KR100992891B1 - Bio active ceramic coatings containing drugs and preparation method thereof - Google Patents

Abstract

The present invention relates to a drug-containing bioactive ceramic composite coating layer and a preparation method thereof. Specifically, a bioactive ceramic composite coating layer coated on a surface of a metal material or a ceramic material, having a density of 95% or more, a thickness in the range of 0.1 to 100 μm, and including a drug, and controlling the concentration and release rate of the drug It relates to controlling the drug release rate by controlling the mixing ratio of the drug and the bioactive ceramic powder and the thickness of the bioactive ceramic composite coating layer, and sprayed on the surface of the metal or ceramic material at room temperature to prevent denaturation due to heat of the drug It can be usefully used as a biomaterial having high affinity.

Drug, antibiotic, antithrombotic agent, composite coating layer, room temperature vacuum powder spray coating

Description

Bio active ceramic coatings containing drugs and preparation method

The present invention relates to a drug-containing bioactive ceramic composite coating layer and a preparation method thereof.

Biomaterials mainly used to replace human or animal tissues damaged by accidents or diseases, especially hard tissues such as bones or teeth, include low reactivity metallic materials such as stainless steel, cobalt-chromium alloys, pure titanium and titanium alloys. And bioinert ceramic materials such as zirconia and alumina, or bioactive ceramic materials such as hydroxyapatite (Ca ₅ (PO ₄ ) ₃ (OH); HA).

Among the materials, hydroxyapatite is composed of components similar to bones and teeth of the human body, and has the best biocompatibility, while having low strength and easy fracture due to the weak brittleness peculiar to ceramics. In order to solve this problem, a method of forming a hydroxyapatite film on a brittle strong metal material surface has been published.

As described above, when the complex formed with a film of hydroxyapatite on the surface of the metal material is implanted in vivo, the hard tissues such as hydroxyapatite and bone of the implanted complex are strongly bound to improve biocompatibility and bone adhesion, thereby improving the stability of artificial implant prosthesis. Can be increased.

Furthermore, after a prosthetic procedure such as an implant, the recovery time of the damaged area and the time for reliably combining the implant and bone are shortened, preventing acute inflammation that may occur early after the operation, and the bone adhesion period between the implant and the bone Research has been actively conducted on implants coated with drugs such as antibiotic anti-inflammatory agents to shorten the recovery time.

The method of coating the drug on the implant surface can be largely divided into three techniques.

The first method is to coat a functional polymer mixed with a drug on the surface of a metal implant. The functional polymer coating method has a problem that the polymer is easily deteriorated or deteriorated and the biocompatibility is bad.

The second method is to form a hydroxyapatite coating on the surface of the metal implant and then physically adsorb the drug thereon. The physical adsorption method has a problem that it is difficult to control the release rate of the drug adsorbed on the surface.

The third is biomimetic (Biomimetic) in a manner crystallized complex of hydroxyapatite with the drug using a coating method at the same time, Ca ² from an aqueous solution containing Ca and P components under appropriate pH ^+, PO ₄ ^{3 -} to precipitate the ions generated The method of coating the hydroxide apatite crystals on the surface of the metal implant enables the simultaneous coating of the hydroxyapatite and the drug by adding the drug to the aqueous solution.

Since the biomolecular method utilizes the deposition of ions, the deposition rate of the coating layer is very slow at 0.5 μm or less per hour, the coating process is complicated, and it is difficult to accurately control the concentration of the drug in the coating layer, Since it is difficult and only a hydrophilic material can be added, there is a problem that the type of drug that can be used is limited and the bonding strength between the coating layer and the surface of the metal material is about 10 MPa, which is very limited in industrial application.

On the other hand, stainless steel or cobalt-based alloy vascular dilatation metal stents are artificial tubes used when the blood flow is not smooth due to narrowing of the inner diameter of the arteries due to the deposition of blood clots in the arteries caused by atherosclerosis, which is used for living body The problem is that the vascular endothelial tissue grows through the stent mesh inserted into the blood vessel and the blood vessel is narrowed again.

In order to solve this problem, conventionally, the anticoagulant such as heparin (Heparin) is coated on the surface of the stent, or paclitaxel (antithrombotic agent), sirolimus (Sirolimus), an immunosuppressive agent, and then A drug eluting stent has been developed that is designed to release a drug slowly by coating a polymer membrane thereon.

The drug-eluting stent has solved the problem of restraining blood vessels, but after all of the drug is released, the exposed metal or polymer reacts with blood to form a blood clot, which causes a serious problem such as myocardial infarction.

Therefore, the biomolecular method was applied to a metal stent, and a method of coating a hydroxyapatite and paclitaxel as an antithrombotic agent on a metal stent was proposed. However, it did not solve problems such as weak adhesion.

Thus, the present inventors mixed the bioactive ceramic material with the drug and sprayed the coating on the surface of the metal material at room temperature, thereby preventing the deformation of the drug, increasing the deposition rate, and allowing the drug to be used without limitation of the type of the drug. The present invention was completed by controlling the mixing ratio of the active ceramic tm material and the drug and the thickness of the coating layer to control the drug concentration.

An object of the present invention is to provide a bioactive ceramic composite coating layer capable of drug release control.

Another object of the present invention to provide a method for producing the bioactive ceramic composite coating layer.

In order to achieve the above object, the present invention provides a bioactive ceramic composite coating layer capable of controlling drug release by controlling the mixing ratio of the drug and the bioactive ceramic powder and the thickness of the bioactive ceramic composite coating layer.

In addition, it provides a method for producing the bioactive ceramic composite coating layer.

The bioactive ceramic coating layer according to the present invention controls the drug release rate by controlling the mixing ratio of the drug and the bioactive ceramic powder and the thickness of the bioactive ceramic composite coating layer, and sprayed on the metal material or ceramic material surface to denature due to heat of the drug It can be usefully used as a biomaterial having high biocompatibility by preventing.

Hereinafter, the present invention will be described in detail.

The present invention is coated on the surface of a metal material or ceramic material, the density is greater than 95%, the thickness ranges from 0.1 to 100 ㎛, including the drug, but the bioactive ceramic composite coating layer capable of controlling the concentration and release rate of the drug To provide.

The metal material or the ceramic material serves as a base material for supporting the bioactive ceramic composite coating layer of the present invention, and is not limited as long as it is a material having excellent biocompatibility. Preferably, stainless steel, bitumium (cobalt-chromium alloy), Alumina, zirconia, titanium or alloys thereof.

The thickness of the bioactive ceramic composite coating layer is preferably in the range of 0.1-100 μm. If the thickness is less than 0.1 μm, it is difficult to uniformly coat all surfaces of the base material, and if the thickness is more than 100 μm, the coating layer may be easily peeled off, making it difficult to secure the thickness uniformity of the coating layer.

This is because the internal density of the bioactive ceramic composite coating layer is 95% or more, preferably 100%, and is advantageous for bone cell formation in the above range.

The content of the drug in the bioactive ceramic composite coating layer is preferably 1 to 30% by weight based on the total weight of the composite coating layer. If the content of the drug is less than 1% by weight, there is a problem that the drug effect does not appear, if it exceeds 30% by weight there is a problem that can not form a dense coating layer.

The concentration control of the drug according to the present invention can be performed by adjusting the thickness of the composite coating layer.

Increasing the thickness of the composite coating layer containing the drug increases the amount of drug that can be released in a certain area, and decreasing the thickness decreases the amount of drug that can be released.

In addition, the concentration control of the drug according to the present invention can be controlled by adjusting the mixing ratio of the bioactive ceramic powder and the drug.

In order to form the composite coating layer, when the bioactive ceramic powder and the drug are mixed, by adjusting the mixing ratio of the drug with respect to the bioactive ceramic powder, the amount of the drug that can be released from the composite coating layer of a certain area and thickness is controlled. The concentration of the drug can be controlled.

The control of the release rate of the drug may be made by a composite coating layer in which the bioactive ceramic powder and the drug are uniformly mixed.

The drug of the recoated form on the conventional ceramic coating layer has a problem that can not control the release rate of the drug in vivo.

The drug release rate of the ceramic coating layer according to the present invention can be variously controlled according to the type of bioactive ceramic material. Bioactive ceramic materials differ in their solubility in vivo from their type. This depends on the type of bioactive ceramic material mixed with the drug and means that a difference occurs in the rate at which the drug is released. Therefore, the drug release rate of the composite coating layer according to the present invention can be appropriately controlled as needed by varying the combination of the drug and the bioactive ceramic material used.

The bioactive ceramic material constituting the bioactive ceramic composite coating layer according to the present invention may be hydroxyapatite (HA), fluorine-containing hydroxyapatite (FHA), tri-calcium phosphate (TCP), Preference is given to using bioglass or mixed ceramic powders thereof.

The solubility of the bioactive ceramic materials listed above decreases in the order of bioglass, calcium triphosphate, hydroxyapatite. Thus, the rate of drug release can be controlled through various combinations with drugs that exploit this difference in solubility.

Furthermore, the ceramic composite coating layer according to the present invention is an antibiotic anti-inflammatory agent beta lactam antibiotics (penicillins, cephalosporins), aminoglycoside antibiotics (kanamycin, gentamicin, ribostomycin, tobramycin) , Streptomycin, amikacin, neomycin, etc.), tetracycline antibiotics (tetracycline, metacycline, doxycycline, minocycline, etc.), lincoside antibiotics (lincomycin, clindamycin), macrolide antibiotics Antibiotics such as spiramycin, midecamycin, probemycin, erythromycin, clarithromycin, vancomycin, cefarexin, cefacller, cephamandol, cephalodine, amocillin, carbenicillin, ethidronate and heparin , Anti-thrombotic agents such as paclitaxel, ticlopyrin, immunosuppressive agents of sirolimus (rapamycin), and the like, but are not limited thereto. It doesn't work.

The drug may prevent side effects such as inflammatory diseases and vascular restenosis, which may be caused by transplantation of external hard tissues as antibiotics, anti-thrombotic substances or immunosuppressive substances, thereby increasing affinity with body tissues.

In addition, the present invention comprises the steps of primary heat treatment (step 1) the bioactive ceramic powder consisting of ultra-fine particles at a temperature in the range of 1,000-1,300 ℃;

Pulverizing by applying a mechanical impact force to the powder obtained in step 1 to prepare an average particle diameter of the powder particles in the range of 0.1-5 μm (step 2);

Mixing the bioactive ceramic powder obtained in step 2 with a drug (step 3); And

It provides a method for producing a bioactive ceramic composite coating layer comprising the step (step 4) of coating a bioactive ceramic powder comprising a drug obtained in step 3 on a metal material or a ceramic material surface in a vacuum atmosphere at room temperature.

Hereinafter, the present invention will be described in detail step by step.

In the method for producing a bioactive ceramic composite coating layer according to the present invention, step 1 includes a step of heat-treating the bioactive ceramic powder composed of ultrafine particles at a temperature in the range of 1,000-1,300 ° C.

The bioactive ceramic powder may be used by using hydroxyapatite (HA), fluorine-containing hydroxyapatite (FHA), tri-calcium phosphate (TCP), bioglass, or a mixed ceramic powder thereof. desirable.

The bioactive ceramic powder is commercially available, and the raw material powder may have an average particle diameter in the range of 10-20 nm, but is not limited thereto. In the heat treatment of step 1, it is possible to obtain a ceramic powder having a particle size distribution of 5-20 μm.

In the method for producing a bioactive ceramic composite coating layer according to the present invention, step 2 includes the step of pulverizing by applying a mechanical impact force to the powder obtained in step 1 to prepare an average particle diameter of the powder particles in the range of 0.1-5 ㎛. .

The purpose of pulverization by applying mechanical impact force is to increase the internal energy stored in the form of cracks or dislocations inside the fine crystals constituting the pulverization and raw material particles, and to apply the coating material at the time of forming a coating layer, which is a post-process. By reducing the impact force or pressure for crushing the particles, it is an object to facilitate the crushing of particles during the formation of the coating layer.

To this end, the powder particles heat-treated in step 1 is preferably formed of particles having an average particle diameter in the range of 0.1 ㎛ to 5 ㎛ by the application of mechanical impact force.

The application of mechanical impact force may be performed by, for example, a ball mill process, but is not limited thereto.

In the method of manufacturing a bioactive ceramic composite coating layer according to the present invention, step 3 includes mixing the bioactive ceramic powder obtained in step 2 with a drug.

The mixing ratio of the bioactive ceramic powder and the drug of step 3 is preferably 1 to 30% by weight based on the total weight of the composite coating layer. If the content of the drug is less than 1% by weight there is a problem that the drug effect does not appear, if it exceeds 30% by weight there is a problem that does not form a dense coating layer. In this case, the mixing may be mixed by a dry mixing method or a wet mixing method, and when the wet mixing method is used, the method may further include drying by a lyophilization method. Drying through the lyophilization method can prevent the drug deterioration.

 In the method of manufacturing a bioactive ceramic composite coating layer according to the present invention, step 4 includes coating the bioactive ceramic powder containing the drug obtained in step 3 on the metal material or the surface of the ceramic material in a vacuum atmosphere at room temperature. do.

Step 4 may be performed by a room temperature vacuum powder spray coating apparatus shown in FIG. 1. The room temperature vacuum powder spray coating apparatus shown in FIG. 1 includes a powder dispersion container 1 for forming a gas inlet at the bottom thereof and containing the bioactive ceramic coating powder of the present invention; A metal material substrate 4 such as titanium or an alloy thereof, which is in communication with the powder dispersion cylinder 1 and the nozzle tube and at the end of which the hydroxyapatite coating powder is placed inside the vacuum chamber 2, or ceramic such as alumina or zirconia A nozzle unit 3 for injecting into the material substrate 4; A vacuum pump (5) for adjusting the degree of vacuum of the vacuum chamber (2); It comprises a motor stage 6 capable of starting left and right to provide a uniform coating to the substrate 4.

Using the coating apparatus configured as described above, the bioactive ceramic composite powder including the drug prepared in Step 3 is placed in the powder dispersion container 1 and shaken up and down, or through other movements, such as vibration by vibrators. While the powder is scattered, an appropriate amount of oxygen is supplied through a gas inlet made on the bottom surface of the powder dispersion container 1. Oxygen supplied to the powder dispersion container 1 is loaded with the bioactive ceramic composite powder containing the drug dispersed in the air, and is introduced to the nozzle unit 3 in the vacuum chamber 2. The bioactive ceramic composite powder containing the injected drug is sprayed onto a metal titanium substrate 4, for example, a coating material located in a vacuum chamber 2 maintained in a vacuum atmosphere at room temperature (eg, about 25 ° C.) through a nozzle, and then 100 nm or less. A coating layer having a thickness of 0.1 μm to 100 μm having a particle size distribution of is formed.

In this case, oxygen, nitrogen, helium, argon or air may be used as the carrier gas, and the flow rate of the injected gas is preferably injected at 0.1 to 50 L per minute.

The coating is carried out at room temperature to prevent alteration of the drug contained in the bioactive ceramic composite powder, the vacuum is preferably 0.1 to 10 torr. This is because the density may be 95% or more, preferably 95 to 100%, in the vacuum range only.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are merely to illustrate the invention, the present invention is not limited by the examples.

< Example  1> Preparation of bioactive ceramic-antibiotic composite coating layer

Step 1. Heat treatment of bioactive ceramic powder

A hydroxyapatite powder having a commercially available average particle diameter of 12 nm was heat-treated in a known state at 1200 ° C. for 2 hours to prepare an average particle diameter of 16.6 μm.

Step 2. Mechanical Crushing

The powder obtained in step 1 was ball milled for 24 hours using a 5 mm zirconia ball and a plastic barrel to prepare a bioactive ceramic powder having an average particle diameter of 3.2 μm.

Step 3. Mixing of Bioactive Ceramic Powders and Drugs

30 g of granular clarithromycin, a macrolide antibiotic, and 70 g of hydroxyapatite powder of step 2 were mixed dry using a zirconia ball and a zirconia barrel with a diameter of 5 mm through a planetary ball mill for 30 minutes, and the average particle diameter was 1.9 μm. Phosphorus bioactive ceramic powder-antibiotic composite powder was prepared.

Step 4. Form the Bioactive Ceramic Composite Coating Layer

The hydroxyapatite-clarythromycin mixed powder prepared as described above was put into the powder dispersion container 1 of FIG. 1 and shaken up and down, and oxygen was supplied by 30 liters per minute through a gas inlet formed at the bottom of the dispersion container. Oxygen supplied to the powder dispersion container 1 was loaded with the hydroxyapatite-clarythromycin mixed powder particles dispersed in the air and introduced to the nozzle unit 3 in the vacuum chamber 2, and a metal titanium substrate (coating material) to be coated through the nozzle ( 4) was sprayed for 20 seconds (deposition area of 10 mm x 10 mm) to prepare a bioactive mixed coating layer having a thickness of the composite coating layer of 3 ㎛. At this time, the distance between the nozzle and the metal titanium substrate was set to 5 mm.

< Example  2> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 2

In step 4 of Example 1, except that the injection time is 100 seconds was carried out in the same manner to prepare a bioactive mixed coating layer having a thickness of the composite coating layer of 15 ㎛.

< Example  3> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 3

In step 4 of Example 1, except that the injection time is 600 seconds to perform the same to prepare a bioactive mixed coating layer having a thickness of the composite coating layer of 100 ㎛.

< Example  4> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 4

Except for using tricalcium phosphate instead of hydroxyapatite in step 1 of Example 1 was prepared in the same manner as in Example 1.

< Example  5> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 5

In Example 3 of Example 1, except that amoxicillin (Amoxicillin) was mixed with 0.2% by weight instead of clarithromycin as an antibiotic was prepared in the same manner as in Example 1.

< Example  6> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 6

Example 5, except that a mixed carbenicillin (Carbenicillin) instead of amoxicillin (Amoxicillin) as an antibiotic was prepared in the same manner as in Example 5.

< Example  7> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 7

Example 5, was prepared in the same manner as in Example 5 except for mixing cephamandol (Cefamandole) instead of amoxicillin (Amoxicillin) as an antibiotic.

< Example  8> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 8

Example 5, was prepared in the same manner as in Example 5 except for mixing cephalothin (Cephalothin) instead of amoxicillin (Amoxicillin) as an antibiotic.

< Example  9> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 9

Example 5, except that Amoxicillin (Etidronate) in place of Amoxicillin as an antibiotic was prepared in the same manner as in Example 5.

< Example  10> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 10

Example 5, was prepared in the same manner as in Example 5 except for mixing gentamycin (Gentamycin) instead of amoxicillin (Amoxicillin) as an antibiotic.

< Example  11> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 11

Example 5, except that a mixture of tobramycin (Tobramycin) instead of amoxicillin (Amoxicillin) as an antibiotic was prepared in the same manner as in Example 5.

< Example  12> Preparation of Bioactive Ceramic-Antibiotic Composite Coating Layer 12

Example 5, except that a mixture of vancomycin (Vancomycin) instead of amoxicillin (Amoxicillin) as an antibiotic was prepared in the same manner as in Example 5.

<Analysis>

X-ray diffraction

In order to analyze the crystallinity of the composite coating layer of Example 1, it is shown in Figure 2 by X-ray diffraction analysis.

As shown in FIG. 2, it was confirmed that hydroxyapatite and clarithromycin mixed powder were maintained in crystalline state even after the composite coating layer.

2. electron scanning microscope

In order to determine the thickness of the formed composite coating layer, the cross section of Example 1 and Example 4 were photographed and shown in FIGS. 3 and 4.

As shown in FIG. 3, it was confirmed that the composite coating layer of hydroxyapatite and clarithromycin forms a dense coating having a thickness of about 15 μm.

As shown in FIG. 4, as shown in FIG. 4, it was confirmed that the composite coating layer of calcium triphosphate and clarithromycin forms a dense coating having a thickness of about 20 μm.

3. Measurement of UV-Vis spectrophotometer

In order to investigate the antibiotic release amount and the presence or absence of antibiotics in the above examples were analyzed using a UV-Vis spectrophotometer (UV-Vis spectrophotometer).

Analytical sample preparation is as follows. The antibiotics contained in Examples 1 to 11 were immersed in a soluble dimethyl sulfoxide solution for spectrophotometric analysis and left for 5 days at the same temperature as 36.5 ° C. to induce the dissolution of the antibiotic in the composite coating layer. The coating specimens were removed and UV-Vis analysis was performed on the remaining dimethyl sulfoside solution, as shown in FIGS. 5 to 7.

As shown in FIG. 5, absorption peaks corresponding to 260 nm and 280 nm wavelengths of clarithromycin dissolved from the composite layers of Examples 1 to 3 were detected to confirm that clarithromycin was contained in the composite coating layer. It was confirmed that the intensity of the absorption peak was increased in proportion to release clarismycin in proportion to the thickness of the coating layer.

As shown in FIG. 6, Example 4 also detected absorption peaks corresponding to clarithromycin at wavelengths of 260 nm and 280 nm, as in Examples 1 to 3, thereby confirming that clarithromycin was contained in the calcium triphosphate composite coating layer. .

As shown in FIG. 7, absorption peaks corresponding to the respective antibiotics were detected in the wavelength region of 200 to 450 nm from Examples 5 to 7 to confirm that the antibiotics were contained in the composite coating layer.

1 is a schematic view of a ceramic composite coating apparatus for producing one embodiment according to the present invention;

2 is an X-ray diffraction graph of one embodiment according to the present invention ((a) bioactive ceramic-drug mixed powder, (b) Example 1);

3 is a scanning electron microscope photograph taken in cross section of an embodiment according to the present invention;

4 is a scanning electron microscope photograph taken in cross section of an embodiment according to the present invention;

5 is an ultraviolet-visible spectrophotometer (UV-Vis) graph ((a) Clariomycin (b) Example 1, (c) Example 2, (d) Example 3 of an embodiment according to the present invention. );

Figure 6 is an ultraviolet-visible spectrophotometer (UV-Vis) graph ((a) clarithromycin (b) Example 4) of one embodiment according to the present invention; and

7 is a result of ultraviolet-visible spectrophotometer (UV-Vis) analysis of one embodiment according to the present invention ((a) Example 5, (b) Example 6, (c) Example 7, (d) Example 8, (e) Example 9, (f) Example 10, (g) Example 11, (h) Example 12).

<Explanation of symbols for the main parts of the drawings>

1: powder dispersion container 2: vacuum chamber

3: nozzle part 4: substrate

5: vacuum pump 6: motor stage

Claims (17)

delete delete delete delete delete delete delete delete Heat-treating the bioactive ceramic powder consisting of the ultrafine particles at a temperature in the range of 1,000-1,300 ° C. (step 1); Pulverizing by applying a mechanical impact force to the powder obtained in step 1 to prepare an average particle diameter of the powder particles in the range of 0.1 to 5 μm (step 2); Mixing the bioactive ceramic powder obtained in step 2 with a drug by dry mixing (step 3); And The bioactive ceramic powder containing the drug obtained in step 3 is coated with a metal material or the surface of the ceramic material in a vacuum atmosphere at room temperature (step 4), the density is greater than 95%, thickness 0.1-100 ㎛ , 1 to 30% by weight of the drug based on the total weight of the composite coating layer, the method of manufacturing a bioactive ceramic composite coating layer capable of controlling the concentration and release rate of the drug. delete delete 10. The method of claim 9, wherein the concentration control of the drug is controlled by controlling the thickness of the composite coating layer. 10. The method of claim 9, wherein the concentration control of the drug is controlled by controlling the mixing ratio of the bioactive ceramic powder and the drug. 10. The method of claim 9, wherein the control of drug release rate is dependent on the solubility of the bioceramic material mixed with the drug. 10. The method of claim 9, wherein the control of the drug release rate is performed by selecting a combination of a bioceramic material having a different solubility from the drug. The bioactive ceramic material constituting the bioactive ceramic composite coating layer comprises: hydroxyapatite (HA), fluorine-containing hydroxyapatite (FHA), tri-calcium phosphate (TCP) ), Bioglass or a method for producing a bioactive composite coating layer comprising a mixed ceramic powder thereof. The drug according to claim 9, wherein the drug is an antibiotic anti-inflammatory beta-lactam antibiotics (penicillins, cephalosporins), aminoglycoside antibiotics (kanamycin, gentamycin, ribostamycin, tobramycin, streptomycin, ah Micacin, neomycin), tetracycline antibiotics (tetracycline, metacycline, doxycycline, minocycline), lincoside antibiotics (lincomycin, clindamycin), macrolide antibiotics (spiramycin, midecamycin) Antibiotics such as heparin, paclitaxel, and ticlochlorine, e.g., mycomycin, erythromycin and clarithromycin) An antithrombotic agent such as pyrine and an immunosuppressive agent of sirolimus (rapamycin).

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