Silica hydrogel composite comprising an active agent

Abstract

The invention relates to a silica hydrogel composite, which is shear thinning. The silica hydrogel composite comprises a) up to 85 weight-% of silica particles having a maximum diameter of ≤1000 µm, and b) a silica sol having a silica content of ≤5 weight-%. According to the invention the silica particles comprise an encapsulated agent selected from a GLP-1 receptor agonist, a dual GIP / GLP-1 receptor agonist, or a triple GIP / GLP-1 / GCG receptor agonist.

Description

[0001] SILICA HYDROGEL COMPOSITE COMPRISING AN ACTIVE AGENT

[0002] This invention relates to a silica hydrogel composite comprising silica particles and silica sol according to preambles of the enclosed independent claims. The invention relates also to the use of the silica hydrogel composites.

[0003] BACKGROUND OF THE INVENTION

[0004] Minimally invasive injectable API (active pharmaceutical ingredient) delivery systems utilizing thin needles (syringes, autoinjectors) for the injection of, e.g. suspensions, gels and gel-particle combinations, are attractive options for controlled drug delivery. This is true especially for parenteral long-acting release of APIs, such as small-molecule drugs, peptides, proteins, polypeptides, fusion proteins, mRNA, vaccine antigens, viral vectors, adjuvants, lipid nanoparticles, and many more.

[0005] Hydrogels are potential solutions for long-acting injectable controlled release materials when combined with other morphologies, e.g., with silica particles of different size, such as nanoparticles or microparticles. The resulting structures can be adjusted to be injectable with thin needles to obtain minimally invasive administration solutions, and the silica particles in the hydrogel can be adjusted to release the API for a prolonged period of time, e.g., from weeks to several months. The release would not be totally independent of the properties of API or other therapeutic and / or biologically active agents present. For example, for the spray- dried silica microparticles a higher API payload usually increases the initial burst. However, the combined structure of particles and hydrogels still have a major impact on the release kinetics. The hydrogel comprising silica particles thus forms a controlled-release carrier or matrix material for the API.

[0006] When dealing with different types of APIs, they may affect differently the controlled- release carrier or matrix material, such as injectable silica hydrogels composites comprising particles, such as silica microparticles, which controls the release rate of the API. Hence, specific adjustments of controlled release carrier or matrix material properties are sometimes needed depending on specific properties of APIs. Different API concentrations in controlled-release carrier or matrix material may also create challenges, e.g., there may be certain concentrations, where the effect of the API is small, but in some concentrations, typically at higher concentrations, the effect may be strong. Usually there is some difference in the dissolution and release rates between the silica microparticles and the injectable silica hydrogel composite comprising the same silica microparticles due to three-dimensional structure of injectable silica hydrogel composite, but the difference is not very big, because the solid network in the silica hydrogel composite is mainly composed of the silica microparticles, and the solid content is typically 40 - 50 weight-%. Thus, the pores in the hydrogel structure can be quite large, and the surface roughness is at the micrometer level meaning that the hydrogel surface structure is not a specifically compact structure. Hence, a big difference between the dissolution and release rate are not expected between the silica microparticles and the same microparticles in the injectable silica hydrogel composite.

[0007] In many medical conditions the subcutaneous injection is commonly used as the administration route. Injections are often taken once a week for a longer period of time starting with 2 x 1 month’s periods and continuing after that according to the need of the patient. Especially for younger and older patient groups, or for persons with limited memory or concentration, it may be challenging to remember or commit to the proper administration schedule. Hence, to decrease the number of injections, a long-acting injectable formulation, e.g., 1 - 3 months’ formulations, or even longer- acting formulations would be beneficial.

[0008] Glucagon-like peptide 1 (GLP-1 ) receptor agonist, a dual glucose dependent insulinotropic polypeptide and glucagon-like peptide 1 (GIP / GLP-1 ) receptor agonist and a triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon- like peptide 1 and glucagon (GCG) receptors (triple GIP / GLP-1 / GCG receptor agonist) are known medications for used as antidiabetic or weight management medicament. GLP-1 receptor agonists and a dual GIP and GLP-1 receptor agonist are used to treat, e.g., type 2 diabetes, obesity, and to control the blood sugar levels. A triple GIP / GLP-1 / GCG receptor agonist is currently tested in clinical experiments. For these GLP-1 receptor agonist, dual GIP / GLP-1 receptor agonist and triple GIP / GLP-1 / GCG receptor agonist the subcutaneous injection is commonly used as the administration route, and the injections are often taken once a week for a longer period of time. The treatment would clearly benefit from long-acting controlled- release administration form.

[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 disclosed shear-thinning hydrogel compositions are allsilica systems, where other solid components than biologically active agents or active pharmaceutical ingredients only comprise silica.

[0010] OBJECT AND SUMMARY OF THE INVENTION

[0011] An object of this invention is to minimise or possibly even eliminate the disadvantages existing in the prior art.

[0012] One object of the present invention is to provide a long-acting controlled-release administration form for a GLP-1 receptor agonist, a dual GIP / GLP-1 receptor agonist, or a triple GIP / GLP-1 ZGCG receptor agonist, or corresponding receptor agonists used as antidiabetic or weight management medication.

[0013] A further object of the present invention is to provide use for the silica hydrogel composite with encapsulated GLP-1 receptor agonist, dual GIP / GLP-1 receptor agonist or triple GIP / GLP-1 / GCG receptor agonist or corresponding receptor agonists used as antidiabetic or weight management medication.

[0014] A still further object of the present invention is to provide a method for preparing the silica hydrogel composite with encapsulated GLP-1 receptor agonist, dual GIP / GLP- 1 receptor agonist or triple GIP / GLP-1 / GCG agonist or corresponding receptor agonists used as antidiabetic or weight management medication.

[0015] These objects are attained with the invention having the characteristics presented below in the characterising parts of the independent claims. Some preferred embodiments of the invention are presented in the dependent claims.

[0016] The embodiments mentioned in this text relate, where applicable, to all aspects of the invention, even if this is not always separately mentioned.

[0017] A typical silica hydrogel composite according to the present invention is shear thinning and comprises a) up to 85 weight-% of silica particles having a maximum diameter of <1000 pm, and comprising an encapsulated agent selected from a GLP-1 receptor agonist, a dual GIP / GLP-1 receptor agonist, or a triple GIP / GLP-1 / GCG receptor agonist, and b) a silica sol having a silica content of <5 weight-%.

[0018] A typical use of the silica hydrogel composite according to the present invention is for an injectable formulation.

[0019] A typical silica hydrogel composite of according to the present invention is for use as antidiabetic or weight management medicament.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 illustrates the dissolution rate of silica from three different silica microparticles comprising tirzepatide, a dual GIP / GLP-1 receptor agonist.

[0022] Figure 2 illustrates the release rate of tirzepatide, a dual GIP / GLP-1 receptor agonist from three different formulations of the silica microparticles.

[0023] Figure 3 illustrates the release of tirzepatide (API), a dual GIP / GLP-1 receptor agonist from the injectable hydrogel composite comprising silica microparticles, which comprise 20 weight-% of tirzepatide as encapsulated agent. Figure 4 illustrates average plasma tirzepatide concentration (ng / ml) by time (days) of silica hydrogel composite (filled squares) and commercial reference material (filled circles). Error bars represent standard deviation between different animals.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] The gist of the present invention is that the GLP-1 receptor agonist, dual GIP / GLP- 1 receptor agonist and triple GIP / GLP-1 / GCG receptor agonist can surprisingly be encapsulated in the silica microparticles of the silica hydrogel composite with relatively high payloads. This is possible despite the lipidated structures, i.e. the fatty acid side chains, of the said receptor agonists, increasing their hydrophobicity. It was unexpectedly found that the release rates of GLP-1 receptor agonist, dual GIP / GLP-1 receptor agonist and triple GIP / GLP-1 / GCG receptor agonist can be controlled from the silica hydrogel composites in spite of their specific molecular structure. The hydrophobic lipidated structure of the receptor agonist can also be used in the fine-tuning of the release rate of the active pharmaceutical ingredient.

[0026] In the present context, the viscoelastic properties of the materials, such as sols, gels, are 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:

[0027] 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

[0028] 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. 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 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.

[0029] 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 lowest amplitude in the sweep.

[0030] 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, i.e., a colloidal dispersion, where solid phase(s) form(s) the continuous phase and the liquid(s) is / are homogeneously dispersed in the continuous phase. The solid phase(s) may comprise silica as such and / or silica as partly or fully hydrolysed. The liquid phase may comprise, in addition to water, ethanol and residuals of silica precursors. The gel is viscoelastic and the elastic properties dominate, which is indicated by rheological measurements under small angle oscillatory shear in the linear viscoelastic region that the elastic modulus, G’ is greater than the viscous modulus, G”. In the present context, preferably G’ is <100 x G”; more preferably G’ is >3 x G” and / or G’ is <30 x G”; more preferably G’ is >5 x G” and / or G’ is <10 x G”. Hydrogel should be understood to be a gel, where the liquid phase is water or where the liquid phase is substantially water-based. The liquid phase of a 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-%, even more preferably >95 weight-%, of water. The liquid phase can additionally comprise small amount of other liquids, typically organic solvents, e.g. ethanol. Preferably, the concentration of such solvents, e.g. ethanol, is <10 weight-%, more preferably <3 weight-%, even more preferably <1 weight-%. In the present context, the silica hydrogel composite is considered a hydrogel since it fulfils the basic criteria of a hydrogel. Accordingly, the term “hydrogel” is synonymous, interchangeable and equivalent to the term “silica hydrogel composite” in the present context. The silica hydrogel composite of the invention may preferably comprise 20 - 80 weight-% or 25 - 70 weight-%, more preferably 30 - 60 weight-%, more preferably 40 - 55 weight-% of water.

[0031] 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. 10-100-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”.

[0032] 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 and / or 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 in the linear viscoelastic region) is greater than the viscous modulus G”. Preferably G’ is <10x G”. For example, G’ is <1200 kPa, preferably <700 kPa, sometimes even <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.

[0033] So / 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, where the liquid phase(s), is / are the continuous phase and the solid phase(s) is / are homogeneously dispersed in the said liquid phase(s). In the present context, so / refers to silica sol, where the liquid phase(s) may comprise, in addition to water, for example ethanol and / or residuals of silica precursors. The solid phase(s) of silica sol may comprise colloidal particles of silica, possibly as partly or fully hydrolysed, and / or aggregates of said colloidal particles. In opposition to gel, a sol has clear flow properties and the liquid phase is dominating. In the present context, the term so / refers to and encompasses colloidal dispersions wherein the solid particles are <50 nm.

[0034] 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 the silica sols. Higher R-values, such as revalues between 300 and 400 are typical, when the silica sols are mixed with the ready-made silica microparticles to form a hydrogel composite. 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.

[0035] 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 are >50 nm.

[0036] 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 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 sol-gel transfer for the ready-made powders is possible especially for colloidal powders of particles with diameter ca. 5 pm or less. 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. Gel point shall be understood to mean the time point when a sol 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. 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.

[0037] 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.

[0038] Silica particles 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 particles comprise or consist of sol-gel derived silica.

[0039] 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 particles. 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 sol-gel 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 microparticles, by dip / drain / spin-coating to films, by extrusion to monolithic structures or by spinning to fibres.

[0040] Silica refers in the present context to amorphous silica as such, amorphous silica containing water, fully or partly hydrolysed amorphous silica, silica in water- dissolved form, such as silicic acid, or any mixtures of these.

[0041] Encapsulated agents are selected from glucagon-like peptide 1 (GLP-1 ) receptor agonist, a dual glucose dependent insulinotropic polypeptide and glucagon-like peptide 1 (GIP / GLP-1 ) receptor agonist or a triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon (GCG) receptors (triple GIP / GLP-1 / GCG receptor agonist). The encapsulated agent is inside of the silica microparticles of the silica hydrogel composite.

[0042] The burst, initial burst or burst release should be understood to be the amount of the encapsulated agent 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.

[0043] In the present context solid content refers to the proportion of non-volatile material weight (after the volatile material, such as solvent, has evaporated or vaporized) to the total weight of the material (before evaporation or vaporization of the volatile material). In the present context, when the silica hydrogel composite comprises a particular weight per cent (weight-%) of silica particles, then the weight-% is calculated from the total weight of the silica hydrogel composite, i.e. from the amount of silica particles and silica sol used to obtain the silica hydrogel composite. Thus, if e.g. 100 g of silica particles is mixed with 900 g of silica sol, then the weight-% of silica particles in the silica hydrogel composition is 10 weight-%. If the silica hydrogel composite is obtained by first preparing a suspension of the silica particles, then the percentage is calculated from the original weight of the silica particles in comparison to the final total weight of the silica hydrogel composite, which is then the weight of the silica particles + the weight of liquid used to make a suspension of the silica particles + the weight of the silica sol.

[0044] The shear-thinning, injectable silica hydrogel composite of the present invention, comprising silica microparticles with encapsulated agent selected from GLP-1 receptor agonists, dual GIP / GLP-1 receptor agonists or triple GIP / GLP-1 / GCG receptor agonists, addresses practical challenges with the said receptor agonists. Furthermore, the present invention shows that the said receptor agonists surprisingly affect the release from the silica microparticles and from the injectable silica hydrogel composites. One specific feature of the invention is that the higher payload of the said receptor agonists in the silica microparticles resulted in a lower than expected initial burst. In addition, the dissolution rate of silica and the release rate of the said receptor agonists from the injectable silica hydrogel composites were clearly slower than the dissolution and release rates from the silica microparticles, which were used as the solid phase in the injectable hydrogel composites. Surprisingly, the difference was unexpectedly big between the silica microparticles and the injectable silica hydrogel composite comprising the same microparticles. The GLP-1 , dual GIP / GLP-1 or triple GIP / GLP-1 / GCG receptor agonists, despite their fatty acid side chains, can thus be encapsulated in the silica microparticles in high payloads, and their release rates can be controlled from the silica hydrogel composites in spite of their specific molecular structure. According to one embodiment of the invention the encapsulated agent comprises a hydrophobic fatty acid side chain, i.e. has a hydrophobic structure. The hydrophobic fatty acid side chain may have a carbon chain length of at least 5 carbon atoms, for example a carbon chain length of 5 - 26 carbon atoms, preferably 16 - 22 carbon atoms. The hydrophobic structure makes the encapsulated agent significantly different from other active pharmaceutical ingredients typically used in the silica hydrogel composite technology. The hydrophobic structure can also be used in the fine-tuning of the release rate of the encapsulated agent. It is speculated, without wishing to be bound by a theory, that the fatty acid side chain, and the hydrophobicity caused by it, changes the release behaviour of the silica microparticles and injectable silica hydrogel composite comprising the same microparticles. Surprisingly, that change can be used to decrease the burst by increasing the concentration of the encapsulated agent. The change in the concentration of encapsulated agent also affects the dissolution rate of silica and release rate from the injectable silica hydrogel composites. The dissolution rate of silica and the release rate of the encapsulated agent is slower than expected from injectable silica hydrogel composites. Because also the dissolution rate of silica is decreased more than expected, the encapsulated agent with the hydrophobic fatty acid side chain also affects the hydrophobicity of the silica microparticles, which slowed down the dissolution rate of silica. Hence, the molecules comprising a fatty acid side chain, which are used as antidiabetic or weight management medication can be encapsulated in the silica microparticles and injectable silica hydrogel composites to reach optimal release behaviour.

[0045] The components of the silica hydrogel composite are: silica particles, preferably silica microparticles, prepared by, e.g., spray-drying; and silica sols, e.g., silica sols comprising silica nanoparticles and / or silica nanoparticle agglomerates. After combination of the components, or after combination of the components and application into tissue or tissue fluids or to simulated body / tissue fluids, an integrated structure is formed that can be defined to be a silica hydrogel composite.

[0046] The silica hydrogel composite may also comprise an additional agent, such as a polysaccharide, citric acid, salts of citric acid, or any of their mixtures, in the liquid phase of the hydrogel. The additional agents may function as rheology modifiers. The salts of citric are preferably selected from monosodium citrate or its hydrates, disodium citrate or its hydrates, or trisodium citrate or its hydrates, and most preferably from trisodium citrate or its hydrates. The polysaccharide may be alginic acid, alginate or their salts, or from hyaluronic acid, hyaluronate or their salts, most preferably from alginic acid, alginate or their salts. Even monosaccharides and / or disaccharides can be used as an additional agent, either alone or as a mixture with citric acid or any of its salts.

[0047] The silica hydrogel composite comprises or preferably consists of a continuous solid phase with liquid homogeneously dispersed within the solid phase and where the elastic modulus of the silica hydrogel composite is higher than its viscous modulus indicating that the solid phase dominates the properties of the silica hydrogel composite, and it is non-flowing at rest, e.g., as stored in a syringe. Despite this, the hydrogel composite is shear-thinning and easily injectable from syringes or autoinjectors through thin needles, when stress is applied due to injection.

[0048] The silica hydrogel composite is an injectable gel. 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 composites are injectable, flowing and / or extrudable, because they are 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 original viscosity of the silica hydrogel composite is restored.

[0049] The silica hydrogel composites are applicable for long-acting, e.g., from weeks to 12 months, release of the encapsulated agent selected from GLP-1 receptor agonists, dual GIP / GLP-1 receptor agonists or triple GIP / GLP-1 / GCG receptor agonists.

[0050] The silica hydrogel composite may comprise silica sol having a solid content of <5 weight-%, preferably <3 weight-%, more preferably <1 weight-%, calculated from the total weight of the silica sol. The silica content of the silica sol may be in a range of 0.1 - 5 weight-%, preferably 0.5 - 3 weight-%, more preferably 0.6 - 1 weight-%, calculated from the total weight of the silica sol. The silica sol comprises silica nanoparticles as a solid phase and water as a liquid phase. The silica sol comprises more than 50 weight-% of water, calculated from the total weight of the silica sol. Preferably the liquid phase of the silica sol comprises >80 weight-%, more preferably >90 weight-% and even more preferably >97 weight-%, of water, calculated from the total weight of the silica sol. It is assumed that the silica nanoparticles may be incorporated or merged with the surface of the silica particles and thus enhance the formation of the silica network of the hydrogel composite. The silica sol may comprise 0.1 - 5 weight-%, preferably 0.5 - 3 weight-%, more preferably 0.6 - 1 weight-%, of silica nanoparticles, calculated from the total weight of the silica sol. Preferably, the silica present in the silica sol mainly originates from silica nanoparticles. For example, 0.6 weight-% of silica nanoparticles correspond to R- value of 500, 0.82 weight-% of silica nanoparticles correspond to R-value of 400, and 5 weight-% of silica nanoparticles correspond to ca. R value of 5, when tetraethyl orthosilicate (TEOS) is used as the silica precursor.

[0051] According to one embodiment of the invention, the silica particles comprised in the silica hydrogel composite may comprise from 0.1 to 70 weight-%, preferably from 0.3 to 50 weight-%, more preferably from 0.5 to 45 weight-%, even more preferably from 1 to 30 weight-% of the encapsulated agent, calculated from the total weight of silica microparticle.

[0052] Silica particles in the silica hydrogel composite have a maximum diameter of <1000 pm. According to one embodiment at least 90 % of the silica particles comprised in the silica hydrogel composite may be microparticles having a diameter in a range of 1 - 300 pm, preferably 1 - 100 pm, more preferably 1 - 30 pm, even more preferably 1 - 20 pm. According to one embodiment at least 95 % of the silica particles may be microparticles having a diameter at least 1 pm or over. Particle size can be measured by using laser diffraction.

[0053] According to one embodiment of the invention the silica hydrogel composite comprises silica sol comprising silica nanoparticles which may have a diameter in a range of 5 - 1000 nm, preferably 50 - 1000 nm or 100 - 1000 nm, and more preferably 200 - 1000 nm. The particle diameter can be determined by using dynamic light scattering. Silica nanoparticles in the silica sol contribute to the gel formation as they merge to the surface of much larger silica microparticles, wherein the whole structure turns into a non-flowing hydrogel structure.

[0054] The silica hydrogel composite may comprise up to 85 weight-%, preferably up to 80 weight-%, of silica particles having a maximum diameter of <1000 pm, calculated from the total weight of the silica hydrogel composite. According to one embodiment, the silica hydrogel composite may comprise 5 - 85 weight-%, preferably 5 - 80 weight-%, more preferably 20 - 80 weight-%, even more preferably 30 - 80 weight- %, of the silica particles, calculated from the total weight of the silica hydrogel composite.

[0055] According to one embodiment the silica hydrogel composite may have a solid content in a range of 20 - 75 weight-%, preferably 30 - 60 weight-%, more preferably 40 - 55 weight-%, calculated from the total weight of the silica hydrogel composite.

[0056] The silica hydrogel composite may have an elastic modulus G’ <1200 kPa, preferably <700 kPa or <300 kPa, sometimes even <100 kPa, measured under small angle oscillatory shear in a linear viscoelastic region, at 20 - 25 °C.

[0057] According to one embodiment of the invention the encapsulated agent comprises or consists of a dual GIP-GLP-1 receptor agonist comprising tirzepatide and / or its pharmaceutically accepted salts. The dual GIP-GLP-1 receptor agonist may consist of tirzepatide and / or its pharmaceutically accepted salts. The silica hydrogel composite comprising dual GIP-GLP-1 receptor agonist and / or its pharmaceutically accepted salts as encapsulated agent may be for used as antidiabetic or weight management medicament. According to one embodiment of the invention, the silica particles in the silica hydrogel composite may comprise from 0.1 to 70 weight-%, preferably from 0.3 to 50 weight-%, more preferably from 0.5 to 45 weight-%, even more preferably from 0.5 to 30 weight-% of the dual GIP / GLP-1 receptor agonist as the encapsulated agent, calculated from the total weight of silica microparticle.

[0058] According to another embodiment of the invention the encapsulated agent comprises or consists of a GIP / GLP-1 / GCG receptor triple agonist comprising retatrutide and / or its pharmaceutically accepted salts. The GIP / GLP-1 / GCG receptor triple agonist may consist of retatrutide and / or its pharmaceutically accepted salts. The silica hydrogel composite comprising triple GIP / GLP-1 / GCG receptor agonist and / or its pharmaceutically accepted salts as encapsulated agent may be for use as antidiabetic or weight management medicament. According to one embodiment of the invention, the silica particles in the silica hydrogel composite may comprise from 0.1 to 70 weight-%, preferably from 0.3 to 50 weight-%, more preferably from 0.5 to 45 weight-%, even more preferably from 0.5 to 30 weight-% of the triple GIP / GLP-1 / GCG receptor agonist as the encapsulated agent, calculated from the total weight of silica microparticle.

[0059] According to yet another embodiment, the encapsulated agent comprises or consists of a GLP-1 receptor agonist comprising liraglutide and / or its pharmaceutically accepted salts. The GLP-1 receptor agonist may consist of liraglutide and / or its pharmaceutically accepted salts. The silica hydrogel composite comprising GLP-1 receptor agonist and / or its pharmaceutically accepted salts as encapsulated agent may be for use as antidiabetic or weight management medicament. According to one embodiment of the invention, the silica particles in the silica hydrogel composite may comprise from 0.1 to 70 weight-%, preferably from 0.3 to 50 weight-%, more preferably from 0.5 to 45 weight-%, even more preferably from 0.5 to 30 weight-% of the GLP-1 receptor agonist as the encapsulated agent, calculated from the total weight of silica microparticle.

[0060] Tirzepatide, liraglutide and retatrutide are used to treat type 2 diabetes and obesity, and to control the blood sugar levels. The silica hydrogel composites according to the present invention comprising an encapsulated agent selected from a GLP-1 receptor agonist, a dual GIP / GLP-1 receptor agonist, or a triple GIP / GLP-1 / GCG receptor agonist, are suitable for use in treatment of type 2 diabetes, or can be used to control the blood sugar levels. In another embodiment according to the present invention silica hydrogel composites according to the present invention comprising an encapsulated agent selected from a GLP-1 receptor agonist, a dual GIP / GLP-1 receptor agonist, or a triple GIP / GLP-1 / GCG receptor agonist, are suitable for use in treatment of obesity, or can be used to manage weight, especially in obese patients.

[0061] A method according to the present invention for treating type 2 diabetes or obesity, or controlling the blood sugar levels, or managing weight, comprises administering silica hydrogel composites according to the present invention comprising an encapsulated agent selected from a GLP-1 receptor agonist, a dual GIP / GLP-1 receptor agonist, or a triple GIP / GLP-1 / GCG receptor agonist to a patient.

[0062] The silica hydrogel composite may be for parenteral administration or surgical implantation. Preferably the silica hydrogel composite is administrated parenterally. Parental administration may be selected from a group consisting of intravenous, intraarterial, intracardiac, topical, transdermal, intradermal, subcutaneous, intramuscular, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intraosseous, intraarticular, intraocular, intrasternal, intravesical and intracavernosal administration.

[0063] Preferably the silica microparticles are selected from a group consisting of spray- dried silica particles, silica fibre fragments and moulded or casted silica monoliths, as such or as crushed.

[0064] EXAMPLES

[0065] The following non-limiting examples illustrate some embodiments of the invention.

[0066] Example 1

[0067] Preparation of Silica Microparticles Comprising Tirzepatide

[0068] Tirzepatide is a GIP / GLP1 -receptor agonist used as antidiabetic and weight management medicament. Three silica sols were mixed with active pharmaceutical ingredient tirzepatide solutions in three different concentrations to prepare silica microparticles with three different payloads of tirzepatide as described below.

[0069] Three identical silica sols were prepared by hydrolyzing tetraethyl orthosilicate (TEOS by Merck) in water. The molar water-to-TEOS ratio for the three 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 R5 silica sols were cooled down to ca. 0 °C in an ice-bath.

[0070] 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.

[0071] 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 were 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).

[0072] 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. In the spraydrying of the silica microparticles with Buechi S-300 spray-dryer, the inlet temperature was 100 °C, outlet temperature 51 °C, aspirator at 20 m3 / h, pump at ca. 6 ml / min and the atomization air flow was at 670 l / h.

[0073] The resulting particle size distributions of the silica microparticles comprising tirzepatide were measured by laser diffraction (HELOS 2370, Sympatec) and the results are shown in Table 1. The measured mean values D10, D50 and D90 indicate the percentage (10 %, 50 %, and 90 %) of particles below a certain size. Table 1 Particle size distributions of the silica microparticles comprising tirzepatide.

[0074] Three parallel measurements for determining dissolution rate of silica and release rate of tirzepatide were conducted in 50 mM TRIS buffer, pH 7.4, at 37 °C. The dissolution conditions were kept in sink conditions (below ca. 20 % of the saturation solubility limit of silica and tirzepatide to ensure free dissolution and no decrease of dissolution or release rate due to dissolution products). It is known from a large number of experiments that the in vitro in sink dissolution rate of silica and release rate of an API correlate with in vivo release. For example, the dissolution rates and release rates are usually ca. 10 times slower in subcutaneous or intramuscular tissue than in the in vitro in sink conditions at pH 7.4 and 37 °C.

[0075] The in vitro in sink dissolution rates of silica and release rates of tirzepatide from the silica microparticles are summarized in Figure 1 and Figure 2. The release rates are quite similar, only some decrease in rates can be observed at the end of the release. There was some burst (fast early phase release, measured here after 1 hour of release) for every formulation: ca. 10 % for the silica microparticles with the payload of 5 weight-%, ca. 8 % for the silica microparticles with the payload of 10 weight-%, and ca. 6 % for the silica microparticles with the payload of 20 weight-%. Surprisingly the burst was the smallest with highest tirzepatide payload, with 20 weight-%. Usually it is expected that the burst is higher when the payload is higher. There were small differences in the particle size distributions between the formulations, but it does not explain with the dissolution and release results, because a slightly larger silica microparticles showed a slightly faster dissolution rate of silica and release rate of tirzepatide. It shows that the concentration of tirzepatide in the silica microparticles affects the dissolution and release more than the small differences in the particle size.

[0076] Example 2

[0077] Injectable Silica Hydrogel Composite Comprising Silica Microparticles with Encapsulated Tirzepatide

[0078] Injectable silica hydrogel composites were prepared by using the silica microparticles comprising 20 weight-% of tirzepatide from Example 1 .

[0079] The R400 silica sol (corresponds to ca. 0.8 weight-% of silica nanoparticles) was made by hydrolyzing TEOS in molar water-to-TEOS ratio of 400 at pH 2. After the hydrolysis, the pH was adjusted to pH 6.1.

[0080] Silica hydrogel composites were prepared by mixing the silica microparticles comprising 20 weight-% of tirzepatide into the R400 silica sol at pH 6.1 in 1 :1 ratio (weight-to-volume). The resulting mixtures were transferred into syringes, and the syringes were attached into a roller mixer, and they were kept at room temperature until a hydrogel structure was formed.

[0081] Despite the properties of tirzepatide, such as increased hydrophobicity, it was possible to form a homogeneous mixture, even if e.g., the wetting of the silica microparticles in the R400 silica sol was slow. After proper wetting, the mixtures were kept in the roller mixer for 72 hours to ensure formation on a shear-thinning silica hydrogel composite structure.

[0082] Elastic modulus G’ and loss modulus G” was measured for the obtained silica hydrogel composite. The measurement results are shown in Tables 2a and 2b. It can be seen from the measured values that the silica hydrogel composite was shear thinning and the elastic modulus G’ in the linear viscoelastic region, i.e. the silica hydrogel composite is a gel at rest, e.g. when stored in a syringe.

[0083] The dissolution rate of silica and release rate of tirzepatide from the injectable silica hydrogel composites comprising silica microparticles with 20 weight-% of encapsulated tirzepatide, mixed with R400 silica sol in ratio 1 :1 weight-to-volume are shown in Figure 3. Corresponding results for the plain silica microparticles comprising 20 weight-% of tirzepatide are shown in Figure 1 and 2. When comparing the results in Figures 1 , 2 and 3, it can be observed that 83 % of silica and 94 % of tirzepatide were released in seven days from the plain silica microparticles comprising 20 weight-% of tirzepatide, but from the injectable silica hydrogel composite comprising the same silica microparticles, only 56 % of silica and 68 % of tirzepatide were released in seven days. The difference is larger than expected from the three-dimensional structure of the injectable hydrogel composite in the in vitro measurements, and it is suggested to depend on the hydrophobic nature of tirzepatide.

[0084] Table 2a Viscosity values under shear. Table 2b Elastic and loss modulus values .

[0085] Example 3

[0086] In Vivo Experiments Comparing Injectable Silica Hydrogel Composite Comprising Silica Microparticles with Encapsulated Tirzepatide and a Commercial Prefilled Pen with Tirzepatide in Solution

[0087] Silica hydrogel composite comprising silica microparticles with encapsulated tirzepatide was prepared using R10-100 microparticles with 7.6 % (w / w) of tirzepatide and R400 silica sol as generally described in Examples 1 and 2. The final silica hydrogel composite comprising 37 mg / ml of tirzepatide was prefilled in syringes for subcutaneous administration in 6 minipigs. The ready-to-use prefilled syringes with an injection volume of 0.3 ml were used to study the pharmacokinetics of 11 mg tirzepatide in a single dose. After the administration, three of the animals were followed for 28 days and the other three for 84 days. Blood sampling from the animals were collected from jugular vein to determine the level of tirzepatide at 0 min, 30 min, 60 min, 4 h, 8 h, 24 h, 2 d, 3 d, 4 d, 7 d, 14 d, 21 d, 28 d, 56 d and 84 d.

[0088] A commercial prefilled pen for self-administration with tirzepatide in solution was used as reference material. 3 minipigs were administered with commercial reference material with dose of 2.5 mg tirzepatide dose in 0.6 ml volume. After the administration animals were followed for 14 days. Blood sampling from the animals were collected from jugular vein to determine the level of tirzepatide at 0 min, 30 min, 60 min, 3 h, 6 h, 12 h, 24 h, 2 d, 3 d, 7 d, 12 d and 14 d. Whole blood samples were collected into EDTA (K2) coated tubes. The EDTA collection blood sample tube was centrifuged for plasma separation within 30 minutes of the collection of the blood sample. The separated plasma samples were transferred into plastics tubes and frozen within 1 hour after the collection of the blood sample. Frozen plasma samples were stored at about -20°C. The plasma samples were prepared for analysis by protein precipitation. 30 pl of sample mini pig plasma was mixed with 60 pl of acetonitrile containing the internal standard (50 nM repaglinide). Sample was 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.

[0089] 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.

[0090] The average concentrations and standard deviations are depicted in Figure 4, where filled squares represent silica hydrogel composite and filled circles represent commercial reference material. Initial absorption was slower in the silica hydrogel composite compared to the commercial reference with t(max) at 6 hours when calculated from average plasma concentrations and 6 hours, 12 hours or 24 hours when calculated with individual animals. With silica hydrogel composite t(max) is 168 hours when calculated from average plasma concentrations and 72 hours (1 animal) or 168 hours (5 animals) when calculated with individual animals. For human use the commercial reference material is administered once a week and in this study average tirzepatide plasma concentration was on average 525 ng / ml at 7 days time point. For silica hydrogel composite similar concentration (598 ng / ml on average) is reached at 14 days time point. Overall, the results demonstrates that the release of tirzepatide is slower from silica hydrogel composite compared to the commercial reference material.

[0091] 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 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 particles having a maximum diameter of <1000 pm, and comprising an encapsulated agent selected from a GLP-1 receptor agonist, a dual GIP / GLP-1 receptor agonist, or a triple GIP / GLP-1 / GCG receptor agonist, and b) a silica sol having a silica content of <5 weight-%.

2. The silica hydrogel composite of claim 1 , characterized in that the silica sol has the silica content of <3 weight-%, preferably <1 weight-%.

3. The silica hydrogel composite of claim 1 or 2, characterized in that the silica particles comprise from 0.1 to 70 weight-%, preferably from 0.3 to 50 weight-%, and more preferably from 1 to 30 weight-% of the encapsulated agent.

4. The silica hydrogel composite of any of preceding claims, characterized in that at least 90 % of the silica particles are microparticles having a diameter in a range of 1 - 300 pm, preferably 1 - 100 pm, more preferably 1 - 30 pm, even more preferably 1 - 20 pm.

5. The silica hydrogel composite of any of preceding claims, characterized in that the silica sol comprises silica nanoparticles, preferably having a diameter in a range of 5 - 1000 nm, preferably 50 -1000 nm, more preferably in a range of 100 -1000 nm, even more preferably in a range of 200 -1000 nm.

6. The silica hydrogel composite of any of preceding claims, characterized in that the silica hydrogel composite comprises up to 80 weight-%, preferably from 20 to 80 weight-%, more preferably from 30 to 80 weight-% of the silica particles.

7. The silica hydrogel composite of any of preceding claims, characterized in that the silica hydrogel composite has a solid content in a range of 20 - 75 weight-%, preferably in a range of 30 - 60 weight-%, more preferably in a range of 40 - 55 weight-%, calculated from the total weight of the silica hydrogel composite.

8. The silica hydrogel composite of any of preceding claims, characterized in that the silica hydrogel composite has an elastic modulus <1200 kPa, preferably <700 kPa, sometimes even <100 kPa, measured under small angle oscillatory shear in a linear viscoelastic region, at 20 - 25 °C.

9. The silica hydrogel composite of any of preceding claims, characterized in that the encapsulated agent comprises a hydrophobic fatty acid side chain having a carbon chain length of at least 5 carbon atoms.

10. The silica hydrogel composite of any of preceding claims, characterized in that the encapsulated agent comprises a dual GIP / GLP-1 receptor agonist comprising tirzepatide or its pharmaceutically accepted salts.11 .The silica hydrogel composite of any of preceding claims, characterized in that the encapsulated agent comprises a triple GIP / GLP-1 / GCG receptor agonist, comprising retatrutide or its pharmaceutically accepted salts.

12. The silica hydrogel composite of any of preceding claims characterized in that the encapsulated agent comprises a GLP-1 receptor agonist comprising liraglutide or its pharmaceutically accepted salts.

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

14. Use of the silica hydrogel composite according to any of claims 1 to 13 for an injectable formulation.

15. The silica hydrogel composite of any of claims 1 to 13 for use as antidiabetic or weight management medicament.

16. The use of the silica hydrogel composite of claim 14 or 15, characterized in that the silica hydrogel composite is administrated parenterally.

17. The use of the silica hydrogel composite according to claim 16, characterized in that the parenteral administration is selected from the group consisting of intravenous, intraarterial, intracardiac, topical, transdermal, intradermal, subcutaneous, intramuscular, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intraosseous, intraarticular, intraocular, intrasternal, intravesical and intracavernosal administration.

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