Hydroxyapatite-particle-containing material, hydroxyapatite-encapsulated liposome, and liposome-containing composition

Abstract

To provide a new composite material including hydroxyapatite particles that enables the activity of the hydroxyapatite particles to be utilized more effectively.SOLUTION: A hydroxyapatite-particle-containing material according to one embodiment of the present invention contains hydroxyapatite particles, a phospholipid, a dispersant, and water.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a hydroxyapatite particle-containing material, a hydroxyapatite-encapsulating liposome, and a liposome-containing composition. [Background technology]

[0002] Hydroxyapatite particles are known to have biocompatibility and physiological activity.

[0003] For example, Patent Document 1 discloses that amorphous hydroxyapatite of 100 nm or less acts on epidermal keratinocytes in the skin, promoting cellular metabolism, repairing damage to skin cells caused by external stimuli, and maintaining a youthful skin condition, and is suitable as a cosmetic product that acts on hair papillae, activating cells, preventing hair loss, and promoting hair growth. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2001-302454 Summary of the Invention [Problem to be solved by the invention]

[0005] However, it has been found that in compositions containing hydroxyapatite particles according to the prior art, the activity of the hydroxyapatite particles may not be fully exhibited in some cases.

[0006] Therefore, an object of the present invention is to provide a novel composite material containing hydroxyapatite particles that can more effectively utilize the activity of the hydroxyapatite particles. [Means for solving the problem]

[0007] Aspect (1) of the present invention is The hydroxyapatite particle-containing material contains hydroxyapatite particles, phospholipids, and a dispersant. Aspect (2) of the present invention is the hydroxyapatite particle-containing material, which contains water. Aspect (3) of the present invention is In the hydroxyapatite particle-containing material of aspect (1) or (2), the dispersant is one or more selected from the group consisting of acetic acid, citric acid, monosodium citrate, disodium citrate, and trisodium citrate. Aspect (4) of the present invention is In the hydroxyapatite particle-containing material of aspect (1) or (2), the hydroxyapatite particles are encapsulated in liposomes. Aspect (5) of the present invention is In the hydroxyapatite particle-containing material of aspect (1) or (2), the phospholipid is adsorbed onto the hydroxyapatite particles. Aspect (6) of the present invention is The hydroxyapatite particle-containing material according to aspect (1) or (2) is characterized in that the phospholipid is lecithin. Aspect (7) of the present invention is The hydroxyapatite particle-containing material of aspect (1) or (2) satisfies at least one of the following (1) and (2): (1) In the FT-IR spectrum, 1200 cm -1 ~1500cm -1 It has two or more peaks in the range. (2) In the FT-IR spectrum, 1700 cm -1 ~1750cm -1 The maximum absorption intensity in the range of 1030cm -1 ~1100cm -1 The absorption intensity is 10% or less of the maximum absorption intensity in the range. Aspect (8) of the present invention is A composition comprising the hydroxyapatite particle-containing material of embodiment (1) or (2). Aspect (9) of the present invention is The composition of embodiment (8) is a pharmaceutical composition. Aspect (10) of the present invention is The composition of embodiment (8) is a cosmetic composition. Aspect (11) of the present invention is Contains at least hydroxyapatite particles and water, A hydroxyapatite particle-containing material that satisfies at least one of the following (1) and (2): (1) In the FT-IR spectrum, 1200 cm -1 ~1500cm -1 It has two or more peaks in the range. (2) In the FT-IR spectrum, 1700 cm -1 ~1750cm -1 The maximum absorption intensity in the range of 1030cm -1 ~1100cm -1 The absorption intensity is 10% or less of the maximum absorption intensity in the range. A twelfth aspect of the present invention is the hydroxyapatite particle-containing material of the eleventh aspect, which contains water. Aspect (13) of the present invention is The hydroxyapatite particle-containing material according to aspect (11) or (12) is included, The liposome-containing composition is a hydroxyapatite-encapsulating liposome, wherein the hydroxyapatite particle-containing material is a liposome and the hydroxyapatite particle encapsulated in the liposome. Aspect (14) of the present invention is The liposome-containing composition of embodiment (13) is a pharmaceutical composition. Aspect (15) of the present invention is The liposome-containing composition of embodiment (13) is a cosmetic composition. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a novel composite material containing hydroxyapatite particles, which can more effectively utilize the activity of the hydroxyapatite particles. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a TEM image of a first hydroxyapatite particle-encapsulating liposome according to the present example. [Figure 2-1] 1 is a chart of an FT-IR measurement of a highly crystalline hydroxyapatite particle alone. [Figure 2-2] 1 is a chart of an FT-IR measurement of a first hydroxyapatite particle-encapsulating liposome containing highly crystalline hydroxyapatite particles. [Figure 2-3] 10 is a chart of an FT-IR measurement of a second hydroxyapatite particle-encapsulating liposome containing low-crystalline hydroxyapatite particles. [Figure 3-1] 1 is a chart of a TG-DTA measurement of a highly crystalline hydroxyapatite particle alone. [Figure 3-2] 1 is a chart of a TG-DTA measurement of a first hydroxyapatite particle-encapsulating liposome containing highly crystalline hydroxyapatite particles. [Figure 3-3] 10 is a chart showing the results of TG-DTA measurement of a second hydroxyapatite particle-encapsulating liposome containing low-crystalline hydroxyapatite particles. [Figure 4] 3 is a TEM image of liposomes encapsulating hydroxyapatite particles. [Figure 5] 10 is a chart of an FT-IR measurement of a fourth hydroxyapatite particle-encapsulating liposome containing low-crystalline hydroxyapatite particles. [Figure 6] 10 is a chart of a TG-DTA measurement of a fourth hydroxyapatite particle-encapsulating liposome containing low-crystalline hydroxyapatite particles. DETAILED DESCRIPTION OF THE INVENTION

[0010] In the present specification, when multiple upper limit values ​​and multiple lower limit values ​​are separately described, it should be understood that all numerical ranges that can be set by freely combining these upper limit values ​​and lower limit values ​​are described in the present specification.

[0011] Unless otherwise specified, each component classified in this specification can be used alone or in combination of two or more types.

[0012] The hydroxyapatite particle-containing material according to the present disclosure will be specifically described below, but the present invention is not limited thereto.

[0013] <<<<First Form>>>> The hydroxyapatite particle-containing material according to the present disclosure contains at least hydroxyapatite particles. In other words, the hydroxyapatite particle-containing material according to the present disclosure is a hydroxyapatite particle composite material in which hydroxyapatite particles are composited with a component (second component) other than the hydroxyapatite particles. Possible forms of the composite with hydroxyapatite particles include, for example, (Form A) a form in which the second component forms an outer shell covering one or more hydroxyapatite particles, forming a single material (e.g., a particulate material) as a whole, and (Form B) a form in which the second component is interposed between the hydroxyapatite particles, causing the hydroxyapatite particles to bond or aggregate to form a single material (e.g., a particulate material) as a whole. A specific example of Form A is a structure in which hydroxyapatite particles are encapsulated in liposomes formed by phospholipids. A specific example of Form B is a structure in which phospholipids are adsorbed onto hydroxyapatite particles.

[0014] The second component (component to be composited with hydroxyapatite particles) constituting the hydroxyapatite particle-containing material (hydroxyapatite particle composite material) is a component that can interact with the hydroxyapatite particles, and examples thereof include phospholipids, anionic surfactants, cationic surfactants, carboxylic acids, sulfonic acids, polyhydric alcohols, polyethers, and esters.

[0015] The hydroxyapatite particle-containing material according to the present disclosure preferably contains water, which may be, for example, in the form of a complex with another component (e.g., present as the internal aqueous phase of liposomes) and / or present substantially as a dispersion medium or solvent (e.g., present as the external aqueous phase of liposomes).

[0016] Hereinafter, as a hydroxyapatite particle-containing material, a liposome composite material in which hydroxyapatite particles are composited with liposomes formed from phospholipids will be mainly described, but the present disclosure is not limited thereto. Regarding hydroxyapatite particle-containing materials in which a material other than liposomes is composited with a second component other than phospholipids, it is believed that the activity of the hydroxyapatite particles can be effectively utilized by the interaction between the hydroxyapatite particles and the second component, so that the FT-IR spectrum, TG-DTA, zeta potential, etc., described below, satisfy the required properties.

[0017] In the present disclosure, the internal aqueous phase refers to the aqueous phase encapsulated in the liposome.

[0018] In the present disclosure, the external aqueous phase refers to an aqueous solution in which liposomes are dispersed. For example, in the case of an injection, the solution occupying the outside of the liposomes in the liposome dispersion packaged and stored in a vial or prefilled syringe is the external aqueous phase. Similarly, in the case of a liquid dispersed at the time of administration using the attached dispersion liquid or other dissolving liquid, the solution occupying the outside of the liposomes in the liposome dispersion is the external aqueous phase.

[0019] In the following description, there may be cases where the term "liposome" is used without distinguishing between a liposome as a membrane structure and a liposome composite material comprising a liposome and an internal aqueous phase encapsulated in the liposome.

[0020] The structure, components, physical properties / properties, production method, uses, etc. of the liposome according to the present disclosure will be described below.

[0021] <<<Structure>>> The liposomes according to the present disclosure encapsulate hydroxyapatite particles. More specifically, it is believed that a membrane formed by a phospholipid bilayer structure forms a capsule structure, and the hydroxyapatite particles are encapsulated in the capsule structure.

[0022] In other words, the liposome according to the present disclosure is a hydroxyapatite particle-encapsulating liposome comprising a hydroxyapatite particle and a membrane vesicle made of phospholipid that encapsulates the hydroxyapatite particle.

[0023] Liposomes according to the present disclosure may be either unilamellar or multilamellar, but are preferably multilamellar.

[0024] <<particle size>> Liposome particle size PS L is preferably 10 nm or more, 20 nm or more, 30 nm or more, or 70 nm or more, and is preferably 1000 nm or less, 500 nm or less, 300 nm or less, 200 nm or less, or 150 nm or less. L The standard deviation of is preferably 20 nm or less, 15 nm or less, or 10 nm or less. The lower limit is not particularly limited, but is, for example, 0 nm or more, 1 nm or more, 2 nm or more, 3 nm or more, 4 nm or more, or 5 nm or more.

[0025] Hydroxyapatite particle size PS H Liposome particle size PS L Ratio of (PS L / PS H ) is preferably greater than 1.0 and not greater than 10.0, and more preferably greater than 1.0 and not greater than 3.0.

[0026] Liposome particle size PS L By setting the content within this range, the physical properties inherent to the hydroxyapatite particles can be maintained.

[0027] Liposome particle size PS L is the average particle size measured by a dynamic light scattering particle size distribution analyzer.

[0028] <<<Ingredients>>> <<Phospholipids>> Known phospholipids can be used as the phospholipids constituting the liposomes. More specifically, examples of phospholipids include phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylinositol, etc. The phospholipids may be hydrogenated products of these phospholipids. The phospholipids may be naturally derived or synthetic.

[0029] The phospholipid is preferably phosphatidylcholine. It is believed that the activity of the hydroxyapatite particles (e.g., the collagen production promoting effect) is enhanced by using a liposome formed from phosphatidylcholine in combination with hydroxyapatite particles.

[0030] <<Hydroxyapatite particles>> Hydroxyapatite particle size PS H is preferably 10 nm or more, 15 nm or more, or 20 nm or more, and is preferably 1000 nm or less, 700 nm or less, 500 nm or less, 300 nm or less, 100 nm or less, or 70 nm or less. H In this case, the particle size PS of the hydroxyapatite particles is preferably 10 to 1000 nm, and more preferably 20 to 700 nm. H The standard deviation of is preferably 20 nm or less, 15 nm or less, or 10 nm or less. The lower limit is not particularly limited, but is, for example, 0 nm or more, 1 nm or more, 2 nm or more, 3 nm or more, 4 nm or more, or 5 nm or more.

[0031] The shape of the hydroxyapatite particles is not particularly limited, but is preferably spherical. Here, "spherical" means that the aspect ratio of the object (particle) is 1.35 or less (more preferably 1.25 or less, and even more preferably 1.20 or less).

[0032] Hydroxyapatite particle size PS H The aspect ratio is measured, for example, by the following method. In an SEM image of an object (particle), two line segments are drawn on the particle with both ends positioned on the particle's periphery. In this case, one of the two line segments is assumed to have the longest length. Furthermore, the other of the two line segments is drawn at the midpoint of the first line segment so that they intersect at right angles. Of the two line segments drawn in this way, the length of the shorter line segment is assumed to be the minor axis, and the length of the longer line segment is assumed to be the major axis. The average value of the major axis and the minor axis is defined as the particle size. The ratio of the major axis to the minor axis (major axis / minor axis) is defined as the aspect ratio. However, particles with blurred contours, particles that are too close to other particles and have unclear boundaries, particles that are partly hidden in the shadow of other particles, etc. are excluded from the measurement. The average particle size and average aspect ratio of 100 to 150 hydroxyapatite particles were calculated to determine the particle size PS of the hydroxyapatite particles. H and aspect ratio.

[0033] The hydroxyapatite particles are preferably heat-treated. More specifically, the half-width (2θ) of the hydroxyapatite particles at d=2.814, as measured by X-ray diffraction (XRD), preferably satisfies 0.2 to 0.9, more preferably 0.5 to 0.8. From the viewpoint of increasing the rate of absorption of the hydroxyapatite particle-containing material into the body, the half-width of the hydroxyapatite particles at d=2.814 is preferably 0.5 to 1.2, more preferably 0.6 to 1.1, and particularly preferably 0.7 to 1.0. In particular, such hydroxyapatite particles having a half-width of 0.7 or more at d=2.814 are sometimes referred to as amorphous (or low-crystalline) hydroxyapatite particles. From the viewpoint of enhancing the stability of the hydroxyapatite particle-containing material, the half-width of the hydroxyapatite particles at d = 2.814 is preferably 0.1 or more and 0.8 or less, more preferably 0.2 or more and 0.8 or less, and particularly preferably 0.2 or more and less than 0.7. In particular, such hydroxyapatite particles having a half-width of less than 0.7 at d = 2.814 are sometimes referred to as crystalline (or highly crystalline) hydroxyapatite particles.

[0034] The half-value width can be adjusted by appropriately adjusting the heat treatment temperature and heat treatment time. When the above half-value width is desired, for example, the heat treatment temperature (maximum temperature reached) can be set to 30 to 800°C, and the holding time in that temperature range can be set to more than 0 hours and 1 hour or less. More specifically, the heat treatment temperature may be in the form of a low temperature treatment or a high temperature treatment. Examples of low-temperature treatment include treatment at 30°C or higher, 35°C or higher, 40°C or higher, or 50°C or higher, and 100°C or lower, 90°C or lower, or 80°C or lower. Examples of high temperature treatment include a temperature above 100°C, 150°C or higher, 200°C or higher, or 250°C or higher, and 800°C or lower, 750°C or lower, or 700°C or lower.

[0035] The hydroxyapatite particles preferably do not contain calcium carbonate. The hydroxyapatite particles being "free of calcium carbonate" means that they do not substantially contain calcium carbonate, and more specifically, they satisfy all of the following criteria (1) to (3). (1) According to the results of X-ray diffraction analysis, the calcium carbonate has a formula weight ratio of calcium carbonate (formula weight: 100.09) / hydroxyapatite (formula weight: 1004.62) of 0.1 / 99.9 or less. (2) In the thermogravimetric differential thermal analysis (TG-DTA) measurement, no weight loss of 2% or more accompanied by a clear endotherm at 650°C to 800°C is observed. (3) In the chart showing the absorbance calculated by the Kubelka-Munk (KM) formula for the spectrum obtained in FT-IR measurement, the wave number is 860 cm -1 ~890cm -1 The peak appearing between 877 cm and 877 cm is attributed to calcium carbonate. -1 Peak separation is performed using software such as fityk 0.9.4 under the following conditions: Function Type: Gaussian, Fitting Method: Levenberg-Marquardt.

[0036] Furthermore, when the hydroxyapatite particles are "free of calcium carbonate," it is preferable that they further satisfy the following criterion (4). (4) When tested in accordance with the Quasi-drug Raw Materials Standards 2006 (hydroxyapatite), the amount of bubbles generated is 0.25 mL or less.

[0037] The use of such hydroxyapatite particles makes it easier for the properties inherent to the hydroxyapatite particles to be exhibited. In particular, when the hydroxyapatite particles are used in a liposome composite material, the particle size of the liposomes can be made uniform and the stability of the hydroxyapatite particles in the liposomes can be improved, thereby further enhancing the effects of the present disclosure.

[0038] Such hydroxyapatite particles can be produced according to the methods disclosed in, for example, JP 2020-005995 A, JP 2018-035085 A, JP 2018-033640 A, JP 2018-033639 A, JP 2018-033638 A, JP 2018-002580 A, JP 2016-222537 A, etc.

[0039] <<Other ingredients>> Liposomes usually contain a liquid medium. More specifically, liposomes usually contain an internal aqueous phase that is a solution or dispersion of each component. The liquid medium that constitutes the internal aqueous phase will be described later.

[0040] Furthermore, the liposome according to the present disclosure may contain components other than the hydroxyapatite particles and the liquid medium (other components).

[0041] The liposomes according to the present disclosure may contain appropriate components such as drugs and additives depending on their intended use, etc. Examples of components contained in the liposomes according to the present disclosure include vitamins, glycyrrhizinic acid, astaxanthin, coenzyme Q10, α-lipoic acid, ceramide, arbutin, hyaluronic acid, linoleic acid, tranexamic acid, kojic acid, enzymes, peptides, collagen, elastin, sugars, alcohols, oils, antioxidants, preservatives, pigments, pearlizing agents, thickeners, surfactants, stabilizers, chelating agents, colorants, fragrances, buffers, pH adjusters, adrenocortical hormones, anti-inflammatory drugs, immunosuppressants, anticancer drugs, antibacterial drugs, antiviral drugs, angiogenesis inhibitors, cytokines, anticytokine antibodies, molecularly targeted drugs, steroids, antihistamines, local anesthetics, anti-inflammatory agents, antibacterial agents, antipruritics, skin protectants, and blood circulation promoters. These ingredients may be in the form of derivatives, analogs, hydrolysates, salts, etc. Furthermore, these ingredients may be synthetic substances or natural product extracts.

[0042] As described below, a preferred method for producing liposomes according to the present disclosure includes a step of forming liposome particles by emulsification in an aqueous phase containing a dispersant. Therefore, liposomes according to the present disclosure may contain (encapsulate) the dispersant derived from the production process. In this case, the content of the dispersant in the internal aqueous phase of the liposomes is generally considered to be the same as the content of the dispersant in the aqueous phase used in the production process of the liposome particles.

[0043] The liposome may contain each component in the membrane (lipophilic region) or between membranes in multiple lamellae (hydrophilic region).

[0044] <<<Physical properties / properties>>> <<FT-IRスペクトル> > Hereinafter, preferred characteristics of the liposome according to the present disclosure in the FT-IR spectrum will be described.

[0045] From the viewpoint of forming an interaction between the surface of the hydroxyapatite particles and the phospholipids contained therein, the liposome according to the present disclosure has a viscosity of 1200 cm -1 ~1500cm -1 It is preferable that the wavelength has two or more peaks in the range.

[0046] Similarly, from the viewpoint of forming an interaction between the surface of the encapsulated hydroxyapatite particles and the phospholipid, the liposome according to the present disclosure has a viscosity of 1700 cm -1 ~1750cm -1 The maximum absorption intensity in the range of 1030cm -1 ~1100cm -1 It is preferable that the absorption intensity is 10% or less of the maximum absorption intensity in the range.

[0047] It is believed that the liposomes according to the present disclosure have such characteristics in the FT-IR spectrum (satisfying at least one of the above, and more preferably satisfying both of the above), which results in the strong fixation of the hydroxyapatite particles and phospholipids, thereby stabilizing the liposome structure.

[0048] Liposomes according to the present disclosure have a viscosity of 1030 cm -1 ~1100cm -1 It is preferable that the peak is in the range of

[0049] In this case, the 1030 cm -1 ~1100cm -1 The position of the peak in the range of 1030 cm appears when measuring phospholipids alone. -1 ~1100cm -1 The position of the peak in the range of 1030 cm appears when measuring hydroxyapatite particles alone. -1 ~1100cm -1 It is preferable that the peak position is shifted to the lower wavenumber side than the peak position in the range of .

[0050] Liposomes according to the present disclosure have a viscosity of 1000 cm -1 ~1150cm -1 It is preferable that the peaks are in the range of

[0051] Liposomes according to the present disclosure have a viscosity of 1200 cm -1 ~1300cm -1 It is preferable that the peak is in the range of

[0052] Liposomes according to the present disclosure have a viscosity of 1350 cm -1 ~1410cm -1 It is preferable that there is no peak in the range.

[0053] Liposomes according to the present disclosure have a viscosity of 1450 cm -1 ~1500cm -1 It is preferable that the peak is in the range of

[0054] Liposomes according to the present disclosure have a viscosity of 1700 cm -1 ~1900cm -1 It is preferable that the peak is in the range of

[0055] Liposomes according to the present disclosure have a viscosity of 2800 cm -1 ~3000cm-1 It is preferable that the peak is in the range of

[0056] Liposomes according to the present disclosure have a viscosity of 2850 cm -1 ~2950cm -1 It is preferable that the peaks are in the range of

[0057] Liposomes according to the present disclosure have a viscosity of 1200 cm -1 ~1220cm -1 It is more preferable that the peak is in the range of

[0058] Liposomes according to the present disclosure have a viscosity of 1220 cm -1 ~1240cm -1 It is more preferable that the peak is in the range of

[0059] The liposomes according to the present disclosure have a viscosity of 1550 cm -1 ~1610cm -1 It is more preferable that the peak is in the range of

[0060] Liposomes according to the present disclosure have a viscosity of 1700 cm -1 ~1750cm -1 It is more preferable that there is no peak in the range.

[0061] Liposomes having such a spectrum can be obtained according to the method described below.

[0062] The FT-IR spectrum is measured according to the following method.

[0063] <Measurement method> 650cm using the PerkinElmer FT-IR Spectrum 100 by total reflection measurement -1 ~4000cm -1 The range was measured eight times.

[0064] In this measurement, the presence or absence of a peak was confirmed at 800 cm -1 and 4000cm -1The line segment connecting these two points is taken as the baseline, and the determination is made based on whether or not there is a convexity below the baseline.

[0065] < <tg-dta>> Hereinafter, preferred characteristics of the liposome according to the present disclosure in TG-DTA (thermogravimetric-differential thermal analysis) measurement will be described.

[0066] The liposomes according to the present disclosure preferably exhibit a weight loss of 40% or more accompanied by a clear endothermic reaction in the range of 25°C to 150°C.

[0067] Furthermore, it is preferable that the liposome according to the present disclosure exhibits a weight loss of 2.0% or more (preferably 5.0% or more, more preferably 8.0% or more) without a clear endothermic reaction in the range of 150°C to 250°C.

[0068] It is believed that the liposomes according to the present disclosure have such characteristics in TG-DTA measurement, which improves structural stability (for example, retention of the internal aqueous phase).

[0069] Liposomes having such thermal properties can be obtained according to the method described below.

[0070] TG-DTA measurements are carried out according to the following method.

[0071] <Measurement method> Measurements were performed in a temperature range of 25°C to 1000°C under a nitrogen flow at a rate of 10°C / min using a thermogravimetric differential thermal analyzer (TG-DTA) (Seiko Instruments, EXSTAR6000).

[0072] <<Zeta potential>> The zeta potential is preferably −40 mV to −1 mV, and more preferably −30 mV to −5 mV.

[0073] By setting the zeta potential within this range, the dispersion stability of the liposomes is excellent when the liposomes are prepared into a liposome dispersion liquid or the like.

[0074] Liposomes having such a zeta potential can be obtained according to the method described below.

[0075] The zeta potential of the liposomes is measured according to the following method.

[0076] <Measurement method> The measurements were carried out at 25°C in 0.1 mM and 1 mM aqueous sodium chloride solutions using a zeta potential measurement system (ELSZ-2000Z, manufactured by Otsuka Electronics Co., Ltd.).

[0077] Here, the liposomes according to the present disclosure can be used as a composition by combining them with other components. In other words, the technology according to the present disclosure can be a liposome-containing composition containing liposomes. In other words, the liposome-containing composition according to the present disclosure includes liposomes and an external aqueous phase. The liquid medium constituting the external aqueous phase will be described later.

[0078] Other components of the liposome-containing composition may be selected appropriately depending on the intended use, and are not limited in any way.

[0079] When the liposome-containing composition is used as a pharmaceutical composition, preferred other ingredients include, for example, alcohols, sugars, proteins, amino acids, water-soluble vitamins, fat-soluble vitamins, lipids, mucopolysaccharides, surfactants, etc.

[0080] Furthermore, when the liposome-containing composition is used as a cosmetic composition, preferred other ingredients include, for example, astringents, bactericides / antibacterial agents, whitening agents, ultraviolet absorbers, moisturizers, cell activators, anti-inflammatory / antiallergic agents, antioxidants / active oxygen scavengers, oils and fats, waxes, hydrocarbons, fatty acids, alcohols, esters, surfactants, fragrances, etc.

[0081] Furthermore, the liposome-containing composition may contain the same components as those exemplified as components that may be contained in the liposomes according to the present disclosure.

[0082] <<<Liposome manufacturing method>>> A specific example of the method for producing liposomes according to the present disclosure will be described.

[0083] The liposomes according to the present disclosure can be produced, for example, by carrying out the steps shown below. (a) Preparation of oil phase (b) Preparation of aqueous phase (c) Formation of liposome particles by emulsification

[0084] In the method for producing liposomes according to the present disclosure, particle size regulation using an extruder, sterile filtration, and the like may be carried out.

[0085] In the liposome production method according to the present disclosure, replacement of the liposome external aqueous phase liquid by dialysis, removal of external aqueous phase components by dialysis, etc. may be carried out. In this case, the external aqueous phase in the liposome production method according to the present disclosure may be different from the external aqueous phase in the liposome-containing composition.

[0086] Furthermore, when the liposome according to the present disclosure contains other components such as a drug, the components may be encapsulated in the liposome particles by remote loading.

[0087] <<(a) Preparation of oil phase>> (a) In preparing the oil phase, the phospholipids and other components constituting the liposomes are mixed with an organic solvent, and the mixture is heated to dissolve the above components, thereby producing the oil phase. The organic solvent used in the oil phase is not particularly limited, but for example, a volatile organic solvent can be used.

[0088] Examples of volatile organic solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, isobutanol, and t-butanol, hydrocarbons such as hexane, pentane, benzene, and toluene, and halogen-containing hydrocarbons such as dichloromethane and chloroform. Among these, halogen-containing hydrocarbons are more preferred.

[0089] The concentration of each component constituting the liposome is not particularly limited and can be adjusted appropriately.

[0090] <<(b) Preparation of aqueous phase>> As the aqueous phase, water (distilled water, water for injection, etc.), physiological saline, various buffer solutions, aqueous solutions of sugars (sucrose, etc.), and mixtures thereof (aqueous solvents) can be used.

[0091] The buffer solution is not limited to organic or inorganic solutions, but a buffer solution having a buffering effect at a hydrogen ion concentration close to that of body fluids is preferably used, and examples thereof include phosphate buffer solution, Tris buffer solution, citrate buffer solution, acetate buffer solution, and Good's buffer.

[0092] Hydroxyapatite particles to be encapsulated in liposomes are dispersed in advance in the aqueous phase.

[0093] The aqueous phase preferably contains a dispersant. The dispersant is not particularly limited, but preferably has a molecular weight (or a number average molecular weight measured by GPC) of 10,000 or less, 5,000 or less, 2,000 or less, 1,000 or less, or 500 or less.

[0094] The dispersant is preferably water-soluble. More specifically, the dispersant preferably has a solubility in water (25°C) of 1 mg / mL or more, 5 mg / mL or more, 10 mg / mL or more, 20 mg / mL or more, 40 mg / mL or more, 50 mg / mL or more, or 70 mg / mL or more.

[0095] Specific examples of dispersants include acetic acid, citric acid, polyacrylic acid, etc. These may be added in the form of a salt such as monosodium citrate, disodium citrate, or trisodium citrate. That is, the aqueous phase preferably contains, as a dispersant, one or more selected from the group consisting of acetic acid, citric acid, monosodium citrate, disodium citrate, and trisodium citrate.

[0096] It is believed that the inclusion of a dispersant in the aqueous phase allows the hydroxyapatite particles to be appropriately dispersed, optimizing the formation of liposomes in the emulsification step (by acting on phospholipids, etc.), making it easier to obtain the liposomes according to the present disclosure. In particular, by using the preferred dispersant described above, the dispersant is selectively present in the hydroxyapatite particle dispersion, improving dispersion stability and making it easier to prevent the dispersant from mixing with phospholipids (lipophilic regions), which makes it easier to stabilize the formed liposome membrane structure.

[0097] The amount (content) of the dispersant added is preferably, for example, 0.001% by mass or more, 0.005% by mass or more, 0.01% by mass or more, or 0.02% by mass or more, based on the total aqueous phase. The amount (content) of the dispersant added is preferably 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, 5% by mass or less, 1% by mass or less, 0.5% by mass or less, 0.1% by mass or less, 0.09% by mass or less, 0.08% by mass or less, or 0.05% by mass or less, based on the total aqueous phase. By adjusting the dispersant content to such an amount, the dispersibility of each component is appropriate, the buffering effect is adequate, making it easy to adjust the pH when the composition is prepared, and irritation caused by the dispersant when administered to humans is suppressed, making it easier to form liposomes with excellent performance. Here, as described above, the liposomes according to the present disclosure may contain (encapsulate) the dispersant. Even when a dispersant is encapsulated in liposomes in this way, the content of the dispersant in the internal aqueous phase of the liposome (content relative to the entire internal aqueous phase) is preferably within the range described above. The content of the dispersant in the external aqueous phase of the liposome (content relative to the entire external aqueous phase) can also be within the same range. The content of the dispersant in the internal aqueous phase of the liposome and the content of the dispersant in the external aqueous phase of the liposome may be the same or different.

[0098] The pH of the aqueous phase is preferably not less than 3, and more preferably not less than 5. The pH can be measured using a general pH measuring device.

[0099] The internal aqueous phase of the liposome may be an aqueous solution in which the liposome is dispersed during production, or may be newly added water, physiological saline, various buffer solutions, or aqueous solutions of sugars, or mixtures thereof. It is preferable that the water used as the external or internal aqueous phase does not contain impurities (dust, chemicals, etc.).

[0100] Physiological saline refers to an inorganic salt solution adjusted to be isotonic with the human body and may further have a buffer function. Examples of physiological saline include saline containing 0.9 w / v% (mass / volume percent) sodium chloride, PBS, and Tris-buffered saline.

[0101] <<(c) Liposome particle formation by emulsification>> In the emulsification process, the oil phase and the aqueous phase are mixed and emulsified by stirring the aqueous solution containing lipids. The oil phase, in which lipids are dissolved in an organic solvent, and the aqueous phase are mixed, stirred, and emulsified to prepare an O / W (oil-in-water) emulsion of the oil phase and the aqueous phase. After mixing, liposomes are formed by removing part or all of the organic solvent from the oil phase by evaporation. Alternatively, part or all of the organic solvent in the oil phase evaporates during the stirring and emulsification process, forming liposomes.

[0102] As a stirring method, for example, ultrasonic waves or mechanical shearing force can be used to reduce particle size. Furthermore, to achieve a uniform particle size, extruder treatment or microfluidizer treatment, in which the mixture is passed through a filter with a specific pore size, can be used. By using an extruder or the like, multivesicular liposomes formed as a by-product can be broken down into univesular liposomes.

[0103] The emulsification step is not limited as long as it is an emulsification step, but is preferably a step of applying high shear and microparticulating the emulsion using an organic solvent. The high shear is defined by the peripheral speed of the stirring blade of the emulsifier, and is preferably 5 m / s to 32 m / s, and particularly preferably 20 m / s to 30 m / s. If necessary, liposomes can be formed by evaporating (removing) the organic solvent used in the emulsification step.

[0104] The liquid temperature in the emulsification step for producing liposomes can be adjusted as appropriate, but it is preferable that the liquid temperature when mixing the oil phase and the aqueous phase be equal to or higher than the phase transition temperature of the lipid used. For example, when a lipid with a phase transition temperature of 35°C to 40°C is used, the liquid temperature is preferably 35°C to 70°C.

[0105] The emulsification step is preferably performed under a high-pressure environment. More specifically, the emulsification step preferably employs a high-pressure emulsification method. For example, in the emulsification step, pressure is preferably applied when the oil phase and the aqueous phase are mixed and stirred to obtain an emulsion. The pressure conditions are, for example, preferably 0.2 MPa or more, 0.5 MPa or more, 1.0 MPa or more, 2.0 MPa or more, 5.0 MPa or more, 10 MPa or more, or 15 MPa or more, and preferably 250 MPa or less, 200 MPa or less, 150 MPa or less, 100 MPa or less, 50 MPa or less, or 40 MPa or less.

[0106] In the emulsification step, the organic solvent and water may be evaporated from the aqueous solution containing liposomes. The evaporation here refers to the forced removal of part or all of the organic solvent derived from the oil phase and the water derived from the aqueous phase, or the natural evaporation of part or all of the organic solvent derived from the oil phase and the water derived from the aqueous phase during the stirring and emulsification process.

[0107] The evaporation method is not particularly limited, and may be, for example, at least one of a step of evaporating the organic solvent and water by heating, a step of leaving the mixture to stand or continuing gentle stirring after emulsification, and a step of vacuum degassing.

[0108] <<<Application>>> According to the present disclosure, novel liposomes encapsulating hydroxyapatite particles (in other words, liposome composite materials or liposomes encapsulating hydroxyapatite particles) are provided. Such liposomes are believed to prevent aggregation and precipitation of hydroxyapatite particles and to have high stability over time. Therefore, they are believed to exhibit excellent functions such as improved affinity and penetration into cells, and sufficient physiological activity of hydroxyapatite.

[0109] Furthermore, the liposomes according to the present disclosure can form a structure similar to that of a cell membrane, which can further increase cell affinity and strengthen the effect on fibroblasts, etc. Therefore, in addition to the above effects, the use of the liposomes according to the present disclosure can achieve a significant collagen production promoting effect, etc., compared to the use of hydroxyapatite particles alone.

[0110] The liposomes or liposome-containing compositions according to the present disclosure can be used in various applications to which hydroxyapatite particles are applied, and are preferably used, for example, for pharmaceuticals (pharmaceutical compositions) and cosmetics (cosmetic compositions).

[0111] Furthermore, the liposomes or liposome-containing compositions according to the present disclosure have the sustained drug release properties inherent to liposomes, and are therefore preferably used in drug delivery systems.

[0112] Specific uses of the pharmaceuticals or pharmaceutical compositions include injections (dermal fillers, etc.), anticancer drugs, painkillers, immunosuppressants, and the like.

[0113] Specific uses of the cosmetics or cosmetic compositions include breast enlargement promoters, basic cosmetics or makeup (facial cleansers, lotions, serums, ointments, creams, emulsions, lotions, packs, bath additives, etc.), hair growth agents, dentifrices, etc.

[0114] <<<<Second Form>>>> The second embodiment is a hydroxyapatite particle-containing material containing hydroxyapatite particles, phospholipids, and a dispersant. That is, the hydroxyapatite particle-containing material according to the second embodiment is a material that contains hydroxyapatite particles and is composited with phospholipids and a dispersant as components other than the hydroxyapatite particles (second components).

[0115] The form in which the hydroxyapatite particles and the second component are composited can be exemplified by the same forms as those in the first form. More specifically, possible composite forms with hydroxyapatite particles include, for example, (form A) a form in which the second component has an outer shell that covers one or more hydroxyapatite particles, forming a single material (e.g., a particulate material) as a whole, and (form B) a form in which the second component is interposed between the hydroxyapatite particles, causing the hydroxyapatite particles to bond or aggregate together, forming a single material (e.g., a particulate material) as a whole. A specific example of Form A is a structure in which hydroxyapatite particles are encapsulated in liposomes formed by phospholipids. A specific example of Form B is a structure in which phospholipids are adsorbed onto hydroxyapatite particles.

[0116] For example, when the hydroxyapatite particle-containing material according to the second embodiment is a hydroxyapatite-encapsulating liposome, the liposome is formed by phospholipids, and the dispersant is thought to be present in the internal aqueous phase or between membranes in multi-lamellar structures.

[0117] The hydroxyapatite particles, the second component (phospholipid, dispersant and other components) and the like constituting the hydroxyapatite particle-containing material according to the second embodiment are as described above.

[0118] The hydroxyapatite particle-containing material according to the second embodiment is a material defined from a different perspective than the hydroxyapatite particle-containing material according to the first embodiment. The hydroxyapatite particle-containing material according to the second embodiment can incorporate all of the features (preferable structure, components, physical properties / characteristics, manufacturing method, uses, etc.) described for the hydroxyapatite particle-containing material according to the first embodiment.

[0119] For example, the dispersant is preferably one or more selected from the group consisting of acetic acid, citric acid, monosodium citrate, disodium citrate, and trisodium citrate. Also, the phospholipid is preferably lecithin. The hydroxyapatite particles are preferably amorphous. The hydroxyapatite particle-containing material according to the second embodiment has a peak at 1030 cm in the FT-IR spectrum. -1 ~1100cm -1 and a peak in the range of 1220 cm -1 ~1240cm -1 It is preferable that the peak is in the range of The hydroxyapatite particle-containing material according to the second embodiment has a peak at 1700 cm in the FT-IR spectrum. -1 ~1750cm -1 The maximum absorption intensity in the range of 1030cm -1 ~1100cm -1 It is preferable that the absorption intensity is 10% or less of the maximum absorption intensity in the range. The hydroxyapatite particle-containing material according to the second embodiment may be in the form of a composition (for example, a pharmaceutical composition, a cosmetic composition, etc.) containing the hydroxyapatite particle-containing material.

[0120] It is believed that by configuring the hydroxyapatite particle-containing material in this way, the activity of the hydroxyapatite particles can be utilized more effectively. [Example]

[0121] Hereinafter, the hydroxyapatite particle-containing material (particularly, the hydroxyapatite-encapsulating liposome) according to the present disclosure will be described in detail with reference to examples, but the present disclosure is not limited thereto in any way.

[0122] <<<The first hydroxyapatite-encapsulated liposomes>>> <<Manufacturing method>> <First hydroxyapatite particles (highly crystalline)> The first hydroxyapatite particles (highly crystalline hydroxyapatite particles) were obtained as follows. Calcium nitrate tetrahydrate, diammonium hydrogen phosphate aqueous solution, and ammonia water were added to a reaction vessel containing deionized water while stirring (calcium:phosphate (molar ratio) = 5:3) to obtain primary particles of hydroxyapatite. The supernatant liquid from the reaction vessel was then transferred to a wastewater container, followed by the addition of deionized water, stirring with a stirrer, and the transfer of the supernatant liquid to a wastewater container. This process was repeated twice. The reaction vessel containing the precipitate was then frozen overnight at -10°C to -25°C. It was then thawed at room temperature, and the thawed precipitate was collected by filtration. Approximately 400 g of the precipitate was then placed in a baking dish and placed in a baking furnace. The temperature was raised to 600°C over a little over an hour, maintained at 600°C for an hour, and then cooled over at least an hour for baking. Deionized water was then added to the baked product, which was then subjected to ultrasonic irradiation for at least 30 minutes. The product was then transferred to a pod mill, milled with grinding balls, and crushed for an hour. After the grinding was completed, the mixture was transferred to a beaker with handles and sieved using a sieve with 150 μm openings to remove unground sintered bodies. After this, washing with deionized water was repeated six times. After that, the mixture was dried at 60°C to 80°C to obtain first hydroxyapatite particles. The half-width of the obtained hydroxyapatite particles at d=2.814 was 0.65. The average particle size and standard deviation of the obtained hydroxyapatite particles were calculated (nine images were taken using SEM, and the particle size of 12 particles in each image was measured, confirming the particle size of a total of 108 particles, and then the average value and standard deviation were calculated).The average particle size was 34 nm, and the standard deviation was 4 nm.

[0123] <Hydroxyapatite particle-encapsulated liposomes> First hydroxyapatite particle-encapsulating liposomes were obtained by high-pressure emulsification as follows. The first hydroxyapatite particles were suspended in water to a concentration of 10% by mass to obtain a hydroxyapatite particle dispersion. 280 g of fractionated lecithin (Tsuji Oil Mills, SLP-PC70), 38 g of disodium citrate (Fujifilm Wako Pure Chemical Industries, Ltd.), 2000 g of 10% by mass hydroxyapatite particle dispersion, 1550 g of purified water, and 18 g of Hysorb EPH were mixed and stirred at 70°C to dissolve. High-pressure emulsification was performed at a pressure of 200 MPa using a high-pressure emulsifier (Sugino Machine, Starburst Mini) to obtain an emulsion dispersion containing liposomes.

[0124] FIG. 1 shows a TEM image of the first hydroxyapatite particle-encapsulating liposome obtained.

[0125] The first hydroxyapatite particle-encapsulating liposomes obtained had a number average particle size of 37 nm with a standard deviation of 10 nm.

[0126] <<<The second hydroxyapatite-encapsulated liposome>>> <<Manufacturing method>> <Second hydroxyapatite particles (low crystallinity)> The second hydroxyapatite particles (low-crystalline hydroxyapatite particles) were obtained as follows. Calcium nitrate tetrahydrate, diammonium hydrogen phosphate aqueous solution, and ammonia water were added to a reaction vessel containing deionized water while stirring {calcium:phosphate (molar ratio) = 5:3}, and the mixture was stirred for 18 hours while heating at 30°C to obtain primary hydroxyapatite particles. The supernatant liquid in the reaction vessel was then transferred to a wastewater container, and deionized water was added, stirred with a stirrer, and the supernatant liquid was transferred to a wastewater container. This process was repeated twice to obtain a hydroxyapatite particle dispersion. The powder obtained by drying the obtained hydroxyapatite particle dispersion liquid at 35° C. or less had a half-width of 0.84 at d=2.814. The average particle size and standard deviation of the obtained hydroxyapatite particles were calculated (nine images were taken using SEM, and the particle size of 12 particles in each image was measured, confirming the particle size of a total of 108 particles, and then the average value and standard deviation were calculated).The average particle size was 29 nm, and the standard deviation was 8 nm.

[0127] <Hydroxyapatite particle-encapsulated liposomes> Second hydroxyapatite particle-encapsulating liposomes were obtained by high-pressure emulsification as follows. The second hydroxyapatite particles were suspended in water to a concentration of 10% by mass to obtain a hydroxyapatite particle dispersion. 280 g of fractionated lecithin (Tsuji Oil Mills, SLP-PC70), 38 g of disodium citrate (Fujifilm Wako Pure Chemical Industries, Ltd.), 2000 g of 10% by mass hydroxyapatite particle dispersion, 1550 g of purified water, and 18 g of Hysorb EPH were mixed and stirred at 70°C to dissolve. High-pressure emulsification was performed at a pressure of 200 MPa using a high-pressure emulsifier (Sugino Machine, Starburst Mini), to obtain an emulsion dispersion containing liposomes.

[0128] The resulting second hydroxyapatite particle-encapsulating liposomes had a number average particle size of 35 nm with a standard deviation of 8 nm.

[0129] <<<Physical properties / properties>>> Next, FT-IR measurement and TG-DTA measurement were performed on the hydroxyapatite particles alone (first hydroxyapatite particles) and the hydroxyapatite particle-encapsulated liposomes (first hydroxyapatite particle-encapsulated liposomes, second hydroxyapatite particle-encapsulated liposomes). Furthermore, the zeta potential of the first hydroxyapatite particle-encapsulating liposome was measured. The FT-IR measurement results of the first hydroxyapatite particles (highly crystalline hydroxyapatite particles), the first hydroxyapatite particle-encapsulating liposomes, and the second hydroxyapatite particle-encapsulating liposomes are shown in Figures 2-1, 2-2, and 2-3, respectively. The TG-DTA measurement results for the first hydroxyapatite particles (highly crystalline hydroxyapatite particles), the first hydroxyapatite particle-encapsulated liposomes, and the second hydroxyapatite particle-encapsulated liposomes are shown in Figures 3-1, 3-2, and 3-3, respectively. The TG-DTA results confirmed a 1.7% weight loss without a clear endothermic change in the temperature range of 150 to 250°C for the first hydroxyapatite particles, a 12.7% weight loss without a clear endothermic change in the temperature range of 150 to 250°C for the first hydroxyapatite particle-encapsulated liposomes, and a 10.7% weight loss without a clear endothermic change in the temperature range of 150 to 250°C for the second hydroxyapatite particle-encapsulated liposomes. The zeta potential measurement results are shown in Table 1. The unit of each value in Table 1 is [mV].

[0130] [Table 1]

[0131] As shown in Figures 2 and 3 and Table 1, the liposomes encapsulating hydroxyapatite particles had distinctive properties that differed from those of the hydroxyapatite particles alone.

[0132] <<<Evaluation>>> Next, a test to evaluate collagen production was conducted as a comparative evaluation between hydroxyapatite particles alone (first hydroxyapatite particles) and liposomes encapsulating hydroxyapatite particles (first hydroxyapatite particle-encapsulating liposomes, second hydroxyapatite particle-encapsulating liposomes).

[0133] <<Evaluation method>> Normal human fibroblasts were added to 10 mL of sample-containing 10% FBS-containing DMEM medium, centrifuged (200 × g, 5 minutes), suspended in 10 mL of medium, and cultured for 24 hours. The amount of collagen in the medium was quantified by ELISA. The experiment was repeated three times under each condition (n = 3). The samples used were VC ethyl (positive control), the prepared hydroxyapatite particles, and hydroxyapatite particle-encapsulated liposomes. The evaluation was performed by varying the concentration (mass%) of hydroxyapatite particles and hydroxyapatite particle-encapsulated liposomes in the medium. The results are shown in Table 2.

[0134] <<Evaluation Results>> When comparing hydroxyapatite particles and hydroxyapatite particle-encapsulated liposomes at each concentration, no significant difference in type I collagen was observed at 0.01% (p>0.05 (t test)). However, at 0.05%, the amount of type I collagen tended to be higher with the addition of hydroxyapatite particle-encapsulated liposomes than with hydroxyapatite particles (p<0.1 (t test)). At 0.1%, the amount of type I collagen was significantly higher with the addition of hydroxyapatite particle-encapsulated liposomes than with the addition of hydroxyapatite particles (p<0.05 (t test)). Note that "p(t test)" refers to the p-value obtained by the "t test" (generally, a value of 0.05 or less indicates a significant difference, while a value greater than 0.05 indicates little or no difference).

[0135] [Table 2]

[0136] <<<The third hydroxyapatite-encapsulated liposome>>> <<Manufacturing method>> The third hydroxyapatite-encapsulated liposome was produced using the same production method as the second hydroxyapatite-encapsulated liposome, except that the amount of disodium citrate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was changed to 1.14 g.

[0137] FIG. 2 shows a TEM image of the obtained third hydroxyapatite particle-encapsulating liposome.

[0138] The third hydroxyapatite particle-encapsulating liposome obtained had a number average particle size of 37 nm with a standard deviation of 8 nm.

[0139] <<Physical properties / properties>> Similar to the second hydroxyapatite particle-encapsulating liposome, the third hydroxyapatite particle-encapsulating liposome was subjected to FT-IR measurement and TG-DTA measurement, and the measurement results are shown in Figures 5 and 6, respectively.

[0140] Comparing Figures 2-3 and 5, and Figures 3-3 and 6, it can be seen that even when the content of dispersant is reduced, liposomes encapsulating hydroxyapatite particles have similar characteristics in FT-IR and TD-DTA measurements.

[0141] Table 3 shows the zeta potential of the third hydroxyapatite particle-encapsulating liposome and the zeta potential of the second hydroxyapatite particles (dispersant-added dispersion) used in producing the third hydroxyapatite particle-encapsulating liposome.

[0142] [Table 3]

[0143] 5 and 6 and Table 3, it can be seen that even when the content of the dispersant is reduced, liposomes encapsulating hydroxyapatite particles having characteristic properties are formed.

[0144] It was confirmed that the third hydroxyapatite particle-encapsulating liposome exhibited collagen production function equivalent to that of the second hydroxyapatite particle-encapsulating liposome. [Industrial Applicability]

[0145] The hydroxyapatite particle-containing material according to the present invention can more effectively utilize the activity of the hydroxyapatite particles, and is therefore suitable for use in a variety of applications such as pharmaceutical compositions, cosmetic compositions, and medical devices.

Claims

1. A hydroxyapatite particle-containing material comprising hydroxyapatite particles, phospholipids, and a dispersant.

2. The hydroxyapatite particle-containing material according to claim 1, which contains water.

3. 3. The hydroxyapatite particle-containing material according to claim 1, wherein the dispersant is at least one selected from the group consisting of acetic acid, citric acid, monosodium citrate, disodium citrate, and trisodium citrate.

4. 3. The hydroxyapatite particle-containing material according to claim 1, wherein the hydroxyapatite particles are encapsulated in liposomes.

5. 3. The hydroxyapatite particle-containing material according to claim 1, wherein the phospholipid is adsorbed onto the hydroxyapatite particles.

6. 3. The hydroxyapatite particle-containing material according to claim 1, wherein the phospholipid is lecithin.

7. The hydroxyapatite particle-containing material according to claim 1 or 2, which satisfies at least one of the following (1) and (2): (1) In the FT-IR spectrum, 1200 cm －１ ~1500cm －１ It has two or more peaks in the range. (2) In the FT-IR spectrum, 1700 cm －１ ~1750cm －１ The maximum absorption intensity in the range of 1030 cm －１ ~1100cm －１ The absorption intensity is 10% or less of the maximum absorption intensity in the range.

8. A composition comprising the hydroxyapatite particle-containing material according to claim 1 or 2.

9. The composition of claim 8 which is a pharmaceutical composition.

10. The composition of claim 8 which is a cosmetic composition.

11. Contains at least hydroxyapatite particles, A hydroxyapatite particle-containing material that satisfies at least one of the following (1) and (2): (1) In the FT-IR spectrum, 1200 cm －１ ~1500cm －１ It has two or more peaks in the range. (2) In the FT-IR spectrum, 1700 cm －１ ~1750cm －１ The maximum absorption intensity in the range of 1030 cm －１ ~1100cm －１ The absorption intensity is 10% or less of the maximum absorption intensity in the range.

12. The hydroxyapatite particle-containing material according to claim 11, which contains water.

13. The hydroxyapatite particle-containing material according to claim 11 or 12, The liposome-containing composition, wherein the hydroxyapatite particle-containing material is a hydroxyapatite-encapsulating liposome containing a liposome and the hydroxyapatite particle encapsulated in the liposome.

14. 14. The liposome-containing composition of claim 13, which is a pharmaceutical composition.

15. The liposome-containing composition of claim 13, which is a cosmetic composition.

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