JP2010167040A - Medicine slowly releasing body - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine slowly releasing body which carries a medicine and releases it when embedded in a living body, and particularly, which has a dynamic property close to that of an original bone when used as an artificial bone for a part where large loads are applied. <P>SOLUTION: The medicine slowly releasing body is formed of plastic, is composed of a substantial body and a surface layer formed on the surface of the body and having small diameter pores and large diameter pores, a part of the small diameter pores and the large diameter pores form open pores opened on the surface of the surface layer. The open pores includes small diameter open pores whose average open pore diameter is ≤5 μm and large diameter open pores whose average open pore diameter is 10 to 200 μm. On the inner wall surface of the large diameter open pores, communicating holes which communicates the small diameter pores and the large diameter pores are formed to form a surface foam body, which carries the medicine on its surface layer. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a sustained-release drug, and more particularly to a sustained-release drug that is supported by a drug and that is released when embedded in a living body.

  In the medical field and regenerative medical engineering field, as a means for locally administering a drug or a means for regenerating lost tissue, a sustained-release drug made by impregnating a drug into a porous body is implanted in the affected area. It has been proposed to do.

  For example, Patent Document 1 describes a method of impregnating a porous calcium phosphate-based sintered block with a drug, and Patent Documents 2 and 3 support a drug together with a bioabsorbable polymer in pores inside the ceramic porous body. Artificial bone is described. Patent Document 4 describes drug sustained-release granules having a coating layer made of a soluble organic compound impregnated with a drug in the pores of porous calcium phosphate compound granules, and Patent Document 5, A sustained-release agent carrier having a hollow portion for holding a drug solution inside a ceramic porous granule is described. Furthermore, Patent Document 6 describes a drug sustained-release calcium phosphate cement comprising a calcium phosphate cement containing a drug and a liquid agent. Since all of these are low in strength compared to living bones, for example, when used as an artificial bone, it is considered that there is a limitation on the use site such as use only at a site where no load is applied.

  Patent Document 7 discloses a method for producing a medical porous body in which a drug is carried during the production of a medical porous body in a medical porous body made of a polymer. However, since this medical porous body has a porous structure as a whole, when it is used as an artificial bone as in the case of the sustained-release drug described in the above-mentioned patent document, the use site is limited. it is conceivable that.

Japanese Patent Laid-Open No. 10-279471 Special table 2007-222611 JP 2004-159971 A Japanese Patent No. 2842647 Japanese Patent No. 3152665 gazette Japanese Patent No. 2927007 JP 2005-80927 A

  An object of the present invention is to provide a sustained-release drug that is supported by a drug and is released when the drug is embedded in a living body, and particularly when used as an artificial bone in a part where a large load is applied. It is to provide a drug sustained-release body having mechanical properties close to those of the original bone.

  The other subject of this invention is providing the manufacturing method of the chemical | medical agent sustained release body which can manufacture the chemical | medical agent sustained release body which has a complicated shape by a simple method.

As means for solving the problems,
(1) formed of plastic,
A substantial portion and a surface layer formed on the surface thereof, and having a small diameter pore and a large diameter pore;
A part of the small-diameter pores and the large-diameter pores form open pores that open on the surface of the surface layer,
The open pores include small open pores having an average open pore size of 5 μm or less and large open pores having an average open pore size of 10 to 200 μm,
A sustained-release drug, characterized in that a surface foam formed by forming the small-diameter pores and communication holes communicating with the large-diameter pores on the inner wall surface of the large-diameter open pores carries the drug on the surface layer. Is the body.

  The drug sustained-release body according to the present invention is formed of plastic, and includes a substantial part and a surface layer formed on the surface thereof and having small diameter pores and large diameter pores, and one of the small diameter pores and the large diameter pores. Part has open pores that open to the surface of the surface layer, and the open pores have small open pores having an average open pore size of 5 μm or less and large open pores having an average open pore size of 10 to 200 μm. A surface foam formed by forming the small-diameter pores and communication holes communicating with the large-diameter pores on the inner wall surface of the large-diameter open pores carries the drug on the surface layer. Therefore, when this drug sustained-release body is embedded in a living body, the drug is gradually released over a long period of time. When this drug sustained-release body is used as an artificial bone, the drug can be gradually released over a long period of time, and the bone tissue can enter the inside of the surface layer. As a result, new bone is formed so as to fill the space existing inside the surface layer while slowly releasing drugs such as anti-inflammatory agents and osteogenesis-inducing factors. Can be combined. In addition, since the drug sustained-release body according to the present invention does not have pores in the entire volume, but has a large number of pores on the surface thereof, it is easy to maintain strength according to the application site.

  In addition, when the drug sustained-release body is formed of an engineering plastic, particularly polyether ether ketone, a drug sustained-release body having high mechanical strength can be provided. Therefore, when this drug sustained-release body is applied as an artificial bone to a site where a bond with bone is necessary and a large load is continuously applied over a long period of time, stress shielding, that is, stress applied to the bone It is possible to prevent the occurrence of bone loss and bone density that may occur due to the shielding of the bone.

  Furthermore, the drug sustained-release body has a bioactive substance such as hydroxyapatite on the surface layer of the drug sustained-release body and / or the inner wall surface of the small-diameter open pores and the large-diameter open pores. When this drug sustained-release body is used as an artificial bone, the chemical reaction between this bioactive substance and the bone tissue of the living body begins, and the formation of new bone is performed rapidly. It is possible to combine with the bone at an early stage. When this drug sustained-release body is used as a transdermal device, since the bioactive substance has a property of adsorbing many biomolecules, the adhesion between the skin and the drug sustained-release body can be improved. . As a result, it is possible to prevent bacterial infection from occurring through the gap formed between the skin and the transdermal device. Further, when the bioactive substance is a drug particle or drug layer containing a drug and a bioactive substance, the drug is gradually released over a long period of time.

  The method for producing a sustained-release drug according to the present invention is a method in which almost all steps can be performed in a liquid phase, so that it is not necessary to use a special device, and the sustained-release drug having a complicated shape is used. Even a body can be easily manufactured.

FIG. 1 is a schematic view showing an embodiment of a surface foam in a drug sustained-release body according to the present invention. 2 (a) and 2 (b) are schematic views showing one embodiment of a drug sustained-release body having a bioactive substance. FIG. 3 is a scanning electron micrograph of the surface of the surface foam in Example 1.

  FIG. 1 is a schematic view showing an embodiment of a surface foam constituting the drug sustained-release body according to the present invention. As shown in FIG. 1, the surface foam 1 includes a substantial portion 2 and a surface layer 5 formed on the surface thereof and having small diameter pores 3 and large diameter pores 4, and the small diameter pores 3 and the large diameter pores 1. A part of the diameter pore 4 forms an open pore 6 that opens on the surface of the surface layer 5, and the open pore 6 has a small-diameter open pore 13 having an average open pore diameter A of 5 μm or less and an average open pore diameter B. The large-diameter open hole 14 has a diameter of 10 to 200 μm, and the large-diameter open hole 14 is formed with a communication hole 7 communicating with the small-diameter hole 3 and the large-diameter hole 4 on the inner wall surface. In the drug sustained-release body according to the present invention, the drug is carried on the surface layer 5 of the surface foam 1.

  The surface layer 5 has a plurality of small-diameter pores 3 and large-diameter pores 4 having different sizes, and these pores communicate with independent pores 8 formed independently and two or more independent pores 8. The continuous ventilation hole 9 formed in this way is formed. Some of the small-diameter pores 3 and large-diameter pores 4 form open pores 6 that open on the surface of the surface layer 5, and these open pores 6 have an average open pore size A of 5 μm or less, preferably 3 μm or less. It has pores 13 and large-diameter open pores 14 having an average open pore size B of 10 to 200 μm, preferably 30 to 150 μm. On the inner wall surface of the large-diameter open hole 14, a communication hole 7 formed so as to communicate with the small-diameter hole 3 and the large-diameter hole 4 is formed. The communication hole 7 is preferably formed with a plurality of communication holes 7 with respect to one open hole 6, and the small diameter communication hole diameter C formed in communication with the small diameter hole 3 is 5 μm or less, preferably 3 μm or less. The small-diameter communication hole 15 and the large-diameter communication hole 16 are formed with a large-diameter communication hole 16 having a large-diameter communication hole diameter D of 10 to 200 μm, preferably 30 to 150 μm. The small diameter pores 3 and the large diameter pores 4 have a spherical shape and / or an oblate shape and / or an oblong shape and / or a shape formed by combining these shapes. Since the surface layer 5 has such pores, when the drug sustained-release body is embedded in the living body, the drug is gradually released over a long period of time. When this drug sustained-release body is used as an artificial bone, the drug can be gradually released over a long period of time, and the bone tissue can enter the inside of the surface layer. As a result, new bone is formed so as to fill the space existing in the surface layer while slowly releasing drugs such as anti-inflammatory agents and osteogenesis-inducing factors. Can be combined. Further, the more the communication holes 7, especially the large diameter communication holes 16 are formed on the inner wall surface of the large diameter open hole 14 formed by the large diameter pores 4, the bone tissue reaches from the surface of the surface layer 5 to the deep part. Since new bone can be formed in the deep part of the surface layer 5, the bone and the biological implant can be more firmly bonded.

  The average open pore diameter of the small diameter open pores 13 and the average open pore diameter of the large open pores 14 opened on the surface of the surface layer 5 are determined by observing the surface of the surface layer 5 with a scanning electron microscope. It can be obtained using the image shown.

  First, an SEM image in which the surface of the surface layer 5 is set to a predetermined magnification, for example, 300 times, is obtained by a scanning electron microscope. Next, the major and minor diameters of the open pores in the outermost part of the relatively large surface in the entire field of view of the SEM image, for example, the open pores having an average diameter of about 10 μm or more are measured. Subsequently, the average open pore diameter of the large-diameter open pores 14 can be obtained by calculating the arithmetic average of these measured values.

  The small-diameter open pores 13 are usually present in a skeleton portion between the large-diameter open pores 14 and the large-diameter open pores 14. When measuring the average open pore diameter of the small-diameter open pores 13, it is preferable to further increase the magnification of the scanning electron microscope in order to reduce the measurement error. For example, an SEM image in which the scanning electron microscope is set to 3000 times is obtained. Next, the major axis and minor axis of the open pores formed in the skeleton portion are measured. That is, the major and minor diameters of all the open pores except the large-diameter open pores 14 previously measured are measured. Subsequently, the average open pore diameter of the small-diameter open pores 13 can be obtained by calculating the arithmetic average of these measured values.

  When there are a large number of large-diameter open pores 14 or small-diameter open pores 13 on the SEM image, for example, 50 or more, five straight lines are drawn at random so as to cross the SEM image. The diameter open hole 14 or the small diameter open hole 13 is selected according to the above-mentioned criteria, and the major axis and the minor axis are measured. Subsequently, the average open pore diameter of the large-diameter open pores 14 and the small-diameter open pores 13 can be obtained by calculating the arithmetic average of these measured values.

  The diameter of the communication hole 7 in which the small diameter pore 3 and the large diameter pore 4 are formed in communication with the open pore 6 opened on the surface of the surface layer 5 is obtained from an SEM image taken at a predetermined magnification as described above. Alternatively, it can be determined using a mercury porosimeter.

  The area ratio of each of the small-diameter open pores 13 and the large-diameter open pores 14 when the outermost surface of the surface layer 5 is projected is not particularly limited, and may be appropriately adjusted in consideration of the sustained release amount and the sustained release period of the drug. it can. When the drug sustained-release body according to the present invention is used as, for example, an artificial bone, the small-diameter opening is within a range where the total area ratio of the small-diameter open pores 13 and the large-diameter open pores 14 is 99% or less. The area ratio of the pores 13 is preferably 5 to 90%, particularly preferably 15 to 80%, and the area ratio of the large-diameter open pores 14 is preferably 10 to 95%. 85% is particularly preferred. When the area ratio of the small-diameter open pores 13 is within the above range, the drug can be sufficiently loaded, and the drug can be released over a long period of time after the drug sustained-release body is embedded in the living body. it can. In particular, when a large number of small-diameter open pores 13 are formed, the drug carried on the surface layer 5 is released little by little compared to the case where the surface of the drug sustained-release body is formed flat. The reason for this is that the smaller the pore size of the open pores, the more difficult it is for the bodily fluid to enter the pores, and the drug carried in the pores is less likely to come into contact with the bodily fluid, so the drug is less likely to be released. Presumed to be. Therefore, as the average open pore diameter A of the small-diameter open pores 13 is smaller and the area ratio of the small-diameter open pores 13 is larger, the drug is released for a longer period of time. In addition, when the area ratio of the large-diameter open pores 14 is within the above range, the bone tissue can be infiltrated into the surface layer 5, so that new bone is formed inside the surface layer 5, and as a result. The sustained-release drug can be provided that can be combined with bone.

  The area ratio of the small-diameter open pores 13 and the large-diameter open pores 14 when the outermost surface of the surface layer 5 is projected is obtained by image analysis software (for example, manufactured by Scion) Scion Image) can be used to calculate the areas of the small-diameter open pores 13 and the large-diameter open pores 14, respectively. As in the case of calculating the average open pore diameter described above, the scanning electron microscope image is displayed at an appropriate magnification for measuring the areas of the small diameter open pore 13 and the large diameter open pore 14. The area ratio of the large-diameter open pores is calculated from the area of the large-diameter open pores relative to the area S of the entire image, and the area ratio of the small-diameter open pores is calculated from the area of the small-diameter open pores relative to the area S of the entire image.

  The porosity of the small-diameter pores 3 and the large-diameter pores 4 in the surface layer 5 is not particularly limited, and can be appropriately adjusted in consideration of the sustained release amount and the sustained release period of the drug. When the drug sustained-release body according to the present invention is used as, for example, an artificial bone, the porosity of the small-diameter pore 3 is within a range where the total porosity of the small-diameter pore 3 and the large-diameter pore 4 is 99% or less. Is preferably 5 to 50%, particularly preferably 10 to 40%, and the porosity of the large-diameter pores 4 is preferably 20 to 90%, particularly preferably 30 to 80%. . If the porosity of the small-diameter pores 3 is within the above range, a large amount of scaffolds to which proteins and cells involved in bone formation adhere can be secured, so that new bone is easily formed inside the surface layer, and the drug is released slowly. The body and bone can be firmly bonded. When the porosity of the large-diameter pore 4 is in the above range, the bone tissue is easily retained after entering the inside of the surface layer 5, and a space for forming new bone is sufficiently secured. Since a new bone is formed so as to be buried, the bone and the biological implant can be combined more firmly. In addition, when the porosity of the small diameter pores 3 and the large diameter pores 4 is within the above range, the drug supported on the surface layer 5 can be delivered at an appropriate sustained release rate, that is, a desired amount of the drug over a desired period. Can be released.

  The porosity of the small-diameter pores 3 and the porosity of the large-diameter pores 4 of the surface layer 5 are obtained by image analysis software (for example, Scion manufactured by Scion Co., Ltd.) obtained by photographing a cross section perpendicular to the surface of the surface layer 5 with a scanning electron microscope. Image) can be used to calculate the areas of the large pores 4 and the small pores 3 respectively. That is, each porosity can be estimated by calculating | requiring each area ratio of the small diameter pore 3 and the large diameter pore 4 similarly to calculating the area ratio of the small diameter open pore and large diameter open pore mentioned above.

  The thickness of the surface layer 5 can be appropriately adjusted in consideration of a site to which the drug sustained-release body according to the present invention is applied, a sustained release amount and a sustained release period of the drug, and the like. When the drug sustained-release body according to the present invention is used as, for example, an artificial bone, it is preferably 10 to 1000 μm, particularly preferably 20 to 200 μm. Within the above range, an appropriate amount of drug can be carried on the surface layer 5, so that a desired amount of drug can be released over a desired period of time. In addition, after the drug sustained-release body is embedded in the body, a large number of open pores 6 opened on the surface of the surface layer 5 and the small-diameter pores 3 and the large pores formed inside the open pores 6 and the surface layer 5 are used. Bone tissue can enter the inside of the surface layer 5 through the communication hole 7 formed by the communication with the radial pore 4. As a result, since new bone is formed inside the surface layer 5, it is possible to provide a sustained-release drug that can be combined with living bone.

  The drug sustained-release body according to the present invention is formed of a commonly used plastic, and an appropriate plastic can be selected depending on the site where the drug sustained-release body is used. The When the drug sustained-release body according to the present invention is used as an artificial bone or an artificial tooth root, the substance forming the drug sustained-release body is a plastic whose mechanical properties are close to bone, that is, an elastic modulus of 1 to 50 GPa, The bending strength is preferably 100 MPa or more.

  Examples of the plastic whose mechanical properties are close to those of bones or teeth include engineering plastics and fiber reinforced plastics. Engineering plastics include, for example, polyamide, polyacetal, polycarbonate, polyphenylene ether, polyester, polyphenylin oxide, polybutylene terephthalate, polyethylene terephthalate, polysulfone, polyethersulfone, polyphenylene sulfide, polyarylate, polyetherimide, polyetherether Examples include ketones, polyamideimides, polyimides, fluororesins, ethylene vinyl alcohol copolymers, polymethylpentene, phenol resins, epoxy resins, silicone resins, diallyl phthalate resins, polyoxymethylenes, polytetrafluoroethylenes, and the like.

  Examples of plastics that serve as a matrix of fiber reinforced plastic include, in addition to the engineering plastics, polyethylene, polyvinyl chloride, polypropylene, EVA resin, EEA resin, 4-methylpentene-1 resin, ABS resin, AS resin, ACS resin, and the like. , Methyl methacrylate resin, ethylene vinyl chloride copolymer, propylene vinyl chloride copolymer, vinylidene chloride resin, polyvinyl alcohol, polyvinyl formal, polyvinyl acetoacetal, polyfluorinated ethylene propylene, polytrifluoroethylene chloride, methacrylic resin, renor Resin, polyallyl ether ketone, polyether sulfone, polyketone sulfide, polystyrene, polyamino bismaleimide, urea resin, melamine resin, xylene resin, isophthalic acid series Fat, aniline resins, furan resins, polyurethane, alkylbenzene resin, guanamine resin, poly ether resins.

  When the sustained-release drug according to the present invention is used as an artificial bone or an artificial tooth root, among these, polyether ether ketone (PEEK) is particularly preferable as the substance forming the sustained-release drug. When a drug sustained-release body formed by PEEK is embedded in a site where a large load is continuously applied over a long period of time, PEEK has biocompatibility and mechanical properties similar to bone. That is, it is possible to prevent the occurrence of bone loss and bone density that may occur due to shielding of stress applied to the bone.

Examples of the fiber in the fiber reinforced plastic include carbon fiber, glass fiber, ceramic fiber, metal fiber, and organic fiber.
For carbon fibers, carbon nanotubes are also included here.
Examples of the glass fiber include fibers such as borosilicate glass (E glass), high strength glass (S glass), and high elasticity glass (YM-31A glass).
Ceramic fibers include silicon carbide, silicon nitride, alumina, potassium titanate, boron carbide, magnesium oxide, zinc oxide, aluminum borate, boron and other fibers,
As metal fibers, tungsten, molybdenum, stainless steel, steel, tantalum fibers,
As the organic fiber, fibers such as polyvinyl alcohol, polyamide, polyethylene terephthalate, polyester, aramid, or a mixture thereof can be used.

  In addition, in the substance forming the drug sustained-release body, an antistatic agent, an antioxidant, a light stabilizer such as a hindered amine compound, a lubricant, an antiblocking agent, an ultraviolet absorber, an inorganic filler, a pigment, etc. Various additives such as coloring agents may be contained.

  The drug sustained-release body according to the present invention carries a drug on its surface layer 5. As this drug, various drugs can be used depending on the required functions of the sustained-release drug according to the present invention. Examples of the drug include anti-inflammatory agents, antibiotics, antithrombotic agents, antitumor agents, anticoagulants, vascular cell growth promoters, vascular cell growth inhibitors, anticancer agents, vasodilators, and osteogenesis inducers. Can be mentioned. As an osteogenesis inducing factor, various osteogenesis-related proteins that are extracted from bone tissue can be used. For example, osteogenesis factor (BMP), transforming growth factor (TFG-β), cartilage-derived formation factor (CDMP), osteoinductive factor (OIF), insulin-like growth factor (IGF), platelet-derived growth factor (PDFG), fibroblast growth factor (FGF) and the like. As long as these drugs do not react with each other, two or more kinds of drugs selected from these may be supported on the surface layer 5.

  The drug sustained-release body according to the present invention preferably has a bioactive substance on the surface of the surface layer and / or the inner wall surface of the small diameter pore and the large diameter pore, and includes the bioactive substance and the drug. It is particularly preferred to have drug particles and / or drug layers. Here, when the bioactive substance carrying the drug is formed in the form of particles, this is referred to as drug particles, and when the bioactive substance carrying the drug is formed in layers, this is referred to as the drug layer. These are not strictly distinguished. If the drug sustained-release body has a bioactive substance, drug particles and / or drug layer, the bioactive substance has the property of binding to bone and adsorbing biomolecules. This is particularly effective when used in a site that needs to be bonded to a living tissue such as bone or skin. For example, when the drug sustained-release body is used as an artificial bone, it becomes easy to bond with bone, and when used as a transdermal device, it becomes easy to adhere to the skin. Furthermore, when the drug sustained-release body has drug particles and / or drug layers, the drug is released over a long period of time, and therefore an effect corresponding to the type of the drug is obtained over a long period of time. .

  2A and 2B are schematic views of a drug sustained-release body which is an example of a drug sustained-release body having a bioactive substance, drug particles, and / or a drug layer. In the following description, the bioactive substance, drug particles, and drug layer are simply referred to as bioactive substances. As shown in FIG. 2A, the bioactive substance 210a may be formed on the entire surface of the inner wall surface 211a of the open pores 206a and the surface of the surface layer 205a in the surface layer 205a. Alternatively, as shown in FIG. 2B, the bioactive substance 210b may be formed on part of the inner wall surface 211b of the open pore 206b and / or part of the surface of the surface layer 205b. However, when the drug sustained-release bodies 212a and 212b have only drugs instead of drug particles or drug layers having bioactive substances, the drugs are released only from the surface foam. 2 (b), a part of the inner wall surface 211b of the open pores 206b and / or a part of the surface of the surface layer 205b is provided on the surface of the surface layer 205b. Is preferably formed. Further, when the bioactive substances 210a and 210b are formed on the inner wall surfaces 211a and 211b of the open pores 206a and 206b, the bioactive substances 210a and 210b are formed so as to fill the open pores 206a and 206b. Instead, as shown in FIGS. 2 (a) and 2 (b), a bioactive substance is formed on part or the entire inner wall surfaces 211a and 211b of the open pores 206a and 206b opened on the surfaces of the surface layers 205a and 205b. 210a and 210b are preferably formed. For example, as shown in FIG. 2 (a), all of the small-diameter open pores 213a may be filled with the bioactive substance 210a, but the large-diameter open pores 214a hold the volume of the large-diameter open pores 214a. It is preferable that the bioactive substance 210a is formed on the inner wall surface 211a. Further, the large-diameter communication holes 216a formed in communication with the large-diameter pores 204a are not blocked by the bioactive substance 210a, and the large-diameter communication holes can penetrate the living tissue or release the medicine. It is preferable that a large-diameter communication hole 216a having a hole diameter D is formed. If the open pores 206a are formed in the surface layer 205a and the large-diameter communication holes 216a communicating with the open pores 206a are formed, the sustained-release drug 212a is embedded in the living body, and then the surface layer 205a is opened from the open pores 206a. The living tissue can enter the inside of the body, or the drug can be released from the inside of the surface layer 205a. As a result, the chemical reaction between the biologically active substance 210a present on the inner wall surface 211a of the open pore 206a and the biological tissue such as bone and skin starts, so that the bondability with the biological tissue can be further improved.

  The area ratio of the bioactive substances 210a and 210b when the surface layers 205a and 205b are projected is preferably at least 5% or more, and particularly preferably 20% or more. The bioactive substances 210a and 210b exist not only on the bioactive substances 210a and 210b existing on the surfaces of the surface layers 205a and 205b but also on the inner wall surfaces 211a and 211b of the open pores 206a and 206b, and the surface layers 205a and 205b. Also included are bioactive substances 210a and 210b that are visible from the outside. When the bioactive substances 210a and 210b are present on the surfaces of the inner wall surfaces 211a and 211b and / or the surface layers 205a and 205b of the open pores 206a and 206b in the surface layers 205a and 205b within the above range, the sustained drug release body 212a, Since the chemical reaction between the biologically active substances 210a and 210b and the biological tissue starts after the 212b is embedded in the living body, the bondability between the biological tissue such as bone and skin and the drug sustained release bodies 212a and 212b is improved. Can be made. When the bioactive substances 210a and 210b are drug particles and / or drug layers containing a bioactive substance and a drug, the drug is released over a long period of time, so that the effect according to the type of the drug is long. Obtained over a period of time.

  The area ratio of the bioactive substances 210a and 210b when the surface layers 205a and 205b are projected is based on image analysis software (for example, Scion Image manufactured by Scion) obtained by scanning the surface of the surface layers 205a and 205b with a scanning electron microscope. Can be obtained by binarizing the bioactive substances 210a and 210b and other parts, and then calculating the area ratio of the bioactive substance to the total area of the image.

  The bioactive substances 210a and 210b are preferably contained in an amount of 0.5 to 30% with respect to the volume of the surface layers 205a and 205b. The bioactive substances 210a and 210b are in an independent state on the inner wall surfaces 211a and 211b of the open pores 206a and 206b in the surface layers 205a and 205b and / or the surface of the surface layers 205a and 205b and / or the inside of the surface layers 205a and 205b. These bioactive substances 210a and 210b are combined and exist in a state of being stretched inside the surface layers 205a and 205b in a dendritic shape. When the bioactive substances 210a and 210b within the above range are present in the surface layers 205a and 205b, the chemical sustained release bodies 212a and 212b are embedded in the living body, and then the chemicals between the bioactive substances 210a and 210b and the living tissue are chemically treated. Since the reaction starts, the bondability between the biological tissue such as bone and skin and the drug sustained release bodies 212a and 212b can be improved. When the bioactive substances 210a and 210b are drug particles and / or drug layers, the drug is released over a long period of time, so that an effect corresponding to the type of the drug is obtained over a long period of time.

  The volume ratio of the bioactive substances 210a and 210b included in the surface layers 205a and 205b can be obtained in the same manner as the method for measuring the area ratio of the bioactive substances 210a and 210b described above. That is, if the area ratio of the bioactive substances 210a and 210b in the cross section orthogonal to the surfaces of the surface layers 205a and 205b can be calculated, the volume ratio of the bioactive substances 210a and 210b can be estimated from the calculated values.

The bioactive substances 210a and 210b are not particularly limited as long as they have a high affinity with a living body and have a property of chemically reacting with bone tissues and skins including teeth. For example, calcium phosphate-based materials and bioglass And inorganic materials such as crystallized glass (also referred to as glass ceramics) and calcium carbonate. Examples of calcium phosphate materials include calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, α-type tricalcium phosphate, β-type tricalcium phosphate, Examples thereof include dolomite, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, fluorapatite, carbonate apatite, and chlorapatite. Examples of the bioglass include SiO ₂ —CaO—Na ₂ O—P ₂ O ₅ glass, SiO ₂ —CaO—Na ₂ O—P ₂ O ₅ —K ₂ O—MgO glass, and SiO ₂ —. Examples include CaO—Al ₂ O ₃ —P ₂ O ₅ glass. Examples of the crystallized glass include SiO ₂ —CaO—MgO—P ₂ O ₅ glass (also referred to as apatite wollastonite crystallized glass), CaO—Al ₂ O ₃ —P ₂ O ₅ glass, and the like. Is mentioned. These calcium phosphate materials, bioglass and crystallized glass are, for example, “Chemical Handbook Applied Chemistry 6th Edition” (The Chemical Society of Japan, published on January 30, 2003, Maruzen Co., Ltd.), “Development of Bioceramics” And Clinical "(edited by Hideki Aoki et al., Published on April 10, 1987, Quintessence Publishing Co., Ltd.).

  Among these, as the bioactive substances 210a and 210b, calcium phosphate-based materials are preferable in that they are excellent in bioactivity. Furthermore, since the composition, structure, and properties are similar to actual bones, the stability in the body environment is excellent. Hydroxyapatite is particularly preferred because it does not show significant solubility in the body.

  In addition, the bioactive substances 210a and 210b are preferably low crystalline. The term “low crystallinity” as used herein means a state in which the degree of crystal development is low. In the case of hydroxyapatite, 2θ = 2.878 ° and the interplanar spacing (d value) = 3. A half-width of 44 ° diffraction line is 0.2 ° or more. When the drug sustained-release body is used as an artificial bone, the bioactive substance has a crystallinity equivalent to that of bone hydroxyapatite (half-value width: about 0.4 ° under the above condition) (half-value under the same condition). When the value range is 0.2 to 1.0 °, the drug sustained-release body and the bone can be quickly combined.

  The crystallinity of the bioactive substances 210a and 210b is, for example, when the bioactive substance is formed by a method in which the bioactive substance is immersed in a solution containing calcium and / or phosphorus, and the type and composition ratio and / or immersion of the components of the solution. The temperature can be adjusted.

  Next, an example of the “method for producing a sustained-release drug” according to the present invention will be described.

  In step 1, a microporous substrate having a large number of micropores on the surface of a plastic substrate formed into a desired shape is prepared. As a method for forming micropores on the surface of a plastic substrate, a known method can be adopted. For example, a plastic substrate is used as a corrosive solution such as concentrated sulfuric acid, concentrated nitric acid, or chromic acid. And a method of immersing the substrate in a cleaning solution in which the plastic does not elute, for example, pure water. When, for example, polyether ether ketone (PEEK) is used as the plastic, micropores can be formed by immersing PEEK in concentrated sulfuric acid for a predetermined time and then immersing it in pure water.

  The pore size of the micropores formed on the surface of the plastic substrate may be a pore size that allows the foaming agent used in step 2 to enter the plastic substrate. It can select suitably according to the kind of agent. For example, when sodium carbonate is employed as the foaming agent, the pore diameter of the micropores is preferably 0.1 to 200 μm. The porosity of the micropores formed on the surface of the plastic substrate is sufficient if the foaming agent used in step 2 can be sufficiently retained. For example, when sodium carbonate is used as the foaming agent, The porosity of the layer in which the micropores of the plastic substrate are formed is preferably 10 to 90%. When the porosity is in a low range within the range of the porosity, for example, pores are formed to communicate from the surface of the plastic base material in the internal direction or from the surface of the plastic base material. It is preferable that the hole is formed so that the foaming agent is held from the surface of the plastic substrate to a desired depth, such as a columnar hole formed perpendicular to the direction. The thickness of the layer in which a large number of micropores are formed may be equal to the thickness of the surface layer in the surface foam as the final product, and is preferably 10 to 1000 μm. The thickness, pore diameter, and porosity of the layer having a large number of micropores are determined depending on the time and / or temperature at which PEEK is immersed in concentrated sulfuric acid when, for example, concentrated sulfuric acid is used as the PEEK corrosive solution. The thickness can be adjusted. In addition, the pore diameter and the porosity can be adjusted by the type and / or temperature of the cleaning solution that is subsequently immersed in concentrated sulfuric acid.

  Next, as step 2, the microporous substrate obtained in step 1 is immersed in a solution containing a foaming agent for a predetermined time, and the foaming agent is held on the surface of the microporous substrate having a large number of micropores. A foaming agent holding substrate is produced. The foaming agent may be any substance that can form a desired porous structure on the surface of a plastic substrate, and as such a foaming agent, an inorganic foaming agent such as carbonate or aluminum powder, Examples thereof include organic foaming agents such as azo compounds and isocyanate compounds. In particular, the foaming agent is preferably a substance that does not adversely affect the living body, and as such a foaming agent, carbonates are preferable, and examples thereof include sodium hydrogen carbonate, sodium carbonate, and potassium carbonate.

  Next, as step 3, the foaming agent holding substrate obtained in step 2 is immersed in a foaming solution for swelling the plastic and foaming the foaming agent for a predetermined time, so that the swelling of the plastic and the foaming of the foaming agent are performed. A foamed substrate formed by proceeding simultaneously is prepared. Examples of the foaming solution include acidic solutions such as concentrated sulfuric acid, hydrochloric acid, and nitric acid. When the material for forming the foaming agent holding substrate is PEEK and the foaming agent is carbonate, the foaming solution is preferably concentrated sulfuric acid having a concentration of 90% or more.

  Next, as a step 4, the foamed base material obtained in the step 3 is immersed in a coagulation solution that solidifies the swollen plastic to produce a surface foam. Examples of the coagulation solution, that is, a solution from which the plastic does not elute, include aqueous solutions such as water, acetone, and ethanol. When the material forming the foamed substrate is PEEK, in addition to the coagulating solution listed above, an inorganic acid aqueous solution such as sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid or the like having a concentration of less than 90%, or a water-soluble organic solvent is used. Can be mentioned. Examples of the water-soluble organic solvent include N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, ethylene glycol, diethylene glycol, trietylene glycol, propylene glycol, diester. Alcohols such as propylene glycol, glycerol ethanol, propanol, butanol, pentanol, hexanole and their aqueous solutions, polyethylene glycol, polypropylene glycol, polyvinyl pyrrolidone, etc. Mention may be made of molecules or their aqueous solutions and mixtures thereof.

  The foamed substrate obtained in step 3 may be immersed in at least one solution selected from a plurality of types of solutions that can be used as a coagulation solution, or may be sequentially immersed in a plurality of types of solutions. Further, a mixture of at least two kinds of solutions may be used.

  After step 4, it is preferable to wash the foaming agent and coagulation solution remaining on the surface foam with pure water.

  A porous structure formed on the surface of a plastic substrate, that is, a large-diameter open pore diameter, a small-diameter open pore diameter, a communicating pore diameter, a porosity, etc. that define the porous structure of the surface layer of the surface foam is a foaming agent. It can be adjusted by appropriately selecting the type and concentration of the foaming solution, the type and concentration of the foaming solution, the immersion time in the foaming solution, the type and concentration of the coagulation solution, the immersion time in the coagulation solution, the temperature in each step, and the like.

  Among these, the surface layer of the surface foam has a desired porous structure by changing at least one selected from the type of coagulation solution, the concentration of the coagulation solution, and the immersion time in the coagulation solution. The surface foam which has can be obtained easily. By changing these parameters, the solidification rate of the swollen plastic on the surface of the foam substrate can be controlled. As the type and concentration of the coagulation solution, it is preferable to appropriately select at least one of water and a low coagulation solution that requires a longer time than water to coagulate the swollen plastic. When the material forming the foamed substrate is PEEK, sulfuric acid having a concentration of less than 90% can be used as the low coagulation solution.

  For example, when a foamed base material formed by PEEK is immersed in sulfuric acid having a concentration of 86% as a low coagulation solution, PEEK solidifies more slowly than when immersed in water. That is, the coagulation rate becomes slow. Therefore, the porous structure on the surface of the foamed substrate changes as time elapses when the foamed substrate is immersed in the low coagulation solution.

  Below, the large-diameter pores 4 and the large-diameter pores 4 defined in the above-mentioned surface foam 1 communicate with the surface structure of the foam substrate due to the difference in the immersion time of the foam substrate in the low coagulation solution. The large-diameter communication holes 16 and the small-diameter pores 3 formed as described above will be described separately.

  The hole diameters of the large-diameter open holes 14 and the large-diameter communication holes 16 where the large-diameter holes 4 open on the surface gradually increase as the immersion time elapses. When a predetermined time or more elapses, these pore sizes become smaller. Further, the number of large-diameter open holes 14 and large-diameter communication holes 16 gradually decreases as the immersion time elapses. It is understood that the pore diameter increases as the immersion time elapses, and a plurality of pores formed by the foaming agent are connected and enlarged while the swollen PEEK is gradually solidified. On the other hand, when the predetermined time or more elapses, the pore diameter becomes small because the foaming agent is weakened while the swollen PEEK is slowly solidified, and all the pores including the pores that are connected and enlarged are included. Is considered to be reduced in diameter. In addition, the number of large-diameter open holes 14 and large-diameter communication holes 16 decreases as the immersion time elapses because the plurality of large-diameter open holes 14 and large-diameter communication holes are formed while the swollen PEEK is slowly solidified. It is understood that 16 is connected and integrated.

  The pore diameter and porosity of the small-diameter open pore 13 where the small-diameter pore 3 opens on the surface gradually decrease as the immersion time elapses. The large pores are formed by the action of the foaming agent, whereas the small pores 3 are thought to be formed based on the phase separation phenomenon of the swollen PEEK. The swollen PEEK is less likely to cause phase separation with a low-coagulation solution that gradually solidifies, and the longer the dipping time of the low-coagulation solution, the more the coagulation proceeds while the swollen PEEK and the low-coagulation solution are homogenized. For this reason, it is considered that the number and the pore diameter of the small-diameter open pores 13 are reduced and the porosity is also lowered.

  As described above, it is possible to obtain the surface foam 1 in which the porous structure of the surface layer 5 of the surface foam 1 is different due to the difference in the immersion time of the foam base in the low coagulation solution. In particular, if the solidification is completed quickly by immersing in water or the like at a time when the diameters of the large-diameter open pores 14 and the large-diameter communication holes 16 are maximized, the surface has good communication properties to the inside of the surface layer 5. The foam 1 can be provided.

  In the above description, the sulfuric acid having a concentration of 86% has been described as an example of the low coagulation solution. However, when a low concentration sulfuric acid is used as the low coagulation solution, the change in the structure of the surface of the foam base material with the passage of time. The situation is different. For example, when sulfuric acid having a lower concentration is used, PEEK swollen in a shorter time than when sulfuric acid having a concentration of 86% is solidified, so that the large pores 4 are solidified before the effectiveness of the foaming agent is weakened. Sometimes. In that case, even if the foamed base material is immersed in the low coagulation solution for a long time, the diameters of the large-diameter open holes 14 and the large-diameter communication holes 16 do not decrease or decrease in number.

  Depending on the type and concentration of the low coagulation solution, as described above, the method of changing the structure of the surface of the foamed substrate with the passage of the immersion time is different. Therefore, select the desired low coagulation solution, immerse the foam substrate for a predetermined time, and when the surface structure of the foam substrate has the desired porous structure, soak in water and quickly swell Since the plastic can be solidified, a surface foam in which the surface layer 5 has a desired porous structure can be obtained. In order to solidify the swollen plastic, in addition to immersing the foamed substrate in water, the swollen plastic may be dipped in a low coagulation solution for a sufficient time to solidify.

  Next, as step 5 (a), the surface foam obtained in step 4 is immersed in a solution containing a drug for a predetermined time to produce a drug sustained-release body carrying the drug on the surface layer of the surface foam. To do. The drug can be appropriately selected depending on the required function. For example, at least one drug can be selected from the drugs described above. When the drug is a liquid drug, a diluted solution as it is or diluted is used. When the drug is a solid drug, a drug solution dissolved or suspended in an appropriate solvent is used. The concentration of the diluting solution and the chemical solution is appropriately adjusted in a range that is not less than the effective concentration of the drug to be used and does not harm the living body. The time for immersing the surface foam in the solution containing the drug is not particularly limited as long as the drug is supported on the surface layer of the surface foam, and it is preferable to immerse for 10 minutes or more.

  In step 5 (a), it is preferable to perform defoaming treatment while immersing the surface foam in a solution containing a drug. By carrying out the defoaming treatment, the drug can be infiltrated into the pores of the surface foam. Moreover, the time for immersing the surface foam in the solution containing the drug can also be shortened.

  After taking out the surface foam from the solution containing the drug, it is preferable to dry it sufficiently at room temperature.

  Next, another example of the “method for producing a sustained-release drug” in the present invention will be described. This method for producing a sustained-release drug is an example where the sustained-release drug has drug particles and / or a drug layer containing a bioactive substance and a drug on the surface of the surface layer and / or the inner wall surface of the open pores. It is.

First, a surface foam is produced by the steps 1 to 4 described above.
Next, as step 5 (I), the surface foam obtained in step 4 is immersed in both a calcium solution containing at least 10 mM calcium ions and a phosphate solution containing at least 10 mM phosphate ions. At least one of the calcium solution and the phosphoric acid solution contains a drug. Further, the surface foam may be dipped first from either the calcium solution or the phosphoric acid solution. Below, the case where a surface foam is first immersed in a calcium solution is demonstrated.

  First, the surface foam is immersed in a calcium solution containing at least 10 mM calcium ions for a predetermined time. This calcium solution may contain at least calcium ions, and may contain sodium ions, potassium ions, magnesium ions, carbonate ions, silicate ions, sulfate ions, nitrate ions, chlorine ions, hydrogen ions, and the like. It is preferable that phosphate ions are not substantially contained. Examples of calcium solutions include aqueous solutions of compounds that are usually highly water-soluble and do not adversely affect the human body. Examples include calcium chloride, calcium hydroxide, calcium nitrate, calcium formate, calcium acetate, calcium propionate, and butyric acid. Examples thereof include calcium, calcium lactate, and a mixed solution thereof, and an aqueous solution of calcium chloride is preferable.

  After being immersed in the calcium solution for a predetermined time, the surface foam is immersed in a phosphate solution containing at least 10 mM phosphate ions. This phosphate solution only needs to contain at least phosphate ions, and may contain sodium ions, potassium ions, magnesium ions, carbonate ions, silicate ions, sulfate ions, nitrate ions, chlorine ions, hydrogen ions, and the like. Although it is good, it is preferable that calcium ions are not substantially contained. Examples of the phosphoric acid solution include aqueous solutions of compounds that are usually highly water-soluble and do not adversely affect the human body. For example, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate , Potassium dihydrogen phosphate, and a mixed solution thereof, and an aqueous solution of dipotassium hydrogen phosphate is preferable.

  The drug is contained in at least one of a calcium solution and a phosphoric acid solution. The drug can be appropriately selected depending on the required function. For example, at least one drug can be selected from the drugs described above. The concentration of the drug is appropriately adjusted as long as it is not less than the effective concentration of the drug to be used and does not harm the living body.

  The order in which the surface foam is immersed in the above two types of aqueous solutions is not particularly limited. For example, when hydroxyapatite is produced as a bioactive substance in the surface layer, that is, in the porous structure, It is preferable from the viewpoint of the amount of production that the production reaction proceeds in an alkaline region having lower solubility, and therefore, the pH of the solution immersed in the latter half is preferably an alkaline region having a pH of 8 to 10.

  The time for immersing the surface foam in the calcium solution and the phosphoric acid solution is preferably immersed for 1 minute or more, particularly preferably 3 minutes or more. If it is within the above range, calcium ions, phosphate ions, and the drug are sufficiently infiltrated into the surface foam, and the bioactive substance and the drug are coexisted on the inner walls of the open pores and the continuous vents in the surface layer of the surface foam. Can be sunk. In addition, when it is desired to increase the production amount of the bioactive substance, the operation of immersing in each solution may be repeated a plurality of times.

  In step 5 (I), it is preferable to perform defoaming treatment while immersing the surface foam in each of the calcium solution and the phosphoric acid solution. By performing the defoaming treatment, calcium ions, phosphate ions and a drug can be sufficiently infiltrated into the pores of the surface foam. Moreover, the time for immersing the surface foam in the calcium solution and the phosphoric acid solution can also be shortened.

  After the surface foam is taken out from the calcium solution and the phosphoric acid solution, it is preferable to sufficiently dry at room temperature.

  Next, another example of the “method for producing a sustained-release drug” in the present invention will be described. This method for producing a sustained-release drug may be used when the sustained-release drug has drug particles and / or a drug layer containing a bioactive substance and a drug on the surface of the surface layer and / or the inner wall surface of the open pores. It is an example.

First, a surface foam is produced by the steps 1 to 4 described above.
Next, as step 5 (i), the surface foam obtained in step 4 is immersed in both a calcium solution containing at least 10 mM calcium ions and a phosphate solution containing at least 10 mM phosphate ions. This calcium solution and phosphoric acid solution do not contain any drug. That is, a bioactivity having a bioactive substance on the surface of the surface layer and / or the inner wall surface of the open pores by the same procedure as in Step 5 (I) except that the drug is not contained in the calcium solution and the phosphate solution. A substance holder is produced.

Next, as step 5 (ii), the bioactive substance holding body obtained in step 5 (i) is immersed in a simulated body fluid containing a drug. A simulated body fluid is a solution that has a concentration of inorganic ions almost equal to that of human plasma and is supersaturated with respect to apatite. For details, see “Machanizm of apatite formation on CaO—SiO ₂ —P ₂ O ₅ glasses in”. a simulated body fluid ", Journal of Non-Crystalline Solids, 143, 84-92, 1992.

  The drug can be appropriately selected depending on the required function. For example, at least one drug can be selected from the drugs described above. The concentration of the drug is appropriately adjusted as long as it is not less than the effective concentration of the drug to be used and does not harm the living body.

  The time for immersing the bioactive substance holding body in the simulated body fluid containing the drug is preferably immersed for 1 hour or longer, particularly preferably 3 hours or longer. When the bioactive substance holding body is immersed in the simulated body fluid containing the drug within the above range, the drug can be sufficiently supported on the surface layer of the surface foam and the bioactive substance. The simulated body fluid is preferably maintained at the same temperature as that of the living body, that is, at a temperature around 37 ° C.

  In step 5 (ii), it is preferable to perform a defoaming process when the bioactive substance holder is immersed in a simulated body fluid containing a drug. By performing the defoaming treatment, the simulated body fluid containing the drug can be sufficiently infiltrated into the pores of the bioactive substance holding body.

  The method of supporting the bioactive substance and the drug on the surface layer of the surface foam is not limited to the above method, and various methods can be adopted. For example, a surface foam is immersed in a solution containing a drug and a large amount of a bioactive substance in advance and dried to fix the bioactive substance and the drug inside the surface layer having a porous structure in the surface foam. It is also possible to obtain a sustained-release drug.

  The drug sustained-release body according to the present invention has various uses, and can be suitably used, for example, as a medical material that is required to bind to a living tissue, and particularly, artificial bone, artificial tooth root, and transdermal. It can be used for devices. The artificial bone can be applied as, for example, a bone filling material, an artificial joint, an osteosynthesis material, an artificial vertebral body, an intervertebral body spacer, or a vertebral body cage. A transdermal device is a medical device that penetrates the skin from the outside of the body to the inside of the body and is responsible for nutritional supplementation, drug solution injection, blood circulation, and the like, and is associated with any artificial organ. The drug sustained-release body is used in various shapes, for example, a particle shape, a fiber shape, a block shape, a film shape, etc. according to the method of use and the use site in the living body.

  The drug sustained-release body can form, shape and / or prepare a plastic such as PEEK into a desired shape, and then form a surface layer having a porous structure on the surface of the plastic substrate. After the surface layer having a porous structure is formed on the surface of the plastic substrate, the surface foam can be molded, shaped and / or prepared into a desired shape. Since most processes can be processed in the liquid phase according to the manufacturing method described above, a plastic such as PEEK is molded, shaped and / or prepared into a complicated shape, and then applied to the surface portion of the plastic substrate. It is possible to easily form a surface layer having a porous structure.

  The surface layer may be formed on the entire surface portion of the plastic substrate, or may be formed only on a surface that needs to be bonded or adhered to a living tissue such as bone, tooth, or skin. In addition, when there are drug particles and / or a drug layer containing a bioactive substance and a drug on at least the inner wall surface of the open pores and / or the surface of the surface layer in the surface layer, the binding to the biological tissue is further enhanced. This is preferable because the property or adhesion is improved.

  Next, the present invention will be described with reference to examples. However, the present invention is not limited to the following examples.

Example 1
In this example, PEEK is used as a substance that forms a drug sustained-release body. A drug sustained-release body was prepared according to the following procedure.

  First, as step 1, the surface of a disk body (diameter 10 mm, thickness 2 mm, Victrex 450G) formed of PEEK is polished with sandpaper (# 1000) and concentrated sulfuric acid (concentration: 97%) for 5 minutes. Soaked. The disc body pulled up from the concentrated sulfuric acid was immersed in pure water for 5 minutes, and then repeatedly washed until the pH of the pure water became neutral to obtain a microporous substrate having micropores on the surface. When the surface of the microporous substrate was observed with a scanning electron microscope, it had a large number of pores, the pore diameter of these pores was 1 to 2 μm, and the inside was a network structure.

  Next, as step 2, this microporous substrate was immersed in an aqueous potassium carbonate solution (concentration: 3M) for 60 minutes, whereby potassium carbonate was retained on the surface of the microporous substrate to obtain a foaming agent retaining substrate.

  Next, as Step 3, the foaming agent holding base material is immersed in concentrated sulfuric acid (concentration: 97%) as a foaming solution for 1 minute to swell the surface of PEEK in the foaming agent holding base material, and at the same time, the foaming agent Foamed potassium carbonate in the holding substrate was obtained to obtain a foamed substrate.

  Next, as Step 4, the surface of PEEK is solidified by lifting the foamed base material from concentrated sulfuric acid and immersing in pure water for 10 minutes, and after repeatedly washing until the pH of the pure water becomes neutral, at 120 ° C. The surface foam was obtained by drying for 3 hours.

  The result of having observed the surface of the produced surface foam with a scanning electron microscope is shown in FIG. 3 (magnification rate 300 times). On the surface of the surface foam, a large number of small pores formed by small pores having an open pore diameter of 1 to 4 μm and large pores formed by large pores having an open pore diameter of 100 to 200 μm were confirmed. . Moreover, many small diameter communication holes and large diameter communication holes formed by communicating with the small diameter pores and the large diameter pores were confirmed on the inner wall surface of the large diameter open pores formed by the large diameter pores.

  Using the photographs taken at magnifications of 3000 times and 300 times, the major and minor diameters of the large and small diameter open pores were measured as described above, and the arithmetic average of these measured values was calculated. The average open pore size of the small open pores was 2.4 μm, and the average open pore size of the large open pores was 106 μm.

  As described above, the image of the surface foam surface taken with a scanning electron microscope is binarized into large-diameter open pores and other portions using image analysis software (Scion Image, manufactured by Scion). Thus, the area ratio of the small diameter open pores and the large diameter open pores to the total area of the photograph was calculated to be 16% and 64%, respectively.

  When a cross section perpendicular to the surface of the produced surface foam was observed with a scanning electron microscope, a layer having a thickness of about 70 μm having many pores was confirmed on the surface of the surface foam.

  With respect to the surface layer formed with a large number of pores in the produced surface foam, a photograph of a cross section perpendicular to the surface of the surface foam was taken with a scanning electron microscope at a magnification of 300 times and a magnification of 3000 times. Using the analysis software (Scion Image, manufactured by Scion), the areas of small pores and large pores were respectively calculated. As described above, the porosity of the small pores and the porosity of the large pores were calculated from the area ratio of the small pores and the large pores with respect to the total area of the photograph, and were 12% and 58%, respectively.

  When the pore diameter of the communicating holes was measured with a mercury porosimeter for the surface layer formed with a large number of pores in the produced surface foam, more mercury was injected than untreated PEEK in the pore diameter range of 1 to 100 μm. It was. Therefore, it was found that the communication holes were formed with a wide pore size distribution within this range. This agreed with the observation result of the surface layer with a scanning electron microscope.

  Next, as step 5 (a), defoaming treatment was performed for 10 minutes in a vacuum desiccator while the obtained surface foam was immersed in a 5% by mass aqueous solution of vancomycin. In addition, baicomycin is an antibiotic. After that, it was taken out from the vancomycin aqueous solution and naturally dried to obtain a sustained-release drug product comprising vancomycin supported on the surface layer of the surface foam.

(Example 2)
In this example, PEEK is used as a substance that forms a drug sustained-release body, and drug sustained-release drug particles and / or drug layers containing hydroxyapatite and a drug are supported on the surface layer of the drug sustained-release body. It is an Example which shows a body. A drug sustained-release body was prepared according to the following procedure.

First, in the same manner as in Example 1, a surface foam was obtained by steps 1 to 4.
Next, as the step 5 (I), the obtained surface foam is removed in a vacuum desiccator for 10 minutes while being immersed in a calcium aqueous solution (calcium ion concentration: 100 mM) containing 5% by mass of vancomycin and calcium chloride. The foam was treated. Subsequently, defoaming treatment was performed in a vacuum desiccator for 10 minutes while immersing vancomycin in a phosphoric acid aqueous solution (phosphate ion concentration: 100 mM) containing 5% by mass and dipotassium hydrogen phosphate. After repeating this operation three times, it was taken out from the phosphoric acid aqueous solution and naturally dried to obtain a sustained-release drug product in which hydroxyapatite and vancomycin were coprecipitated in the surface layer of the surface foam.

(Example 3)
In this example, PEEK is used as a substance that forms a drug sustained-release body, and drug sustained-release drug particles and / or drug layers containing hydroxyapatite and a drug are supported on the surface layer of the drug sustained-release body. It is another Example which shows a body. A drug sustained-release body was prepared according to the following procedure.

First, in the same manner as in Example 1, a surface foam was obtained by steps 1 to 4.
Next, as step 5 (i), the obtained surface foam was subjected to defoaming treatment for 10 minutes in a vacuum desiccator while being immersed in a calcium aqueous solution containing calcium chloride (calcium ion concentration: 100 mM). Subsequently, defoaming treatment was performed in a vacuum desiccator for 10 minutes while immersing in a phosphoric acid aqueous solution (phosphate ion concentration: 100 mM) containing dipotassium hydrogen phosphate. Then, it was taken out from the phosphoric acid aqueous solution and dried at 120 ° C. for 3 hours to obtain a calcium phosphate holder in which calcium phosphate microcrystals were formed in the surface layer of the surface foam.

  Next, as step 5 (ii), the obtained calcium phosphate holder was immersed in a simulated body fluid containing 5% by mass of vancomycin and held at 37 ° C. for 3 days. Then, it removed from the simulated body fluid and naturally dried to obtain a drug sustained-release body having a hydroxyapatite having vancomycin supported in the surface layer of the surface foam.

1 Surface foam 2, 202a, 202b Substrate 3, 203a, 203b Small diameter pores 4, 204a, 204b Large diameter pores 5, 205a, 205b Surface layer 6, 206a, 206b Open pores 7, 207a, 207b Communication holes 8 Independent pores 9 communication vents 13, 213a, 213b small-diameter open pores 14, 214a, 214b large-diameter open pores 15 small-diameter communication holes 16, 216a, 216b large-diameter communication holes 210a, 210b bioactive substances 211a, 211b inner wall surfaces 212a, 212b Body A Average open pore diameter of small pores B Average open pore diameter of large pores C Small communication hole diameter D Large communication hole diameter

Claims (1)

Formed by plastic,
A substantial portion and a surface layer formed on the surface thereof, and having a small diameter pore and a large diameter pore;
A part of the small-diameter pores and the large-diameter pores form open pores that open on the surface of the surface layer,
The open pores include small open pores having an average open pore size of 5 μm or less and large open pores having an average open pore size of 10 to 200 μm,
A sustained-release drug, characterized in that a surface foam formed by forming the small-diameter pores and communication holes communicating with the large-diameter pores on the inner wall surface of the large-diameter open pores carries the drug on the surface layer. body.

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