RU2847399C2 - Porous inorganic particle, composite filler and product using said filler - Google Patents

Abstract

FIELD: cosmetic surgery.

SUBSTANCE: porous inorganic particle comprising a sintered framework of hydroxyapatite-based particles and pores distributed in the sintered framework. The hydroxyapatite-based particles comprise first hydroxyapatite-based particles having a maximum diameter of 10 to 500 nm and second hydroxyapatite-based particles having a maximum diameter of 1 to 10 μm. The porous inorganic particle has a core-shell structure, wherein the core contains not less than 70% by volume of all second hydroxyapatite-based particles, and the shell contains not less than 70% by volume of all first hydroxyapatite-based particles. The composite filler contains a porous inorganic particle and a biodegradable carrier.

EFFECT: filler characterised by high strength, bioactivity and biodegradability.

17 cl, 4 dwg, 2 tbl, 2 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

CROSS-REFERENCE TO A RELATED APPLICATION

This application claims priority from Korean Patent Application No. 10-2022-0036793, filed on March 24, 2022, in the Korean Intellectual Property Office, the disclosure of which is incorporated herein by reference in its entirety.

The present invention relates to a porous inorganic particle and composite fillers and an article using said particles.

BACKGROUND OF THE INVENTION

Filler is an auxiliary material or filling that is injected or inserted into wrinkles or sunken scars and is widely used in cosmetic surgery of parts of the human body, such as wrinkles, scars, or vocal cords, that need to be filled with volume.

Fillers are classified as permanent, semi-permanent, and temporary depending on the length of time they remain in the tissue, and specific examples of fillers include collagen, fat, hyaluronic acid, hydroxyapatite, polymethacrylic acid, Botox, and the like.

The traditionally used hyaluronic acid filler provides a satisfactory effect of feeling the volume of the area to be corrected, but this filler has such disadvantages that the elasticity of the skin cannot be significantly improved, the decomposition occurs too quickly, and the maintenance period of the filler effect is short.

In addition, calcium filler not only stimulates the production of natural collagen and provides a fundamental effect of improving skin condition, but also has the advantage of slow decomposition and a long maintenance period, but has the disadvantage of low bioactivity and slow skin improvement effect.

To overcome the shortcomings of such single-component fillers, a method has been proposed using a composite filler, which is a mixture of a biocompatible polymer, such as carboxymethyl cellulose, and calcium particles. The composite filler, made of carboxymethyl cellulose and calcium particles, overcomes the shortcomings of single-component fillers and maintains the original volume. It then forms natural collagen by stimulating the tissue with calcium particles, resulting in improved skin condition.

However, calcium particles incorporated into carboxymethyl cellulose composite fillers, and the calcium particles commonly used, are spherical, high-density solid particles with smooth surfaces, which have the disadvantage of low bioactivity. Furthermore, difficulties have arisen during orthodontic procedures due to the low biodegradability of carboxymethyl cellulose.

Therefore, there is a need to develop a filler that has increased bioactivity compared to existing calcium particles, quickly shows skin improvement effects, and allows for the maintenance of initial volume and corrective procedures.

ESSENCE OF THE INVENTION

Technical problem

The aim of the present invention is to create a porous inorganic particle with high production efficiency and very high bioactivity and strength.

Another objective of the present invention is to create a composite filler in which a porous inorganic particle obtained by a method with high production efficiency is introduced into the composite filler in order to improve the bioactivity characteristics of the composite filler and enhance the effect of improving the condition of the skin, while achieving high biodegradability and the possibility of carrying out corrective procedures.

Another objective of the present invention is to create a product using a composite filler with increased bioactivity.

Technical solution

In order to achieve the above mentioned objectives, a porous inorganic particle is proposed, which comprises a sintered framework of calcium-based particles, and pores distributed in the sintered framework, and has a core-shell structure with a core having high porosity, and a shell having a porosity lower than the porosity of the core, wherein the calcium-based particles comprise first calcium-based particles having a maximum diameter from 10 nm to 500 nm, and second calcium-based particles having a maximum diameter from 1 μm to 10 μm.

The present application also provides a composite filler comprising a porous inorganic particle and a biodegradable carrier.

The present application further proposes a product containing a composite filler.

DETAILED DESCRIPTION

Below, a detailed description will be given of a porous inorganic particle in accordance with specific embodiments of the invention, a composite filler and an article using this filler.

Unless otherwise specified in this description, technical terms used herein are intended to refer to particular embodiments only and are not intended to limit the present invention.

In this document, singular forms include references to plural forms unless the context clearly requires otherwise.

In this document, the expression "including" or "comprising" means a specific feature, area, whole, step, action, element and/or component, but does not exclude the presence or addition of another specific feature, area, whole, step, action, element, component and/or group.

Terms including ordinal numbers such as "first," "second," and the like are used only to distinguish one component from another and are not limited by ordinal numbers. For example, a first component may be referred to as a second component, or, similarly, a second component may be referred to as a first component, without departing from the scope of the present invention.

The present invention will now be described in detail.

1. Porous inorganic particles

According to one embodiment of the invention, a porous inorganic particle may be provided that comprises a sintered framework of calcium-based particles and pores distributed in the sintered framework and has a core-shell structure with a core having a high porosity and a shell having a porosity lower than the porosity of the core, wherein the calcium-based particles comprise first calcium-based particles having a maximum diameter of 10 nm to 500 nm and second calcium-based particles having a maximum diameter of 1 μm to 10 μm.

The inventors of the present invention have found that the porous inorganic particle of one embodiment not only has higher porosity and specific surface area than existing high-density solid particles and therefore has increased biological activity to quickly induce the filler treatment effect, but is also characterized by a high particle production rate, does not require additional drying steps, which increases productivity, does not use organic solvents and is therefore obtained by a safe spray drying method, without the risk of explosion, thereby maximizing production efficiency.

In particular, since the porous inorganic particle contains two types of calcium-based particles classified into types according to the maximum particle diameter, it can have a core-shell structure with different porosities inside the particle, which ensures sufficient porosity, increases bioactivity and simultaneously increases the strength of the particle itself.

Namely, when the entire particle has uniform porosity, due to the fact that the porous structure appears even on the outer side of the particle, the strength of the particle decreases, whereas the porous inorganic particle according to one embodiment has a structure in which the core near the center of the particle has high porosity, and the outer shell of the particle, located further from the center of the particle, has a porosity lower than the porosity of the core, which can increase the strength of the particle.

According to one embodiment, a porous inorganic particle may include a sintered scaffold of calcium-based particles. Calcium-based particles refer to particles containing elemental calcium and may consist of elemental calcium alone or a mixture of elemental calcium and another element.

More specifically, calcium-based particles may include hydroxyapatite. Hydroxyapatite is a calcium phosphate compound, an inorganic substance found in human teeth and bones. It is highly biostable and stimulates natural collagen production, resulting in dramatic wrinkle reduction.

The calcium-based particles may comprise a first calcium-based particle having a maximum diameter of from 10 nm to 500 nm, or from 10 nm to 400 nm, or from 10 nm to 300 nm, or from 10 nm to 250 nm, or from 100 nm to 500 nm, or from 100 nm to 400 nm, or from 100 nm to 300 nm, from 100 nm to 250 nm, or from 150 nm to 500 nm, or from 150 nm to 400 nm, or from 150 nm to 300 nm, from 150 nm to 250 nm, and a second calcium-based particle having a maximum diameter of from 1 μm to 10 μm, or from 1 μm to 5 μm, or from 1 μm to 3 μm, or from 2 μm to 10 μm, or from 2 μm to 5 μm, or from 2 µm to 3 µm. This means that calcium-based particles can include two types of particles in a complex, which are divided into types based on the maximum particle diameter.

The diameter of calcium-based particles is the distance between two points at which a straight line passing through the particle's center of gravity intersects the outer boundary line of the particle, with the largest value of these diameters corresponding to the maximum diameter. Examples of specific methods for measuring the maximum diameter of calcium-based particles are not specifically limited, but can be confirmed, for example, using transmission electron microscopy (TEM) or scanning electron microscopy (SEM) images (TEM or SEM images).

Since calcium-based particles include two types of particles, separated by the maximum particle diameter as described above, it is possible to obtain a core-shell structure with different porosities within the particle, which provides sufficient porosity to enhance bioactivity and also increases the strength of the particles themselves.

The shape of the calcium-based particles is not particularly limited, and various shapes of well-known hydroxyapatite can be used without limitation. Examples of calcium-based particle shapes include spherical, rod-shaped, needle-shaped, linear, plate-shaped, sheet-shaped, and the like. Examples of specific methods for measuring the shape of the calcium-based particles are not particularly limited, but can be confirmed, for example, using TEM or SEM imaging.

However, for example, the shapes of the first calcium-based particles and the second calcium-based particles can be spherical. When the shape of the first calcium-based particles, having a maximum diameter of 10 nm to 500 nm, is spherical, the porous inorganic particle can be produced in a spherical shape using a spray-drying process.

In addition, when the shape of the calcium-based secondary particles having a maximum diameter of 1 μm to 10 μm is not spherical, the microroughness of the surface of the calcium-based secondary particles increases, which may create a problem in that a large injection force is required when injected into the body.

The content of the second calcium-based particles may be from 2 parts by weight to 10 parts by weight, or from 2 parts by weight to 5 parts by weight, or from 3 parts by weight to 10 parts by weight, or from 3 parts by weight to 5 parts by weight, relative to 1 part by weight of the first calcium-based particles.

When the content of the second calcium-based particles is excessively reduced to less than 2 parts by weight relative to 1 part by weight of the first calcium-based particles, there is a disadvantage that the core formation by the second calcium-based particles is unsatisfactory, which makes it difficult to maintain a large specific surface area of the core of the porous inorganic particle, and then it is impossible to obtain a porous inorganic particle of a spherical shape.

However, when the content of the second calcium-based particles is excessively increased to more than 10 parts by weight relative to 1 part by weight of the first calcium-based particles, there is a disadvantage that the second calcium-based particles form pores excessively, and then the formation of the shell layer by the first calcium-based particles becomes insufficient, and the strength of the particles decreases.

A sintered calcium-based particle scaffold is a product obtained by applying high temperatures during the sintering process to an aggregate of multiple calcium-based particles. Sintering refers to the phenomenon whereby, when a powder, which is an aggregate of multiple particles, is heated to a temperature equal to or lower than its melting point, the powder melts, adheres, and solidifies. Thus, the porous inorganic particles correspond to secondary particles obtained by sintering a calcium-based powder containing a large number of primary calcium-based particles.

Moreover, the porous inorganic particle may include pores distributed within the sintered scaffold. Since the sintered scaffold of calcium-based particles contains pores, the porous inorganic particle may exhibit porosity. More specifically, the pores may be distributed within and/or on the surface of the sintered scaffold of calcium-based particles.

The term "pore" refers to the empty space within a sintered framework of calcium-based particles and can be used to refer to a pore, cavity, hole, void, or similar term. As used herein, the term "porous particles" can refer to particles that have pores within and/or on the surface of the particles.

Since the porous inorganic particle contains pores distributed in the sintered framework, the biological activity of the sintered framework is enhanced due to the increase in surface area due to the pores, and a significant effect of improving skin condition can be quickly realized.

As described below, pores can be created during the sintering process of calcium-based particles. More specifically, the pores correspond to the spaces that form between calcium-based particles when the sintering conditions are adjusted during the sintering process.

Moreover, the porous inorganic particle may have a core-shell structure, with a highly porous core and a shell with a porosity lower than that of the core. Depending on the radius, which is the distance from the center of gravity of the porous inorganic particle to the outer boundary line of the particle, the region on the inner side of the position corresponding to 90%, 80%, 70%, 60%, or 50% of the diametrical radius starting from the center of gravity of the porous inorganic particle may be defined as the core. Furthermore, the remaining region outside the core may be defined as the shell.

In particular, the porous inorganic particle may have a shell thickness of 10 μm to 45 μm, 10 μm to 42 μm, 10 μm to 40 μm, 10 μm to 22 μm, or 10 μm to 20 μm. The core thickness of a porous inorganic particle refers to the distance between two points at which a straight line passing through the center of gravity of the porous inorganic particle intersects the outer surface of the core. The core thickness of a porous inorganic particle can be obtained using SEM. When the core thickness of a porous inorganic particle is not constant, the arithmetic mean of the maximum and minimum thickness values can be calculated as the shell layer thickness.

When the aforementioned core thickness range is met, the porous inorganic particle can sufficiently provide core porosity. When the core thickness is reduced excessively, providing porosity becomes difficult.

In particular, the core diameter of the porous inorganic particle may be from 20 μm to 90 μm, or from 20 μm to 84 μm, or from 20 μm to 80 μm, or from 20 μm to 44 μm, or from 20 μm to 40 μm. The core diameter of the porous inorganic particle means the distance between two points at which a straight line passing through the center of gravity of the core inside the porous inorganic particle intersects the outer boundary line of the core, with the largest value of such diameters corresponding to the maximum diameter. Examples of specific methods for measuring the core diameter of the porous inorganic particle are not particularly limited, but can be confirmed, for example, using SEM images. The core diameter of the porous inorganic particle corresponds to a value approximately twice the aforementioned core thickness.

When the aforementioned core diameter range is satisfied, the porous inorganic particle can sufficiently provide porosity around the core. If the core diameter is excessively reduced, it becomes difficult to provide porosity.

The thickness of the shell of the porous inorganic particle may be from 0.1 μm to 25 μm, or from 0.1 μm to 20 μm, or from 0.1 μm to 15 μm, or from 0.1 μm to 10 μm, or from 1 μm to 25 μm, or from 1 μm to 20 μm, or from 1 μm to 15 μm, or from 1 μm to 10 μm, or from 2 μm to 25 μm, or from 2 μm to 20 μm, or from 2 μm to 15 μm, or from 2 μm to 10 μm. The thickness of the shell of the porous inorganic particle means the difference value (L1-L2) obtained by subtracting the thickness of the core (L2) from the distance (L1) from the center of gravity of the porous inorganic particle to the point at which a straight line passing through the center of gravity intersects the outer surface of the shell. The shell thickness of a porous inorganic particle can be obtained using SEM. When the shell thickness of a porous inorganic particle is variable, the shell thickness can be calculated as the arithmetic mean of the maximum and minimum thickness values.

When the above-mentioned shell thickness range is met, the porous inorganic particle can sufficiently provide shell strength. When the shell thickness is excessively reduced, it becomes difficult to ensure strength.

The porous inorganic particle may have a core diameter of 20 µm to 90 µm and a shell thickness of 2 µm to 50 µm.

More precisely, the porous inorganic particle has a core diameter to shell thickness ratio (core diameter : shell thickness) of 1:1 to 100:1, or 2:1 to 100:1, or 5:1 to 100:1, or 7:1 to 100:1. In this range, it is possible to simultaneously provide porosity near the core and provide strength due to the shell.

The porosity of the shell may be lower than that of the core. As shown in Figs. 1 and 2, the porous inorganic particle obtained in accordance with the present invention has many pores distributed in the core, which ensures very high biological activity, and has comparatively fewer pores in the shell than in the core, or has no porosity, in the absence of pores, which ensures very high strength.

The above-described properties are considered to arise as a result of the fact that, during spray drying for producing porous inorganic particles, the second calcium-based particles having a maximum diameter of 1 μm to 10 μm constitute the skeleton of the core of the porous inorganic particle, and the first calcium-based particles having a maximum diameter of 10 nm to 500 nm, which is smaller than the maximum diameter of the second calcium-based particle, move outward from the skeleton of the core of the porous inorganic and form a shell, and therefore the core consists mainly of the second calcium-based particles, and the shell consists of the second calcium-based particles and the first calcium-based particles.

In particular, the core can have a porosity of 60% to 80%, and the shell can have a porosity of 0% to 60%. Porosity was analyzed using SEM images.

At the same time, at least 70 vol.% of all first calcium-based particles may be contained in the shell. The porous inorganic particles comprise first calcium-based particles and second calcium-based particles, wherein at least 70 vol.%, or at least 80 vol.%, or at least 90 vol.%, or no more than 100 vol.%, or from 70 vol.% to 100 vol.%, or from 80 vol.% to 100 vol.%, or from 90 vol.% to 100 vol.% of all first calcium-based particles may be contained in the shell.

The fact that at least 70 vol.% of all the first calcium-based particles are in the shell is believed to mean that the first calcium-based particles are mainly in the shell, and in particular, the value of at least 70 vol.% of all the first calcium-based particles can be confirmed by measuring the volume of all the first calcium-based particles.

Whether the first calcium-based particles and the second calcium-based particles are in a particular zone is determined by whether each of the first calcium-based particles or the second calcium-based particles is in a particular zone, and is determined by excluding particles that are outside the boundary of a particular zone.

Conversely, no more than 30 vol.%, or no more than 20 vol.%, or no more than 10 vol.%, or 0 vol.% or more, or from 0 vol.% to 30 vol.%, or from 0 vol.% to 20 vol.%, or from 0 vol.% to 10 vol.% of all the second calcium-based particles may be in the shell.

At the same time, at least 70 vol.% of all the second calcium-based particles may be contained in the core. The porous inorganic particles include the first calcium-based particles and the second calcium-based particles, wherein at least 70 vol.%, or at least 80 vol.%, or at least 90 vol.%, or no more than 100 vol.%, or from 70 vol.% to 100 vol.%, or from 80 vol.% to 100 vol.%, or from 90 vol.% to 100 vol.% of all the second calcium-based particles may be contained in the core.

The fact that at least 70 vol.% of all calcium-based second particles are in the shell is believed to mean that the calcium-based second particles are mainly in the core, and in particular, the value of at least 70 vol.% of all calcium-based second particles can be confirmed by measuring the volume of all calcium-based second particles.

Conversely, no more than 30 vol.%, or no more than 20 vol.%, or no more than 10 vol.%, or 0 vol.% or more, or from 0 vol.% to 30 vol.%, or from 0 vol.% to 20 vol.%, or from 0 vol.% to 10 vol.% of all calcium-based second particles may be present in the core.

According to an embodiment, a porous inorganic particle may comprise a shell comprising at least 70% by volume of all first calcium-based particles and a core comprising at least 70% by volume of all second calcium-based particles. As described above, in the porous inorganic particle, the second calcium-based particles may be distributed primarily in the core, and the first calcium-based particles may be distributed primarily in the shell layer.

Furthermore, porous inorganic particles may include a product of thermally treating composite particles containing a biocompatible binder, first calcium-based particles, and second calcium-based particles. Thermal treatment of the composite particles containing the biocompatible binder, first calcium-based particles, and second calcium-based particles removes the biocompatible binder by thermal decomposition, and partially sinters the calcium-based particles, which may create fine pores within the calcium-based particles. Information regarding the first calcium-based particle and the second calcium-based particle may include all of the above.

The mass-average molar mass of the biocompatible binder may be from 100,000 g/mol to 200,000 g/mol or from 140,000 g/mol to 190,000 g/mol. In the present description, the mass-average molar mass means the mass-average molar mass based on polystyrene measured by gel permeation chromatography (GPC). In the process of determining the mass-average molar mass based on polystyrene measured by the GPC method, a generally known analyzing device, a detector such as a refractometric detector, and an analytical column can be used. A commonly used mode can be used with respect to temperature, solvent, and flow rate. In particular, the measurement was performed, for example, using a Waters PL-GPC220 and a Polymer Laboratories PLgel MIX-B chromatograph with a 300 mm column. The evaluation temperature was 160°C, 1,2,4-trichlorobenzene was used as the solvent, and the flow rate was 1 mL/min. The sample with a concentration of 10 mg/10 mL was supplied in an amount of 200 μL, and the molecular weight values were obtained using a calibration curve constructed using a polystyrene standard. Nine kinds of polystyrene standards with molecular weights of 2000/10000/30000/70000/200000/700000/2000000/4000000/10000000 were used.

The biocompatible binder may include one or more polymers selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, and polyethyleneglycol. That is, the biocompatible binder may include polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, polyethyleneglycol, or a mixture of two or more of these.

In another specific example, the biocompatible binder could be polyvinyl alcohol. Polyvinyl alcohol has a boiling point of 228°C and can be evaporated at temperatures no lower than 228°C.

Therefore, the thermal treatment of the composite particle may include a first thermal treatment of the composite particles at a temperature of 450°C to 550°C and a second thermal treatment at a temperature of 600°C to 1200°C. During the first thermal treatment of the composite particles at a temperature of 450°C to 550°C or 480°C to 520°C, the biocompatible binder is evaporated and removed by thermal decomposition.

More specifically, in the first heat treatment, the temperature is increased to a temperature of 450°C to 550°C or 480°C to 520°C at a heating rate of 2°C/min to 8°C/min or 4°C/min to 6°C/min, and then the heat treatment may be performed at a temperature of 450°C to 550°C or 480°C to 520°C for a period of 1 hour to 3 hours.

In addition, in the process of secondary heat treatment of the composite particles at a temperature of 600°C to 1200°C or 600°C to 1000°C, sintering of the composite particles including pores and calcium-based particles occurs, so that a sintered framework can be formed from the above-mentioned calcium-based particles and porous inorganic particles including pores distributed in the sintered framework.

If the sintering temperature is excessively lowered to temperatures lower than 600°C during the secondary heat treatment, it is difficult to ensure sufficient strength of the sintered framework, and if the sintering temperature is excessively raised to temperatures higher than 1200°C, all pores may be removed and non-porous inorganic particles may be formed.

More specifically, in the secondary heat treatment process, the temperature may be increased to a temperature of 600°C to 1200°C at a heating rate of 2°C/min to 8°C/min or 4°C/min to 6°C/min, and then the heat treatment may be performed at a temperature of 600°C to 1200°C for 1 hour to 3 hours.

At the same time, the content of calcium-based particles may be at least 30 parts by weight, or at least 40 parts by weight, or at least 50 parts by weight, or at least 100 parts by weight, or at most 90 parts by weight, or at most 80 parts by weight, or at most 70 parts by weight, or at most 60 parts by weight, or from 30 parts by weight to 100 parts by weight, or from 40 parts by weight to 100 parts by weight, or from 50 parts by weight to 100 parts by weight, or from 30 parts by weight to 90 parts by weight, or from 40 parts by weight to 90 parts by weight, or from 50 parts by weight to 90 parts by weight, or from 30 parts by weight to 80 parts by weight, or from 40 parts by weight to 80 parts by weight, or from 50 parts by weight to 80 parts by weight, or from 30 parts by weight to 70 parts by weight, or from 40 parts by weight to 70 parts by weight, or from 50 parts by weight to 70 parts by weight, or from 30 parts by weight to 60 parts by weight, or from 40 parts by weight to 60 parts by weight, or from 50 parts by weight to 60 parts by weight in relation to 1 part by weight of the biocompatible binder material.

In this case, the content of calcium-based particles means the total content of the first calcium-based particles and the second calcium-based particles.

If the calcium-based particle content is excessively high relative to 1 part by weight of the biocompatible binder, the composite particles will hardly form during spray drying due to the relative reduction in the binder weight. Conversely, if the calcium-based particle content is excessively low relative to 1 part by weight of the biocompatible binder, the strength of the composite particles after sintering will be low due to the relative reduction in the mass of the calcium-based particles, which will make shape retention difficult and may cause particle deformation.

More specifically, the content of the first calcium-based particles may be from 5 parts by weight to 30 parts by weight, or from 5 parts by weight to 20 parts by weight, or from 5 parts by weight to 15 parts by weight, relative to 1 part by weight of the biocompatible binder. The content of the second calcium-based particles may be from 35 parts by weight to 100 parts by weight, or from 35 parts by weight to 50 parts by weight, or from 35 parts by weight to 45 parts by weight, relative to 1 part by weight of the biocompatible binder.

In addition, the content of the second calcium-based particles may be 2-10 parts by weight, or 2-5 parts by weight, or 3-10 parts by weight, or 3-5 parts by weight, relative to 1 part by weight of the first calcium-based particles.

Furthermore, composite particles comprising a biocompatible binder, first calcium-based particles, and second calcium-based particles may be the product of spray-drying a composition comprising the biocompatible binder, first calcium-based particles, and second calcium-based particles. A spray-drying product is a product obtained by spray-drying a composition comprising the biocompatible binder, first calcium-based particles, and second calcium-based particles. Spray drying is characterized by high particle production rates, does not require additional drying steps, which increases productivity, does not use organic solvents, and is therefore produced safely by spray-drying without the risk of explosion, thereby maximizing production efficiency.

Thus, this method may offer significant efficiency advantages over the emulsion method, which is another production method that can be used to form particles. This is because the emulsion method has disadvantages, such as the need for an additional oil or organic solvent to form the emulsion, and the associated washing and drying steps, which reduce productivity.

The shape of the composite particle is not specifically limited, but may be, for example, spherical. Examples of specific methods for measuring the shape of the composite particle are not specifically limited, but may be confirmed, for example, using SEM images.

The average maximum diameter of composite particles can range from 1 μm to 100 μm. The diameter of composite particles is the distance between two points at which a straight line passing through the particle's center of gravity intersects the particle's boundary line, with the largest value of these diameters corresponding to the maximum diameter. Furthermore, the value obtained by measuring the maximum diameter of a set of composite particles and calculating their arithmetic mean is called the average maximum diameter. Examples of specific methods for measuring the maximum diameter of composite particles are not specifically limited, but can be confirmed, for example, using SEM images.

A composite particle may be a group of individual particles with an average maximum diameter of 1 μm to 100 μm, and the individual particles within the group may have an average maximum diameter of 1 μm to 100 μm. More specifically, 95% or 99% of the individual particles within the group may have a maximum diameter of 1 μm to 100 μm.

The shape of the porous inorganic particles is not specifically limited, but can be, for example, spherical. Examples of a specific method for measuring the shape of a porous inorganic particle are not specifically limited, but can be confirmed, for example, using SEM imaging. When porous inorganic particles satisfy a spherical shape, they can be injected into the body with low injection force, and they elicit a weak immune response in the body.

In addition, the specific surface area of the porous inorganic particle can be greater than 0.1 ^m2 /g or not less than 0.5 ^m2 /g, or not less than 1 ^m2 /g, or not less than 3 ^m2 /g, or not less than 4 ^m2 /g, or not less than 5 ^m2 /g, or not more than ^{10 m2} /g, or not less than 0.1 ^m2 /g and not more than 10 ^m2 /g, or from 0.5 m2/g to 10 ^m2 /g, or from 1 ^m2 /g to 10 ^m2 /g, or from 3 ^m2 /g to 10 ^m2 /g, or from 4 ^m2 /g to 10 ^m2 /g, or from 5 ^m2 /g to 10 ^m2 /g. The specific surface area was measured using a specific surface area analyzer using the BET method. When the specific surface area of the porous inorganic particle is in the above range, the porosity and specific surface area are greater than those of conventional high-density solid particles, and therefore, the bioactivity is higher, leading to an accelerated filler treatment effect. On the other hand, when the specific surface area of the porous inorganic particles is excessively reduced to 0.1 ^m2 /g or lower, or to similar values, the porosity and specific surface area are as small as those of conventional high-density solid particles, the bioactivity is reduced, and the filler treatment effect is weakened, which may create the problem of requiring a large number of particles. Furthermore, when the specific surface area of the porous inorganic particles is excessively increased, the strength of the sintered framework of the inorganic particle is reduced, which may create a problem that the applied process is limited in terms of composite filler production.

In addition, the total pore volume of the porous inorganic particles may be not less than 0.001 ^cm3 /g, or not less than 0.01 ^cm3 /g, or not less than 0.013 ^cm3 /g, or not less than 0.015 ^{cm3 /} g, or not more than 0.05 ^cm3 /g, or from 0.001 ^cm3 /g to 0.05 ^cm3 /g, or from 0.013 ^cm3 /g to 0.05 ^cm3 /g, or from 0.015 ^cm3 /g to 0.05 ^cm3 / ^g . The total pore volume means the sum of the volume of all pores contained in the porous inorganic particle and was measured using a specific surface area analyzer by the BET method. When the total pore volume of porous inorganic particles is within the above range, their porosity and specific surface area exceed those of conventional high-density solid particles, resulting in higher bioactivity, which accelerates the filler treatment effect. On the other hand, when the total pore volume of porous inorganic particles is excessively reduced to less than 0.001 ^cm3 /g, their porosity and specific surface area are as small as those of conventional high-density solid particles, resulting in reduced bioactivity and weakened filler treatment effect, which may lead to the problem of requiring a large number of particles. Furthermore, when the total pore volume of porous inorganic particles is excessively increased, the strength of the sintered framework of the inorganic particle decreases, which may limit the applicable process in terms of composite filler production.

In addition, the average value of the maximum diameter of the porous inorganic particles may be from 1 μm to 1000 μm, or from 10 μm to 100 μm, or from 10 μm to 45 μm, or from 40 μm to 1000 μm, or from 40 μm to 100 μm, or from 40 μm to 45 μm. The diameter of the porous inorganic particles means the distance between two points at which a straight line passing through the particle's center of gravity intersects the particle boundary line, with the largest value of these diameters corresponding to the maximum diameter. In addition, the value obtained by measuring the maximum diameter of a plurality of porous inorganic particles and calculating their arithmetic mean is called the average value of the maximum diameter. Examples of specific methods for measuring the maximum diameter of composite particles are not particularly limited, but can be confirmed, for example, using SEM images.

The porous inorganic particles may be a group of individual particles having an average maximum diameter from 1 μm to 1000 μm, or from 10 μm to 100 μm, or from 10 μm to 45 μm, or from 40 μm to 1000 μm, or from 40 μm to 100 μm, or from 40 μm to 45 μm, and the individual particles contained in the said group may have an average maximum diameter from 1 μm to 1000 μm, or 10 μm to 100 μm, or from 10 μm to 45 μm, or from 40 μm to 1000 μm, or from 40 μm to 100 μm, or from 40 μm to 45 μm. More precisely, 95% or 99% of the individual particles contained in the group may have a maximum diameter of 1 µm to 1000 µm, or 10 µm to 100 µm, or 10 µm to 45 µm, or 40 µm to 1000 µm, or 40 µm to 100 µm, or 40 µm to 45 µm.

When the average maximum diameter of porous inorganic particles is within the above range, the skin improvement effect can be maximized without side effects or pain during treatment. If the average maximum diameter of porous inorganic particles is excessively reduced to 1 μm, an exaggerated reaction to foreign materials may occur. On the other hand, if the average maximum diameter of porous inorganic particles is excessively increased to more than 1000 μm, not only does the specific surface area per particle mass decrease, weakening the treatment effect, but it may also cause severe pain during treatment.

At the same time, the porous inorganic particles have a compressive strength of not less than 20 MPa, or not less than 21 MPa, or not less than 22 MPa, or not less than 30 MPa, or not less than 35 MPa, or not less than 100 MPa, or not less than 70 MPa, or from 20 MPa to 100 MPa, or from 21 MPa to 100 MPa, or from 22 MPa to 100 MPa, or from 30 MPa to 100 MPa, or from 35 MPa to 100 MPa, or from 20 MPa to 70 MPa, or from 21 MPa to 70 MPa, or from 22 MPa to 70 MPa, or from 30 MPa to 70 MPa, or from 35 MPa to 70 MPa.

Compressive strength is defined as the load per unit area at which a porous inorganic particle fails under a compressive force acting in one direction during a uniaxial compression test. Examples of methods and devices for measuring compressive strength are not specifically limited, and a conventional method for measuring the compressive strength of small particles can be used without limitation. In one example, compressive strength can be measured using a microcompression testing device.

When porous inorganic particles have a compressive strength within the specified range, their shape can be stably maintained due to their high strength. On the other hand, if the compressive strength is excessively reduced to less than 20 MPa, etc., the particle strength becomes low, making it difficult to maintain shape and potentially leading to particle deformation.

2. Composite filler

According to another embodiment of the invention, a composite filler may be provided comprising a porous inorganic particle according to one embodiment and a biodegradable carrier.

The authors of the present invention have experimentally discovered that, in the case of a composite filler according to another embodiment, it includes porous inorganic particles according to one embodiment together with a biodegradable carrier, combines the stability of the biodegradable carrier and the biological activity of the porous inorganic particles, eliminates the disadvantages of a single-component filler and maintains the original volume, and, in addition, produces natural collagen by stimulating tissues with calcium particles, thereby exhibiting the effect of improving the condition of the skin itself, and complements the present invention.

In particular, the porous inorganic particle not only has higher porosity and specific surface area than existing high-density solid particles, and has enhanced biological activity to quickly induce the effect of filler treatment, but also has the characteristic of high particle production speed, does not require additional processes in the drying stages, which ensures high productivity, does not use organic solvents, and is therefore obtained by a safe spray drying method without the risk of explosion, thereby maximizing the production efficiency.

Since the porous inorganic particle contained in the composite filler of another embodiment comprises a sintered scaffold of calcium-based particles and pores distributed within the sintered scaffold as described above, it results in increased bioactivity and rapid onset of skin-improving effects. Information regarding the porous inorganic particle includes all of the above-described embodiments.

Additionally, the composite filler may include a biodegradable carrier. The biodegradable carrier serves as the base, matrix, or support for the composite filler, and porous inorganic particles may be dispersed within or on the biodegradable carrier, as described below.

Examples of the biodegradable carrier are not particularly limited, and various biodegradable carriers widely used in the field of fillers can be used without limitation. For example, the biodegradable carrier includes gelatin, hyaluronic acid (HA), carboxymethylcellulose (CMC), chondroitin (sulfate), dextran (sulfate), chitosan, collagen, carboxymethylchitin, fibrin, pullulan, polylactide, polyglycolide (PGA), polylactide-polyglycolide copolymer (PLGA), polyanhydride, polyorthoester, polyester containing ester groups, polycaprolactone, polyethylene glycol (PEG), cyclodextrin, poloxamer, or a mixture of two or more of the above substances.

In a preferred embodiment, hyaluronic acid can be included as a biodegradable carrier. Hyaluronic acid is a biosynthesized natural substance, present in large quantities in the skin of animals and similar creatures. Due to its high number of hydroxyl groups (-OH), it is hydrophilic and acts as a humectant in the skin of animals and similar creatures. Hyaluronic acid is present in human skin and has a moisturizing effect, and is therefore often included in cosmetic formulations. Hyaluronic acid reacts with the CD44 protein, expressed in various epithelial cells, to regulate various physiological effects.

The composite filler may contain 1-50 parts by weight, 1-30 parts by weight, or 1-10 parts by weight of porous inorganic particles relative to 100 parts by weight of the biodegradable carrier. If the content of porous inorganic particles is excessively low relative to 100 parts by weight of the biodegradable carrier, the skin-improving effect caused by biological activity may not be observed. Furthermore, if the content of porous inorganic particles is excessively high relative to 100 parts by weight of the biodegradable carrier, the porous inorganic particles in the composite filler may be unevenly dispersed, which may hinder smooth injection into the body.

At the same time, the composite filler may have a bioactivity of not less than 15 mg/(kg⋅g) or not less than 16 mg/(kg⋅g), or not less than 17 mg/(kg⋅g), or not less than 18 mg/(kg⋅g), or not less than 19 mg/(kg⋅g), or not higher than 100 mg/(kg⋅g), or from 15 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 16 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 17 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 18 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 19 mg/(kg⋅g) to 100 mg/(kg⋅g) according to the following equation 1.

[Equation 1]

Bioactivity = {[Content of ion (either calcium ion or phosphorus ion) in body fluid (mg/kg)] - [Content of ion (either calcium ion or phosphorus ion) in body fluid after immersion of composite filler in body fluid for 8 days (mg/kg)]}/(Content of inorganic particles (g) in composite filler).

When the bioactivity of the composite filler is in the above range according to Equation 1, the filler has increased bioactivity, quickly shows skin improvement effects, and allows for the maintenance of the original volume and the implementation of corrective procedures.

However, if the bioactivity according to Equation 1 is excessively reduced to less than 15 mg/(kg⋅g) or the like, there is a disadvantage that the biological activity is low and the effect of improving the skin condition is delayed.

In particular, the composite filler may have a bioactivity of not less than 21 mg/(kg⋅g) or not less than 22 mg/(kg⋅g), or not less than 23 mg/(kg⋅g), or not less than 25 mg/(kg⋅g), or not less than 28 mg/(kg⋅g), or not less than 29 mg/(kg⋅g), or not higher than 100 mg/(kg⋅g), or from 21 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 22 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 23 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 25 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 28 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 29 mg/(kg⋅g) to 100 mg/(kg⋅g) according to the following equation 2.

[Equation 2]

Bioactivity = {[Content of calcium ion in body fluid (mg/kg)] - [Content of calcium ion in body fluid after immersion of composite filler in body fluid for 8 days (mg/kg)]}/(Content of inorganic particles (g) in composite filler).

In addition, the composite filler may have a bioactivity of not less than 15 mg/(kg⋅g) or not less than 16 mg/(kg⋅g), or not less than 17 mg/(kg⋅g), or not less than 18 mg/(kg⋅g), or not less than 19 mg/(kg⋅g), or not less than 21 mg/(kg⋅g), or not less than 22 mg/(kg⋅g), or not higher than 100 mg/(kg⋅g), or from 15 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 16 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 17 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 18 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 19 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 21 mg/(kg⋅g) to 100 mg/(kg⋅g), or from 22 mg/(kg⋅g) to 100 mg/(kg⋅g) in accordance with the following equation 3.

[Equation 3]

Bioactivity = {[Content of phosphorus ion in body fluid (mg/kg)] - [Content of phosphorus ion in body fluid after immersion of composite filler in body fluid for 8 days (mg/kg)]}/(Content of inorganic particles (g) in composite filler).

At the same time, the composite filler may additionally contain various additive components typically included in the composition of fillers, for example, a lubricant such as glycerin, a phosphate buffer, and the like, if necessary.

3. Product

According to another embodiment of the invention, an article may be provided comprising a composite filler according to another embodiment. Information regarding the composite filler includes all of the above-described information in the other embodiment.

Product examples are not specifically limited and may be used without restriction, depending on the intended use of the filler. Examples of products include food, pharmaceuticals, cosmetics, and the like.

Beneficial effects

According to the present invention, a porous inorganic particle characterized by high production efficiency and very high bioactivity and strength, and a composite filler and article using said particle can be proposed.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 - SEM images of the surface and cross-section of the porous inorganic particles obtained in Example 1.

Fig. 2 - SEM images of the surface and cross-section of the porous inorganic particles obtained in Example 2.

Fig. 3 - SEM images of the surface and cross-section of the porous inorganic particles obtained in Comparative Example 1.

Fig. 4 - SEM images of the surface and cross-section of the porous inorganic particles obtained in Comparative Example 2.

The invention is now described in detail with reference to the following examples. However, these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

<EXAMPLE>

Example 1

(1) Production of porous inorganic particles

Polyvinyl alcohol (PVA, weight-average molar mass: 146,000~186,000 Da, hydrolyzed 99+%) was stirred in water at 90°C to prepare an aqueous solution with 1 wt% PVA.

Hydroxyapatite (HAp) powder (1st HAp) of spherical particles with a maximum diameter of 200 nm and hydroxyapatite (HAp) powder (2nd HAp) of spherical particles with a maximum diameter of 2.5 μm were added to an aqueous PVA solution at a weight ratio of 1st HAp/2nd HAp/PVA corresponding to 10/40/1 to prepare a suspension.

The suspension was spray dried (using a Mini B-290 spray dryer). Once drying was complete, the particles were collected, placed in a crucible, heated at 500°C for 2 hours in a chamber furnace to remove PVA, and then sintered at 1000°C for 2 hours to obtain a porous inorganic particle.

(2) Production of composite filler

0.4 g of porous inorganic particles were mixed with 9.6 g of hyaluronic acid to obtain a composite filler.

Example 2

The porous inorganic particle and the composite filler were produced in the same manner as in Example 1, except that the sintering temperature was changed to 1200°C, as shown in Table 1 below.

<COMPARATIVE EXAMPLE>

Comparative example 1

A porous inorganic particle and a composite filler were produced in the same manner as in Example 2, except that hydroxyapatite (HAp) powder (2nd HAp) of spherical particles with a maximum diameter of 2.5 μm was added at a weight ratio of 1st HAp/2nd HAp/PVA 0/50/1, without using 1st HAp, as shown in Table 1 below.

Comparative example 2

A porous inorganic particle and a composite filler were produced in the same manner as in Example 2, except that hydroxyapatite (HAp) powder of needle-shaped particles (1st HAp) with a maximum diameter of 150 nm was added at a weight ratio of 1st HAp/2nd HAp/PVA of 12/0/1, without using 2nd HAp, as shown in Table 1 below.

<EXPERIMENTAL EXAMPLE>

The physical properties of the inorganic particles and composite fillers obtained in the Examples and Comparative Examples were measured by the following methods, and the results are shown in Table 1, Table 2 and the figures.

1. Particle shape

The surface shapes and cross-sectional shapes of the inorganic particles obtained in the Examples and Comparative Examples were confirmed by SEM images, which are shown in Figs. 1–4, respectively.

2. Particle size

For the inorganic particles obtained in the Examples and Comparative Examples, the maximum diameter of every 100 particles was measured using SEM images, and the arithmetic mean of these values was calculated.

3. Porosity

For the inorganic particles obtained in the Examples and Comparative Examples, the cross-sectional shape of the particles was confirmed using SEM images, and the porosity was expressed as follows according to the presence or absence of pores.

ο: presence of pores inside the particle in SEM cross-sectional image

X: No pores inside the particle in the cross-sectional SEM image

4. Specific surface area and total pore volume

The specific surface area and total pore volume of the inorganic particles obtained in the Examples and Comparative Examples were measured using a specific surface area analyzer by the BET method.

5. Particle strength

The compressive strength of the inorganic particles obtained in the Examples and Comparative Examples was measured by a microcompression testing apparatus and evaluated as the particle strength.

[Table 1]

Experimental results of approximate measurements for examples and comparative examples

Category Weight ratio of 1st HAp/2nd HAp/PVA Maximum diameter and shape of 1st HAp Maximum diameter and shape of the 2nd HAp Sintering temperature Particle shape Particle size (µm) Porosity Specific surface area ( ^m2 /g) Total pore volume ( ^cm3 /g) Compressive strength (MPa) Example 1 10/40/1 200 nm
spherical 2.5 µm
spherical 1000°C Fig. 1 42 ο 5 0.0155 22 Example 2 10/40/1 200 nm
spherical 2.5 µm
spherical 1200°C Fig. 2 44 ο 4 0.0131 38 Comparative example 1 0/50/1 - 2.5 µm
spherical 1200°C Fig. 3 34 ο 4 0.0123 15 Comparative example 2 12/0/1 150 nm
needle-shaped form - 1200°C Fig. 4 49 X 0.1 0.0009 75

The data in Table 1 confirmed that, in the case of the inorganic particles contained in the composite fillers in the examples, a porous inorganic particle having pores within the particles was obtained, and both the specific surface area and the pore volume were significantly increased compared with Comparative Example 2. In addition, it was confirmed that, in the case of the inorganic particles contained in the composite fillers in the examples, the compressive strength of the porous inorganic particle was from 22 MPa to 38 MPa, which was significantly higher compared with Comparative Example 1.

On the other hand, it was confirmed that the compressive strength of the porous inorganic particle contained in the composite filler in Comparative Example 1 was 15 MPa, which was lower than that of the examples. Furthermore, it was confirmed that the inorganic particles contained in the composite filler in Comparative Example 2 produced non-porous inorganic particles containing no pores within the particles.

6. Bioactivity

After immersing the composite filler obtained in the examples and comparative examples in the model body fluid for 8 days, a sample was prepared by the acid hydrolysis method, and the content of Ca ions and P ions in the sample (unit: mg/kg) was measured using an inductively coupled plasma optical emission spectrometry (ICP-OES) device, and the bioactivity was evaluated according to the following equation 1. The measured content of Ca ions and P ions in the model body fluid was 42 mg/kg, which means that the larger the value in the following equation 1, the higher the bioactivity.

[Equation 1]

Bioactivity = {[Content of ion (either calcium ion or phosphorus ion) in body fluid (mg/kg)] - [Content of ion (either calcium ion or phosphorus ion) in body fluid after immersion of composite filler in body fluid for 8 days (mg/kg)]}/(Content of inorganic particles (g) in composite filler).

[Table 2]

Experimental results of approximate measurements for examples and comparative examples

Category Bioactivity of Ca ion (mg/(kg⋅g)) Bioactivity of P ion (mg/(kg⋅g)) Example 1 29.2 22.2 Example 2 27.8 19.4 Comparative example 1 27.8 20.8 Comparative example 2 20.8 12.5

The data in Table 2 confirmed that, in the case of the composite filler in Example 1, the bioactivity of the Ca ion was 29.2 mg/(kg⋅g), and the bioactivity of the P ion was 22.2 mg/(kg⋅g), which was significantly higher than the bioactivities in the comparative examples and, therefore, was a very high bioactivity. On the other hand, the composite filler in Example 2 showed the same level of bioactivity as in Comparative Example 1 and exhibited higher bioactivity compared to Comparative Example 2.

Claims (40)

1. A porous inorganic particle containing a sintered framework of hydroxyapatite-based particles, pores distributed in the sintered framework, a core-shell structure with a core having high porosity and a shell having a porosity lower than the porosity of the core, wherein the hydroxyapatite-based particles comprise first hydroxyapatite-based particles having a maximum diameter of 10 to 500 nm and second hydroxyapatite-based particles having a maximum diameter of 1 to 10 μm, and The shell contains at least 70% by volume of all first particles based on hydroxyapatite, and the core contains at least 70% by volume of all second particles based on hydroxyapatite. 2. A porous inorganic particle according to claim 1, in which the content of the second hydroxyapatite-based particles is from 2 to 10 parts by weight relative to 1 part by weight of the first hydroxyapatite-based particles. 3. A porous inorganic particle according to claim 1, in which The porous inorganic particle has a core diameter of 20 to 90 μm and a shell thickness of 0.2 to 50 μm. 4. A porous inorganic particle according to claim 1, in which The porous inorganic particle is characterized by a core diameter to shell thickness ratio (core diameter:shell thickness) of 1:1 to 100:1. 5. A porous inorganic particle according to claim 1, in which the porous inorganic particle has a total pore volume of at least 0.001 ^cm3 /g. 6. A porous inorganic particle according to claim 1, in which the porous inorganic particle has a specific surface area greater than 0.1 ^m2 /g. 7. A porous inorganic particle according to claim 1, in which the porous inorganic particle has a compressive strength of at least 20 MPa. 8. A porous inorganic particle according to claim 1, in which each of the first hydroxyapatite-based particles and the second hydroxyapatite-based particles has a spherical shape. 9. The porous inorganic particle of claim 1, in which each of the first hydroxyapatite-based particles and the second hydroxyapatite-based particles contains hydroxyapatite. 10. A porous inorganic particle according to claim 1, in which The porous inorganic particle comprises a product of thermal treatment of composite particles containing a biocompatible binder material, first particles based on hydroxyapatite and second particles based on hydroxyapatite. 11. The porous inorganic particle of claim 10, in which The biocompatible binder comprises one or more polymers selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and polyethyleneglycol. 12. The porous inorganic particle of claim 10, in which heat treatment of composite particles contains the first heat treatment of composite particles at a temperature of 450 to 550°C and the second heat treatment of composite particles at a temperature of 600 to 1200°C. 13. The porous inorganic particle of claim 10, in which The content of the first particles based on hydroxyapatite is from 5 to 30 parts by weight in relation to 1 part by weight of the biocompatible binder material. 14. The porous inorganic particle of claim 10, wherein The content of the second particles based on hydroxyapatite is from 35 to 100 parts by weight relative to 1 part by weight of the biocompatible binder material. 15. A composite filler containing a porous inorganic particle according to claim 1 and a biodegradable carrier. 16. The composite filler according to claim 15, in which the composite filler is characterized by a bioactivity of at least 15 mg/(kg⋅g) in accordance with the following equation 1: [Equation 1] Bioactivity = {[Content of ion (either calcium ion or phosphorus ion) in body fluid (mg/kg)] - [Content of ion (either calcium ion or phosphorus ion) in body fluid after immersion of composite filler in body fluid for 8 days (mg/kg)]}/(Content of inorganic particles (g) in composite filler). 17. The composite filler according to claim 15, in which The biodegradable carrier contains hyaluronic acid.