JP2009298699A - Antibacterial medicine-containing capsule, and artificial joint attached with the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antibacterial medicine-containing capsule capable of holding a large amount of a medicine gradually released as sustained by a desired rate, and an artificial joint attached with the capsule. <P>SOLUTION: This capsule filled with the antibacterial medicine to achieve the above purpose is provided with that the capsule is constituted by a porous member, attached to at least a part of the artificial joint and gradually releases the filled antibacterial medicine as sustained through the porous member to a joint capsule or in a bone. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a capsule attached to an artificial joint and containing an antibacterial drug, and an artificial joint to which the capsule is attached.

Artificial joints are widely used for the purpose of reconstruction when joint function is lost due to illness or injury. Artificial joints are useful medical devices, but have several problems, the most serious of which is the infection problem.
For example, when an artificial hip joint is inserted into the medullary cavity of the femur, if the sterilization is not complete, bacteria etc. will grow in the artificial hip joint part, especially in the joint capsule, and in the worst case, the large hip prosthesis may be removed and re-inserted. Replacement surgery must be performed, which is a heavy burden on the patient.
Various methods have been taken to prevent such postoperative infections. Patent Document 1 discloses a method of depositing hydroxyapatite on an implant surface and drying it to form a hydroxyapatite layer having a large specific surface area, and impregnating the hydroxyapatite layer with an antibiotic or the like (Patent Document). 1). Since the hydroxyapatite layer deposited on the implant surface is impregnated with antibiotics, the antibiotics impregnated with the hydroxyapatite layer can suppress infection caused by artificial joint replacement after the implant is attached to the human body. .
JP 2005-506879 A

  However, in the implant produced by the above method, it is difficult to set the pore diameter and porosity of the hydroxyapatite layer coating in an inclined manner. Therefore, the pore diameter and porosity of the coating are uniform, and the drug is constant. It dissolves rapidly at the rate, and the sustained release of the drug at the desired rate is not possible.

  In addition, since the coating layer made of hydroxyapatite or the like has a thickness limitation, it is difficult to hold the coating layer impregnated with a large amount of drug.

  Furthermore, in the implants prepared by the above method, natural and organic antibacterial agents that are soluble in water can be retained and used in the coating layer, but their antibacterial performance is low and, like antibiotics, resistant bacteria. Is likely to occur. On the other hand, it is disadvantageous for non-soluble antibacterial agents such as inorganic antibacterial agents which have the highest antibacterial performance and do not generate resistant bacteria. This is because a non-soluble antibacterial agent is mixed with the suspension and applied to the surface of the coating layer, but this is only on the surface of the apatite layer like dust and has no retention. This is because it is hard to say that it is practical.

  Therefore, the present invention has been made in view of the above-mentioned problems, and the object of the present invention is to provide an antibacterial drug-containing capsule that can be slowly and slowly released at a desired rate and can retain a large amount of drug. It is to provide an artificial joint to which it is attached.

  As a result of intensive studies, the present inventors have found that when an antibacterial drug such as an antibiotic is contained in a porous capsule, the porous layer is coated on the implant and the antibacterial drug is applied to the porous layer. It was found that more drug can be retained than when impregnated, and that the drug can be released slowly at a desired rate by controlling the pore diameter and porosity of the porous wall.

  The present invention has been made on the basis of such knowledge, and the gist thereof is a capsule filled with an antibacterial drug, the capsule being formed of a porous member, and at least one of an artificial joint. The antibacterial drug-containing capsule is attached to the part and gradually releases the filled antibacterial drug into the joint capsule or bone through the porous member.

  In the antibacterial drug-containing capsule according to the present invention, the porous wall portion of the capsule preferably has an average porosity of 10% to 80%. Here, when the average porosity is less than 10%, the pores are in a dispersed state and cannot communicate with each other, and the antibacterial drug cannot be released from the capsule. On the other hand, if the average porosity exceeds 80%, the mechanical strength decreases, which is not preferable.

  Moreover, it is preferable that the porous wall part of the said capsule consists of porous ceramics, a porous metal, or a porous resin.

  In the capsule containing antibacterial drug according to the present invention, the antibacterial drug filled in the capsule is a beta-lactam antibacterial agent such as penicillin, an aminoglucoside antibacterial agent such as gentamicin, a ciprofloxacin fluoroquinolone antibacterial agent , Macrolide antibiotics such as erythromycin, glucopeptide antibiotics such as teicoplanin, lincomycin antibiotics such as clindamycin, tetracycline antibiotics such as tetracycline, ST combinations, metronidazole, and ketolide antibiotics It is preferably at least one selected from the group consisting of

  Antibacterial drugs include animal drugs such as chitin and chitosan, microbial drugs such as polylysine, enzyme drugs such as lysozyme, plant drugs such as hinokitiol, and metal ions such as silver, copper and zinc. Inorganic chemicals supported on phosphates such as silicates and zirconium phosphates, alcoholic chemicals such as ethyl alcohol, alcoholic chemicals such as benzenecarboxylic acid, ester chemicals such as methylparaben, nitrile chemicals such as TPN, Sampras Halogen drugs such as oxine, pyridine / quinoline drugs such as oxine, isothiazolone drugs such as caisson, imidazole / thiazole drugs such as TBZ, anilide drugs such as halcarban, biguanide drugs such as chlorohexidine gluconate, carbam, etc. Thiocarbamate Agent, surfactant system agents such as benzalkonium chloride is preferably at least one selected from organic metal-based drugs such as oxine copper.

  The antibacterial agent is preferably mixed with a gelling agent such as gelatin, agar, carrageenan or pectin. By mixing the antibacterial drug with such a gelling agent, the sustained release period of the antibacterial drug can be adjusted.

  Further, the present invention provides an artificial joint to which any one of the above antibacterial drug-containing capsules is attached, and when the artificial joint is inserted into a bone, the antibacterial drug filled in the capsule is added to the joint. The artificial joint is characterized by being released slowly into a capsule or bone.

  According to the antibacterial drug-containing capsule according to the present invention, the capsule is most effective when placed in a joint capsule with high possibility of infection, and effectively suppresses the growth of bacteria in the joint capsule or Can be sterilized. Further, as described above, the drug can be gradually released by controlling the porosity and the pore diameter, and controlling the pore diameter, the number of pores, and the pore distribution. Since the capsule has a hollow portion inside and has a sufficiently large space, a sufficient amount of drug can be held.

  Furthermore, inorganic antibacterial agents that could not be effectively retained by the prior art can also be retained in a sufficient amount for the prevention and treatment of infection by using the present invention.

  Hereinafter, preferred embodiments of an antibacterial drug-containing capsule according to the present invention and an artificial joint to which the capsule is mounted will be described in detail with reference to the drawings. However, the antibacterial drug-containing capsule according to the present embodiment and the artificial joint to which the capsule is attached are illustrated, and the present invention is not limited to these embodiments. In addition, in each figure, about the common part, the same code | symbol is attached | subjected and the overlapping description is abbreviate | omitted. The number of arrangement of each component, the arrangement position, and the like are not limited, and can be appropriately set depending on the intended purpose, application, desired performance, and the like of the antibacterial drug-containing capsule.

(Antimicrobial drug-containing capsules)
FIG. 1 is a schematic view showing an example of an antibacterial drug-containing capsule according to an embodiment of the present invention. The antibacterial drug-containing capsule 1 includes a hollow part 2 filled with an antibacterial drug and a porous wall part 3 covering the hollow part 2. As shown in FIG. 2, the antibacterial drug-containing capsule 1 is attached to the stem 4, and when the stem 4 is inserted into the medullary cavity (not shown) of the femur and the joint capsule is regenerated, the capsule 1 becomes a joint. Located in the package. When bacteria or the like enter the joint capsule and propagate (infection occurs), it is necessary to perform a reoperation, but if the antibacterial drug-containing capsule according to the present invention is used, it contains an antibacterial drug. Since the capsule is placed in the joint capsule and bacteria and the like in the joint capsule are sterilized, there is no need for reoperation.
In the present invention, a porous hydroxyapatite layer is formed on the implant surface, and more antibacterial drugs can be retained than those obtained by impregnating the hydroxyapatite with antibiotics. It is possible to sterilize. Insufficient sterilization in infection treatment leads not only to the recurrence of infection but also to the generation of resistant bacteria. Therefore, placing a sufficient amount of antibacterial agent at the site of infection is an important factor in preventing infection and treating infection.
The antibacterial drug-containing capsule 1 according to the present invention includes a porous portion at least in part. The porous part is preferably a porous ceramic, a porous metal, or a porous resin. Examples of the porous ceramics include oxide ceramics such as aluminum oxide (alumina) and zirconium oxide (zirconia), calcium phosphates such as hydroxyapatite (HA), tricalcium phosphate (TCP), and quaternary calcium phosphate (TeCP). A sintered body made of ceramics or phosphate glass ceramics is preferable. The porous ceramic may be a sintered body made of these composites. This is because even if the capsule 1 is disposed in the human body, it is non-toxic and harmless to the living body and has a high mechanical strength. The porous metal is preferably titanium, titanium-based alloy, zirconium, tantalum, cobalt-chromium-based alloy, or stainless steel, and the porous resin is polyethylene, polyurethane, acrylic resin, or epoxy resin. Is preferred.

  Moreover, the shape of the capsule may be any shape. However, when the capsule is screwed into the stem using a hand or a wrench, it is preferably a polygonal column. Moreover, when the capsule is fitted using a hammer or the like, the shape may be any.

  The thickness of the capsule wall is preferably 0.1 mm to 2 mm, and more preferably 0.5 mm to 1.0 mm. If the thickness is reduced, the sustained release time can be shortened, but the structural strength is lowered. Further, if the thickness is increased, the structural strength is improved, but the sustained release time becomes longer. Therefore, the thickness is preferably set to 0.5 mm to 1.0 mm.

  The pore diameter of the capsule is preferably 0.1 μm to 300 μm. Furthermore, the porosity is preferably 10 to 80%. By adjusting the pore diameter and porosity of the capsule, the gradual period of the antibacterial drug filled in the capsule can be adjusted. By setting it as the above ranges, the sustained release period of the antibacterial drug can be set to 1 day to 90 days.

  The capsule is effective not only for preventing infection in a short period after artificial joint surgery but also for preventing infection for a longer period. That is, even after all of the antibacterial drug has disappeared, the antibacterial effect can be regained by replenishing the antibacterial drug or replacing it with a new one.

  When a specific example of use is described in terms of an artificial hip joint, it is preferable to attach the capsule to an artificial hip joint femoral side part (stem), but it may be attached to an artificial hip joint acetabular part (cup). It can also be attached to the head of a screw screw, in which case it can be placed on any native bone. Further, in cases where it is difficult to attach to an artificial joint or to fix to a natural bone, it can be fixed to a cartilage tissue with a thread or a wire.

(Method for producing capsule containing antibacterial drug)
As a method for producing the porous ceramic, after mixing a pore material such as carbon powder having a predetermined particle size and naphthalene powder with ceramic powder, molding by a method such as casting molding, extrusion molding, press molding, rubber press molding, firing, A grinding method or a method of cutting and firing after molding is effective. The amount of pore agent added is adjusted so that the pores are sufficiently communicated. A method using a foaming agent such as hydrogen peroxide or a method of adjusting the sintering temperature to make it porous can also be used. In addition, a powder sintering method that forms a three-dimensional object by continuously forming a thin layer made of a powder material, irradiating the layer with laser light, and instantaneously sintering it to form a hardened layer, in a binder Fine powders of ceramics, metal, etc. are mixed and dried to form thin sheets beforehand, and laser irradiation is performed on each of these sheets in the same manner as above to form a sintered body, and this process is continuously performed to form a three-dimensional object It is also possible to use a green tape laser sintering method or a laser processing method in which fine holes are processed with a laser beam after a dense ceramic body is manufactured. According to these production methods, porous capsules can be directly produced, a wide variety of materials can be used, and the environmental load can be reduced, which is desirable. Many of these methods can be applied to the production of porous metals and plastics.

  The method for producing an antibacterial drug-containing capsule according to the present invention will be described by taking hydroxyapatite as an example. For example, polyethyleneimine or the like is added as a crosslinkable resin to hydroxyapatite powder, and mixed and crushed using ultrapure water as a dispersion medium to prepare a slurry. Next, a foaming agent (a kind selected from polyoxyethylene lauryl ether, lauryl betaine, lauryl sulfate triethanolamine, etc.) is added to the slurry and stirred to foam.

  Further, a crosslinking agent (sorbitol polyglycidyl ether, etc.) is added, the foam slurry is placed in a mold, the foam structure is fixed and dried, and then sintered at a temperature of about 1100 ° C. to 1300 ° C. to sinter hydroxyapatite porous Get the body. This calcination is performed for 0.5 to 3 hours.

Next, the green tape laser sintering method will be described in detail based on FIGS. 3 (A) and 3 (B).
First, as shown in FIG. 3A, a green tape is manufactured. A slurry 5 is prepared by mixing ceramics and / or metal fine particles, a binder, and a solvent constituting the capsule. Here, any material can be used as the ceramic and the metal, but aluminum oxide (alumina), zirconium oxide (zirconia), hydroxyapatite (HA), tricalcium phosphate (TCP), and the like which do not affect the human body. Calcium tetraphosphate (TeCP), calcium phosphate glass ceramics, titanium, titanium alloy, zirconium, tantalum, cobalt-chromium alloy, stainless steel, or the like is used. In addition, an acrylic resin or a styrene resin is used as a binder, and water, ethyl alcohol, butyl alcohol, isopropyl alcohol, or toluene is used as a solvent. Subsequently, the slurry 5 mixed as described above is formed into a sheet having a constant thickness in the same manner as the doctor blade method. Thereafter, the sheet is dried to volatilize and solidify the solvent in the slurry. Thereafter, the sheet is cut into a certain size.

  Subsequently, as shown in FIG. 3B, one sheet of the sheet cut into a certain size is stacked, and the sheet 6 is irradiated with laser light 7 according to the three-dimensional CAD data of the capsule. Sinter metal or ceramics in the part. Subsequently, the second sheet 6 is laminated, and the laser beam 7 is irradiated in the same manner as described above to sinter the metal or ceramic in the irradiated portion. By repeating this process a plurality of times, the portion 8 solidified by sintering is taken out from the laminated green tape and processed into a predetermined shape, whereby an antibacterial drug-containing capsule can be produced.

  The production method can adjust the pore diameter and porosity of the produced capsules by adjusting the concentration of the metal or ceramic contained in the green tape, and thereby the antibacterial agent filled therein can be adjusted. Since the release rate can be adjusted, it is preferably used. In addition, this manufacturing method is preferable because any material can be used and a complicated shape can be manufactured.

  In addition, when the antibacterial drug capsule is made of a porous metal body, it can be made using a sintered body of metal powder or metal particles as described above, but it is made by sintering and fixing a metallic mesh. You can also

  In addition, there is an advantage not found in other methods when fine hole processing is performed using a laser beam or the like after the whole is formed of a dense ceramic body or metal body. That is, the hole diameter, the number of holes, and the hole distribution can be arbitrarily controlled. As a specific example, holes having a diameter of 76 μm were processed at a pitch of 100 μm using a laser beam on a titanium plate having a thickness of 0.2 mm.

  In the case of a porous ceramic body or a porous metal body, the drug is preferably released slowly by adjusting its porosity and pore diameter.

  In the case of drilling with a laser beam or the like, it is preferable to adjust the hole diameter, quantity, and hole distribution density.

  The size of the antibacterial drug-containing capsule can be increased as long as it does not cause a problem in the function of the artificial joint. If the size is large, a large amount of drug can be held in the capsule.

  It is preferable that the capsule is usually composed of two parts, a main body and a lid. This is to store the antibacterial drug in the hollow portion inside the capsule. In the case of a drug with low viscosity and easy impregnation, it can be stored even if it is integrally molded.

(Antimicrobial agent)
As the antibacterial agent filled in the capsule according to the present invention, any of an antibacterial agent, a natural antibacterial agent, an inorganic antibacterial agent, and an organic antibacterial agent may be used. Any two or more of them may be mixed and used.
Specific examples of antibacterial agents include beta-lactam antibacterial agents such as penicillin, aminoglucoside antibacterial agents such as gentamicin, ciprofloxacin fluoroquinolone antibacterial agents, macrolide antibacterial agents such as erythromycin, and glucopeptides such as teicoplanin. Antibacterial agents, lincomycin antibiotics such as clindamycin, tetracycline antibiotics such as tetracycline, ST combination, metronidazole, and ketolide antibiotics.
Specific examples of natural antibacterial agents include animal drugs such as chitin and chitosan, microbial drugs such as polylysine, enzyme drugs such as lysozyme, plant drugs such as hinokitiol, and the like.
Further, examples of the inorganic antibacterial agent include those in which metal ions such as silver, copper, and zinc are supported on a silicate such as zeolite or a phosphate such as zirconium phosphate.
Specific examples of organic antibacterial agents include alcohol drugs such as ethyl alcohol, alcohol drugs such as benzenecarboxylic acid, ester drugs such as methylparaben, nitrile drugs such as TPN, halogen drugs such as Sampras, and oxine Pyridine / quinoline drugs such as caisson, isothiazolone drugs such as caisson, imidazole / thiazole drugs such as TBZ, anilide drugs such as halcarban, biguanide drugs such as chlorohexidine gluconate, thiocarbamate drugs such as carbam, chloride Surfactant drugs such as benzalkonium, oxine copper and the like.

  These antibacterial drugs are preferably mixed with a gelling agent. This is because the sustained release period of the antibacterial drug can be adjusted by mixing with a gelling agent and filling it into the capsule according to the present invention. Particularly in the case of a liquid drug, mixing with a gelling agent is effective. The sustained release period is adjusted by adjusting the content of the gelling agent in the gel. That is, a gel using a large amount of gelling agent is hard and difficult to impregnate moisture, so that drug elution is suppressed. On the other hand, when a small amount of gelling agent is used, the gel is soft and impregnated with a large amount of water, so that the elution of the drug is not significantly suppressed. Thus, by using a gelling agent, it can be extended 1.5 times-20 times when not using the sustained-release period of an antimicrobial agent. As the gelling agent, gelatin, agar, carrageenan or pectin is preferably used.

Example 1
Examples of the antibacterial drug-containing capsules according to the present invention will be described below together with comparative examples, but it goes without saying that the capsules targeted by the present invention are not limited to the following examples.
A slurry was prepared by mixing hydroxyapatite as ceramics, water-soluble acrylic resin as a binder, and pure water as a solvent. Subsequently, the slurry was formed into a 0.2 mm sheet in the same manner as the doctor blade method. Then, the solvent in the slurry was volatilized and solidified by drying this sheet, and then the sheet was cut into a plurality.

One piece of the cut sheet was laminated, and the sheet was irradiated with laser light in accordance with the three-dimensional CAD data of the capsule to sinter hydroxyapatite in the irradiated portion. Then, the 2nd sheet | seat was laminated | stacked, the laser beam was irradiated similarly to the above, and the hydroxyapatite was sintered in the irradiated part. This process was repeated a plurality of times, and the portion solidified by sintering was taken out from the laminated green tape and processed into a capsule shape, thereby producing an antibacterial drug-containing capsule.
It is comprised from two members, a container-shaped part and the cover part fitted to it exactly. Penicillin powder (gelled with agar) as an antibacterial drug was put into the capsule, and the container part and the lid part were fitted and screwed into the stem driving hole behind the tapered part of the artificial hip joint stem. .

(Example 2)
Naphthalene powder was added as a pore agent to the hydroxyapatite powder, mixed well, and then press molded using a mold. The molded body was sintered at 1150 ° C. and ground into a capsule shape to produce a container part and a lid part. Gentamicin powder was placed in the container. The capsule material had a porosity of 40% and a pore diameter of 80-200 μm.

(Example 3)
Titanium beads having a diameter of 200 μm were poured into a capsule-shaped tungsten mold and heat-treated in a vacuum furnace at 1300 ° C. for 2 hours to produce a capsule container and a lid. The capsule material had a porosity of 30% and a pore diameter of 20-40 μm. In this capsule, ceramic powder loaded with silver ions, which is a typical inorganic antibacterial agent, was put in, and showed good elution of silver ions in bovine serum.

  The antibacterial drug-containing capsule according to the present case is a container that contains an antibacterial drug and can be gradually released. In particular, the capsule is attached to a part of an artificial joint, and is placed in the joint capsule or the medullary cavity after the artificial joint is mounted. By slowly releasing an antibacterial drug, it is used to suppress and sterilize bacterial growth in the joint capsule and around the stem.

FIG. 1 is a schematic view showing an example of an antibacterial drug-containing capsule according to an embodiment of the present invention. FIG. 2 is a schematic view showing an example of a sustained release capsule attached to a stem. FIG. 3 is a schematic view showing a manufacturing process by a green tape laser sintering method.

Claims (7)

  A capsule filled with an antibacterial drug, the capsule being composed of a porous member, attached to at least a part of an artificial joint, and the filled antibacterial drug via the porous member Antibacterial drug-containing capsules that are gradually released into the bone or bone.   The antibacterial drug-containing capsule according to claim 1, wherein the porous member has an average porosity of 10% to 80%.   2. The antibacterial drug-containing capsule according to claim 1, wherein the porous wall portion is made of porous ceramics, porous metal or porous resin.   The above antibacterial agents include beta-lactam antibacterial agents such as penicillin, aminoglucoside antibacterial agents such as gentamicin, ciprofloxacin fluoroquinolone antibacterial agents, macrolide antibacterial agents such as erythromycin, and glucopeptide antibacterial agents such as teicoplanin. It is at least one selected from the group consisting of a drug, a lincomycin antibiotic such as clindamycin, a tetracycline antibiotic such as tetracycline, an ST combination, metronidazole, and a ketolide antibiotic Item 4. The antibacterial drug-containing capsule according to any one of Items 1 to 3.   The above antibacterial drugs include animal drugs such as chitin and chitosan, microbial drugs such as polylysine, enzyme drugs such as lysozyme, plant drugs such as hinokitiol, and metal ions such as silver, copper and zinc, silicic acid such as zeolite. Inorganic chemicals supported on phosphates such as salts and zirconium phosphate, alcoholic chemicals such as ethyl alcohol, alcoholic chemicals such as benzenecarboxylic acid, ester chemicals such as methylparaben, nitrile chemicals such as TPN, Sampras, etc. Halogen drugs such as pyridine, quinoline drugs such as oxine, isothiazolone drugs such as caisson, imidazole thiazole drugs such as TBZ, anilide drugs such as halcarban, biguanide drugs such as chlorohexidine gluconate, carbam, etc. Thiocarbamate The antibacterial agent according to any one of claims 1 to 3, wherein the agent is at least one selected from surfactant surfactants such as benzalkonium chloride, and organic metal agents such as oxine copper. Contains capsules.   The antibacterial drug-containing capsule according to claim 4 or 5, wherein the antibacterial drug is mixed with a gelling agent such as gelatin, agar, carrageenan or pectin.   An artificial joint comprising the antibacterial drug-containing capsule according to any one of claims 1 to 6, wherein the antibacterial drug filled in the capsule is inserted into the bone when the artificial joint is inserted into a bone. A prosthetic joint characterized by being gradually released into the bone or bone.

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