Injectable compound depot

Abstract

The present invention relates to an injectable composite depot that exhibits shear-thinning properties. The composite depot comprises up to 85% by weight of silica microparticles having a maximum diameter of 1000 μm or less and preferably containing at least one encapsulated biologically active agent. The microparticles are combined with a silica sol having a silica content of 5% by weight or less, preferably 2% by weight or less, and more preferably 1% by weight or less. The injectable composite depot further comprises at least one pharmaceutically inactive additive encapsulated in the silica microparticles and / or present in the silica sol.

Description

Technical Field

[0001] The present invention relates to an injectable composite depot according to the preamble of the appended independent claims.

Background Art

[0002] Minimally invasive injectable delivery systems that utilize thin needles, such as suspensions, gels, and combinations of gels and particles, are attractive options for controlled drug delivery, particularly for the parenteral long-term release of pharmaceutical active ingredients (APIs). Injectable delivery systems may also be used for topical administration, in which case gels or combinations of gels and particles can be used for the sustained release of APIs, such as in eye drops. Injectable formulations typically contain both a liquid phase and a solid phase, such as gels, combinations of gels and particles, and suspensions.

[0003] For example, when dealing with small molecule drugs, peptides, proteins, polypeptides, fusion proteins, mRNA, vaccine antigens, viral vectors, adjuvants, lipid nanoparticles, and many other different types of APIs, it may be necessary to modify the components used in the injectable formulation in order to achieve the desired rheology and injectability, as well as the desired controlled release rate. The presence of an API can potentially change the properties of both the solid and liquid phases of an injectable formulation, and the API can have different effects on the solid and liquid phases. If the API is present in both the solid and liquid phases at different concentrations, the release rate can be further affected. If the API is uniformly distributed in the solid phase, for example, in microparticles in a suspension or gel, the surface chemistry of the solid phase can also potentially change for each API, which affects the stability, rheology, and injectability of the suspension or gel. The potency of APIs can vary greatly, and therefore the concentration of APIs in the injection and on the surface of the particles can also vary greatly.

[0004] The biodegradable materials used in injectable formulations may require fine-tuning of desired properties, such as controlled release rate and injectability. This is particularly true when the release of an API is controlled by the biodegradation rate of the solid components of the injectable formulation in body fluids, for example, by the dissolution rate of microparticles containing encapsulated or embedded APIs. When the required dose of the API is high, and / or when injectability requires rheological properties that can only be achieved at high concentrations of solid components, the concentration of solids, such as microparticles, in the suspension or gel may be high. When the dissolution rate of solid components, such as microparticles, primarily controls the release rate of the API, a high concentration of solid components in the injectable volume can significantly delay the release rate. Depending on the location in the body and the local flow rate of body fluids, the dissolution of solid components may locally result in a concentration of dissolved products exceeding sink conditions (free dissolution), which slows the dissolution rate and therefore delays the release of the API. In extreme cases, the dissolution of solid components may even locally saturate body fluids with respect to the dissolved products within the tissue. In that case, the release rate of the API depends entirely on the fluid flow rate, that is, how quickly the fluid is replaced locally by the flow. Therefore, high concentrations of solid components in dissolution-rate-dependent injectable controlled-release depots may limit the possibility of achieving various API release rates. In addition, high local concentrations of dissolved solid product may cause undesirable tissue reactions and increase the tolerability risk to the injectable depot.

[0005] In international publication 2014 / 207304 by Jokinen et al., a shear-reducing composite hydrogel composition formed from spray-dried silica microparticles containing an encapsulated drug and a silica sol is disclosed. The disclosed shear-reducing hydrogel composition is all-silica-based, containing only silica as a solid component other than the biologically active drug or pharmacokinetic ingredient. Hydrogel compositions prepared from silica microparticles and silica sol, i.e., all-silica depots, function very well in most cases when injected through a fine needle. However, if the weight-to-volume ratio of silica microparticles to silica sol is less than 0.5, the hydrogel structure may be weak, the material may flow, and / or the material may be injectable through a fine needle. Also, in some cases, the use of a smaller amount of silica-based solid may be desirable to fine-tune the release rate of the API. The shear-reducing hydrogel composition also functions very well in many payloads with many types of pharmacokinetic ingredients. However, with some APIs, there may be challenges regarding the formation of a non-flowing hydrogel structure and injectability. For example, due to changes in nanoscale roughness on spray-dried silica microparticles, or due to encapsulated APIs, the surface of the silica microparticles may become more hydrophobic and / or its surface charge may change. This may inhibit wetting and gel formation, as well as injection of the hydrogel composition through a fine needle.

[0006] There is interest in further improving injectable compound depots and enabling their use with a wide variety of APIs and bioactive drugs. Furthermore, there is interest in further modifying the rheology and injectability of injectable compound depots. [Overview of the project]

[0007] The objective of this invention is to minimize, or even eliminate, the disadvantages present in the prior art, if possible.

[0008] One object of the present invention is an injectable composite depot having modified rheology and injectability.

[0009] A further object of the present invention is to provide an injectable compound depot with improved controlled release of pharmaceutical active ingredients and / or biologically active drugs.

[0010] Another object of the present invention is to provide applications for injectable compound depots having one or more encapsulated drugs.

[0011] A further object of the present invention is to provide an injectable compound depot for medical use, having one or more encapsulated drugs.

[0012] These objectives are achieved by the present invention, which has the following features in the feature section of an independent claim.

[0013] Some preferred embodiments of the present invention are shown in the dependent claims.

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

[0015] Typical injectable compound depots exhibit shear-thinning properties. a) Silica microparticles having a maximum diameter of 1000 μm or less, preferably containing at least one encapsulated biologically active agent, preferably a pharmaceutically active agent, in a maximum of 85% by weight, preferably up to 80% by weight, b) A silica sol having a silica content of 5% by weight or less, preferably 2% by weight or less, more preferably 1% by weight or less, Includes combinations of, The above-mentioned injectable composite depot comprises at least one pharmaceutically inactive additive encapsulated in the above-mentioned silica microparticles and / or present in the above-mentioned silica sol.

[0016] A typical injectable formulation according to the present invention comprises an injectable compound depot according to the present invention, preferably comprising a biologically active agent, more preferably a pharmaceutically active agent.

[0017] A typical use of the injectable compound depot of the present invention is for administering one or more biologically active agents, preferably one or more pharmaceutical active ingredients.

[0018] A typical injectable compound depot according to the present invention is intended for use as a pharmaceutical product. [Brief explanation of the drawing]

[0019] [Figure 1] Figure 1 shows the injection force required for injection through a 25G needle (inner diameter 0.25-0.26 mm) for various injectable compound depots, with and without pharmaceutically inactive additives in the silica microparticles and / or silica sol. [Figure 2] Figure 2 shows the injection force required for injection through a 25G needle (inner diameter 0.25-0.26 mm) for various injectable compound depots, with and without pharmaceutically inactive additives in the silica microparticles and / or silica sol. [Figure 3] Figure 3 shows the injection force required for injection through a 25G needle (inner diameter 0.25-0.26 mm) for various injectable compound depots, with and without pharmaceutically inactive additives in the silica microparticles and / or silica sol. [Figure 4] Figure 4 shows the cumulative in vitro dissolution rate of silica and the release rate of the active pharmaceutical ingredient, with and without the presence of pharmaceutically inactive additives in the silica microparticles and / or silica sol. [Figure 5] Figure 5 shows the cumulative in vitro dissolution rate of silica and the release rate of the active pharmaceutical ingredient, with and without the presence of pharmaceutically inactive additives in the silica microparticles and / or silica sol. [Figure 6]Figure 6 shows the cumulative in vitro dissolution rate of silica and the release rate of the pharmaceutical active ingredient with and without a pharmaceutically inactive additive in silica microparticles and / or silica sol. [Figure 7] Figure 7 shows the viscoelasticity, i.e., the storage modulus (elastic modulus) and the loss modulus (viscosity modulus), of an injectable composite depot containing silica microparticles mixed with silica sol with and without a pharmaceutically inactive additive. MODE FOR CARRYING OUT THE INVENTION

[0020] The gist of the present invention is to improve the rheological properties and injectability of a silica-based injectable composite depot by using a pharmaceutically inactive additive as a rheology modifier. Surprisingly, by incorporating a pharmaceutically inactive additive into the silica microparticles of the injectable composite depot and / or into the silica sol, it has been found that the rheological properties of the depot and the compatibility of biologically active agents such as pharmaceutical active ingredients with the injectable composite depot are improved. Some biologically active agents and pharmaceutical active ingredients (APIs) encapsulated in the silica microparticles, which are the main component of the injectable composite depot, may inhibit the formation of the injectable composite depot structure and, therefore, may also change its rheological properties and injectability. It has now been found that these problems can be overcome by using a pharmaceutically inactive additive. The pharmaceutically inactive additive is unexpectedly effective in controlling and modifying the rheological properties of the silica-based injectable composite depot. The ability to vary the rheological properties of the injectable composite depot also affects other properties of the injectable composite depot, which broadens the possibility of fine-tuning the properties of the injectable composite depot in the parenteral administration of biologically active agents and / or pharmaceutical active ingredients (APIs). The pharmaceutically inactive additive can also be used to reduce the concentration level of locally biodegradable silica in the tissue, which can be utilized for fine-tuning the release rate of biologically active agents and / or APIs. The change in the silica concentration in the injectable composite depot can also have a favorable effect on the local tolerance of the composite depot.

[0021] Term A depot should be understood as a drug delivery system suitable for the controlled release of pharmaceutically active agents such as pharmaceutical active ingredients and / or biologically active agents.

[0022] In the context of the present disclosure, a gel should be understood as a homogeneous mixture of at least one solid phase and at least one liquid phase, preferably one liquid phase, i.e., a colloidal dispersion, in which the solid phase forms the continuous phase and the liquid phase is uniformly dispersed in the continuous phase. A gel is viscoelastic, with elasticity being dominant at rest, as shown by rheological measurements under small angle oscillatory shear. When the loss factor (loss tangent) of the gel, tanδ = (G'' / G'), is less than 1, elasticity is dominant and the gel is non-fluid. The combined effect of the storage modulus (elastic modulus) G' and the loss modulus (viscosity modulus) G'' can also be represented in the form of the complex modulus (complex shear modulus), G* = G' + iG''. In the context of the present invention, a gel means a hydrogel (see below) in which the continuous phase contains silica itself, partially hydrolyzed silica, and / or fully hydrolyzed silica. Silica itself, partially hydrolyzed silica, and / or fully hydrolyzed silica are the main components of the continuous solid phase.

[0023] A hydrogel should be understood as a gel in which the liquid phase is water or the liquid phase is aqueous. The liquid phase of the hydrogel contains more than 50% by weight of water, calculated from the total weight of the liquid phase. Preferably, the liquid phase of the hydrogel contains more than 80% by weight, more preferably more than 90% by weight, and even more preferably more than 97% by weight of water. The liquid phase may further contain a small amount of other liquids, typically organic solvents such as ethanol. Typically, the concentration of such a solvent, such as ethanol, is less than 10% by weight, more preferably less than 3% by weight, and even more preferably less than 1% by weight, calculated from the total weight of the liquid phase. In the context of the present invention, the injectable composite depot of the present invention meets the basic criteria of a hydrogel and is thus considered a hydrogel.

[0024] A sol should be understood as a homogeneous mixture of at least one liquid phase and at least one solid phase, i.e., a colloidal dispersion or colloidal suspension, where the liquid phase is a continuous phase and the solid phase is uniformly dispersed within the liquid phase. In contrast to gels, silica sols have distinct fluidity, the liquid phase is dominant, i.e., the sol loss coefficient, tanδ=(G'' / G'), is greater than 1. In silica sols, the liquid phase mainly contains water, optionally containing small amounts of ethanol and silica precursor residues. The solid phase in silica sols includes colloidal silica nanoparticles, partially or completely hydrolyzed silica, aggregates of the nanoparticles, or any combination thereof.

[0025] A suspension should be understood as a mixture, or dispersion, of at least one liquid phase, preferably one liquid phase and at least one solid phase, where the liquid phase is a continuous phase and the solid phase is uniformly dispersed in the liquid phase. In the context of this disclosure, a suspension encompasses a diluted mixture of silica sol and silica microparticles, where the silica microparticles preferably contain a biologically active agent. A suspension also encompasses a mixture of silica sol, silica microparticles, and a pharmaceutically inactive additive, such as an alginate. A suspension has distinct fluidity, with the liquid phase being dominant, i.e., the sol loss coefficient, tanδ=(G'' / G'), is greater than 1. Since a suspension is not colloidal, it is typically required to mix the suspension, preferably continuously, to maintain a stable state.

[0026] In the context of this disclosure, the gelation point or gelation is understood to mean the point at which a flowing silica sol or suspension transforms into a non-flowing, predominantly elastic viscoelastic gel, where rheological measurements under small-angle vibrational shear show that the storage modulus (elastic modulus) G' is greater than the loss modulus (viscosity modulus) and the loss factor is less than 1. Viscoelasticity is generally measured using a rheometer (a measuring device for determining the correlation between deformation, shear stress, and time) under vibrational shear with small shear stress (small deformation angle). The measurement is carried out by ensuring an appropriate signal for a particular measurement system. That is, a strain sweep is generally performed at a constant frequency to find an appropriate signal and linear viscoelastic region for the rheometer system, and then the actual measurement is performed with constant strain and varying frequency. By varying the frequency, the elastic modulus and viscosity modulus change, and from these measurements, it can be determined whether the solid or liquid phase is dominant. In the form of silica sol, the liquid state is dominant, but the system contains varying amounts of solid phase, and the system is still fluid. Typically, a sharp increase in kinematic viscosity and storage modulus (elastic modulus) is observed before the gelation point, and this continues to rise after the gelation point as the structure develops. In the context of the present invention, the injectable composite depot is obtained after the combination of silica nanoparticles and a silica sol containing preferably pharmaceutically inactive additives has reached its gelation point. This means that the injectable composite depot has undergone gelation.

[0027] Accordingly, in the context of this disclosure, an injectable composite depot refers to a hydrogel comprising at least one pharmaceutically inactive additive and preferably one or more pharmaceutically and / or biologically active agents. In the hydrogel of the injectable composite depot, the solid phase comprises silica microparticles, and the liquid phase comprises water, optionally ethanol, and / or a residue of a silica precursor. The silica microparticles contain pharmaceutically and / or biologically active agents, which are optionally present but preferred. pharmaceutically inactive additives, such as alginates and / or citrates, may be present in the solid phase and / or liquid phase. When stored in a static state, for example, in a syringe, the injectable composite depot is non-flowing and structurally stable, and under shear, it exhibits shear-thinning behavior, i.e., viscosity decreases, making it easy to inject through an 18-31G needle (outer / inner diameter 1.27 / 0.84 mm-0.261 / 0.133 mm). Structural stability is demonstrated by rheological measurements under small-angle vibrational shear. Before injection, if stored, for example, in a syringe and / or aluminum foil, at a temperature below 37°C, e.g., room temperature of 20-25°C, or refrigeration temperature of 2-8°C, the injectable composite depot is a gel, i.e., the storage modulus (elastic modulus) G' is greater than the loss modulus (viscosity) G'', and the loss coefficient tanδ=(G'' / G') is less than 1. When the storage modulus (elastic modulus) is greater than the loss modulus (viscosity) and the loss coefficient is less than 1, the injectable composite depot is non-flowing. Silica nanoparticles and / or aggregated silica nanoparticles in the silica sol fuse or integrate with the surface of the silica nanoparticles, and in this process, the injectable composite depot acquires its non-flowing and structurally stable structure when stationary. Therefore, the presence of silica nanoparticles is important for obtaining the injectable composite depot. The non-flowing structure prevents phase separation of the solid phase and ensures the structural stability of the injectable composite depot. In other words, the silica microparticles and pharmaceutically inactive additives of the injectable compound depot are embedded in a hydrogel structure, and they do not precipitate or separate, for example, at the bottom of the container in which the injectable compound depot is stored, such as a syringe, at temperatures typically below 25°C.The injectable compound depot has a hydrogel structure and remains stable and non-flowing when stored in a static state, for example, in a pre-filled, ready-to-use syringe. However, because the hydrogel structure of the injectable compound depot is very loose, it becomes shear-thinning when shear stress is applied, for example, when injected through a thin needle from a syringe, using an 18-31G needle (outer / inner diameter 1.27 / 0.84mm-0.261 / 0.133mm). The same rheological properties and injectability can also be utilized in topical administration of gel eye drops from extrudeable devices, such as bottles, packs, and strips.

[0028] In the context of this disclosure, "injectable" means parenteral administration via surgical administration devices, such as needles, catheters, or combinations thereof, or topical administration of gel eye drops from extrudeable devices, such as bottles, packs, and strips.

[0029] In the context of this disclosure, shear viscosity reduction refers to the rheological properties of an injectable composite depot. Each time the shear rate of such an injectable composite depot changes or a shear stress is applied to the depot, the injectable composite depot gradually transitions to a new equilibrium state. The viscosity of the shear viscosity reduction composition increases with decreasing shear rate, and decreases with increasing shear rate. Therefore, shear viscosity reduction refers to the effect on the viscosity of an injectable composite depot, i.e., its resistance to flow, which decreases with increasing shear stress.

[0030] In the context of this invention, a biologically active agent refers to any organic or inorganic agent that is biologically active, that is, that induces a statistically significant biological response in a living tissue, organ, or organism. A biologically active agent may be a medicine, medicinal product, active pharmaceutical ingredient, vitamin, phytochemical, peptide, protein, fusion protein, polysaccharide, or polynucleotide, such as DNA and RNA, vaccine antigen, or viral vector. Preferably, the biologically active agent is an active pharmaceutical ingredient.

[0031] In the context of this invention, the term "pharmaceutical active ingredient (API)" refers to any substance or mixture of substances intended for use in the manufacture of a drug (pharmaceutical) product and which, when used in the manufacture of the drug, becomes the active ingredient of the drug. Such substances are intended to provide pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to affect the structure or function of a body. In the context of this disclosure, the terms "pharmaceutical active ingredient" and "pharmaceutically active agent" are used synonymously and are fully interchangeable.

[0032] Encapsulated drugs should be understood as drugs, active pharmaceutical ingredients (APIs), or other therapeutic and / or biologically active agents, or delivery devices, encapsulated within silica microparticles of an injectable composite depot.

[0033] In the context of this invention, a pharmaceutically inactive additive refers to any functional, pharmaceutically inactive component that improves the processing or characteristics of an injectable complex depot, such as gel formation, parenteral or topical administration, or the fine-tuning of the in vivo release rate of the active pharmaceutical ingredient (API) and other therapeutically and biologically active agents. A pharmaceutically inactive additive is a non-silica-based or non-silica-containing substance, compound, or component. A non-pharmaceutically active additive may be present in a silica sol and / or in silica microparticles, i.e., encapsulated within the silica microparticles of the injectable complex depot.

[0034] In the context of this disclosure, solids refer to the proportion of nonvolatile substances remaining after the evaporation of the volatile solvent. More specifically, solids may refer to the solids of a silica sol, or the solids of a mixture of a silica sol, a pharmaceutically inactive additive, such as an alginate, a citrate, and other additives as desired, or the solids of silica microparticles, or the solids of an injectable compound depot containing at least silica microparticles, a silica sol, at least one pharmaceutically active additive, and a biologically active agent as desired.

[0035] All-silica depot, all-silica injectable depot, injectable silica depot, or all-silica system refers to an injectable depot that does not contain additives such as alginates or citrates.

[0036] Features of the present invention According to the present invention, an injectable composite depot contains at least one pharmaceutically inactive additive present in, i.e., encapsulated in, silica microparticles and / or present in a silica sol. The at least one pharmaceutically inactive additive functions as a rheological modifier. A pharmaceutically inactive additive that affects surface properties may be incorporated into the microparticles and / or the silica sol. When incorporated into microparticles, the pharmaceutically inactive additive indirectly affects the rheological properties through a change in the surface properties of the microparticles. Alternatively, or additionally, a pharmaceutically inactive additive that directly alters the rheological properties of the injectable composite depot may be incorporated into the silica sol. A pharmaceutically inactive additive may be used to achieve a desired target product profile of the injectable composite depot. Suitable pharmaceutically inactive additives may be added to the liquid phase and / or solid phase during the manufacture of the injectable composite depot to optimize the total amount of encapsulated drug and / or the surface chemistry of the microparticles and to obtain desirable rheological properties for the injectable composite depot. Pharmacokinetically inactive additives may also be useful in the manufacture of injectable compound depots that do not contain encapsulated drugs or embedded APIs. Such injectable compound depots can be used, for example, as placebo materials in preclinical in vivo experiments or clinical trials, or they can be added to increase the total solids content of the injectable compound depot for desired rheological properties.

[0037] Pharmacokinetically inactive additives can be used to affect, for example, reduce the total solid content of an injectable complex depot. This is advantageous when the desired amount of a bioactive drug, such as an API, in a single shot or single dose can already be achieved at a low concentration of microparticles in the injectable complex depot. In these cases, the microparticle concentration may not be high enough to provide the appropriate rheological properties for injection. This problem can now be solved by using a pharmaceutically inactive additive that can reduce the total solid content of the injectable complex depot while maintaining rheological properties and injectability. Lower concentrations of silica microparticles in the injectable complex depot also reduce the influence of dissolution products on the release rate of bioactive drugs, such as APIs, providing more options for setting different controlled release rates at different locations in the body. The effect achieved is greater when the injectable complex depot is intended for use in confined spaces and with low fluid flow (e.g., intravitreous after intravitreal injection), but this effect also affects other common routes of administration of injectable drugs, namely subcutaneous and intramuscular injection. The potential tolerability risks are also reduced.

[0038] A first additive may be selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, or salts thereof, or any combination thereof; preferably from oligosaccharides, polysaccharides, or salts thereof, or any combination thereof; more preferably from polysaccharides or salts thereof, even more preferably from alginic acid, alginate salts, or salts thereof, or from hyaluronic acid, hyaluronic acid, or salts thereof, most preferably from alginic acid, alginate salts, or salts thereof. Suitable monosaccharides can be selected from, for example, glucose, fructose, dextrose, galactose, or mixtures thereof; suitable disaccharides can be selected from sucrose, trehalose, maltose, lactose, or mixtures thereof, preferably trehalose; suitable oligosaccharides can be selected from melegitose, raffinose, or various decomposition forms of polysaccharides, or any mixtures thereof. Suitable polysaccharides may be selected from starch, glycogen, chitin, chitosan, dextran, cellulose, cellulose derivatives having different molecular weights, or mixtures thereof. The first additive, i.e., monosaccharides, disaccharides, oligosaccharides, and polysaccharides, can form gel and shear-reducing structures together with water. Since the first additive directly affects the rheological properties of the injectable composite depot, it is preferably incorporated into the silica sol of the injectable composite depot to obtain the greatest effect. If the first additive is incorporated into silica microparticles, it is unlikely that the gel properties of the final injectable depot will be improved to the same extent. According to one preferred embodiment of the present invention, the first additive present in the silica sol is selected from alginic acid, alginate, or salts thereof. Preferably, the first additive present in the silica sol is sodium alginate.

[0039] A first additive, selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, salts thereof, or any combination thereof, when incorporated into a silica sol, can form a gel and / or shear-reducing structure in the absence of a crosslinking agent, such as a crosslinking salt, such as calcium chloride. According to one preferred embodiment, calcium salts of alginate are excluded from the candidates for the first additive. Thus, the first additive is not calcium alginate, i.e., the injectable compound depot does not contain calcium alginate.

[0040] According to one embodiment, pharmaceutically inactive additives may be present in the silica sol to affect the rheological properties of the injectable compound depot. Preferably, the silica sol contains a first additive selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, or salts thereof, or any combination thereof. According to one particular embodiment, the silica sol contains a first additive which is trehalose. It was unexpected that the first additive, selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, or salts thereof, could function as a rheological modifier even when the molecular size of the first additive was relatively small (e.g., monosaccharides or disaccharides such as trehalose).

[0041] While we do not wish to be bound by any theory, it is presumed that the function of the first additive, selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, or salts thereof, such as alginic acid, alginates, or salts thereof, hyaluronic acid, hyaluronic acid, or salts thereof, or trehalose, is based on the aforementioned ability of the first additive to form a gel or a highly viscous fluid. Silica sols containing silica microparticles, silica nanoparticles, and / or aggregates of silica nanoparticles, and the first additive can together form an improved injectable composite depot, preferably in the absence of crosslinking salts. Generally, silica nanoparticles contribute to gel formation by fusing to the surface of the silica microparticles. Desired rheological properties, namely having a non-flowable material at rest (such as in a pre-filled syringe during storage) and having appropriate shear-thinning viscosity under stress (e.g., when injecting the depot through a fine needle), can be obtained when silica microparticles, a silica sol containing silica nanoparticles, and the first additive at an appropriate concentration are combined. Therefore, the properties of the injectable composite depot can be adjusted by selecting an appropriate combination of silica microparticles, silica nanoparticles in silica sol, and a first additive such as alginate. This can be done in a limited number of experiments by those skilled in the art.

[0042] The presence of a first additive in the silica sol influences the hydrogel formation mechanism, allowing control over the final rheological properties of the injectable composite depot. Therefore, the presence of a first additive, selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, or salts thereof, in the silica sol can be used to adjust and / or fine-tune the rheological properties of the injectable composite depot. The first additive can, if necessary, function as an effective rheological modifier. Using the first additive, it is possible to balance or counteract rheological changes caused by the active pharmaceutical ingredient present in the silica microparticles. For example, if the active pharmaceutical ingredient in the silica microparticles alters the surface chemistry of the microparticles, thereby altering the rheology of the depot in an undesirable manner, the viscosity and viscoelasticity of the injectable composite depot can be adjusted using the first additive, such as alginic acid, alginate, or trehalose (e.g., by decreasing or increasing the viscosity and storage modulus).

[0043] The first additive in the silica sol, such as monosaccharides, disaccharides, oligosaccharides, polysaccharides, salts thereof, or any combination thereof, may have a concentration in the range of 0.25 to 1.5% by weight, preferably 0.50 to 1.25% by weight, more preferably 0.75 to 1.25% by weight, or 0.75 to 1.0% by weight, calculated from the total weight of the silica sol and the pharmaceutically inactive additives present in the sol. The first additive (particularly monosaccharides, disaccharides, oligosaccharides, polysaccharides, alginic acid, alginates, hyaluronic acid, and trehalose) has been observed to be compatible with silica microparticles and silica nanoparticles in the silica sol, resulting in a non-flowing gel structure at rest, rapid gel formation, and / or providing an easily injectable composite depot. These improvements can be achieved, in particular, when the concentration of microparticles in the injectable composite depot is low (e.g., when the weight-to-volume ratio of microparticles to silica sol is 0.5:1.0 or less). By using 0.25 to 1.5% by weight, preferably 0.50 to 1.25% by weight, more preferably 0.75 to 1.25% by weight, or 0.75 to 1.0% by weight of a first additive in the silica sol, the weight-to-volume ratio of silica microparticles to silica sol can be in the ranges of 0.1:1.0 to 0.8:1.0, 0.2:1.0 to 0.7:1.0, 0.3:1.0 to 0.6:1.0, and 0.4:1.0 to 0.5:1.0. According to another embodiment, the weight-to-volume ratio of silica microparticles to silica sol can be in the ranges of 0.1:1.0 to 0.5:1.0, 0.2:1.0 to 0.4:1.0, and 0.3:1.0 to 0.4:1.0. In some embodiments, lower silica microparticle concentrations may be appropriate depending on the specific properties or overall surface properties of the API. The weight-to-volume ratio of silica microparticles to silica sol can be 0.08:1.0 to 0.9:1.0 or 0.09:1.0 to 0.5:1.0. In all of the weight-to-volume ratios shown here, the silica sol contains pharmaceutically inactive additives when present in the silica sol. Even at these low silica microparticle concentrations, the use of the first additive yields an injectable composite depot with rheological properties at least equivalent to that of a conventional all-silica system (weight-to-volume ratio of silica microparticles to silica sol of 1.0:1.0).The rheological properties may be further improved, as can be seen, for example, by requiring less force for injections through thin needles such as 18-31G with an inner diameter of 0.13-0.84 mm, and / or by reducing the change in the required force during injection.

[0044] When the concentration of silica particles in an injectable complex depot can be lowered by using pharmaceutically inactive additives, the dissolved silica concentration in local tissue when injecting a depot volume (e.g., 50 μl to 1 ml) corresponding to that of a conventional all-silica depot will also be lower. Based on in vitro dissolution tests, injectable complex depots containing pharmaceutically inactive additives, particularly alginates, have been observed to have similar sustained-release properties in vitro for biologically active drugs, such as APIs, and silica, compared to the corresponding silica particles in conventional all-silica systems. This also indicates that sustained-release formulations similar to those that can be produced with conventional all-silica systems can be manufactured using the injectable complex depot of the present invention containing pharmaceutically inactive additives. In addition, injectable complex depots containing pharmaceutically inactive additives can be used in situations where conventional all-silica depots do not function, or at least do not function optimally.

[0045] According to one embodiment of the present invention, the pharmaceutically inactive additive may include a second additive selected from citric acid or a salt of citric acid, preferably monosodium citrate or its hydrate, disodium citrate or its hydrate, or trisodium citrate or its hydrate, most preferably trisodium citrate or its hydrate. The use of citric acid or a salt thereof in injectable compound depots has been observed to improve the injectability of the compound depot, particularly when the encapsulated drug in the silica microparticles, such as a pharmaceutical active ingredient or other biologically active drug, alters the surface properties of the silica microparticles in a manner that would otherwise worsen the injectability of the compound depot. Often, alterations in surface properties are observed in 1) poor wettability of the silica microparticles in the silica sol, 2) prolonged gel formation, and / or 3) formation of brittle gels. The reasons for the changes are presumed to be a reduction in contact points for silica nanoparticles to fuse with the silica microparticle surface, differences in surface chemistry when certain API molecules are located on the microparticle surface (if the API is uniformly distributed within the silica microparticles, some API molecules will be located near or on the surface of the silica microparticles), and / or changes in surface charge. If the pharmaceutically inactive additive according to the present invention is not used, the resulting weak gel may, in some cases, undergo partial phase separation due to the high shear stress when injecting through a fine needle. When phase separation occurs, greater force may be required for injection, or in the worst case, the needle may even become clogged. In injection, the use of high force, for example in delicate administration such as intravitreal or subconjunctival injection, can itself pose a risk of adverse effects from injection. These disadvantages can be eliminated or at least mitigated when the second additive is present in the injectable compound depot.

[0046] The second additive may have a concentration of 5% by weight or less, preferably 3% by weight or less, and more preferably 2% by weight or less. The concentration may be in the range of 0.1 to 5% by weight, preferably 0.1 to 3% by weight, and possibly 0.2 to 2% by weight, calculated from the total weight of silica in the injectable compound depot. Second additives at these concentrations have been observed to improve the injectability of the compound depot, for example, when levothyroxine is used as the active pharmaceutical ingredient.

[0047] The second additive may be encapsulated in or present within the silica microparticles and / or present in the silica sol. This means that citric acid or its salts, e.g., citrate, may be incorporated into the silica microparticles during the manufacture of the silica microparticles and / or added to the silica sol during the manufacture of the injectable compound depot. In either case, the second additive, i.e., citric acid or its salts, affects the surface properties of the silica microparticles and / or silica nanoparticles that are part of the silica sol, either by directly becoming part of the silica microparticles or through ionic interactions. The second additive also functions for particles having a silica surface, e.g., solid particles of pharmaceutical active ingredients coated with a silica surface.

[0048] The second additive may be incorporated or present as citric acid or a salt thereof, for example, monosodium citrate, disodium citrate, or more preferably trisodium citrate. The salts of citric acid, citrates, may be used in an anhydrous form or in a hydrated form, for example, trisodium citrate dihydrate.

[0049] According to one embodiment of the present invention, the pharmaceutically inactive additives present in or encapsulated in the silica nanoparticles and the pharmaceutically inactive additives present in the silica sol may be different from each other. For example, an injectable composite depot may include a first additive present in the silica sol and a second additive encapsulated in the silica nanoparticles. The use of at least two or more pharmaceutically inactive additives in an injectable composite depot provides improved versatility and the possibility of using a variety of bioactive drugs (such as APIs). pharmaceutically inactive additives that can affect the surface charge of nanoparticles and / or microparticles, such as citric acid and its salts, may be incorporated into the silica nanoparticles and the silica sol. This makes it possible to have a greater influence on the surface properties than would be possible if the pharmaceutically inactive additives were present only in the microparticles or only in the silica sol. Additives that directly affect the rheological properties of the injectable composite depot, such as monosaccharides, disaccharides, oligosaccharides, and polysaccharides, such as alginates, may be incorporated into the silica sol, while other additives that affect the surface properties, such as citric acid or its salts, may be incorporated into the silica microparticles. According to one preferred embodiment, a combination of citrate in the silica microparticles and alginate in the silica sol in the injectable composite depot has been shown to provide excellent properties.

[0050] Pharmacokinetically inactive additives may be incorporated into silica microparticles during the manufacture of silica microparticles and / or into silica sols during the manufacture of injectable compound depots.

[0051] Injectable composite depots can be obtained by combining silica microparticles with a silica sol, for example, by mixing them.

[0052] The injectable composite depot contains up to 85% by weight, preferably up to 80% by weight, of silica microparticles having a maximum diameter of 1000 μm or less. According to one preferred embodiment, the injectable composite depot may contain 5 to 85% by weight, preferably 5 to 80% by weight, and more preferably 5 to 50% by weight, of silica microparticles, calculated from the total weight of the injectable composite depot. According to another embodiment, the injectable composite depot may contain 5 to 50% by weight, preferably 5 to 30% by weight, and optionally 5 to 25% by weight, of silica microparticles, calculated from the total weight of the injectable composite depot.

[0053] The silica microparticles of the injectable composite depot may be selected from spray-dried silica microparticles, silica fiber fragments, molded or cast silica monoliths as they are, and / or pulverized, or any mixture thereof. Preferably, the silica microparticles are obtained by a sol-gel method and spray-dried.

[0054] Possible ranges for silica microparticles are 20-99.9% by weight, preferably 30-99.9% by weight, more preferably 50-99.7% by weight, and more preferably 70-99% by weight, calculated from the total weight of the silica microparticles. The silica content of the silica microparticles is at least 20% by weight, preferably at least 30% by weight, more preferably at least 40% by weight, and possibly at least 50% by weight, calculated from the total weight of the silica microparticles. The silica content is at least 30-95% by weight, preferably 40-95% by weight, more preferably 50-93% by weight, or 70-90% by weight, calculated from the total weight of the silica microparticles. In addition to silica, the silica microparticles may contain pharmaceutically inactive additives and pharmaceutically active agents and / or biologically active agents.

[0055] The silica microparticles in the injectable composite depot have a maximum diameter of 1000 μm or less. According to one embodiment, the injectable composite depot comprises silica microparticles which may have a diameter in the range of 1 to 300 μm, preferably 1 to 100 μm, more preferably 1 to 30 μm, even more preferably 0.5 to 20 μm, and possibly even in the range of 0.5 to 15 μm. The particle size can be measured using laser diffraction. The use of pharmaceutically inactive additives increases the degree of freedom in the selection of particle diameter, as it allows even small-diameter silica microparticles to be used without degrading the rheology of the injectable composite depot.

[0056] The injectable compound depot further comprises a silica sol having a silica content of 5% by weight or less, preferably 2% by weight or less, and more preferably 1% by weight or less. The silica content may be in the range of 0.1 to 5% by weight, preferably 0.5 to 2% by weight, and more preferably 0.6 to 1% by 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, and may optionally further contain a small amount of alcohol such as ethanol. The silica sol contains more than 50% by weight of water, calculated from the total weight of the silica sol. Preferably, the liquid phase of the silica sol contains more than 80% by weight, more preferably more than 90% by weight, and even more preferably more than 97% by weight of water. The liquid phase of the silica sol may further contain other liquids, typically organic solvents, such as ethanol. Typically, the concentration of such a solvent, such as ethanol, is less than 10% by weight, preferably less than 3% by weight, more preferably less than 1% by weight, and even more preferably less than 0.5% by weight, calculated from the total weight of the silica sol.

[0057] According to one embodiment of the present invention, the injectable composite depot comprises a silica sol containing silica nanoparticles having a diameter in the range of 10 to 1000 nm, preferably 10 to 500 nm, and more preferably 10 to 190 nm. The particle diameter can be determined using dynamic light scattering. A pharmaceutically inactive additive allows for the use of small-diameter nanoparticles in the silica sol while maintaining the properties of the injectable composite depot within appropriate limits. The silica nanoparticles in the silica sol contribute to gel formation by fusing with the surface of much larger silica nanoparticles, in which case the entire structure transforms into a non-flowing hydrogel structure. This hydrogel is readily injectable through a fine needle (e.g., 18-31G with an inner diameter of 0.13-0.84 mm) and returns to a non-flowing hydrogel after injection into tissue. Thus, the silica nanoparticles and silica nanoparticles together (at rest) develop a non-flowing gel structure, which is also readily injectable through a fine needle, i.e., the gel structure becomes strongly shear-thinning under shear.

[0058] The injectable compound depot preferably contains at least 15% by weight, more preferably at least 20% by weight, and even more preferably at least 50% by weight of silica sol. The amount of silica sol in the injectable compound depot may be in the range of 15 to 95% by weight, preferably 20 to 95% by weight, and more preferably 50 to 95% by weight of silica sol, calculated from the total weight of the injectable compound depot.

[0059] The total silica content in the injectable compound depot may be 85% by weight or less.

[0060] According to one embodiment of the present invention, the injectable composite depot may contain 15 to 95% by weight, preferably 20 to 95% by weight, more preferably 50 to 95% by weight, or 50 to 90% by weight of water, calculated from the total weight of the injectable composite depot.

[0061] The solid content of the injectable compound depot may be 5 to 85% by weight, preferably 5 to 80% by weight, more preferably 5 to 50% by weight, and possibly 10 to 50% by weight, calculated from the total weight of the injectable compound depot.

[0062] Pharmacokinetically inactive additives may be useful in improving the processing or characterization of injectable complex depots containing any type of bioactive agent, including therapeutic or pharmacokinetic ingredients. According to one preferred embodiment, silica microparticles contain at least one encapsulated pharmaceutically active agent and / or bioactive agent. The pharmaceutically active agent and / or bioactive agent may be selected from small molecule drugs, vitamins, phytochemicals, peptides, proteins, fusion proteins, nucleic acids (e.g., DNA, RNA), vaccine antigens, viral vectors, or liposomes that deliver bioactive agents.

[0063] The silica nanoparticles may contain, for example, 0.01 to 70% by weight or 0.1 to 70% by weight, preferably 0.3 to 50% by weight, more preferably 1 to 30% by weight of pharmaceutically active agents and / or biologically active agents, calculated from the total weight of the silica nanoparticles.

[0064] Pharmacokinetically inactive additives may be useful in improving the processing or characterization of injectable complex depots containing therapeutic or pharmacoactive ingredients, or any kind of biologically active agents, such as small molecule drugs, vitamins, phytochemicals, peptides, proteins, fusion proteins, nucleic acids (e.g., DNA, RNA), vaccine antigens, viral vectors, or liposomes that deliver biologically active agents.

[0065] This invention relates to several pK a It is particularly suitable for biologically active drugs, such as pharmaceutically active drugs, which have a high pK value, high charge, and / or amphoteric properties. For example, peptides, polypeptides, and proteins may have different charges at the same pH. aThe range varies, and fusion proteins may have complex charge structures; the high negative charge of nucleic acids can also, in some cases, pose a challenge in providing injectable complex depots. The use of pharmaceutically inactive additives improves gel formation, injectability, and / or fine-tuning of in vivo release rates. Some vitamins, such as vitamin B12 and even vitamin C, appear to benefit from the use of pharmaceutically inactive additives, and these additives can be used to improve properties such as the injectability of injectable complex depots.

[0066] According to one embodiment, the pharmaceutically active agent may be levothyroxine. See sections 2.2, 6.7, and 10.1 for several pKs. a Levothyroxine present in a certain value appears to affect the wettability of silica microparticles, consequently influencing gel formation and injectability. The incorporation of pharmaceutically inactive additives into both the silica microparticles and the silica sol has been observed to significantly improve the properties of injectable compound depots. For example, if citrate is encapsulated in the silica microparticles and alginate is present in the silica sol, the pharmaceutically active agent could be levothyroxine.

[0067] According to one embodiment, biologically active agents are vaccine antigens or viral vectors, which often have large, complex structures and diverse chemical structures, thus posing challenges in fine-tuning the properties of injectable complex depots containing them. Therefore, pharmaceutically inactive additives such as alginates and citrates are excellent tools for improving the properties of silica-based injectable depot platform technologies used to prepare controlled delivery systems for all types of biologically active agents and pharmaceutical active ingredients.

[0068] Injectable compound depots can be used to administer one or more biologically active drugs, preferably one or more active pharmaceutical ingredients. Administration may be topical or parenteral.

[0069] According to one embodiment, administration may be topical, and the biologically active agent may be administered as eye drops, creams, gels, ointments, lotions, or suspensions.

[0070] According to one preferred embodiment, the injectable compound depot is suitable for use as, or in, a topical ophthalmic formulation such as eye drops, ophthalmic cream, or ophthalmic gel. The injectable compound depot may be suitable for topical administration in the form of eye drops, ophthalmic gel, or ophthalmic cream. When the injectable compound depot is intended for an ophthalmic formulation, the pharmaceutically inactive additive present in the silica sol is preferably selected from one or more of the first additives listed above, particularly trehalose. The injectable compound depot intended for an ophthalmic formulation may further contain a second pharmaceutically inactive additive selected from citric acid or a salt of citric acid, preferably monosodium citrate or its hydrate, disodium citrate or its hydrate, or trisodium citrate or its hydrate. The second additive may be present in the ophthalmic formulation such as eye drops, ophthalmic cream, or ophthalmic gel so as to be encapsulated in silica microparticles and / or present in the silica sol.

[0071] According to another embodiment, the administration is parenteral and may be selected from the group consisting of intravenous, intraarterial, intracardiac, percutaneous, transmucosal, intradermal, subcutaneous, intramuscular, intraperitoneal, intracerebral, intraventricular, intramedullary, intraosseous, intraarticular, ophthalmic, intraocular, intravitreous, subconjunctival, anterior chamber, subretinal, retrobulbar, peribulbar, suprachoroidal, periophthalmos, transscleral, intrasternal, near the posterior sclera, subtenon's capsule, intravesical, and intracavernosal. [Examples]

[0072] Several embodiments of the present invention are described in the following non-limiting examples. Each example shows how pharmaceutically inactive additives are used in various silica sols. Some silica sols are used to prepare silica nanoparticles by spray drying, while some silica sols, i.e., highly diluted silica sols such as R400 silica sol (water-to-TEOS molar ratio of 400), are used only in the preparation of the final injectable compound depot. The pharmaceutically active ingredients are mainly encapsulated in the silica nanoparticles. The diluted silica sol (R400) provides the liquid phase and silica nanoparticles required together with the spray-dried silica nanoparticles to prepare a non-flowing gel structure (at rest), which is also readily injectable through a fine needle, i.e., the gel structure undergoes strong shear reduction under shear. The silica nanoparticles in the silica sol contribute to gel formation by fusing with the surface of much larger silica nanoparticles. In some cases, the functionality of the silica sol can be enhanced or improved by the incorporation of pharmaceutically inactive additives.

[0073] Example 1 - Improvement of injectability of an injectable composite depot when a pharmaceutically inactive additive is used in silica microparticles. Silica microparticles containing fluorescein, silica microparticles without fluorescein, and silica microparticles containing both fluorescein and a pharmaceutically inactive additive (trisodium citrate) were prepared.

[0074] Silica sols for spray drying of silica particles were prepared by hydrolyzing tetraethyl orthosilicate (TEOS) in water whose pH was adjusted to 2 using 0.1 M HCl. The molar ratio of water to TEOS was 10. After hydrolysis, the sol was cooled to approximately 0°C in an ice bath. The active model substance was fluorescein (free base, payload of 5 wt% relative to the amount of silica), and a pharmaceutically inactive additive to improve injectability was trisodium citrate dihydrate (0.3 wt% relative to the amount of silica in the sol). Fluorescein and trisodium citrate were dissolved in ethanol at predetermined concentrations, and the solution was combined with the silica sol before spray drying (the volume of added ethanol corresponded to the volume of water that increased the molar ratio of water to TEOS to 100). The pH of the mixture was adjusted to approximately 6.3 using 0.1 M NaOH.

[0075] In the spray drying of silica fine particles using a Buechi-191 spray dryer, the inlet temperature was 120°C, the outlet temperature was 78°C, and the aspirator length was 35m. 3 The pump flow rate was approximately 4 ml / min, and the spray air flow rate was 700 l / hour. Silica particles without fluorescein were prepared using a GEA Niro Mobile Minor spray dryer, with an inlet temperature of 180°C, an outlet temperature of approximately 90°C, an aspirator flow rate of 80 kg / hour, a pump flow rate of 35 g / ml, and a spray air flow rate of 11.8 kg / hour.

[0076] Injectable composite depots were prepared by mixing each batch of silica microparticles described above with a silica sol (R400) at pH 6.2. The silica sol (R400) was prepared by hydrolyzing TEOS at pH 2 with a water-to-TEOS molar ratio of 400, and then adjusting the pH to pH 6.2. The silica microparticles were mixed with the silica sol in a 1:1 ratio (weight to volume), and the resulting mixture was transferred to a syringe (BD, 1 ml, Luer-lok® Tip). The syringe was attached to a roller mixer and kept at room temperature. Within 72 hours, the mixture formed an injectable composite depot with a non-flowing hydrogel structure.

[0077] Next, the injectable compound depots were tested by manual injection through a fine needle. All injectable compound depots containing the pharmaceutically inactive additive (trisodium citrate), and depots containing silica microparticles without the encapsulated drug, could be easily injected through a 25-27G (0.21-0.26 mm inner diameter) needle. Compound depots containing fluorescein but without the pharmaceutically inactive additive (trisodium citrate) were more difficult to inject: these compound depots could be injected using an 18-20G needle (0.337-0.838 mm inner diameter) in the best cases. Differences in particle size distribution (measured using a Sympatec HELOS 2370 laser diffractometer) were small. Particle sizes D10 and D50 were almost identical, and even with the inclusion of the pharmaceutically inactive additive (trisodium citrate), particle size D90 was only slightly lower; that is, particle size does not explain the differences in injectability. The presence of a pharmaceutically inactive additive (trisodium citrate) in silica nanoparticles clearly improves wettability, leading to the much faster formation of a non-flowing gel structure, which can be concluded to indicate a change in surface structure.

[0078] Bromophenol blue, another molecule, was also studied as a model molecule for active substances, both with and without a pharmaceutically inactive additive (trisodium citrate) in the silica nanoparticles.

[0079] When silica nanoparticles contained bromophenol blue as the sole encapsulated agent (without any pharmaceutically inactive additives), a silica sol was prepared containing 50 ml of tetraethyl orthosilicate (TEOS), 31.35 ml of deionized water, and 9.04 ml of 0.1 M HCl. The silica sol was then mixed until the TEOS was hydrolyzed. After hydrolysis, the silica sol was cooled to approximately 0°C, diluted by adding 100 ml of ethanol, and the pH was adjusted to pH 5.0 by adding 0.1 M NaOH. Next, 40 ml of a solution containing 1.35 g of bromophenol blue dissolved in water was added to the silica sol, and the mixture was pumped into a Buechi B-191 spray dryer. In the spray dryer, the inlet temperature was 120°C, the aspirator was at 95%, the pump was at 16%, and the spray air flow rate was 600 ml / hour.

[0080] When preparing silica microparticles in which both bromophenol blue and a pharmaceutically inactive additive (trisodium citrate) were encapsulated within the silica microparticles, a separate silica sol was prepared. 50 ml of tetraethyl orthosilicate (TEOS), 31.35 ml of deionized water, and 9.04 ml of 0.1 M HCl were prepared. The silica sol was then mixed until the TEOS was hydrolyzed. After hydrolysis, the silica sol was cooled to 0°C, diluted by adding 100 ml of ethanol, and the pH was adjusted to pH 5.0 by adding 0.1 M NaOH. Next, 40 ml of an aqueous solution containing a pharmaceutically inactive additive (trisodium citrate hydrate) at a concentration of 57.2 mM (resulting in a payload of 4.33 wt% relative to the amount of silica) and 1.35 g of bromophenol was added to the silica sol, and the mixture was pumped into a Buechi B-191 spray dryer. In the spray dryer, the inlet temperature was 120°C, the aspirator was at 95%, the pump was at 16%, and the spray air flow rate was 600 ml / hour.

[0081] Silica microparticles containing and without trisodium citrate were used as a suspension in water and as an injectable composite depot. When the silica microparticles were mixed with the R400 silica sol prepared as described above in a 1:1 ratio (weight to volume), the injectable composite depot formed a non-flowing hydrogel. When trisodium citrate was present, injection was easy with a 25G needle (inner diameter 0.25-0.26 mm), but when the citrate was absent, injection was difficult and the needle became clogged.

[0082] Example 2 - Preparation of silica microparticles containing and without pharmaceutical active ingredients, and containing and without pharmaceutically inactive additives, for improving the rheological properties and injectability of injectable composite depots. Example 2 illustrates how a pharmaceutically inactive additive (trisodium citrate) can be used to modify the properties of silica microparticles and injectable composite depots.

[0083] Silica microparticles without encapsulated drugs were prepared by spray drying of silica sol. Tetraethyl orthosilicate (TEOS), 0.1 M HCl, and deionized water were used to prepare the silica sol at pH 2, under vigorous mixing, and at room temperature. After hydrolysis of TEOS, the resulting silica sol was cooled to approximately 0°C in an ice bath. Next, ethanol was added to the silica sol, the pH was adjusted to 5.5 using 0.1 M NaOH, and then spray-dried to obtain a molar ratio of H2O:TEOS:HCl:EtOH = 5:1:0.86:13.73.

[0084] Silica microparticles containing encapsulated pharmaceutical active ingredients (levothyroxine), and silica microparticles containing encapsulated pharmaceutical active ingredients (levothyroxine) and pharmaceutically inactive additives, were prepared by spray drying of silica sol. Trisodium citrate dihydrate was used as a pharmaceutically inactive additive to improve wettability, gel formation, and injectability. The same silica sol was used for both silica microparticles containing levothyroxine and silica microparticles containing both levothyroxine and trisodium citrate dihydrate. The silica sol was prepared by hydrolyzing TEOS in deionized water using 0.1 M HCl as a catalyst, with a molar ratio of H2O:TEOS:HCl of 5:1:0.86. Levothyroxine sodium was dissolved in ethanol, and the solution was added to the silica sol, and the pH was adjusted to pH 5.5 by adding 0.1 M NaOH. This resulted in the final ratio of H2O:TEOS:HCl:EtOH = 5:1:0.86:28.98. For silica microparticles containing pharmaceutically inactive additives, trisodium citrate dihydrate was added to the silica sol-ethanol mixture after levothyroxine had completely dissolved. The final concentration of levothyroxine sodium in the solution was 1.8 mg / ml, and the concentration of trisodium citrate was 0.6 mg / ml.

[0085] To prepare the fine particles, three silica sols were prepared: 1) a silica sol free of pharmaceutical active ingredients and pharmaceutically inactive additives, 2) a silica sol containing levothyroxine as an API but free of pharmaceutically inactive additives, and 3) a silica sol containing both levothyroxine as an API and trisodium citrate as a pharmaceutically inactive additive. All of these were spray-dried under the same parameters. The silica sols were then pumped into a Buechi B-290 spray dryer (Buchi AG) at a flow rate of 5.6 ml / min while being mixed. The aspirator air flow rate was 100%, the spray air flow rate was 670 l / h, and the total supply rate was 5.6 ml / min. The inlet and outlet temperatures were 100°C and 60°C-70°C, respectively. The payload (relative to the amount of silica) of levothyroxine and trisodium citrate (if used) in the silica particles was 2% by weight and 0.5% by weight, respectively.

[0086] In this way, three different silica nanoparticles were obtained: 1) Products that do not contain pharmaceutical active ingredients or pharmaceutically inactive additives. 2) Products containing levothyroxine as an API, but without any pharmaceutically inactive additives, and 3) A product containing both levothyroxine as an API and trisodium citrate as a pharmaceutically inactive additive.

[0087] The particle size distribution of silica nanoparticles was measured by laser diffraction using a HELOS 2370 (Sympatec). The particle size distribution is represented by D10, D50, and D90, which indicate the size, and that 10%, 50%, and 90% of the total particles are found at sizes smaller than these. When the silica nanoparticles did not contain APIs or pharmaceutically inactive additives, the particle size distribution was measured as D10 = 1.09 ± 0.00 μm, D50 = 3.02 ± 0.00 μm, and D90 = 7.25 ± 0.01 μm. When the silica nanoparticles contained levothyroxine but did not contain non-pharmaceutically active additives, the particle size distribution was measured as D10 = 1.15 ± 0.02 μm, D50 = 4.17 ± 0.01 μm, and D90 = 11.87 ± 0.04 μm. When silica microparticles contained both levothyroxine and trisodium citrate, the particle size distribution was measured as D10 = 1.09 ± 0.00 μm, D50 = 3.02 ± 0.00 μm, and D90 = 7.25 ± 0.01 μm. Therefore, when silica microparticles contain levothyroxine as an API, there is some difference in the D90 value depending on whether or not the pharmaceutically inactive additive (trisodium citrate) is present in the silica microparticles. However, this difference has not been found to be significant from the standpoint of injectability. In other words, while a slightly narrower particle size distribution may have some effect, the greater effect on injectability stems from differences in surface chemistry, which have been observed in the difficulty of wetting and the prolonged gel formation time of injectable composite depots when the pharmaceutically inactive additive is not used.

[0088] Furthermore, different injectable composite depots were prepared using silica microparticles. One of the prepared injectable composite depots (0.5 g of silica microparticles in 1 ml of R400 silica sol) contained only silica as the solid phase (all-silica depot), and this was used as a reference material in characterizing the rheological properties and injectability of the different composite depots.

[0089] The preparation of different injectable compound depots using three different silica microparticles (described above) began with the preparation of an R400 silica sol (R400 means that the molar ratio of water to TEOS is 400:1, and the silica content in the resulting sol is approximately 0.82% by weight). Using 0.1 M HCl as a catalyst by adjusting the pH to pH 2, the precursor was mixed until TEOS was hydrolyzed.

[0090] To prepare the all-silica depot (reference), spray-dried silica microparticles, free of encapsulated drugs and additives, were added to R400 silica sol while mixing. That is, the system contained only silica as the solid phase. The resulting suspension, containing the silica microparticles in a 0.5:1 ratio (weight to volume) in the R400 silica sol and adjusted to pH 5.9 with 0.1 M NaOH, was transferred to a syringe (1-ml BD Luer-Lok syringe, Becton, Dickinson and Company). The syringe was then continuously mixed at room temperature for 72 hours in a custom-made rotary mixer (DelSiTech, Turku, Finland) to ensure the formation of a stable, non-flowing semi-solid gel structure. The formed all-silica composite was readily injectable through a 25G needle (inner diameter 0.25-0.26 mm). The nanoparticles in the R400 silica sol fused to the surface of the silica microparticles, ensuring that the suspension transformed into a non-flowing and stable semi-solid hydrogel structure when at rest. The semi-solid silica-silica hydrogel also exhibited strong shear-thinning properties, allowing for easy injection through a fine needle. After shearing, for example, after injection, it reverted to a non-flowing form.

[0091] Preparation of the composite depot containing encapsulated levothyroxine-containing silica microparticles began with adding spray-dried microparticles to a silica sol (R400) while mixing. The resulting suspension, containing the silica microparticles in a 0.5–1.0:1 ratio (weight to volume) in the silica sol and adjusted to pH 5.9 with 0.1 M NaOH, was transferred to a syringe (1-ml BD Luer-Lok syringe, Becton Dickinson). The syringe was then continuously mixed at room temperature for 72 hours in a custom-made rotary mixer (Delcytech, Turku, Finland). However, a non-flowing semi-solid gel structure was not formed, and injection of the material through a 25G needle (inner diameter 0.25–0.26 mm) resulted in needle clogging, indicating that the applied shear promoted phase separation of the composite depot.

[0092] Next, an injectable compound depot was prepared containing silica microparticles with encapsulated levothyroxine (2% by weight relative to the amount of silica) and a pharmaceutically inactive agent (trisodium citrate, 0.5% by weight relative to the amount of silica). Preparation was initiated by adding spray-dried silica microparticles to a silica sol (R400) while mixing. The resulting suspension, containing the silica microparticles in a 0.5:1 ratio (weight to volume) in the silica sol and adjusted to pH 5.9 with 0.1 M NaOH, was transferred to a syringe (1-ml BD Luer-Lok syringe, Becton Dickinson). The syringe was then continuously mixed at room temperature for 72 hours in a custom-made rotary mixer (Delcytec, Turku, Finland). A non-flowing and homogeneous gel structure was formed, and the compound depot was readily injectable through a 25G (0.25-0.26 mm inner diameter) needle.

[0093] Example 3 - Improvement of the properties of an injectable composite depot with a pharmaceutically inactive additive in a diluted silica sol. Example 3 demonstrates how the total amount of silica (primarily derived from silica nanoparticles) in an injectable compound depot can be reduced with the help of a pharmaceutically inactive additive (alginate) in the silica sol. The pharmaceutically inactive additive in the silica sol also affects the rheological properties of the injectable compound depot. The silica sol (R400) is not used for spray drying but is used to prepare the final injectable compound depot, in which case the silica nanoparticles of the silica sol support gel formation by fusing with the surface of the silica nanoparticles. Reducing the total amount of silica in the injectable compound depot can be used to adjust the release rate of the pharmaceutical active ingredient in the compound depot. In this case, the silica dissolution products may exceed sink conditions (free dissolution), or even reach saturation with respect to silica dissolution products, for example, at specific local sites in the body. When a biodegradable depot decomposes by dissolution in body fluids, for example in the vitreous humor after intravitreal injection, it may reach near-saturation or saturation levels due to limited space and slow fluid exchange rates. Similar phenomena can occur in subcutaneous, intramuscular, and subconjunctival spaces where the concentration of dissolved products can exceed the sink level (free dissolution). Therefore, for example, if the active pharmaceutical ingredient is encapsulated in silica microparticles, which are the main component of an injectable compound depot, reducing the amount of silica in the injectable compound depot can be used to fine-tune the rate of release of the active pharmaceutical ingredient into the body. Using pharmaceutically inactive additives ensures that the injectable compound depot has the appropriate rheological properties.

[0094] Injectable compound depots containing different amounts of spray-dried silica microparticles, as described in Example 2, and containing and not containing encapsulated drugs and a pharmaceutically inactive second additive, were combined with silica sols containing a pharmaceutically inactive first additive (sodium alginate). In preparing the injectable compound depots, R400 silica sol was first prepared, tetraethyl orthosilicate (TEOS) was hydrolyzed at pH 2, the pH of the silica sol was adjusted to pH 3, and then sodium alginate was added at room temperature while vigorously mixing.

[0095] Different concentrations of sodium alginate were used in conjunction with spray-dried silica microparticles of different concentrations obtained from Example 2. The test concentrations of sodium alginate in silica sol (R400) were calculated from the total weight of silica sol and sodium alginate to be 0.25% by weight, 0.50% by weight, 0.75% by weight, 1.00% by weight, 1.25% by weight, and 1.50% by weight. The concentrations of spray-dried silica microparticles, with or without the encapsulated drug and a pharmaceutically inactive second additive, ranged from 0.1 g to 1.0 g per 1 ml of silica sol-alginate mixture (ratio of 0.1:1 to 1:1, weight to volume). When spray-dried silica microparticles were added to the silica sol-alginate mixture, the pH of the resulting suspension was adjusted to pH 5.9 using 0.1 M NaOH. The suspension was then transferred to a syringe (1 ml BD Luer-Lok syringe, Becton Dickinson). Next, the syringe was continuously mixed in a custom-made rotary mixer at room temperature for 72 hours. Afterward, in most cases, a stable, non-flowing (at rest), semi-solid, and easily injectable gel structure was formed; however, when the silica microparticles contained only levothyroxine, the material became more difficult to inject.

[0096] Spray-dried silica microparticles containing levothyroxine (2% by weight relative to the amount of silica) as an API and trisodium citrate (0.5% by weight relative to the amount of silica) as a second pharmaceutically inactive additive, as described in Example 2, were used in the preparation of an injectable compound depot together with different concentrations of a first pharmaceutically inactive additive (sodium alginate) in silica sol (R400). Different silica microparticle concentrations (0.1 g and 0.5 g per 1 ml of silica sol containing the additives) were also tested. In this example, 1% by weight of alginate in the silica sol-alginate mixture was found to be advantageous in terms of gel formation and injectability through a 25G needle (inner diameter 0.25-0.26 mm) when the silica microparticle concentration was 0.1-0.5 g per 1 ml of silica sol-alginate mixture (ratio of 0.1-0.5:1, weight to volume). This indicates that when 0.1 g of silica microparticles are added to 1 ml of silica sol-alginate mixture, it corresponds to 0.9 wt% of a pharmaceutically inactive additive (alginate) relative to the total mass of the composite depot, and when 0.5 g of silica microparticles are added to 1 ml of silica sol-alginate mixture, it corresponds to 0.7 wt% of a pharmaceutically inactive additive (alginate) relative to the total mass of the composite depot. It was observed that 1 wt% of alginate in silica sol was favorable for 0.1 to 0.5 g of microparticles in 1 ml of silica sol-alginate mixture, but 0.75 wt% and 1.25 wt% of alginate were also found to be effective in terms of gel formation, rheology, and injectability through a 25G needle. For weight-to-volume ratios of 0.6 to 1.0 g of silica microparticles / 1 ml of silica sol-alginate mixture, 0.5 to 0.7 wt% of alginate in the silica sol-alginate mixture was found to be favorable. When 0.75–1.0% by weight of alginate was used, a hard gel was obtained, but it was difficult to inject.

[0097] Furthermore, silica microparticles containing only encapsulated levothyroxine (2% by weight relative to the silica content) were also tested in a silica sol containing alginate as a first pharmaceutically inactive additive at a ratio of 0.1 to 0.5:1 (weight to volume). When 1% by weight of alginate was mixed with the silica sol, the wettability was not good, a non-flowing gel was not formed, and it could not be injected through a 25G needle (inner diameter 0.25 to 0.26 mm).

[0098] Tests were also conducted on four different silica microparticles that did not contain encapsulated drugs or pharmaceutically inactive additives. These silica microparticles were prepared from silica sols R3-50, R5-50, R7.5-50, and R10-50. For preparation, tetraethyl orthosilicate (TEOS) was first hydrolyzed at pH 2 at water-to-TEOS molar ratios of 3, 5, 7.5, and 10. After hydrolysis of TEOS, the silica sol was diluted by adding ethanol in a volume equivalent to the volume of water required to reach a water-to-TEOS molar ratio of 50. The diluted silica sol was pumped into a Buechi B-290 spray dryer at a flow rate of 5.6 ml / min while being mixed. The aspirator air flow rate was 100%, the spray air flow rate was 670 l / hour, and the total supply rate was 5.6 ml / min. The inlet and outlet temperatures were 100°C and 60°C-70°C, respectively. Next, silica microparticles were added in a weight-to-volume ratio of 0.1:1 to silica sol (R400) containing 0.5, 0.75, or 1.0 wt% alginate, which had been mixed with alginate. When spray-dried silica microparticles were added to the silica sol containing alginate, the pH of the resulting suspension was adjusted to pH 5.9 using 0.1 M NaOH. The suspension was then transferred to a syringe (1 ml BD Luer-Lok syringe, Becton Dickinson). The syringe was then continuously mixed in a custom-made rotary mixer at room temperature for 72 hours. All formulations formed relatively good gel structures, except for those containing R3-50 silica microparticles. R10-50 formed the best gel structure when using silica sol (R400) containing 1.0 wt% alginate. R3-50 exhibited the worst wettability in silica sol without additives (R400), while R10-50 had the best (fastest) wettability; however, neither formed a gel at a weight-to-volume ratio of 0.1:1 without alginate. With sufficient alginate, R10-50 formed an injectable compound depot. R5-50 performed well with both silica sol and silica sol containing alginate.This indicates that even different silica microparticles without additives exhibit differences in surface properties, but that with an appropriate amount of alginate at low microparticle concentrations, a non-flowing gel structure can be formed, which can be injected under shear even with a fine needle. This information may be useful in optimizing injectable composite depots, because, in some cases, the use of additive-free silica microparticles can also be utilized to fine-tune rheological properties.

[0099] To demonstrate the injectability of the compound depot, injection force measurements were performed using a 25G 1-inch (0.5 x 25 mm needle gauge) subcutaneous injection needle (Fine-Ject, Henke Sass Wolf) attached to a pre-filled syringe. The force required to continuously push the plunger in one constant stroke was measured using a Lloyd Instruments LR30K plus compression tester equipped with a 250 Newton load cell (grade 0.5%) at a crosshead speed of 1 mm / sec (60 mm / min). The injection volume was 0.3 ml. The results are shown in Figures 1-3.

[0100] Figure 1 shows the injection strength required for injection through a 25G needle (inner diameter 0.25-0.26 mm) for an injectable all-silica depot (black diamond) containing spray-dried R5-50 silica microparticles without enclosed drug in a ratio of 0.5:1 (weight to volume) in R400 silica sol, and for a product containing 1% by weight of alginate in R400 silica sol (white circle), calculated from the total weight of silica sol and alginate. Specifically, Figure 1 shows the injection force for 1) a reference depot (black diamond) (all-silica depot) containing spray-dried R5-50 silica microparticles without encapsulated drug in R400 silica sol alone in a 0.5:1 ratio (weight to volume), and 2) the composite depot of the present invention (white circle) (containing 0.7 wt% alginate relative to the total depot, i.e., 1% alginate in the R400-alginate mixture) containing spray-dried R5-50 silica microparticles without encapsulated drug in a 0.5:1 ratio (weight to volume). As can be seen from Figure 1, all measured forces are less than 20 N, and most are less than 10 N, which means that these forces are generally acceptable values ​​for easy injection. At a 0.5:1 weight to volume ratio, the force is slightly higher when the composite depot contains alginate as a pharmaceutically inactive additive, but the injection appears to be smoother than that of the corresponding reference all-silica depot. In other words, the reference all-silica depot exhibited greater variability due to large aggregates of microparticles and partial phase separation, which could make injection somewhat difficult. Nevertheless, this material was easily injectable even in manual tests using a 25G needle. The 0.5:1.0 weight-to-volume ratio was also close to the minimum for the reference all-silica depot (i.e., silica sol without additives) in terms of gel formation and good injectability, and the reference all-silica depot typically performs better at weight-to-volume ratios greater than 0.5:1.0 up to 1.0:1.0.

[0101] Figure 2 shows the injection force required for injection through a 25G needle (inner diameter 0.25-0.26 mm) when the injectable composite depot contains silica microparticles containing encapsulated levothyroxine (2% by weight relative to the amount of silica) and trisodium citrate (0.5% by weight relative to the amount of silica) in a weight-to-volume ratio of 0.5:1 within an R400 silica sol containing 1% by weight of alginate (i.e., a silica sol containing 0.7% by weight of alginate relative to the total weight of the composite depot), calculated from the total weight of the silica sol and alginate. As can be seen from Figure 2, when trisodium citrate was present in the silica microparticles as a pharmaceutically inactive additive, the properties of the injectable composite depot were improved, providing a stable and easily injectable depot. Silica microparticles containing encapsulated levothyroxine but without a pharmaceutically inactive additive did not form a gel structure at all, and therefore had poor injectability (results not shown in Figure 2). The encapsulated levothyroxine-containing silica microparticles were successfully injectable through a 25G needle when the silica sol contained 1% by weight of alginate as a pharmaceutically inactive additive, calculated from the silica sol-alginate mixture (results not shown in Figure 2). Therefore, in the case of levothyroxine, the presence of trisodium citrate in the silica microparticles is preferable, and the presence of alginate in the silica sol results in smoother injection compared to the reference all-silica depot.

[0102] Figure 3 shows the injection force required for injection through a 25G needle (inner diameter 0.25-0.26 mm) when the injectable composite depot contains R5-100 silica microparticles containing encapsulated levothyroxine (2% by weight relative to silica amount) and trisodium citrate (0.5% by weight relative to silica amount) in an R400 silica sol containing 1% by weight of alginate, calculated from the total weight of silica sol and alginate, in a weight-to-volume ratio of 0.1:1. From Figure 3, it can be seen that the injectable depot is easily injectable.

[0103] The injectable composite depots were further characterized by rheological measurements using an Anton Paar rheometer (MCR302) with a parallel plate (d=25mm) measurement geometry, a gap of 1.0mm, and 25°C. Both vibration measurements for elastic modulus and viscosity, and rotational measurements for viscosity during shear reduction were performed. Vibration measurements were performed both before and after rotational measurements in the linear viscoelastic region to demonstrate that the injectable composite depots exhibited a non-flowing gel structure both before and after the application of shear stress in the rotational measurements. Vibration measurements in the linear viscoelastic region simulated the properties at rest under minimal shear. For all materials examined, the shear strain was 0.1%, the frequency was 1Hz, and the measurements were performed for 120 seconds before shear in the rotational measurements and for 300 seconds after shear in the rotational measurements. The shear rate in the rotational measurements was kept constant at 1000 (1 / s) for 30 seconds for all depots examined.

[0104] The rheological results were obtained for all of the various composite depots examined, namely, 1) All-silica reference deposit in R400 silica sol with a weight-to-volume ratio of 0.5:1 (used in Figure 1); 2) A depot (used in Figure 1) containing encapsulated drug-free silica microparticles in R400 silica sol containing 1% by weight of alginate, calculated from the total weight of silica sol and alginate; and 3) Injectable compound depots containing levothyroxine and trisodium citrate in R400 silica sol containing alginate, in weight-to-volume ratios of 0.5:1 and 0.1:1 (used in Figures 2 and 3); However, the viscosity measurements again showed that the material was a gel, non-flowing at rest, after high shear. The loss factors (ratio of loss modulus (viscosity), G'' to storage modulus (elastic modulus)), G') were all less than 1, which indicates that these materials are non-flowing because the storage modulus (elastic modulus) is greater than the loss modulus (viscosity). The loss factors of an all-silica reference depot with a weight-to-volume ratio of 0.5:1 in R400 silica sol were 0.08-0.09 before shear and 0.147-0.07 after shear. The loss factors of silica microparticles without encapsulated agents, with a weight-to-volume ratio of 0.5:1 in R400 silica sol containing alginate, were 0.15-0.16 before shear and 0.6-0.7 after shear. For an injectable composite depot containing levothyroxine and trisodium citrate in silica microparticles at a weight-to-volume ratio of 0.5:1 in R400 silica sol containing alginate, the loss factor was 0.007-0.01 before shearing and 0.007-0.06 after shearing. For an injectable composite depot containing levothyroxine and trisodium citrate in silica microparticles at a weight-to-volume ratio of 0.1:1 in R400 silica sol containing alginate, the loss factor was 0.15-0.16 before shearing and 0.45-0.6 after shearing. As expected, the values ​​were lower for the injectable composite depot with a weight-to-volume ratio of 0.1:1, but all of the above injectable composite depots were non-flowing gels both before and after shearing.

[0105] The dissolution rate of silica and the release rate of levothyroxine were measured in 50 mM Tris buffer (pH 7.4) at 37°C. Dissolution conditions were maintained at sink conditions (less than approximately 20% of solubility) for both silica and levothyroxine. 10–30 mg of silica microparticles and injectable composite depot samples were added to 50 ml of dissolution buffer, and the buffer was replaced at each sampling time to maintain sink conditions for both dissolved silica and levothyroxine. Dissolution tests were performed in a shaking water bath (Julabo GmbH) at 60 strokes / min, 37°C, for 5–7 days. The dissolved silica concentration was measured at a wavelength of 251.611 nm using a microwave plasma atomic emission spectrometer (MP-AES) (Agilent Technologies, 4210MP-AES). The released levothyroxine was quantified by HPLC (Agilent Technologies 1260 Infinity) equipped with a Phenomenex Luna 3μm C18(2) 150×4.0 mm column. Mobile phase A consisted of 0.1% trifluoroacetic acid (v / v) in water, and mobile phase B consisted of 0.1% trifluoroacetic acid (v / v) in acetonitrile. Absorbance was detected at 225 nm, with an injection volume of 50 μl, a flow rate of 1.0 ml / min, and a column temperature of 25°C. The dissolution rate of silica and the release rate of levothyroxine for silica microparticles and injectable depots are shown in Figures 4-6.

[0106] Figure 4 illustrates the cumulative in vivo dissolution rate of silica under sink conditions for silica microparticles (R5-50) and different injectable composite depots containing R5-50 silica microparticles. Figure 4 shows the results for the following: a) Silica microparticles, see (white circle); b) All-silica injectable reference depot (white square) containing 0.5 g of silica microparticles combined with silica sol; c) An injectable compound depot (black square) containing 0.5 g of silica microparticles in combination with a silica sol containing alginate; and d) An injectable compound depot (black circle) containing 0.1 g of silica microparticles combined with a silica sol containing alginate.

[0107] In the case of an all-silica injectable depot containing silica microparticles in R400 silica sol, the dissolution rate is slightly slower than that of silica microparticles alone. This difference is slightly larger in the case of injectable depots containing alginate and the same silica microparticles, but there is no practical difference when the amount of silica microparticles in the depot differs (0.1:1 ratio vs. 0.5:1 ratio).

[0108] Figure 5 illustrates the cumulative in vivo silica dissolution rate and levothyroxine release rate. Figure 5 shows the dissolution results obtained from the following: a) R5-50 silica microparticles containing 2% by weight of levothyroxine and 0.5% by weight of trisodium citrate relative to the silica content in the microparticles. The results are shown as solid lines connecting black circles for levothyroxine and dashed lines connecting black circles for silica; b) An injectable all-silica reference depot containing 0.5 g of silica microparticles, each containing 2% by weight of levothyroxine and 0.5% by weight of trisodium citrate relative to the silica content in the microparticles, combined with 1 ml of R400 silica sol. The results are shown as solid black triangles for levothyroxine and dashed black triangles for silica; and, c) An injectable compound depot containing 0.5 g of microparticles containing 2% by weight of levothyroxine and 0.5% by weight of trisodium citrate relative to the amount of silica in the microparticles, combined with 1 ml of R400 silica sol containing 1% by weight of alginate, calculated from the total weight of silica sol and alginate. The results are shown as solid black squares for levothyroxine and dashed black squares for silica.

[0109] Figure 6 illustrates the cumulative in vivo silica dissolution rate and levothyroxine release rate. Figure 6 shows the results obtained from the following: a) R5-50 silica microparticles containing 2% by weight of levothyroxine and 0.5% by weight of trisodium citrate relative to the silica content in the microparticles. The results are shown as solid lines connecting black circles for levothyroxine and dashed lines connecting black circles for silica; and, b) An injectable compound depot containing 0.1 g of microparticles containing 2 wt% levothyroxine and 0.5 wt% trisodium citrate relative to the silica content in the microparticles, combined with 1 ml of R400 silica sol containing 1 wt% alginate, calculated from the total weight of silica sol and alginate. The results are shown as solid black squares for levothyroxine and dashed black squares for silica.

[0110] As can be seen from Figures 5 and 6, the effect of a non-flowing gel structure on silica dissolution and levothyroxine release in injectable depots using silica microparticles containing levothyroxine and trisodium citrate is not fully clear. Generally speaking, the non-flowing gel structure of the injectable compound depots described herein does have some effect on the dissolution rate and release rate, but the effect on the dissolution rate appears to depend on the specific formulation of the silica microparticles.

[0111] Example 4 - Addition of trehalose, a pharmaceutically inactive additive, to a silica sol mixed with spray-dried silica microparticles, and the effect of trehalose on the rheological properties of the resulting injectable composite depot. Silica microparticles without encapsulated drugs were prepared by spray drying. These microparticles were mixed with R400 silica sol (water-to-TEOS molar ratio of 400) and R400 silica sol containing 1% by weight, 10% by weight, and 20% by weight of trehalose dihydrate to study the effect of the pharmaceutically inactive additive on the rheological properties of the resulting injectable compound depots.

[0112] Silica sol for spray drying of encapsulated, drug-free silica microparticles was prepared by hydrolyzing tetraethyl orthosilicate (TEOS) in water whose pH was adjusted to 2 using 0.1 M HCl. The molar ratio of water to TEOS was 3. After hydrolysis, the sol was cooled to approximately 0°C in an ice bath. Next, the molar ratio of water to TEOS was increased from 3 to 50 (R3-50) by adding water, and the pH was adjusted to approximately 5.0 using 0.1 M NaOH. The R3-50 silica sol was then pumped into a Buechi S300-1 spray dryer at a flow rate of 6 ml / min. The inlet temperature was 100°C, the outlet temperature was 60-62°C, and the aspirator was 32 m 3 The setting was / hour, and the spray air flow rate was 660-680 l / hour.

[0113] Injectable composite depots were prepared by mixing R3-50 silica microparticles with R400 silica sol, as well as with R400 silica sol containing 1% by weight, 10% by weight, and 20% by weight of trehalose. Before adding trehalose to the R400 silica sol, the pH was first raised to pH 4.5, and then the silica microparticles were added while mixing (0.5 g in 1 ml of R400 silica sol with and without trehalose), further raising the pH to pH 6. This suspension was transferred to a syringe, and the syringe was placed in a roller mixer for 72 hours to ensure the formation of an injectable composite depot structure, which is a non-flowing hydrogel when stationary.

[0114] The obtained injectable composite depot was further characterized by rheological measurements using an Anton Paar rheometer (MCR302) with a parallel serrated plate (d=10 mm) measurement geometry, a gap of 1.0 mm, and 25°C. Vibration measurements were performed to determine the elastic modulus (storage modulus) and viscosity modulus (loss modulus). The vibration measurements were performed in the linear viscoelastic region, which simulates the material's behavior at rest.

[0115] Figure 7 shows the viscoelasticity, i.e., storage modulus (elastic modulus) and loss modulus (viscosity), of injectable composite depots containing silica microparticles mixed with R400 silica sol, with and without the pharmaceutically inactive additive trehalose. Figure 7 shows the results for the following: a) Storage modulus (G') (white circle, solid line) of an injectable composite depot containing silica microparticles in additive-free R400 silica sol; b) Storage modulus (G') (white square, solid line) of an injectable composite depot containing silica microparticles in R400 silica sol containing 1% by weight of trehalose; c) Storage modulus (G') (white triangle, solid line) of an injectable composite depot containing silica microparticles in R400 silica sol containing 10 wt% trehalose; d) Storage modulus (G') of an injectable composite depot containing silica microparticles in R400 silica sol containing 20 wt% trehalose (white diamond, solid line); e) Loss modulus (G') of an injectable composite depot containing silica microparticles in additive-free R400 silica (white circle, dashed line); f) Loss modulus of elasticity (G') (white square, dashed line) of an injectable composite depot containing silica microparticles in R400 silica sol containing 1 wt% trehalose; g) Loss modulus of elasticity (G') (white triangle, dashed line) of an injectable composite depot containing silica microparticles in R400 silica sol containing 10 wt% trehalose; h) Loss modulus of elasticity (G') (white diamond, dashed line) of an injectable composite depot containing silica microparticles in R400 silica sol containing 20 wt% trehalose.

[0116] As shown in Figure 7, there is no significant difference between storage moduli and loss moduli, but there is a slight decreasing trend in moduli as the trehalose concentration in the silica sol increases. As the trehalose concentration in the R400 silica sol increases, the moduli of the injectable composite depots decrease, but they are all still proper non-flowing hydrogels at rest. The storage moduli are almost the same (in the range of 81-86 kPa at 0.1-10 Hz) for injectable composite depots without additives and for injectable composite depots containing 1% by weight of trehalose in the R400 silica sol. For injectable composite depots containing 10% by weight and 20% by weight of trehalose in the R400 silica sol, the storage moduli at 0.1-10 Hz varied between 67-73 kPa and 50-54 kPa, respectively. The loss coefficients (tanδ=G'' / G') of the injectable composite depots were very close to each other. At 0.1 Hz, the loss coefficients were all within the range of 0.04 to 0.05; at 1 Hz, within the range of 0.009 to 0.011; and at 10 Hz, within the range of 0.003 to 0.005. That is, the loss coefficients were clearly less than 1, which means that all the injectable composite depots examined were clearly non-flowing hydrogels at rest. The injectable composite depots are also readily injectable from a syringe through a fine needle such as a 25G needle.

[0117] The results shown in Figure 7 are for injectable compound depots prepared from suspensions containing either 0.5 g of silica microparticles in 1 ml of R400 silica sol without additives, or 0.5 g of silica microparticles in 1 ml of R400 silica sol containing 1% by weight, 10% by weight, or 20% by weight of trehalose. The results indicate that trehalose, a pharmaceutically inactive additive, can be used to adjust and fine-tune the rheological properties of injectable compound depots. Good injectability of injectable compound depots may depend on small rheological changes caused by the pharmaceutically active ingredient. Pharmaceutical ingredients have often been observed to alter the surface chemistry of silica microparticles. Changes in surface chemistry may be strongly dependent on the pharmaceutical ingredient and / or its payload. The presence of a pharmaceutically inactive additive affects the hydrogel formation mechanism, allowing control over the rheological properties of the injectable compound depot, but does not hinder hydrogel formation. When the surface chemistry of silica microparticles containing pharmaceutical active ingredients alters their rheology, and it becomes necessary to use thicker, less patient-acceptable needles for, for example, parenteral injection of injectable compound depots, a pharmaceutically inactive additive, such as trehalose, can be used to reduce viscosity. Furthermore, the rheological properties of injectable compound depots, especially those containing low concentrations of silica microparticles, depend on variations in surface chemistry. Even in these cases, a pharmaceutically inactive additive such as trehalose can be used to adjust the formation of a non-flowing hydrogel structure and the overall rheological properties of the injectable compound depot.

[0118] Even if the present invention has been described with reference to what appears to be the most practical and preferred embodiment at present, it should be understood that it is not limited to the above-described embodiment and is intended to encompass different modifications and equivalent technical solutions within the scope of the appended claims. Accordingly, the embodiments described are illustrative and should not be construed restrictively.

Claims

1. Injectable compound depot, It exhibits shear-reducing viscosity, a) Silica fine particles having a maximum diameter of 1000 μm or less, preferably containing at least one encapsulated biologically active agent, in an amount of up to 85% by weight, preferably up to 80% by weight, b) A silica sol having a silica content of 5% by weight or less, preferably 2% by weight or less, more preferably 1% by weight or less, This includes combinations of the above, The injectable composite depot comprises at least one pharmaceutically inactive additive encapsulated in the silica microparticles and / or present in the silica sol. Injectable compound depot.

2. The injectable compound depot according to claim 1, characterized in that the at least one pharmaceutically inactive additive present in the silica sol is selected from monosaccharides, disaccharides, oligosaccharides, polysaccharides, salts thereof, or any combination thereof; preferably selected from oligosaccharides, polysaccharides, salts thereof, or any combination thereof; more preferably selected from polysaccharides or salts thereof, and even more preferably selected from alginates or salts thereof.

3. The injectable composite depot according to claim 2, characterized in that the first additive in the silica sol has a concentration in the range of 0.25 to 1.5% by weight, preferably 0.50 to 1.25% by weight, more preferably 0.75 to 1.25% by weight or 0.75 to 1.0% by weight, calculated from the total weight of the silica sol and the pharmaceutically inactive additive.

4. The injectable compound depot according to claim 1, claim 2, or claim 3, characterized in that the at least one pharmaceutically inactive additive comprises a second additive selected from citric acid or a salt of citric acid, preferably monosodium citrate or its hydrate, disodium citrate or its hydrate, or trisodium citrate or its hydrate, most preferably trisodium citrate or its hydrate.

5. The injectable composite depot according to claim 4, characterized in that the second additive has a concentration of 5% by weight or less, preferably in the range of 0.1 to 5% by weight, and preferably in the range of 0.1 to 3% by weight, calculated from the total weight of silica in the injectable composite depot.

6. The injectable composite depot according to claim 4 or 5, characterized in that the second additive is encapsulated in the silica microparticles and present in the silica sol.

7. An injectable composite depot according to any one of claims 1 to 6, characterized in that the pharmaceutically inactive additive encapsulated in the silica microparticles and the pharmaceutically inactive additive present in the silica sol are different from each other.

8. The injectable compound depot according to any one of claims 1 to 7, characterized in that the silica fine particles contain 0.01 to 70% by weight, preferably 0.3 to 50% by weight, and more preferably 1 to 30% by weight of a biologically active agent, calculated from the total weight of the silica fine particles.

9. The injectable composite depot according to any one of claims 1 to 8, characterized in that the silica fine particles have a diameter in the range of 1 to 300 μm, preferably 1 to 100 μm, more preferably 1 to 30 μm, and even more preferably 0.5 to 20 μm.

10. The injectable composite depot according to any one of claims 1 to 9, characterized in that the silica sol contains silica nanoparticles having a diameter in the range of 10 to 1000 nm, preferably 10 to 500 nm, and more preferably 10 to 190 nm.

11. The injectable composite depot according to any one of claims 1 to 10, characterized in that it contains 5 to 85% by weight, preferably 5 to 80% by weight, and more preferably 5 to 50% by weight of the silica fine particles, calculated from the total weight of the injectable composite depot.

12. An injectable formulation comprising an injectable compound depot according to any one of claims 1 to 11, preferably comprising a biologically active agent.

13. Use of an injectable compound depot according to any one of claims 1 to 11 for administering one or more biologically active agents, preferably one or more pharmaceutical active ingredients.

14. The use according to claim 13, characterized in that the administration is local or parenteral.

15. The use according to claim 14, characterized in that the administration is local and the topically applied, biologically active agent is administered as eye drops, cream, ointment, lotion, or suspension.

16. The use according to claim 15, characterized in that the pharmaceutically inactive additive is trehalose.

17. The use according to claim 14, characterized in that the administration is parenteral and is selected from the group consisting of intravenous, intraarterial, intracardiac, percutaneous, transmucosal, intradermal, subcutaneous, intramuscular, intraperitoneal, intracerebral, intraventricular, intramedullary, intraosseous, intraarticular, ophthalmic, intraocular, intravitreous, subconjunctival, intraanterior chamber, subretinal, retrobulbar, peribulbar, superchoroidal, periophthalmos, transscleral, intrasternal, near the posterior sclera, subtenon's capsule, intravesical, and intracavernosal.

18. An injectable compound depot according to any one of claims 1 to 11, for use as a pharmaceutical.

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