WO2008035535A1 - Capsule including antibacterial agent and artificial joint having the capsule attached thereto - Google Patents

Abstract

Disclosed is a capsule including an antibacterial agent, which can release the agent slowly at a desired rate and can retain the agent in large quantity. Also disclosed is an artificial joint having the capsule attached thereto. The capsule includes an antibacterial agent, is composed of a porous material, and can be attached to at least a part of an artificial joint to release the antibacterial agent included therein into a joint capsule or a bone slowly through the porous material.

Description

 Specification

 Antibacterial drug-containing capsule and artificial joint to which the capsule is attached

 Technical field

 [0001] 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.

 Background art

 [0002] 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 problem of infection.

 [0003] For example, when an artificial hip joint is inserted into the medullary cavity of the femur, if the sterilization is not complete, bacteria etc. grow in the artificial hip joint part, particularly in the joint capsule and the medullary cavity. It is necessary to remove a large hip prosthesis and perform a replacement surgery, which is a heavy burden on the patient!

 [0004] Various methods have been adopted to prevent such postoperative infections. Patent Document 1 discloses a method in which hydroxyapatite is deposited on an implant surface and dried to form a hydroxyapatite layer having a large specific surface area, and the hydroxyapatite layer is impregnated with an antibiotic or the like ( Patent Document 1). Since the hydroxyapatite layer deposited on the implant surface contains antibiotics, infection with artificial joint replacement can be suppressed with the antibiotics after the implant is attached to the human body Patent Document 1: Special Table 2005— No. 506879

 Disclosure of the invention

 Problems to be solved by the invention

[0005] However, in the implant produced by the above method, it is difficult to set the pore diameter and porosity of the hydroxyapatite layer film in an inclined manner, and therefore the pore diameter and porosity of the coating are uniform. The drug elutes rapidly at a constant rate, and the drug cannot be released slowly at the desired rate. [0006] Further, since the coating layer made of hydroxyapatite or the like is limited in thickness, it is difficult to hold the coating layer impregnated with a large amount of drug.

 [0007] Furthermore, in the implants produced by the above method, the ability to retain and use a natural or organic antibacterial agent that is soluble in water or the like in a coating layer. Resistant bacteria are easily generated. On the other hand, it is disadvantageous for non-soluble antibacterial agents such as inorganic antibacterial agents that have the highest antibacterial performance and do not generate resistant bacteria. The reason is that the non-dissolvable antibacterial agent is mixed with the suspension and the surface of the coating layer is impregnated with this. This is because it is difficult to say that it is practical.

 [0008] Accordingly, the present invention has been made in view of the above-mentioned problems, and an object of the present invention is to provide an antibacterial agent that can be slowly and slowly released at a desired rate and retain a large amount of drug. The object is to provide a medicine-containing capsule and an artificial joint to which the medicine-containing capsule is attached.

 Means for solving the problem

 [0009] As a result of intensive research, the inventors of the present invention made porous capsules containing antibacterial drugs, and contained antibacterial drugs such as antibiotics in the porous capsules. By coating the porous layer on the implant and impregnating the porous layer with the antibacterial drug, more drug can be retained, and by controlling the pore diameter and porosity of the porous wall, The present inventors have found that the drug can be released slowly at a desired rate and have completed the present invention.

 [0010] The present invention has been made on the basis of force and knowledge, and the gist of the present invention is a capsule filled with an antibacterial drug, and the capsule is composed of a porous member. An antibacterial drug-containing capsule that is attached to at least a part of an artificial joint and gradually releases the filled antibacterial drug into a joint capsule or bone via the porous member. The member is in an antibacterial drug-containing capsule, wherein the member has an average porosity of 10% to 80%.

[0011] Here, when the average porosity is less than 10%, the pores are in a dispersed state, cannot be in communication with each other, and the antibacterial drug cannot be released from the capsule! /, . In addition, if the average porosity exceeds 80%, the mechanical strength of the capsule is decreased, which is not preferable. Yes. By setting the average porosity of the porous member of the capsule to 10% to 80%, sustained release in the medium to long term is possible.

[0012] The porous wall portion of the capsule is preferably made of porous ceramics, porous metal, or porous resin.

In the antibacterial drug-containing capsule according to the present invention, the antibacterial drug filled in the capsule is a beta-ratata antibacterial agent such as penicillin, an amino darcoside antibacterial agent such as gentamicin, ciprofloxacin fluo Roquinolone antibiotics, macrolide antibiotics such as erythromycin, darcopeptide antibiotics such as ticobranine, lincomycin antibiotics such as clindamycin, tetracycline antibiotics such as tetracycline, ST combination, metronidazole, and ketolide Preferably at least one selected from the group consisting of antimicrobial agents.

 [0014] Furthermore, 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 metal ions such as silver, copper, and zinc. Inorganic chemicals supported on silicates such as zeolite and phosphates such as zirconium phosphate, alcoholic agents such as ethyl alcohol, alcoholic agents such as benzene carboxylic acid, ester chemicals such as methylparaben, nitrile such as TPN Drugs, halogen drugs such as Sampras, pyridine quinoline drugs such as oxine, isothiazolone drugs such as caisson, imidazole thiazole drugs such as TBZ, anilide drugs such as halcarban, clodin hexidine dalconate Big-anide drugs such as thiocarbamate such as carbam Agents, Benzarukoniumu of which surfactant system agent chloride, is preferably at least selected from organic metallic agents such as Okishin copper is one.

 [0015] 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.

[0016] Further, the present invention provides an artificial joint to which any one of the antibacterial drug-containing capsules is attached, and the antibacterial agent filled in the capsule when the artificial joint is inserted into a bone. The artificial joint is characterized in that the drug is gradually released into the joint capsule or bone. The invention's effect

 [0017] According to the antibacterial drug-containing capsule according to the present invention, the capsule is most effective when placed in a joint capsule having a high possibility of infection, and is effective for the growth of bacteria in the joint capsule. Can be suppressed or sterilized. In addition, controlled release of the drug can be achieved by controlling the porosity and pore diameter as described above, 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.

 [0018] Further, inorganic antibacterial agents that could not be effectively retained by the prior art can be retained in an amount sufficient for the prevention and treatment of infection by using the present invention.

 Brief Description of Drawings

 FIG. 1 is a schematic diagram 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] FIG. 3 is a schematic view showing a production process by a green tape laser sintering method. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, preferred embodiments of an antibacterial drug-containing capsule according to the present invention and an artificial joint to which the capsule is attached 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 merely examples, and the present invention is not limited to these embodiments. In each figure, common parts are denoted by the same reference numerals, and redundant description is omitted. The number of arrangement of each component, the arrangement position, and the like can be appropriately set depending on the purpose, application, desired performance, etc. of the capsule containing the antibacterial drug.

 [0021] (Antimicrobial drug-containing capsule)

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 upper end of the stem 4 and is inserted into the medullary cavity (not shown) of the femur to regenerate the joint capsule. 1 is located in the joint capsule. Stem 4 If it is attached to the lower end of the stem, the stem 4 can be positioned in the medullary cavity of the femur, for example. The ability to perform re-operation when bacteria enter the joint capsule or the medullary cavity and propagate (infection occurs) If the capsule containing the antibacterial drug according to the present invention is used, it is antibacterial Since the capsule containing the drug is placed in the joint capsule or in the medullary cavity and bacteria in the joint capsule and in the medullary cavity are sterilized, there is no need for reoperation.

 [0022] In the present invention, a porous hydroxyapatite layer is formed on the implant surface, and more antibacterial drugs can be retained than the conventional type in which antibiotics are impregnated in the hydroxyapatite. It is possible to sterilize bacteria and the like effectively. Insufficient sterilization in infection treatment will not only cause the infection to recur, but also lead to the development 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.

 [0023] 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 porous ceramics include oxide ceramics such as aluminum oxide (alumina) and zirconium oxide (zircoua), calcium phosphates such as hydroxyapatite (HA), tricalcium phosphate (TCP), and tetracalcium phosphate (TeCP). The sintered body is preferably made of a ceramic ceramic or phosphoric glass ceramic. Further, the porous ceramic may be a sintered body made of these composites. This is because even if the capsule 1 is arranged in the human body, it is non-toxic and harmless to the living body, and has high mechanical strength. The porous metal is preferably titanium, titanium alloy, zirconium, tantalum, cobalt chromium alloy, or stainless steel, and the porous resin is polyethylene, polyurethane, acrylic resin, or epoxy resin. It is preferable.

 [0024] The shape of the capsule may be any shape. When the capsule is screwed to the stem using a hand or a wrench, it is preferably a polygonal columnar shape. Further, when the capsule is fitted using a hammer or the like, any shape may be used.

[0025] The thickness of the capsule wall is preferably 0.5 mm to 2 mm. More preferably, it is Omm. 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 0.5 mm to 1 Omm.

 [0026] The pore size of the pores provided in the capsule is preferably 0.1 μm to 300 μm! / ヽ.

 Furthermore, the porosity is preferably 10 to 80%. By adjusting the pore size and the porosity of the capsule, it is possible to adjust the sustained release period of the antibacterial drug filled in the capsule. By setting the range as described above, the controlled release period of the antibacterial drug is 1 to 90 days.

 [0027] The capsule is effective not only for short-term infection prevention after artificial joint surgery but also for medium- to long-term infection prevention. Even after all the antibacterial drugs have disappeared, the antibacterial effects can be regained by supplementing the antibacterial drugs or replacing them with new ones.

 [0028] When the capsule is applied to an artificial hip joint, the capsule may be attached to an artificial hip joint femoral component (stem) or an artificial hip joint acetabular component (cup). It can also be attached to the screw head of the screw, in which case it can be placed on any native bone. In cases where it is difficult to attach to an artificial joint or to a natural bone, it can be fixed to cartilage with a thread or wire.

 [0029] (Method for producing capsule containing antibacterial drug)

As a method for producing the porous ceramic, after mixing a ceramic powder with a pore material such as carbon powder and naphthalene powder of a predetermined particle size, after molding by a method such as squeeze molding, extrusion molding, press molding, rubber press molding, Effective methods include firing and grinding, or cutting and firing after forming. Adjust the amount of pore agent added so that the pores communicate with each other. Further, a method using a foaming agent such as hydrogen peroxide or a method of adjusting the sintering temperature to make it porous can be used. In addition, a thin layer of powder material strength is formed, and the layer is irradiated with laser light and instantaneously sintered to form a hardened layer. Fine powders of ceramics, metal, etc. are mixed and dried to form thin sheets in advance, and each sheet is irradiated with a laser to form a sintered body, and a three-dimensional object is formed by performing this process continuously. You 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 manufacturing a dense ceramic body. These production methods are desirable because porous capsules can be directly produced, a wide variety of materials can be used, and the environmental load can be reduced. Many of these techniques can also be applied to the production of porous metals and porous plastics.

 [0030] The method for producing an antibacterial drug-containing capsule according to the present invention will be described taking as an example the case of a hydoxy xylate. 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 (at least one selected from polyoxyethylene lauryl ether, lauryl betaine, lauryl sulfate triethanolamine, etc.) is added to the slurry and stirred to foam.

 [0031] Further, a crosslinking agent (sorbitol polyglycidyl ether, etc.) is added, the foam slurry is put in a mold, the foam structure is fixed and dried, and then sintered at a temperature of about 1100 ° C to about 1300 ° C. A hydroxyapatite porous sintered body is obtained. This calcination is carried out for 0.5 to 3 hours.

 Subsequently, based on FIGS. 3 (A) and 3 (B), a detailed description will be given of the case of producing a force psel using the green tape laser sintering method.

First, as shown in FIG. 3A, a green tape is produced. A slurry 5 is prepared by mixing ceramics and / or metal fine particles, a binder, and a solvent that constitute the capsule. Here, the power that can use any material as ceramics and metal Further, quaternary calcium phosphate (Te CP), calcium phosphate glass ceramic, titanium, titanium alloy, zirconium, tantalum, cobalt chromium alloy, stainless steel, or the like can be used. Further, it is possible to use acrylic resin or styrene resin as the binder and water, ethyl alcohol, butyl alcohol, isopropyl alcohol, or toluene as the 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. Then by drying this sheet The solvent in the slurry is volatilized and solidified. Thereafter, the sheet is cut into a certain size.

 Subsequently, as shown in FIG. 3 (B), one sheet of the sheet cut into a certain size is stacked, and laser light 7 is applied to the sheet 6 according to the 3D CAD data of the capsule. Irradiate to solidify the metal or ceramic in the irradiated part. Subsequently, the second sheet 6 is laminated, and the laser beam 7 is irradiated in the same manner as described above to solidify 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.

 [0035] In the production method, the pore diameter and porosity of the produced capsule can be adjusted by adjusting the concentration of the metal or ceramic contained in the green tape, thereby filling the inside. Since the release rate of an antibacterial drug 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.

 [0036] 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 the metallic mesh is fixed by sintering. It is easy to make it.

 [0037] In addition, when a fine hole is processed using a laser beam after forming the entire body with a dense ceramic body or metal body, there is an advantage not found in other methods. 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 interval of 100 μm using a laser beam on a titanium plate having a thickness of 0.2 mm.

 [0038] In the case of a porous ceramic body or a porous metal body, sustained release of the drug is preferably carried out by adjusting the porosity and the pore diameter.

[0039] In addition, in the case of hole drilling with a laser beam or the like, it is preferable to adjust the hole diameter, quantity, and hole distribution density.

[0040] 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 force vessel. [0041] It is preferable that the capsule is generally 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 the capsule is integrally molded.

[0042] (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. You can use any mixture of two or more of these.

 [0043] Specific examples of the antibacterial agent include beta-latatam antibacterial agents such as penicillin, amaminodarcoside antibacterial agents such as gentamicin, ciprofloxacin fluoroquinolone antibacterial agents, macrolide antibacterial agents such as erythromycin, Examples include darcopeptide antibiotics such as ticobranine, lincomycin antibiotics such as clindamycin, tetracycline antibiotics such as tetracycline, ST combinations, metronidazole, and ketolide antibiotics.

 [0044] Specific examples of natural antibacterial agents include animal drugs such as chitin and chitosan, microbial drugs such as polylysine, enzyme drugs such as lysozyme, and plant drugs such as hinokitiol.

 [0045] 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 and a phosphate such as zirconium phosphate.

 [0046] Specific examples of organic antibacterial agents include alcoholic agents such as ethyl alcohol, alcoholic agents such as benzenecarboxylic acid, esteric agents such as methylparaben, nitrile agents such as TPN, and Sampras. Halogen drugs, pyridin 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 clodin hexidine dalconate, Examples include thiocarbamate agents such as carbam, surfactant agents such as benzalkonium chloride, and oxine copper.

[0047] These antibacterial drugs are preferably mixed with a gelling agent. It is possible to adjust the sustained release period of the antibacterial drug by mixing it with the gelling agent and filling it in the capsule according to the present invention. Especially in the case of liquid drugs, mixing with a genolic agent is possible. It is effective. The sustained release period is adjusted by adjusting the content of the gelling agent in the gel. In other words, gels using a large amount of gelling agent do not contain much hard water, so that drug elution is suppressed. On the other hand, when a small amount of gelling agent is used, the gel contains a lot of soft water, so it does not significantly suppress the elution of the drug. By using the gelling agent in this way, it is possible to increase the force 1.5 times to 20 times when the sustained release period of the antibacterial drug is not used. As the gelling agent, gelatin, agar, carrageenan or pectin is preferably used.

 Example

[0048] (Example 1)

 Examples of the antibacterial drug-containing capsules according to the present invention will be described below together with comparative examples. It goes without saying that the capsules targeted by the present invention are not limited to the following examples.

 [0049] A slurry was prepared by mixing hydroxyapatite as a ceramic, a 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. Thereafter, the sheet was dried to evaporate and solidify the solvent in the slurry, and then the sheet was cut into a plurality of pieces.

 [0050] One piece of the cut sheet was laminated, and the sheet was irradiated with laser light according to the 3D CAD data of the capsule to sinter hydroxyapatite in the irradiated portion. Subsequently, a second sheet was laminated and irradiated with laser light in the same manner as above to sinter hydroxyapatite in the irradiated portion. 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 to prepare an antibacterial drug-containing capsule.

 [0051] The antibacterial drug-containing capsule is composed of two members, a container-like part and a lid part that fits snugly. Penicillin powder (which is gelled with agar) is put into the capsule as an antibacterial agent, and then the container part and the lid part are fitted together, and the stem behind the tapered part of the artificial hip joint stem Screwed into the driving hole.

[0052] (Example 2) After adding naphthalene powder as a pore agent and mixing well

Then, press molding was performed using a mold. The molded body was sintered at 1150 ° C and ground into a capsule shape to produce the container and lid. Gentamicin powder was placed in the container. The porosity of this cabcel material was 40% and the pore diameter was 80-200 m.

[0053] (Example 3)

 Capsule containers and lids were made by pouring titanium beads with a diameter of 200 m into capsule-shaped tungsten molds and heat-treating them in a vacuum oven at 1300 ° C for 2 hours. The capsule material had a porosity of 30% and a pore diameter of 20-40 m. This cuff. The cell contained ceramic powder loaded with silver ions, a typical inorganic antibacterial agent, and showed good elution of silver ions in bovine serum.

 Industrial applicability

[0054] 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 after the artificial joint is mounted, It is used to suppress and sterilize bacterial growth in the joint capsule and around the stem by slowly releasing the antibacterial agent into the cavity.

Claims

The scope of the claims  [1] A capsule filled with an antibacterial drug, which is composed of a porous member, attached to at least a part of an artificial joint, and the filled antibacterial drug is placed on the porous member. An antibacterial drug-containing capsule that is gradually released into a joint capsule or bone via the porous member, wherein the porous member has an average porosity of 10% to 80%.  [2] The antibacterial drug-containing capsule according to [1], wherein the porous wall is made of porous ceramics, porous metal or porous resin.  [3] The above antibacterial drugs include beta-latatam antibacterials such as penicillin, amaminodarcoside antibacterials such as gentamicin, ciprofloxacin fluoroquinolone antibacterials, macrolide antibacterials such as erythromycin, ticobranine, etc. At least one selected from the group consisting of a darcopeptide antibacterial agent, a lincomycin antibacterial agent such as clindamycin, a tetracycline antibacterial agent such as tetracycline, an ST combination, metronidazole, and a ketolide antibacterial agent The antibacterial drug-containing potency according to claim 1 or 2.  [4] The above antibacterial drugs are 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 carried on silicates such as zeolite and phosphates such as zirconium phosphate, alcohols such as ethyl alcohol, alcohols such as benzene carboxylic acid, esters such as methylparaben, and TPN Tolyl drugs, halogen drugs such as Sampras, pyridine quinoline drugs such as oxine, isothiazolone drugs such as caisson, imidazole thiazole drugs such as TBZ, anilide drugs such as halcarban, and darconic acid Biguanide drugs such as xidine, thiocarbamate drugs such as carbam Surfactant system agents such as chloride Benzarukoniumu, antibiotic drug-containing capsule according to claim 1 or 2, characterized in that one also less selected from organic metallic agents such as Okishin copper. [5] The antibacterial drug-containing capsule according to claim 3 or 4, wherein the antibacterial drug is mixed with a gelling agent such as gelatin, agar, carrageenan or pectin. Le.  6. An artificial joint to which the capsule containing the antibacterial drug according to any one of claims 1 to 5 is attached, and when the artificial joint is inserted into a bone, the antibacterial drug filled in the capsule is a joint capsule. A prosthetic joint characterized by being gradually released into the bone or bone.