WO2016092929A1 - 皮下注射用剤及び皮下注射用剤を含有する注射器の製造方法 - Google Patents
皮下注射用剤及び皮下注射用剤を含有する注射器の製造方法 Download PDFInfo
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
- A61J1/2096—Combination of a vial and a syringe for transferring or mixing their contents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/36—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests with means for eliminating or preventing injection or infusion of air into body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
Definitions
- the present invention relates to an agent for subcutaneous injection.
- a filler (filler) containing hydroxyapatite is injected subcutaneously.
- Hydroxyapatite has various effects including biocompatibility, and is a material that is expected to have an excellent beauty improvement effect even in subcutaneous injection.
- Patent Document 1 discloses a biomaterial composition using particles containing calcium hydroxyapatite having a particle size of 80 to 200 ⁇ m.
- an object of the present invention is to provide a subcutaneous injection agent that is less prone to inflammation and a syringe containing the subcutaneous injection agent.
- the present invention is as follows.
- the present invention (1) is a method for producing a subcutaneous injection,
- the agent is An agent having a hydrogel containing calcined hydroxyapatite particles,
- the manufacturing method is It is a manufacturing method which has the defoaming process which removes the air contained in the said agent.
- the present invention (2) In a method for producing a syringe containing a subcutaneous injection,
- the agent is An agent having a hydrogel containing calcined hydroxyapatite particles,
- the manufacturing method is A defoaming step for removing air contained in the agent; And a step of filling a syringe with the agent after the defoaming step.
- the present invention (3) In the production method of the invention (1) or (2), the defoaming step is a step of performing defoaming by applying the agent to a centrifuge under reduced pressure.
- the present invention (4) The method according to any one of the inventions (1) to (3), wherein the hydrogel is a carboxymethylcellulose gel.
- the present invention (5) The method according to any one of the inventions (1) to (4), wherein the agent has a viscosity of 50 to 15000 mPa ⁇ s.
- the present invention (6) The method according to any one of the inventions (1) to (5), wherein the average particle diameter of the calcined hydroxyapatite particles is 15 ⁇ m or less.
- the present invention (7) In the production method of the inventions (1) to (6), 90% or more of the calcined hydroxyapatite particles have a particle size of 15 ⁇ m or less.
- the present invention (8) In the production method according to any one of the inventions (1) to (7), the content of the calcined hydroxyapatite particles is 1 to 60% by mass based on the total mass of the agent.
- the present invention (9) The method according to any one of the inventions (1) to (8), wherein the agent passes through a hollow needle having an inner diameter of 0.20 mm or less.
- Drawing 1 is a figure (photograph) which shows a filler before and behind a defoaming process concerning this example.
- the subcutaneous injection preparation according to a preferred embodiment of the present invention will be described in the following order.
- Composition of subcutaneous injection (2) Manufacturing method of subcutaneous injection (3) Action of subcutaneous injection (4) Usage of subcutaneous injection (5) Physical properties of subcutaneous injection
- the agent for subcutaneous injection according to the present embodiment contains hydroxyapatite particles and hydrogel, and may further contain other components.
- the hydroxyapatite particle aggregate is an aggregate of hydroxyapatite particles.
- hydroxyapatite particles Hydroaulic apatite particles
- the physical properties (particularly the particle size) of the hydroxyapatite particles shown here indicate the physical properties of the hydroxyapatite particles contained in the subcutaneous injection agent (the physical properties of the hydroxyapatite particles contained in the subcutaneous injection agent)
- the physical properties of the hydroxyapatite particles, which are constituent materials of the subcutaneous injection are not necessarily the same because there may be a change in form depending on the production stage.
- HAp Hydroxyapatite
- Ca 10 (PO 4 ) 6 (OH) 2 a basic calcium phosphate represented by the chemical formula Ca 10 (PO 4 ) 6 (OH) 2 and naturally exists as a main component of teeth and bones and as an ore.
- Hydroxyapatite particles exhibit high biocompatibility.
- hydroxyapatite particles present in the filler as nanoparticles enhance collagen production by stimulating fibroblasts.
- the hydroxyapatite particles present in the filler as microparticles physically function as a spacer.
- hydroxyapatite particles As the hydroxyapatite particles according to the present embodiment, calcined hydroxyapatite particles (hereinafter referred to as "calcined hydroxyapatite particles” when referred to as “hydroxyapatite particles” unless otherwise specified) are used.
- calcined hydroxyapatite particles By firing the hydroxyapatite particles (for example, at 800 ° C. for 1 hour), the crystallinity of the particles is increased, and aggregates of a plurality of primary particles are fused by heat to become stronger and more stable particles. .
- “hydroxyapatite particles” as used in the present invention is a concept including not only calcined hydroxyapatite particles having a primary particle size but also aggregates in which a plurality of primary particles are
- calcined apatite particles By using such calcined apatite particles, it is possible to obtain a highly effective filler that stimulates fibroblasts and enhances collagen production. That is, by making the hydroxyapatite particles into calcined hydroxyapatite, the effect of promoting collagen production is significantly improved as compared with the uncalcined particles. Furthermore, calcined hydroxyapatite has higher crystallinity and lower solubility in the living body than amorphous hydroxyapatite. Therefore, since the biological activity can be maintained for a long time in the living body, the collagen production promoting effect is easily exhibited for a long time.
- Calcinated hydroxyapatite particles can be obtained by firing amorphous hydroxyapatite. Specifically, for example, calcined hydroxyapatite can be obtained by calcining by a dispersion calcining method. Further, it is preferable to use highly crystalline hydroxyapatite particles having high crystallinity of the hydroxyapatite particles.
- the lower limit of the firing temperature is more preferably 500 ° C. or higher. If the firing temperature is lower than 500 ° C., firing may not be sufficient.
- the upper limit of the firing temperature is more preferably 1800 ° C. or less, further preferably 1250 ° C. or less, and particularly preferably 1200 ° C. or less. When the firing temperature is higher than 1800 ° C., hydroxyapatite may decompose. Therefore, by setting the firing temperature within the above range, it is possible to produce hydroxyapatite that is difficult to dissolve in vivo (high crystallinity). Moreover, it does not specifically limit as baking time, What is necessary is just to set suitably. In some cases, the particles are fused to each other by firing. In such a case, the fired particles can be used after being pulverized.
- Whether or not the hydroxyapatite particles are fired can be determined by the degree of crystallinity of the particles.
- the degree of crystallinity of the hydroxyapatite particles can be measured by an X-ray diffraction method (XRD). It can be said that the narrower the half width of the peak indicating each crystal plane is, the higher the crystallinity is.
- apatite nanoparticles that are difficult to aggregate and have high crystallinity can be obtained by firing with an anti-fusing agent.
- the anti-fusing agent is not particularly limited as long as it can prevent fusion between the hydroxyapatite particles, but is preferably non-volatile at the firing temperature. However, it may be non-volatile so long as it remains at 10% or more after the firing step.
- the anti-fusing agent may be one that is chemically decomposed by heat after completion of the firing step.
- the anti-fusing agent is preferably a substance that is soluble in a solvent, particularly an aqueous solvent. This is because the anti-fusing agent can be removed simply by suspending the hydroxyapatite particles mixed with the anti-fusing agent in an aqueous solvent.
- anti-fusing agents examples include calcium chloride, calcium oxide, calcium sulfate, calcium nitrate, calcium carbonate, calcium hydroxide, calcium acetate, calcium citrate and other calcium salts (or complexes), potassium chloride, Potassium oxide, potassium sulfate, potassium nitrate, potassium carbonate, potassium hydroxide, potassium phosphate and other potassium salts, sodium chloride, sodium oxide, sodium sulfate, sodium nitrate, sodium carbonate, sodium hydroxide, sodium phosphate and other sodium salts, etc. Is mentioned.
- a solution method (wet method) is mentioned, for example. This is a method of synthesizing by reacting calcium ions and phosphate ions in a neutral or alkaline aqueous solution, and there are a method by neutralization reaction and a method by which calcium salt and phosphate are reacted. As described above, crystalline apatite particles with little aggregation are obtained by firing in the presence of an anti-fusing agent.
- the particle size (average particle size) of the hydroxyapatite particles according to the present embodiment is 15 ⁇ m or less, preferably 5 ⁇ m or less, more preferably 1 ⁇ m or less, and even more preferably 100 nm or less. is there.
- the particle size of the hydroxyapatite particles is 15 ⁇ m or less, preferably 5 ⁇ m or less, more preferably 1 ⁇ m or less, and even more preferably 100 nm or less. is there.
- the lower limit of the particle size (average particle size) of the hydroxyapatite particles is not particularly limited, but is, for example, 10 nm or more.
- the average particle diameter of the hydroxyapatite particles (including aggregates) in the filler shown here is measured by measuring the particle diameter of each particle (for example, 50 particles) in an image taken with a microscope, and the average diameter thereof. Determined by It is also possible to swell the filler in water or the like to dissolve the hydrogel, measure the particle diameter of each particle (for example, 50 particles) of the extracted hydroxyapatite, and determine the average diameter.
- the particle size of the hydroxyapatite particles in the agent according to the present embodiment as a practical problem, most of the particles need only be in the desired range, and some of the particles are in the desired range within the range that does not impair the effects of the invention. You may be off. More specifically, preferably 90% or more of the particles are in the desired range (15 ⁇ m or less, preferably 10 ⁇ m or less, more preferably 5 ⁇ m or less, particularly preferably 1 ⁇ m or less), and more Preferably 95% or more of the particles are in the desired range, more preferably 97% or more of the particles are in the desired range, and particularly preferably 99% or more of the particles are in the desired range.
- grains shown here is based on the length measurement result of the particle diameter of each particle
- the particle size of the hydroxyapatite particles is nano-order, the viscosity of the subcutaneous injection may be increased. Such an increase in viscosity is advantageous in that the agent for subcutaneous injection remains under the skin, but if the viscosity becomes too high, injection from the injection needle may be difficult.
- the particle size of the hydroxyapatite particles is preferably 15 nm or more, more preferably 20 nm or more, and particularly preferably 100 nm or more.
- the hydroxyapatite particles in the subcutaneous injection according to the present embodiment function as a component having a collagen production promoting action, a viscosity improving component, and the like, and can further serve as an inducing component of macrophages.
- the hydroxyapatite particles preferably have a particle size of 10 nm to 8 ⁇ m.
- the hydrogel is not particularly limited as long as it can be used as an agent, and examples thereof include carboxymethylcellulose gel (CMC), polyvinyl alcohol gel, polyacrylic acid soda gel ⁇ for example, Carbopol (registered trademark), etc. ⁇ . .
- Carboxymethyl cellulose gel is preferred because of the safety and low cost of cellulose as a raw material.
- Carboxymethylcellulose is a cellulose ether in which a carboxymethyl group is introduced into a hydroxyl group of cellulose.
- CMC Carboxymethylcellulose
- Na-CMC sodium carboxymethyl cellulose
- CMC has a degree of etherification in the range of about 0.5 to 1.0, but it is also possible to produce CMC having a degree of etherification of 3 by etherifying all three hydroxyl groups per cellulose unit. Yes, those having a degree of etherification of 1.0 or more are also commercially available.
- the degree of etherification of CMC is obtained by the ash alkali method issued by CMC Industry Association.
- the degree of etherification is preferably 0.5 or more, more preferably 0.8 or more, and further preferably 1.0 or more.
- the degree of etherification generally indicates the average number of hydroxyl groups substituted with a carboxymethyl group or a salt thereof among the hydroxyl groups in glucose residues constituting cellulose.
- the molecular weight of CMC is preferably 50,000 to 500,000. If the molecular weight is less than 50,000, the viscosity becomes low and the thixotropy deteriorates. On the other hand, if the molecular weight exceeds 500,000, the viscosity becomes too high and the amount of injectable apatite is insufficient.
- the molecular weight shown here shows a weight average molecular weight, and can be measured by gel permeation chromatography.
- carboxymethylcellulose gel is not specifically limited, For example, it can manufacture by mix
- Carboxymethylcellulose (CMC) gel is a physical gel exhibiting thixotropic properties. When the shear stress is zero or close to zero, it behaves as an elastic body and exhibits a behavior as a fluid as the shear rate increases. This means that when ejected from the needle of the syringe, it is easily injected as a fluid with a small force, that is, the treatment is easy and the load on the patient due to the treatment is very small. However, after injecting subcutaneously, maintaining the shape as an elastic body has the effect of staying at a specific site under the skin and stretching the wrinkles.
- the viscosity of the hydrogel is preferably 50 to 15000 mPa ⁇ s, more preferably 55 to 10000 mPa ⁇ s, even more preferably 60 to 1000 mPa ⁇ s, and 65 to 500 mPa ⁇ s. Is more preferable, and 70 to 300 mPa ⁇ s is particularly preferable. If the viscosity of the hydrogel is low, the shape cannot be maintained after subcutaneous injection, and the hydrogel cannot remain at a specific site.
- hydroxyapatite particles hydroxyapatite particles having a small diameter according to this embodiment
- a hollow needle having an inner diameter of 0.20 mm or less is used. Can't pass.
- the viscosity can be measured, for example, using a vibration viscometer according to JIS Z 8803, and specifically, is a value measured by Viscomate MODEL VM-10A.
- Hydroxyapatite particles in the particle size range according to the present embodiment have stronger interaction with the skeleton of the hydrogel than particles exceeding the particle size range according to the present embodiment, so that the filler is prevented from dissolving subcutaneously. There is.
- Other components may appropriately include known additives such as viscosity modifiers (for example, glycerin) and dispersants (for example, polyacrylic acid) as long as the effects of this embodiment are not impaired. Good.
- viscosity modifiers for example, glycerin
- dispersants for example, polyacrylic acid
- the content of hydroxyapatite particles is 1% by mass or more, preferably 15% by mass or more, more preferably, based on the total mass of the subcutaneous injection agent. Is 20% by mass or more, and more preferably 30% by mass or more.
- the content of the hydroxyapatite particles is less than 1% by mass (particularly less than 15% by mass), the separation of the apatite particles and the gel due to long-term storage can be remarkable.
- the upper limit of the content of hydroxyapatite particles is not particularly limited, but is 60% by mass or less, preferably 50% by mass or less, and preferably 45% by mass or less, based on the total mass of the subcutaneous injection. 40% by mass or less is particularly suitable. If this upper limit is exceeded, injection from a fine needle having an inner diameter of 0.20 mm or less (and further, an inner diameter of 0.18 or less) becomes difficult, and the load on the patient during the procedure increases.
- the viscosity of the subcutaneous injection may increase.
- the lower limit is not particularly limited, for example, 20 nm
- the blending amount is 40% by mass or less (more preferably 35% by mass or less)
- it becomes easy to optimize the viscosity of the subcutaneous injection (as a result, even in a thinner injection needle). Available).
- the content of hydrogel is not particularly limited, but is preferably 0.5% by mass to 2.0% by mass in terms of solids based on the total mass of the subcutaneous injection. %, More preferably from 0.6% to 1.5% by weight, and even more preferably from 0.7% to 1.0% by weight.
- the content of other components is not particularly limited, but is preferably 5.0% by mass to 10% by mass, more preferably 6.0% by mass, based on the total mass of the subcutaneous injection. Is 9.0 mass%, and more preferably 6.5 mass% to 8.8 mass%.
- the preparation for subcutaneous injection according to this embodiment can be adjusted by appropriately blending and mixing (stirring) the above raw materials, and the production method is not particularly limited.
- the apatite acts passively. Because of the biocompatibility, the surface of the apatite particles is gradually covered with collagen under the skin, and the size is also recognized as a foreign substance, so that the apatite is phagocytosed by macrophages, and the collagen layer covering the surface remains, It is a mechanism that the wrinkle removal effect lasts.
- the method of using the subcutaneous injection according to this embodiment is not limited in any way, but it can be used in subcutaneous injection after filling a syringe of a general syringe.
- it can be set as the injection agent for syringes which has the hollow needle which has an internal diameter of 0.20 mm or less.
- a suitable method for producing a syringe containing the agent for subcutaneous injection according to this embodiment and the application of the agent for subcutaneous injection according to this embodiment The method will be described. These are merely examples, and the method of using the subcutaneous injection according to the present embodiment is not limited to these.
- the manufacturing method of the syringe containing the agent for subcutaneous injection which concerns on this embodiment is a method characterized by including a defoaming process. Each step will be described below.
- the defoaming process First, in the subcutaneous injection agent according to this embodiment, air contained in the subcutaneous injection agent is removed by the defoaming step. From the characteristics of the subcutaneous injection agent according to this embodiment, a method using a centrifuge is preferable as the defoaming step of the subcutaneous injection agent, and a method using a centrifuge under reduced pressure is most preferable. More specifically, when using a filler having thixotropy, such as carboxymethylcellulose (CMC) gel as a main component, shearing force is applied to the filler by centrifugation, thereby reducing the viscosity of the filler and defoaming. The efficiency can be increased. Further, by performing centrifugation under reduced pressure, it is possible to further increase the defoaming efficiency in combination with the defoaming principle.
- CMC carboxymethylcellulose
- air contained in the subcutaneous injection having a hydrogel containing calcined hydroxyapatite particles can be removed, so that inflammation during subcutaneous injection can be suppressed.
- the agent for subcutaneous injection according to the present embodiment may be sterilized and sterilized as necessary.
- Examples of the sterilization / sterilization method include high-pressure steam sterilization.
- the application method of the subcutaneous injection agent and the syringe containing the subcutaneous injection agent according to the present embodiment is the same as that of the conventional subcutaneous injection agent and the syringe containing the subcutaneous injection agent, and is not particularly limited.
- the agent for subcutaneous injection can be used for a thin injection needle having a large inner diameter of 32G (inner diameter 0.18 mm) or less and a thin injection needle having a normal injection needle 30G (inner diameter 0.14 mm) or less. It can also be used with a thin injection needle of a normal injection needle 32G (inner diameter 0.12 mm) or less.
- the agent for subcutaneous injection according to this embodiment preferably has a thixotropy index at 36-37 ° C. (body temperature) of 0.1 to 0.5 in order to further enhance the effects of the invention. It is more preferable that the value be .about.0.3.
- the thixotropy index is a numerical value measured by the following injection characteristics.
- ⁇ Injection characteristics> A method for evaluating the injection characteristics of the filler filled in the syringe from the needle will be described.
- the fluidity quantitative evaluation apparatus according to the present embodiment is used for the injection characteristic evaluation method. With this fluidity quantitative evaluation apparatus, the injection characteristics can be easily evaluated.
- a viscous liquid fluidity quantitative evaluation device for evaluating the injection characteristics when a viscous liquid filled in a syringe barrel is ejected from an injection needle coupled to the syringe barrel, and the viscous liquid is filled
- a load applying unit that applies a constant load to the pusher of the syringe barrel, and a measuring unit that measures time dependence of the load when the viscous liquid is ejected from the injection needle by the load applying unit.
- the fluidity quantitative evaluation apparatus for a viscous liquid wherein a flow curve when the viscous liquid is ejected from the injection needle is obtained from a measurement result by the measuring means. Details of this fluidity quantitative evaluation apparatus will be described below.
- the syringe is fixed, and for example, a load of 3 kg is momentarily applied to the plunger portion.
- the means for applying the load that is, the load applying means for applying a constant load to the pusher of the syringe barrel filled with the viscous liquid is not particularly limited.
- a syringe pump is used.
- measure the indicated value of the weigh scale in which the filler is discharged from the needle and the load applied to the plunger decreases with time as the filler is discharged.
- This is a measuring means for measuring the time dependence of the load when the viscous liquid is ejected from the injection needle by the load applying means.
- the shear rate is obtained from the indication value of the weigh scale, that is, the time derivative of the measurement result by the measuring means.
- a flow curve that can be generally evaluated with a rheometer can be obtained by plotting the indicated value of the weighing scale, that is, the shear stress, with respect to the shear rate. That is, the flow curve when the viscous liquid is ejected from the injection needle can be acquired from the measurement result obtained by the measuring means. From the acquired flow curve, the fluidity of the viscous liquid can be evaluated.
- the equilibrium constants of gel thixotropy and gel network formation are determined from the slope and intercept of the logarithmic plot of logarithm of shear stress and logarithm of shear rate.
- the fluid is a Newtonian fluid (a normal liquid whose resistance increases according to the applied force), and when it is less than 1, the fluid is shaken as a solid when no force is applied. Shows fluid behavior when force is applied), and when it is greater than 1, it exhibits didarancy (fluid behavior when force is not applied, but increases hardness according to force) .
- the filler according to this embodiment exhibits thixotropic properties and is solid in the syringe. However, when a force is applied to the plunger, it is easily discharged from the needle, and after being injected subcutaneously, it solidifies and stays at the injection site. Immediately demonstrates the effect of stretching.
- the present invention may be the following forms (a) to (j).
- this form (a) Having a hydrogel containing calcined hydroxyapatite particles,
- the content of the calcined hydroxyapatite particles is 1 to 60% by mass based on the total mass of the agent,
- the average particle diameter of the calcined hydroxyapatite particles is 15 ⁇ m or less.
- This form (b) is an agent of the said form (a) whose 90% or more of the said baking hydroxyapatite particle
- grains is a particle size of 15 micrometers or less.
- This form (c) is an agent of the said form (a) or (b) whose said hydrogel is a carboxymethylcellulose gel.
- the present form (d) is the agent according to any one of the above forms (a) to (c), wherein the hydrogel has a viscosity of 50 to 15000 mPa ⁇ s.
- the present form (e) is the agent according to any one of the above forms (a) to (d), wherein the agent passes through a hollow needle having an inner diameter of 0.20 mm or less.
- This form (f) is a method for producing a subcutaneous injection, Having a step of mixing calcined hydroxyapatite particles and hydrogel,
- the content of the calcined hydroxyapatite particles is 1 to 60% by mass based on the total mass of the agent, In the method, the average particle size of the calcined hydroxyapatite particles in the agent is 15 ⁇ m or less.
- This form (g) is a manufacturing method of the said form (f) whose 90% or more of the baking hydroxyapatite particle
- This form (h) is a manufacturing method of the said form (f) or (g) whose said hydrogel is a carboxymethylcellulose gel.
- the present form (i) is the production method of any one of the above forms (f) to (h), wherein the hydrogel has a viscosity of 50 to 15000 mPa ⁇ s.
- the present form (j) is the production method according to any one of the above forms (f) to (i), wherein the agent passes through a hollow needle having an inner diameter of 0.20 mm or less.
- the calcined hydroxyapatite aggregate to be used is selected from those having a particle size of 40 nm, 200 nm, 3 ⁇ m, 7 ⁇ m, and 25 ⁇ m, and the carboxymethyl cellulose gel has a viscosity of 67.3 mPa ⁇ s, 208 mPa ⁇ s, and 514 mPa ⁇ s.
- Subcutaneous injection preparations were prepared in the same manner as described above except that the selection was made and the HAp content was changed.
- the thixotropy index of the subcutaneous injection agent according to each Example was measured by the method described above, it was confirmed to be 0.1 to 0.3. That is, it can be seen that the agent for subcutaneous injection according to the example can pass through a fine needle and can remain subcutaneously for a sufficient time. In consideration of the property of staying subcutaneously, the gel viscosity was 208 mPa ⁇ s better than that of 67.3 mPa ⁇ s.
- the particle size of 100 calcined hydroxyapatite particles (particles in an image photographed with a microscope) contained in the subcutaneous injection agent according to each example was measured, and all of them had a particle size of 15 ⁇ m or less. It was confirmed.
- apatite with a small particle diameter has a strong tendency to become high thixotropic property, that is, a small thixotropy index with a small amount, especially for particles of less than 100 nm.
- FIG. 1 shows photographs before and after the defoaming step when hydroxyapatite 1, CMC-Na1, and HAp content is 30% ⁇ (a) is before defoaming and (b) is after defoaming. ⁇ , And the range surrounded by a round line is the remaining air.
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Abstract
Description
前記剤が、
焼成ハイドロキシアパタイト粒子を含有するハイドロゲルを有する
剤であって、
前記製造方法が、
前記剤に含まれるエアを除去する脱泡工程
を有する製造方法である。
本発明(2)は、
皮下注射用剤を含有する注射器の製造方法において、
前記剤が、
焼成ハイドロキシアパタイト粒子を含有するハイドロゲルを有する
剤であって、
前記製造方法が、
前記剤に含まれるエアを除去する脱泡工程と、
前記脱泡工程後の前記剤をシリンジに充填する工程と
を有する製造方法である。
本発明(3)は、
前記脱泡工程が、減圧下で、前記剤を遠心分離機にかけることによって脱泡を行う工程である、前記発明(1)又は(2)の製造方法である。
本発明(4)は、
前記ハイドロゲルが、カルボキシメチルセルロースゲルである、前記発明(1)~(3)のいずれかの製造方法である。
本発明(5)は、
前記剤の粘度が、50~15000mPa・sである、前記発明(1)~(4)のいずれかの製造方法である。
本発明(6)は、
前記焼成ハイドロキシアパタイト粒子の平均粒径が15μm以下である、前記発明(1)~(5)のいずれかの製造方法である。
本発明(7)は、
前記焼成ハイドロキシアパタイト粒子の90%以上が、15μm以下の粒径である、前記発明(1)~(6)の製造方法である。
本発明(8)は、
前記焼成ハイドロキシアパタイト粒子の含有率が、前記剤の全質量を基準として、1~60質量%である、前記発明(1)~(7)のいずれかの製造方法である。
本発明(9)は、
前記剤が、0.20mm以下の内径を有する中空針を通過する、前記発明(1)~(8)のいずれかの製造方法である。
(1)皮下注射用剤の組成
(2)皮下注射用剤の製造方法
(3)皮下注射用剤の作用
(4)皮下注射用剤の使用方法
(5)皮下注射用剤の物性
以下、本実施形態に係る皮下注射用剤の成分及びその配合量に関して詳述する。
本実施形態に係る皮下注射用剤は、ハイドロキシアパタイト粒子とハイドロゲルとを含み、更にその他の成分を含んでいてもよい。尚、ハイドロキシアパタイト粒子凝集体は、ハイドロキシアパタイト粒子の凝集体である。
先ず、本実施形態に係るハイドロキシアパタイト(水酸化燐灰石)粒子に関し、組成、機能及び特性、入手方法、焼成、粒径に関して説明する。尚、ここで示すハイドロキシアパタイト粒子の物性(特に粒径)は、皮下注射用剤中に含まれるハイドロキシアパタイト粒子の物性を示すものである(皮下注射用剤中に含まれるハイドロキシアパタイト粒子の物性と、皮下注射用剤の構成原料であるハイドロキシアパタイト粒子の物性とは、製造段階による形態変化等が生じる場合もあるため、必ずしも同一とは限らない)。
ハイドロキシアパタイト(HAp:Hydroxyapatite)は、化学式Ca10(PO4)6(OH)2で示される塩基性リン酸カルシウムで、天然には歯や骨の主成分として、また鉱石として存在する。
ハイドロキシアパタイト粒子は、高い生体親和性を示す。特に皮下注射用剤として使用した場合には、ナノ粒子としてフィラー中に存在するハイドロキシアパタイト粒子が、繊維芽細胞を刺激することでコラーゲン産生を増進する。また、マイクロ粒子としてフィラー中に存在するハイドロキシアパタイト粒子は、スペーサーとして物理的に機能する。
本実施形態に係るハイドロキシアパタイト粒子としては、焼成ハイドロキシアパタイト粒子(以下、特に断らない限り、「ハイドロキシアパタイト粒子」とある場合には、「焼成ハイドロキシアパタイト粒子」を意味する。)を用いる。ハイドロキシアパタイト粒子を焼成(例えば、800℃で1時間)することにより、粒子の結晶性が高くなり、且つ複数の一次粒子の凝集体が熱により融着して、より強固で安定な粒子となる。特に、分散焼成法により焼成することが好適であり、融着防止剤を用いて焼成することにより凝集しにくくかつ結晶性の高いアパタイトナノ粒子を得ることができる。このように、本発明でいう「ハイドロキシアパタイト粒子」とは、特に断らない限り、一次粒子サイズの焼成ハイドロキシアパタイト粒子のみならず、複数の一次粒子が融着した凝集体も含む概念である。
一般的なハイドロキシアパタイト粒子の製造方法としては、例えば溶液法(湿式法)が挙げられる。これは、中性若しくはアルカリ性の水溶液中でカルシウムイオンとリン酸イオンとを反応させることにより合成する方法であり、中和反応によるものや、カルシウム塩とリン酸塩を反応させるものがある。前述のように、融着防止剤共存下で焼成することにより凝集の少ない結晶性のアパタイト粒子を得る。
本実施形態に係るハイドロキシアパタイト粒子の粒径(平均粒径)は、15μm以下であり、好適には5μm以下であり、より好適には1μm以下であり、更に好適には100nm以下である。ハイドロキシアパタイト粒子の粒径をこのような範囲とすることで、繊維芽細胞を刺激してのコラーゲン産生増進作用を示す。また、このような範囲とすることで、生体内で異物として認識され難いサイズであることから、マクロファージの誘因が起き難いという作用を示す。ハイドロキシアパタイト粒子の粒径(平均粒径)の下限値は特に限定されないが、例えば10nm以上である。尚、ここで示すフィラー中のハイドロキシアパタイト粒子(凝集体を含む)の平均粒径は、顕微鏡により撮影した画像における各粒子(例えば、50個の粒子)の粒子経を測長し、その平均径により決定する。また、フィラーを水等に膨潤させてハイドロゲルを溶解させて、取り出したハイドロキシアパタイトの各粒子(例えば、50個の粒子)の粒子径を測長し、その平均径により決定することもできる。
ハイドロゲルは、剤に用いることができるものであれば、特に限定されないが、例えば、カルボキシメチルセルロースゲル(CMC)、ポリビニルアルコールゲル、ポリアクリル酸ソーダゲル{例えば、Carbopol(登録商標)等}が挙げられる。原料となるセルロースの安全性、安価であることなどから、カルボキシメチルセルロースゲルが好ましい。
カルボキシメチルセルロース(CMC)は、セルロースの水酸基にカルボキシメチル基が導入されたセルロースエーテルである。本形態において、CMCであれば特に限定されないが、CMCのナトリウム塩であるナトリウムカルボキシメチルセルロース(Na-CMC)が好ましい。
その他の成分としては、本形態の効果を阻害しない範囲内で、粘度調整剤(例えば、グリセリン等)や、分散剤(例えば、ポリアクリル酸等)等の公知の添加剤を適宜含んでいてもよい。
本実施形態に係る皮下注射用剤において、ハイドロキシアパタイト粒子の含有率は、皮下注射用剤の全質量を基準として、1質量%以上であり、好適には15質量%以上であり、より好適には20質量%以上であり、更に好適には30質量%以上である。ハイドロキシアパタイト粒子の含有率をこのような範囲とすることにより、高い弾力を示すとともに、フィラーに配合されたアパタイト粒子の沈降による分離を防止できる。また、ハイドロキシアパタイト粒子の含有率が1質量%未満(特には、15質量%未満)であると、長期保管によるアパタイト粒子とゲルの分離が顕著となり得る。
次に、本実施形態に係る皮下注射用剤の製造方法を説明する。
本実施形態に係る皮下注射用剤を皮下注入後、まず、ハイドロゲルが吸収分解される。本形態に係る焼成ハイドロキシアパタイト粒子は粒径が小さいために、焼成ハイドロキシアパタイト粒子が放出される。そして、焼成ハイドロキシアパタイト粒子による繊維芽細胞刺激によってコラーゲン産生が増進される。前述のように、生体内にて異物として認識され難いサイズであることから、マクロファージの誘因が起き難いという作用を示し、結晶性が高いことから、生体内で長期間生体活性を維持することができる。その結果、コラーゲンリッチ組織が皮下に残存する。
本実施形態に係る皮下注射用剤の使用方法は、何ら限定されるものではないが、一般的な注射器のシリンジに充填した後、皮下用の注射において使用することができる。特に、0.20mm以下の内径を有する中空針を有する注射器用の注射用剤とすることができる。ここで、本実施形態に係る皮下注射用剤の具体的な使用方法として、本実施形態に係る皮下注射用剤を含有する注射器の好適な製造方法及び本実施形態に係る皮下注射用剤の適用方法に関して説明する。尚、これらはあくまで一例であり、本実施形態に係る皮下注射用剤の使用方法はこれらには何ら限定されない。
本実施形態に係る皮下注射用剤を含有する注射器の製造方法は、脱泡工程を含むことを特徴とする方法である。以下各々の工程に関して説明する。
まず、本実施形態に係る皮下注射用剤は、脱泡工程によって、皮下注射用剤に含まれるエアが除去される。本形態に係る皮下注射用剤の特性から、遠心分離機にかける方法が皮下注射用剤の脱泡工程として好適であり、減圧下で遠心分離機にかける方法が最も好適である。より具体的には、カルボキシメチルセルロース(CMC)ゲルを主成分とする等、チクソトロピー性を有するフィラーを用いる場合、遠心分離によってフィラーにせん断力が加えられることで、フィラーを低粘度化させ、脱泡効率を上昇させることが可能となる。更に減圧下で遠心分離を行うことにより、当該脱泡原理と合わせ、脱泡効率を更に上昇させることが可能となる。
・レシピ01 高粘度標準脱泡
1.3KPa 9/3 90sec (圧力 公転/自転比 時間)
・レシピ02 金属系フィラー脱泡
1.3KPa 3/9 120sec
1.3KPa 7/5 90sec
1.3KPa 9/2 60sec
・レシピ03 セラミック系フィラー脱泡
1.3KPa 2/5 60sec
1.3KPa 5/5 60sec
次に、脱泡工程後の皮下注射用剤をシリンジに充填し、本実施形態に係る注射器とする。
更に、本実施形態に係る皮下注射用剤は、必要に応じて、殺菌・滅菌を行ってもよい。殺菌・滅菌方法としては、例えば、高圧蒸気滅菌が挙げられる。
本実施形態に係る皮下注射用剤及び皮下注射用剤を含有する注射器の適用方法としては、従来の皮下注射用剤及び皮下注射用剤を含有する注射器等と同様であり、特に限定されない。
本実施形態に係る皮下注射用剤によれば、カルボキシメチルセルロースゲルを主成分として、平均粒径が15μm以下の焼成ハイドロキシアパタイト粒子を用いることで、前記剤の全質量を基準として、1~60質量%以上の焼成ハイドロキシアパタイト粒子を配合しても、内径0.20mm以下であるような細い注射針においても使用可能となる。内径0.20mmとは、内径が大きい注射針30Gに相当する。本実施形態に係る皮下注射用剤は、内径が大きい注射針32G(内径0.18mm)以下の細い注射針や、通常の注射針30G(内径0.14mm)以下の細い注射針においても使用可能であり、通常の注射針32G(内径0.12mm)以下の細い注射針においても使用可能である。
本実施形態に係る皮下注射用剤は、発明の効果をより高めるために、36-37℃(体温)におけるチクソトロピー指数が、0.1~0.5であることが好適であり、0.1~0.3であることがより好適である。チクソトロピー指数は、下記射出特性によって測定された数値である。
シリンジに充填したフィラーの針からの射出特性を評価する方法を述べる。射出特性の評価方法には、本形態に係る流動性定量評価装置を用いる。この流動性定量評価装置によって、簡易に射出特性を評価することができる。
本形態(a)は、皮下注射用剤において、
焼成ハイドロキシアパタイト粒子を含有するハイドロゲルを有し、
前記焼成ハイドロキシアパタイト粒子の含有率が、前記剤の全質量を基準として、1~60質量%であり、
前記焼成ハイドロキシアパタイト粒子の平均粒径が15μm以下である
剤である。
本形態(b)は、前記焼成ハイドロキシアパタイト粒子の90%以上が、15μm以下の粒径である、前記形態(a)の剤である。
本形態(c)は、前記ハイドロゲルが、カルボキシメチルセルロースゲルである、前記形態(a)又は(b)の剤である。
本形態(d)は、前記ハイドロゲルの粘度が、50~15000mPa・sである、前記形態(a)~(c)のいずれかの剤である。
本形態(e)は、前記剤が、0.20mm以下の内径を有する中空針を通過する、前記形態(a)~(d)のいずれかの剤である。
本形態(f)は、皮下注射用剤の製造方法において、
焼成ハイドロキシアパタイト粒子とハイドロゲルとを混合する工程を有し、
前記焼成ハイドロキシアパタイト粒子の含有率が、前記剤の全質量を基準として、1~60質量%であり、
前記剤中の焼成ハイドロキシアパタイト粒子の平均粒径が15μm以下である
製造方法である。
本形態(g)は、前記剤中の焼成ハイドロキシアパタイト粒子の90%以上が、15μm以下の粒径である、前記形態(f)の製造方法である。
本形態(h)は、前記ハイドロゲルが、カルボキシメチルセルロースゲルである、前記形態(f)又は(g)の製造方法である。
本形態(i)は、前記ハイドロゲルの粘度が、50~15000mPa・sである、前記形態(f)~(h)のいずれかの製造方法である。
本形態(j)は、前記剤が、0.20mm以下の内径を有する中空針を通過する、前記形態(f)~(i)のいずれかの製造方法である。
<原料>
・CMC-Na
・グリセリン
・焼成ハイドロキシアパタイト凝集体
・滅菌水
使用する器具の滅菌を行った。
次に、グリセリン50gをプロペラシャフト付モーターにて300rpmで撹拌した。2分超撹拌しながら、グリセリン中にCMC-Na5gを配合し、15分撹拌し溶液を得た。
得られた溶液を10分超撹拌し、得られたCMC-Naペーストを、1.5cm角にカットし204mlの滅菌水中に配合した。この滅菌水を120分撹拌し、CMC-Naハイドロゲル(粘度208mPa・s)を得た。
得られたCMC-Naハイドロゲル28.0gに、焼成ハイドロキシアパタイト凝集体12.0gを3回に別けて配合し、10分撹拌し、原料フィラーを得た。
得られた原料フィラー30.0gをプロペラ撹拌し、皮下注射用剤(HAp配合率30質量%)を得た。
次に、上記皮下注射用剤に関して、30Gの針を通過可能かの評価を行った。具体的には、皮下注射用剤を脱泡した後、注射器に充填した。次に、得られた注射器の押し出しを行い、注射器中の皮下注射用剤が30G針通過性を確認した。スムーズに通過する場合を◎、押し出しに少し抵抗がある場合を○、押し出しに強い力が必要な場合を△、押し出しが出来ない場合、又はフィラー自体を作成できない場合を×とした。結果を表1に示す。
Claims (10)
- 皮下注射用剤の製造方法において、
前記剤が、
焼成ハイドロキシアパタイト粒子を含有するハイドロゲルを有する
剤であって、
前記製造方法が、
前記剤に含まれるエアを除去する脱泡工程
を有することを特徴とする製造方法。 - 皮下注射用剤を含有する注射器の製造方法において、
前記剤が、
焼成ハイドロキシアパタイト粒子を含有するハイドロゲルを有する
剤であって、
前記製造方法が、
前記剤に含まれるエアを除去する脱泡工程と、
前記脱泡工程後の前記剤をシリンジに充填する工程と
を有することを特徴とする製造方法。 - 前記脱泡工程が、減圧下で、前記剤を遠心分離機にかけることによって脱泡を行う工程である、請求項1又は2に記載の製造方法。
- 前記ハイドロゲルが、カルボキシメチルセルロースゲルであることを特徴とする、請求項1~3のいずれかに記載の製造方法。
- 前記剤の粘度が、50~15000mPa・sであることを特徴とする、請求項1~4のいずれかに記載の製造方法。
- 前記焼成ハイドロキシアパタイト粒子の平均粒径が15μm以下であることを特徴とする、請求項1~5のいずれかに記載の製造方法。
- 前記焼成ハイドロキシアパタイト粒子の90%以上が、15μm以下の粒径であることを特徴とする、請求項1~6のいずれかに記載の製造方法。
- 前記焼成ハイドロキシアパタイト粒子の含有率が、前記剤の全質量を基準として、1~60質量%であることを特徴とする、請求項1~7のいずれかに記載の製造方法。
- 前記焼成ハイドロキシアパタイト粒子が、コラーゲン産生増進用であることを特徴とする、請求項1~8のいずれかに記載の製造方法。
- 前記剤が、0.20mm以下の内径を有する中空針を通過することを特徴とする、請求項1~9のいずれかに記載の製造方法。
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CN110193094A (zh) * | 2018-02-24 | 2019-09-03 | 上海优先生物医学工程有限公司 | 一种软组织填充修复材料及其制备方法和用途 |
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EP3231432A1 (en) | 2017-10-18 |
CA2970595A1 (en) | 2016-06-16 |
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