addition of trehalose. This indicates that addition of trehalose to the formulation is better way to decrease the total silica content compared to addition of API (dexamethasone phosphate). Silica contents in Table 10 were measured by fully dissolving microparticle sample in ammonium bifluoride solution or sodium hydroxide solution and measuring the total silica content of the solution.

[0177] Table 10 Relative non-encapsulated API amount and silica contents of the formulations.

[0178] Six injectable silica hydrogel composites were prepared by using the batches of the different silica microparticles comprising dexamethasone phosphate only or both dexamethasone phosphate and trehalose. Manufacturing was done by mixing the silica microparticles into silica sols (a R400 silica sol, which corresponds to ca. 0.82 weight-% of silica nanoparticles) at pH 6.0-6.8. The silica sol (R400) was made by hydrolysing TEOS in molar water-to-TEOS ratio of 400 at pH 2. The silica microparticles comprising dexamethasone phosphate or both dexamethasone phosphate and trehalose were mixed with the R400 silica sol in 1 :1 ratio (weight-to- volume). pH of the resulting mixture was adjusted to 6.0 - 6.8 and the resulting mixtures were transferred into syringes, and the syringes were attached into a roller mixer at room temperature (25 °C) for 72 hours to ensure formation of a non-flowing hydrogel composite structure.

[0179] The rheological results of the injectable silica hydrogel composites comprising the silica microparticles with encapsulated dexamethasone phosphate or dexamethasone phosphate and trehalose were all clearly shear-thinning under shear in the viscosity measurements, and non-flowing gel structures at rest according to the oscillatory measurements in the linear viscoelastic region. Rheological results are shown in Table 11 .

[0180] Table 11 Rheological results for the silica hydrogel composites comprising dexamethasone phosphate or both dexamethasone phosphate and trehalose in the silica microparticles.

[0181] *LVR=linear viscoelastic region, where the amplitude in the oscillatory measurements is so low that it does not affect the moduli, i.e., it simulates the properties of a material at rest.

[0182] Formulation numbers 1 -1 and 1 -2, where there is more dexamethasone phosphate at the silica microparticle surface, have lower storage modulus and loss modulus values indicating weaker gel structure. It can also be seen that trehalose in formulation number 1-2 strengthen the gel structure by increasing both storage and loss moduli to be 2-3 times higher compared to the reference formulations without trehalose. When comparing formulation numbers 1 -3 and 1 -4 where the dexamethasone phosphate is more evenly distributed in the silica microparticles (i.e. not so much in the surface) both storage and loss moduli are not affected as much. This difference is due to dexamethasone phosphate modifying the surface of the silica microparticles, which decreases the interactions of silica microparticles and silica sol (i.e. silica nanoparticles present in R400 sol), hindering the formulation of proper gel structure. When there is much dexamethasone phosphate at the surface, trehalose compensates the effect of dexamethasone phosphate allowing stronger interactions and formation of better gel structure. With formulation numbers 1 -3, 1-

[0183] 4 and 1 -5 (trehalose loads 0, 3 and 10 %) the interactions are already high without trehalose. In this case storage modulus is decreasing as trehalose content is increasing, due to trehalose itself disrupting the gel formation. With 10 % trehalose load-% loss factor has increased to be 2.4-3.2 times higher compared to reference formulation without trehalose due to trehalose increasing permeability and making the formulation more liquid like. When comparing formulation numbered 1 -5 and 1 - 6, where the trehalose and dexamethasone phosphate contents are reversed it can be again seen that dexamethasone phosphate lowers storage modulus (i.e. making the gel structure weaker). However, all the formulations were injectable through 27 G ultra-thin wall needle with less than 20 N injection forces.

[0184] Example 4

[0185] Silica Microparticles and Injectable Silica Hydrogel Composites Comprising a Protein and Trehalose

[0186] Silica sols for providing silica microparticles containing a vaccine antigen protein as active pharmaceutical agent and / or trehalose were produced by hydrolysis of TEOS in water using 0.1 M HCI as a catalyst at pH 2. In these silica sols, the initial molar ratio of water to TEOS was R5. After hydrolysis, the sols were cooled in an ice bath for 10 minutes.

[0187] Trehalose solution for the vaccine antigen protein solution was prepared by dissolving trehalose in deionized water and after that the solution was cooled to 0-

[0188] 5 °C in an ice bath. The vaccine antigen protein solution was prepared by adding the vaccine antigen protein stock solution into the cold trehalose solution and after that mixture was gently mixed by magnetic stirrer in ice bath. The vaccine antigen protein solution was prepared during the silica sol hydrolysis. Silica sol was diluted and pH adjusted with mixture of cold deionized water and 0.1 M NaOH (e.g., sol pH increased from 2.0 to 5.7). The mixture was mixed by magnetic stirrer in room temperature (25 °C). At this point the R-value (R = molar water-to-tetraethyl orthosilicate (TEOS) ratio) of the sol was diluted from R5 to R55. The pH of the sol was increased before adding of the vaccine antigen protein solution because the vaccine antigen protein was sensitive to low pH.

[0189] Next, the diluted and pH adjusted silica sol was combined with the vaccine antigen protein solution by pipetting the sol into the vaccine antigen protein solution and the pH of combination was approx. 5.8 (no further pH adjustment was required). The final R-value of the formulation was R100. The mixture was gently mixed by magnetic stirrer in ice bath for 5 min before spray drying.

[0190] The mixture was spray dried using Buchi Mini Spray Dryer B-290-1 with high performance cyclone and it was kept in ice bath during spray drying. Inlet temperature was 100 °C, outlet temperature 47-55 °C, aspirator was adjusted to 35 m3 / h, pumping rate to 6.8 ml / min, and atomization flow to 670 l / h.

[0191] The preparation of the injectable silica hydrogel composites was started by preparing a silica sol with high water content (R400 sol, i.e. , the molar water-to- tetraethyl orthosilicate (TEOS) ratio was 400) was produced by hydrolysis of TEOS and deionized water using 0.1 M HCI as a catalyst. The pH of the R400 silica sol was pH2. After the hydrolysis, the pH of the sol was adjusted with 0.1 M NaOH solution to value approximately 6.0. The silica microparticles comprising the vaccine antigen protein and trehalose were then mixed manually with the R400 sol (pH 6) and a weight-volume ratio was 1 .0 g / ml (i.e., 1 g of silica microparticles was mixed with 1 ml of silica sol) meaning that microparticles weight-% in silica sol-silica microparticle mixtures was 50 weight-%. No pH adjustment was required for silica sol- silica microparticle mixtures. The mixtures were kept homogenous by placing the capped syringes in a tube rotator to prevent particle sedimentation from occurring while the suspensions were allowed to form the gel structure at ambient temperature for 2-3 days. The dissolution rate of silica was measured for the silica microparticles comprising 0.040 weight-% or 0.055 weight-% of the vaccine antigen protein and different concentrations of trehalose. The payload of the vaccine antigen protein (still high enough for in vivo experiments) in the silica microparticles was so low that its release rate could not be measured reliably in the in vitro measurements. Hence, only silica dissolution rate was determined. The effect of the encapsulated trehalose was obvious, i.e. , the more there was trehalose, the faster was the dissolution rate of silica.

[0192] In the in vitro measurements in PBS buffer at pH 7.4 at 37 °C, the silica microparticles comprising 0.040 weight-% of vaccine antigen protein and 15.96 weight-% of trehalose (total payload of encapsulates 16.0 weight-%) having particle size distribution of D10=0.96 pm, D50=2.52 pm, and D90=7.63 pm, showed following results: silica had dissolved 40 weight-% at 6 h, 73 weight-% at 24 h, 95 weight-% at 48 h and 99.9 weight-% at 72 h.

[0193] In the in vitro measurements in PBS buffer at pH 7.4 at 37 °C, another silica microparticle formulation comprising 0.055 weigh-% of vaccine antigen protein and 7.945 weight-% of trehalose (total payload of encapsulates 8.0 weight-%) having particle size distribution of D10=1 .03 pm, D50=2.61 pm, and D90=6.99 pm, showed following results: silica had dissolved 21 weight-% at 6 h, 49 weight-% at 24 h, 69 weight-% at 48 h, and 82 % at 72 h.

[0194] Hence, the formulation comprising 15.96 weight-% or trehalose dissolved clearly faster than the formulation comprising 7.945 weight-% of trehalose. The vaccine antigen protein payload was very small in both microparticles, and the particle size distribution were very similar, the faster material had a slightly larger D90. Hence, it is clear that the higher payload of trehalose resulted in faster dissolution rate. A clear effect of trehalose was also observed in the experiment, where the injectability of the silica hydrogel composites were studied by injection force measurements, which represent the real shear stress and shear rate during injection and show more accurately the shear-thinning viscosity behaviour. The injection force measurements were conducted by measuring the needed force, when injecting the silica hydrogel composites from a syringe through thin needles (22G, 23G, 25G and 27G regular or thin wall needles). The plunger of the syringe was pressed using Anton Paar rheometer (MCR302) with a one continuous push at the rate of 1 mm / sec (60 mm / min), which is representative of manual syringe delivery to a patient. In typical manual syringe delivery, pushing force of the thumb finger for 5 s varies between ca. 8-50 N, and forces below 10 N are commonly considered to be easily injectable. Injection force measurements were performed for the silica hydrogel composites formulations comprising silica microparticles with 19.96 weight-% of trehalose and 0.040 weight-% of vaccine antigen protein, as well as 15.96 weight-% of trehalose and 0.040 weight-% of vaccine antigen protein using 27G RW (regular wall; nominal inner diameter 0.21 mm and outer diameter 0.413 mm) and 25G RW needles (nominal inner diameter 0.26 mm, outer diameter 0.46 mm). The silica hydrogel composite comprising 19.96 weight-% of trehalose had better injectability. The force required for injection with a 27G RW needle is less than 10 N and with 25G RW needle approximately 5 N. The silica hydrogel composite formulation comprising silica microparticles with 15.96 weight-% of trehalose was also easy to inject, but it required a bit more injection force with both needles, approximately 12 N with 27G RW needle and 7 N with 25G RW needle. Injection force measurements were also performed for the silica hydrogel compositions comprising silica microparticles with formulations comprising silica microparticles with 11.70-11.97 weight-% of trehalose and 0.028, 0.040 or 0.055 weight-% of vaccine antigen protein using 23G TW having larger inner diameter (thin wall, inner diameter 0.37 mm, outer diameter 0.6 mm) needles, because those materials were difficult to inject with thinner needles, such as 25G RW and 27G RW. As the trehalose amounts of the silica hydrogel composites were close to each other, also injection force results were quite similar. The forces required for injection of injectable silica hydrogel composites with a 23G TW needle were approximately 9 N for the formulation comprising silica microparticles with 11.97 weight-% of trehalose and 0.028 weight-% of vaccine antigen protein and for the formulation comprising silica microparticles with 11 .70 weight of trehalose and 0.055 weight-% of vaccine antigen protein. When the trehalose content in the silica microparticles was further decreased to 9.70 and 9.97 weight-%, vaccine antigen protein payload being 0.055 weight-% and 0.028 weight-%, respectively, yet larger inner diameter for the needle was needed, a 22G TW (thin wall, inner diameter 0.44 mm, outer diameter 0.698 mm). For those silica hydrogel composites, the force needed increased towards the end of the injection reaching 8-9 N in the end, i.e., no plateau in the injection force was reached. The results showed for these silica hydrogel composites that the higher the trehalose concentration, the easier was the injection. Larger inner diameter of the needle was needed as the trehalose concentration in the silica microparticles decreased. When injecting the silica hydrogel composites comprising the silica microparticles with 15.96 weight-% and 19.96 weight-% of trehalose, both could be injected through the 25G RW and 27G RW needles, but the forces needed with 19.96 weight-% were lower than those with 15.96 weight-%.

[0195] Example 5

[0196] Preparation and In Vivo Evaluation in Minipigs of Silica Microparticles and Injectable Silica Hydrogel Composites Comprising Trehalose, Histidine or Ascorbic Acid.

[0197] Four silica microparticle batches were prepared with or without water soluble additive. Used water soluble additives were trehalose, histidine, ascorbic acid.

[0198] Three solutions were prepared for manufacturing of the microparticles:

[0199] First solution was silica sol which was prepared by hydrolysing tetraethyl orthosilicate (TEOS by Merck) in water. The molar water-to-TEOS ratio for the silica sols was 5 (i.e., the R-value is 5, “R5”). The pH for the hydrolysis of TEOS was adjusted to pH 2.0 using 0.1 M HCI (Merck), and after the formation of the silica sol, the temperature was cooled down to ca. 0 °C in an ice-bath.

[0200] Second solution was water with or without trehalose, histidine or aspartic acid. Concentration of the optional water soluble additive was 7.36 mg / ml.

[0201] Third solution was NaOH water solution. Concentration of the NaOH solution differed for each formulation to set the pH of the final solution to 5. Different NaOH amounts were needed to reach the same pH value as water soluble additives also affect the pH. NaOH concentrations can be found in Table 12.

[0202] The three solutions were pumped and combined in continuously stirred tank reactor with flow rates into the reactor: solution 1 : 2.32 ml / min, solution 2: 3.36 ml / ml, and solution 3. 3.31 ml / min.

[0203] Volume of the tank reactor was 60 ml. Flow rate from the reactor to spray dryer was same as the sum of input flow rates, which equals to 9 ml / min in all cases.

[0204] Compositions of the prepared silica microparticles with used water soluble additive are shown in Table 12. Formulation 5-1 was reference sample without water soluble additive. Water soluble additive load-% was 5 % for formulations from 5-2 to 5-4. Load-% indicates the weight-% of substance in relation to silica amount, for example if microparticle has 3.5 weight-% of substance and 70 weight-% silica then the load- % is 5 %.

[0205] Table 12 Compositions of the silica microparticles of Example 5.

[0206] In the spray-drying of the silica microparticles with Buechi B-290 spray-dryer, the inlet temperature was 120 °C, the outlet temperature approximately 50 °C (48-52 °C), aspirator at 20 m3 / h, and the atomization air flow was at 1500 l / h.

[0207] The resulting particle size distributions of the silica microparticles with or without water soluble additive were measured by laser diffraction (HELOS 2370, Sympatec) and the results are shown in Table 13. The measured mean values D10, D50 and D90 indicate the volume percentage (10 %, 50 %, and 90 %) of particles below a certain size (e.g. D502.5 pm means that half of the total volume of the sample is in particles higher 2.5 pm in size). Results show that differences in particle size distributions are small between formulations. This indicates that water soluble additives do not have effect on particle size distribution. Also, SEM pictures (not shown) of the silica microparticles were taken with JEOL JCM-7000 benchtop SEM. Particles were found to be round spheres.

[0208] Table 13 Particle size distributions of the silica microparticles of Example 5.

[0209] Injectable silica hydrogel composites were prepared from all microparticle formulations. Manufacturing was done by mixing the silica microparticles with water and then adding 1.0 M NaOH solution and R6.1 silica sol to make the final R-value of the sol to 400 and pH 6.0. R6.1 corresponds to ca. 18.9 weight-% of silica nanoparticles and R400 corresponds to ca. 0.82 weight-% of silica nanoparticles. The R6.1 silica sol was made by hydrolysing TEOS in molar water-to-TEOS ratio of 6.1 at pH 2. Resulting microparticle-sol mixtures were transferred into syringes. The total amount of silica microparticles with or without water soluble additives was 49 weight-% in the final Injectable silica hydrogel composites.

[0210] In vivo dissolution kinetics of formulations 5-1 , 5-2, 5-3 and 5-4 were tested in minipigs. The ready-to-use syringes with injection volume of 0.3 ml were used to study the dissolution kinetics with subcutaneous administration. Number of injections per group was three for formulation 5-1 , and four for other formulations 5- 2, 5-3 and 5-4. Injections were done to left and / or right side of groin or right side of neck. One or two injections per animal (1 per location). Number of animals was 8.

[0211] After administration, animals were followed for 64 days after which animals were sacrificed and preselected injection sites containing the remaining test item were collected for content analysis (remaining silica and water soluble additive content measurement). After the animals designated for content analysis were sacrificed the implantation sites were collected. Most of the surrounding tissue was removed, and samples were stored at temperature below -20 °C within 30 minutes of removal. Total contents of silica and water soluble additive was analysed from the tissue samples by cutting the remnant to multiple pieces and adding buffered acidic fluoride solution to dissolve silica and therefore release water soluble additive. Water soluble additive and silica contents were measured from the samples. Water soluble additive analyses were done with HPLC. Relative silica and water soluble additive contents were calculated in relation to the total injected silica and water soluble additive doses. The results are shown in Table 14.

[0212] Table 14 Effect of water soluble additives to remaining silica after 64 days in minipigs. Based on the results of Table 14, it seems that Trehalose (Formulation 5-2) does not have effect on silica dissolution as its result was practically same as with reference group. Histidine (Formulation 5-3) caused 52 % more silica to dissolve within in vivo study duration in relation to the reference group (70 % dissolved compared to 46 % dissolved). Ascorbic acid (Formulation 5-4) caused 78 % more silica to dissolve within in vivo study duration in relation to the reference group (82 % dissolved compared to 46 % dissolved). Also, water soluble additive analyses have confirmed that the water soluble additives have remained encapsulated inside microparticles. This applied even for formulation 5-4 with ascorbic acid, despite the ascorbic acid’s tendency to degrade fast.

[0213] Example 6

[0214] Preparation and Injectability Testing of Silica Microparticles and Injectable Silica Hydrogel Composites Comprising Tirzepatide With or Without Either Arginine, Histidine, Methionine or Aspartic Acid.

[0215] Eleven silica microparticle batches were prepared comprising tirzepatide with or without water soluble additive. Used water soluble additives were arginine, histidine, methionine and aspartic acid.

[0216] Three solutions were prepared for manufacturing of the microparticles:

[0217] First solution was silica sol which was prepared by hydrolysing tetraethyl orthosilicate (TEOS by Merck) in water. The molar water-to-TEOS ratio for the silica sols was 20 (i.e. , the R-value is 20, “R20”). The pH for the hydrolysis of TEOS was adjusted to pH 2.5 using 0.1 M HCI (Merck), and after the formation of the silica sol, the temperature was cooled down to ca. 0 °C in an ice-bath.

[0218] Composition of second and third solution varied based on which water soluble additive and how much of it was used. Changes were due to water soluble additive affecting pH, which caused need to add NaOH or HCI to compensate the effect of water soluble additive to pH. Tirzepatide was always incorporated in the second solution and water soluble additive was incorporated either in the second solution or the third solution. NaOH or HCI were incorporated in either the second solution or third solution, depending on the water soluble additive.

[0219] The three solutions were pumped and combined in continuously stirred tank reactor with flow rates into the reactor: solution 1 : 1 .65 - 1 .73 ml / min, solution 2: 2.13 - 4.27 ml / ml, and solution 3: 0 - 2.13 ml / min.

[0220] Volume of the tank reactor was 60 ml. Flow rate from the reactor to spray dryer was same as the sum of input flow rates, which equals to 6 ml / min in all cases. While the flow rates varied based on the formulation, in all but one formulation the final solutions that went to the spray dryer had 30 load-% of tirzepatide and in the one formulation it was 20 load-%. Water soluble additive load-% were 0 - 5%, as shown in Table 15 for each formulation. Load-% indicates the weight-% of substance in relation to silica amount, for example if microparticle has 7 weight-% of substance and 70 weight-% silica then the load-% is 10 %.

[0221] In the spray-drying of the silica microparticles with Buechi B-290 spray-dryer, the inlet temperature was 100 °C, the outlet temperature approximately 60 °C (55-62 °C), aspirator at 25 m3 / h, and the atomization air flow was at 670 l / h.

[0222] Table 15 Compositions of the silica microparticles of Example 6.

[0223] The resulting particle size distributions of the silica microparticles comprising tirzepatide or both tirzepatide and the water soluble additive were measured by laser diffraction (HELOS 2370, Sympatec) and the results are shown in Table 16. The measured mean values D10, D50 and D90 indicate the volume percentage (10 %, 50 %, and 90 %) of particles below a certain size (e.g. D50 2.5 pm means that half of the total volume of the sample is in particles higher 2.5 pm in size). Results in Table 16 show that the differences in particle size distributions are small between formulations. This indicates that the water soluble additives do not have effect on particle size distribution.

[0224] Table 16 Particle size distributions of the silica microparticles comprising tirzepatide and water soluble additive or both tirzepatide and water soluble additive.

[0225] Injectable silica hydrogel composites were prepared from all microparticle formulations. Manufacturing was done by mixing the silica microparticles with water and then adding enough 1 M HCI solution and R6.1 silica sol to make the final R- value of the sol to 400 and pH 6.6. R6.1 corresponds to ca. 18.9 weight-% of silica nanoparticles and R400 corresponds to ca. 0.82 weight-% of silica nanoparticles. The R6.1 silica sol was made by hydrolysing TEOS in molar water-to-TEOS ratio of 6.1 at pH 2. Resulting microparticle-sol mixtures were transferred into syringes. The total amount of silica microparticles comprising tirzepatide or both tirzepatide and water soluble additive was 43 weight-% in the final injectable silica hydrogel composites.

[0226] Injectability of the formulations were evaluated with injection force measurements. Measurements were done with Antor Paar MCR-302 rheometer by moving the plunger 1 mm / s and recording the force required for the movement. 23G thin wall needle (Henke Sass Wolf 4710006025) was used during the measurement. Injection force graphs for formulations 6-1 , 6-2, 6-5, 6-7 and 6-9 (5% water soluble additives) are shown in Figure 7. Injection force graphs for formulations 6-1 , 6-3, 6- 6, 6-8 and 6-10 (2 % water soluble additives) are shown in Figure 8. Injection force for formulations 6-1 , 6-9, 6-11 (5% arginine with two different tirzepatide loads) are shown in Figure 9. Figures 7 - 9 clearly show that aspartic acid makes the injectability worse in every concentration while arginine makes it better in every case even when different tirzepatide load is used. Syringes have different filling volumes which is why graphs stop at different points. At the end of the measurement, the device can also be pushing against empty syringe, thus compressing the plunger. This can show in Figures as high end force.

[0227] Table 17 shows average injection forces, measured from area 50 pl after the start of the measurement and 50 pl before the end of the measurement. Table 17 also shows if the syringe was blocked during the measurement. This was determined by visually examining the syringes after injection force measurement to ensure that the syringes were empty. The amount left was visually determined, based on information about how far the plunger had been pushed, compared to the point where the syringe is known to be empty (determined with empty syringes).

[0228] Table 17 Injectability and average injection forces of silica hydrogel composites comprising tirzepatide with or without water soluble additive.

[0229] Based on the injectability results as shown in Table 17, it can be concluded that injectable silica hydrogel composites produced with microparticles comprising arginine and tirzepatide require less force to inject compared to injectable silica hydrogel composite without arginine. Opposite effect can be seen with aspartic acid. Addition of methionine or histidine do not seem to be affecting the injection force of the formulation. Even though methionine and histidine do not affect formulation injectability in this case, they may have effect on other cases. For example, with microparticles comprising cariprazine with or without methionine it was found that when injectable silica hydrogel composites were produced from both, the hydrogel composite with silica microparticles comprising methionine had overall better injectability (including lower injection forces).

[0230] Example 7

[0231] In Vitro Flow-Through Dissolution of Silica Hydrogel Composites Comprising Tirzepatide with or without Water Soluble Additive in Either Same Particles or Different Particles

[0232] Formulations 6-1 and 6-6 from Example 6 were evaluated using flow-through dissolution, which more accurately reflects the in vivo conditions compared to insink dissolution. Also, a third formulation was prepared and used in the study of Example 7. The third formulation comprised a mixture of same microparticles that were used for formulation 6-1 and placebo microparticles which contained 30 load- % trehalose. Proportion between the said microparticles and placebo microparticles in was 9:1 (i.e. 90 weight-% of total microparticle weight were microparticles of formulation 6-1 and 10 weight-% of total microparticle weight were placebo microparticles with 30% load of trehalose). The third formulation will hereafter be referred to as Formulation 12. Apart from different silica microparticles, Formulation 12 (injectable silica hydrogel composite) was prepared in otherwise same manner as formulations 6-1 and 6-6.

[0233] For flow-through dissolution, 350 - 400 mg of each formulation 6-1 , 6-6 and 12 were sampled into separate 140 ml PP containers which were filled with dissolution medium (0.05 %(v / v) polysorbate 80 (Tween80), 50 mM Tris pH 7.4 (pH adjusted at 37 °C)). Container was attached to peristatic pump (Masterflex Ismatec 78018-22) and sample collection vessel. The flow through sample container was about 40 ml / day. Container was in 37 °C water bath for the duration of the dissolution. While the system does not mimic in vivo situation (e.g. subcutaneous space), it still reflects the conditions compared to in-sink, since in this system the silica hydrogel composites do not dissolve totally freely, but rather the dissolution medium next to the sample is most of the time not in-sink condition. When dissolution does not occur under sink conditions, the dissolution of silica species is governed by their individual dissolution rates. In such cases, silica from rapidly dissolving species can impede the dissolution of slower species by contributing to the saturation of the solution. For example, consider a vessel containing 50 weight-% of species with a dissolution rate ten times higher than the remaining 50 weight-%. If the saturation limit allows only 10 weight-% of the material to dissolve, approximately 90% (or even higher) of the dissolved fraction will originate from the faster-dissolving species, even after an extended period. Conversely, under sink conditions, the entire sample would eventually dissolve, with both species contributing proportionally over time.

[0234] Due to the competitive dissolution mechanics flow-through dissolution can uncover heterogeneity within a sample. Heterogeneity can originate from within particles, between particles from same batch, or from mixing different batches of particles. From the evaluated formulations clear and expected differences can be seen. Reference formulation (Formulation 6-1 ) shows relatively uniform situation where tirzepatide is dissolving in relation to silica but there is some increased tirzepatide release at the start of the dissolution (Figure 10). Formulation 6-6 shows much higher release at the beginning, but also the release stops sooner without having a long tail at the end (Figure 11 ). Formulation 12 shows lowest release at beginning, but duration is practically same as with Formulation 6-1. If daily release should be 1 -5 % of the total tirzepatide amount, and 0.1 -1 % levels would be considered tailing, then the reference formulation (Formulation 6-1 ) would be in the intended range for 45 days and tailing for 32 days. This would mean that the ratio of tailing to intended range would be 0.71. For formulation 6-6, the hypothetical intended range (1 -5 % daily release) lasts for 28 days and hypothetical tailing phase (0.1 - 1 %) for 14 days. This gives a ratio of tailing to intended range which is 0.5. For formulation 12 (Figure 12) hypothetical intended range lasts for 42 days and hypothetical tailing for 28 days, and ratio of tailing to intended range is 0.67. Formulations 6-1 and 12 have practically same duration and tailing, which is expected, due to use of same tirzepatide containing microparticle formulation but formulation 12 also has lower Cmax release compared to Formulation 6-1. During the period of highest release, Formulation 12 is releasing 2.1 % of the total API content per day at day 9, while Formulation 6-1 is releasing 2.9 % of the total API content per day at day 4. This indicates that the addition of hydrophilic microparticles is decreasing burst release due to competitive dissolution mechanism which is in conformity with the invention. Formulation 6-6 had shorter duration but also shorter tailing, due to heterogeneity caused by hydrophilic water soluble additive which is also in conformity with the invention.

[0235] Example 8

[0236] Pharmacokinetics Evaluation of Silica Microparticles and Injectable Silica Hydrogel Composites Comprising Tirzepatide and Arginine, Histidine, Methionine or Aspartic Acid.

[0237] Pharmacokinetics of formulations 6-1 , 6-4, 6-6 and 6-8 from Example 6 were tested in rats to determine the effect of water soluble additives to in vivo release. The ready- to-use syringes with an injection volume of 0.1 ml were used to study the pharmacokinetics with subcutaneous administration. Total doses comprised of about 10 mg tirzepatide in a single dose. Intended number of animals per group was 20, but due to availability of extra animals and lack of syringes with formulation 6-4, the following group divisions were used: group for formulation 6-1 had 20 animals, group for formulation 6-4 had 18 animals, group for formulation 6-6 had 22 animals, and group for formulation 6-8 had 22 animals. After administration, animals were followed for 28, 56 or 84 days, after which animals were sacrificed and the injection sites containing the remaining test item were collected for either histopathological analysis or content analysis (remaining silica and tirzepatide content measurement). Number of animals for each analysis are shown in Table 18. Blood sampling was done for the animals that were designated for content analysis tissue sampling at necropsy. Extra animals above the planned n=4 were excluded from blood sampling as descripted in table 18. Blood samples from the animals were collected from jugular vein to determine the level of tirzepatide at 30 min, 1 h, 4 h, 8 h, 24 h, 30 h, 48 h, 3 d, 4 d, 7 d, 14 d, 21 d, 28 d, 56 d and 84 d. Table 18 Study structure of the in vivo study of Example 8.

[0238] 3.5 mg / ml tirzepatide dissolved in phosphate buffered saline was used as a reference. 1 mg / kg tirzepatide dose was given to 3 additional rats intravenously.

[0239] After administration, animals were followed for 4 days. Blood samples from the animals were collected from jugular vein to determine the level of tirzepatide at 5 min, 15 min, 30 min, 60 min, 2 h, 4 h, 8 h, 24 h, 48 h, 3 d and 4 d. Whole blood samples were collected into EDTA (K2) coated tubes. The EDTA coated blood sample tubes were centrifuged for plasma separation within 30 minutes of the sample collection. The plasma samples were transferred into plastics tubes and frozen within 1 hour after the sample collection. Frozen plasma samples were stored at about -20 °C. The plasma samples were prepared for analysis by protein precipitation. 30 pl sample of minipig plasma was mixed with 60 pl of acetonitrile containing the internal standard (50 nM repaglinide). Samples were mixed on tabletop shaker for 800 rpm for 3 minutes, and then centrifuged for 20 minutes at 2200 x g. Supernatant was transferred to low-binding Waters QuanRecovery analytical plate and diluted with equal volume of ultrapure water, then submitted to analysis with LC-MS / MS.

[0240] Separations were performed with a Waters Acquity LIPLC Premier Peptide CSH C18 2.1 *100 mm (1 .7 pm) column coupled with pre-column filter. The mobile phase consisted of two eluents: A was 0.1 % formic acid in water and B was acetonitrile. A chromatographic run with a gradient was used: 0 min^0.5 min A was 80 % (isocratic); from 0.5 min to 2.5 min A was decreased from 80 % to 20 %, from 2.5 min to 3 min was decreased from 20 % to 5 %, from 2.5 min to 3 min A was increased from 5 to 80 % and lastly A was held constant at 80 % from 3 min to 4 min. The column oven was set to +60 °C. Mass spectrometric detection was carried out using a Waters Xevo TQ-XS triple quadrupole MS.

[0241] After the animals designated for histopathology were sacrificed, the implantation sites and surrounding tissues were sampled, fixed in 4% phosphate-buffered formaldehyde solution and shipped to AnaPath Services GmbH (Liestal, Switzerland), where histopathological processing and histopathology evaluation were performed. All implantation site samples were embedded in paraffin, cut at a thickness of 2 - 4 pm and stained with Haematoxylin and Eosin (H&E) and Masson’s Trichrome stain (MT) according to AnaPath Services GmbH SOP’s. The slides were checked under the microscope for quality before histopathological examination was performed by the study pathologist. A semi-quantitative histopathology evaluation was performed per each implantation site sample on the stained HE and MT sections, according to an adapted ISO 10993-6 scoring.

[0242] At 28-day timepoint all test items produced similar histopathological features and comparable host tissue reactions with total scores between 10.5-12.3. Similar histological scores indicate that injectable silica hydrogel composites comprising water soluble additive were not more harmful to the tissue than injectable silica hydrogel composites without water soluble additive.

[0243] After the animals designated for content analysis were sacrificed, the implantation sites were collected. Most of the surrounding tissue was removed and samples were stored at below-20 °C within 30 minutes of removal. Total contents of silica and tirzepatide was analysed from the tissue samples by cutting the remnant to multiple pieces and adding buffered acidic fluoride solution to dissolve silica and therefore release tirzepatide. Tirzepatide and silica contents were measured from the samples. Relative silica and tirzepatide contents were calculated in relation to the injected silica and tirzepatide doses. The results are shown in Table 19. The average relative ratio of remaining tirzepatide to silica is calculated by taking, for each sample, the ratio of ‘Average tirzepatide remaining relative to total dose’ to ‘Average silica remaining relative to total dose,’ and then averaging these ratios across all samples.

[0244] Table 19 Content analyses of remaining material at injection site at time points 1 , 2 and 3 months.

[0245] When comparing in vivo results of Formulations 6-1 and 6-6 to results of Example 7 it is seen that the effects are to the same direction. This is seen from Cmax, API-to- silica ratios from content analyses of remaining material, and from tirzepatide plasma concentrations at 2- and 3-month time points. Dose adjusted Cmax value for formulation 6-1 was 304 kg*ng / ml / mg, for formulation 6-4 it was 447 kg*ng / ml / mg, for formulation 6-6 it was 383 kg*ng / ml / mg, and for formulation 6-8 it was 378 kg*ng / ml / mg. Dose adjusted concentrations were calculated by dividing the measured plasma concentration (ng / ml) with dose given to that animal (mg / kg). In Example 7 there was 62 % higher Cmax value for formulation 6-6 compared to formulation 6-1 , while in vivo difference based on dose adjusted pharmacokinetic profiles was 26 % to the same direction. On average, formulation 6-6 had lower concentrations at the end of the study of Example 8 compared to formulation 6-1. This was also expected based on results of Example 7. Lower concentration at the end of the study can be seen at 56-day where dose normalized concentration for formulation 6-6 was on average 12 kg*ng / ml / mg and for formulation 6-1 it was 27 kg*ng / ml / mg. At 84-day time point all groups had low concentrations indicating the end of release which is in conformity with content analyses of Table 19. Both formulations 6-1 and 6-6 showing silica being dissolved at the same time is also in conformity with Example 7 results. Dose adjusted pharmacokinetics profile is shown in Figure 13, which also shows that all formulations have good sustained release properties. The effects are expected to be more pronounced in in vitro testing, as geometric influences are stronger in vivo and because in vivo testing exhibits greater variability.

[0246] Overall, the addition of water soluble additives changed pharmacokinetics to the expected direction, the addition was safe based on histopathological results, and pharmacokinetic profiles were good. This is also an indication that water soluble additives can be used to modify formulation’s rheological properties, such as injection force, without compromising in vivo behaviour.

[0247] It will be appreciated that the composites and methods of the present invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It is e.g. apparent for the expert skilled that embodiments of the composites and methods have corresponding method and composite, respectively, embodiments. It will be apparent for the expert skilled in the field that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.

Claims

CLAIMS1. A silica hydrogel composite, which is shear-thinning and comprises a) up to 85 weight-% of silica microparticles having a maximum diameter of < 1 000 pm, combined with b) a silica sol which has a solid content of <5 weight-%, wherein at least one water soluble additive having a solubility in water of at least 3 mg / ml, at pH 7, at 25 °C, is encapsulated in at least some of the silica microparticles.

2. The silica hydrogel composite according to claim 1 , characterized in that the at least one water soluble additive has the solubility in water at least 5 mg / ml, more preferably at least 30 mg / ml, even more preferably at least 50 mg / ml, at pH 7, at 25 °C.

3. The silica hydrogel composite according to claim 1 or 2, characterized in that the silica hydrogel composite comprises at least one water soluble additive in amount in a range of 0.01 - 50 weight-% or 0.01 - 30 weight-%, preferably 0.03 - 20 weight- %, more preferably 0.05 - 15 weight-% or 0.07 - 10 weight-%, calculated from a total weight of the silica in the silica hydrogel composite.

4. The silica hydrogel composite according to claim 1 , 2 or 3, characterized in that the at least one water soluble additive is a saccharide, selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, their salts and derivatives, and any mixtures thereof.

5. The silica hydrogel composite according to claim 4, characterized in that the saccharide is selected from trehalose, cyclodextrin, hyaluronic acid, alginate, their salts and derivatives, and any mixtures thereof, preferably trehalose.

6. The silica hydrogel composite according to any of preceding claims 1 - 5, characterized in that the at least one water soluble additive is selected from Bvitamins, C vitamin, their derivatives, salts and hydroxides, and any mixtures thereof.

7. The silica hydrogel composite of according to any of preceding claims 1 - 6, characterized in that the at least one water soluble additive is selected from natural or synthetic B12 vitamin, their salts, hydroxides and any mixtures thereof.

8. The silica hydrogel composite according to any of preceding claims 1 - 7, characterized in that the at least one water soluble additive is selected from amino acids, such as arginine, aspartic acid, glutamic acid, lysine, proline, glycine, histidine, and methionine.

9. The silica hydrogel composite according to any of preceding claims 1 - 8, characterized in that at least one active pharmaceutical ingredient is encapsulated in at least some of the silica microparticles.

10. The silica hydrogel composites according to claim 9, characterized in that the at least one active pharmaceutical ingredient is selected from a GLP-1 receptor agonists, a dual GIP / GLP-1 receptor agonists, or a triple GIP / GLP-1 / GCG receptor agonists, or their pharmaceutically accepted salts.

11. The silica hydrogel composites according to claim 9, characterized in that the at least one active pharmaceutical ingredient is selected from peptides, proteins, fusion proteins, vaccine antigens, mRNA-based drugs and small-molecule drugs having molecular weight of <1000 Da.

12. The silica hydrogel composite according to claim 9, 10 or 11 , characterized in that at least one active pharmaceutical ingredient is encapsulated in the silica microparticle in amount of 0.001 - 70 weight-%, preferably 0.1 - 50 weight-%, more preferably 1 - 30 weight-%, calculated from the total weight of silica microparticle.

13. The silica hydrogel composite according to claim 9, 10 or 11 , characterized in that at least one active pharmaceutical ingredient is encapsulated in the silicamicroparticle in amount of 0.00001 - 15 weight-% or 0.00002 - 10 weight-%, preferably 0.0001 - 5 weight-% or 0.0003 - 3 weight-%, even 0.0005 - 0.9999 weight-%, calculated from the total weight of silica microparticle.

14. The silica hydrogel composite according to any of preceding claims 1 - 13, characterized in that at least 90 weight-% of the silica microparticles have the diameter in a range of 1 - 300 pm, preferably 1 - 100 pm, more preferably 1.5 - 30 pm, even more preferably 1 .5 - 20 pm.

15. The silica hydrogel composite according to any of preceding claims 1 - 14, characterized in that the silica hydrogel composite comprises 10 - 85 weight-% or 20 - 85 weight-%, preferably 25 - 80 weight-%, more preferably 30 - 75 weight-% of the silica microparticles, calculated from the total weight of the silica hydrogel composite.

16. The silica hydrogel composite according to any of preceding claims 1 - 15, characterized in that the silica hydrogel composite has a solid content in a range of 10 - 75 weight-% or 20 - 75 weight-%, preferably 30 - 60 weight-%, more preferably 40 - 55 weight-%.

17. The silica hydrogel composite according to any of preceding claims 1 - 16, characterized in that the silica sol has the solids content of <3 weight-%, preferably <1 weight-%.

18. The silica hydrogel composite according to any of preceding claims 1 - 17, characterized in that the silica sol comprises silica nanoparticles and agglomerates having a diameter in a range of 5 - 995 nm, preferably 50 - 900 nm, more preferably 50 - 800 nm.

19. The silica hydrogel composite according to any of preceding claims 1 - 18, characterized in that the silica hydrogel composite has an elastic modulus measured under small angle oscillatory shear in a linear viscoelastic region <1500 kPa, typically <1200 kPa.

20. The silica hydrogel composite according to any of preceding claims 1 - 19, characterized in that the silica microparticles are selected from the group consisting of spray dried silica microparticles, silica fibre fragments and moulded or casted silica monoliths as such or as crushed.

21. Use of the silica hydrogel composite according to any of claims 1 to 20 for an injectable formulation.

22. The silica hydrogel composite of any of claims 1 to 21 for administering an active pharmaceutical agent.

23. The silica hydrogel composite of claim 22 characterized in that administration is parenteral.

24. The silica hydrogel composite of claim 23 characterized in that administration is parenteral and selected from the group consisting of intravenous, intraarterial, intracardiac, topical, transdermal, intradermal, subcutaneous, intramuscular, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intraosseous, intraarticular, intraocular, intravitreal, subconjunctival, intrasternal, intravesical and intracavernosal.

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