TWI697335B - Pharmaceutical carrier combination, pharmaceutical composition, use thereof, preparation method and use method thereof - Google Patents

Abstract

The present invention provides a pharmaceutical carrier combination, a pharmaceutical composition containing the same, its use, its preparation method and its use method. The drug carrier combination includes a first mixed material and a second mixed material. The first mixed material includes a hydrophilic polymer material, tricalcium phosphate and a water-soluble dispersant. The second mixed material includes a moisturizing material and divalent cation salts. The pharmaceutical composition comprises the aforementioned pharmaceutical carrier combination and pharmaceutical ingredients. The pharmaceutical composition is used for preparing anti-inflammatory drugs or antibiotic drugs. The preparation method of the drug carrier combination includes mixing the components in the first mixed material and mixing the components in the second mixed material. The use method of the drug carrier combination is to mix the first mixed material with the drug component, and then mix with the second mixed material. Through the above-mentioned drug carrier combination, the effect of effective drug release at the surgical site can be achieved.

Description

Pharmaceutical carrier combination, pharmaceutical composition, its use, its preparation method and its use method

The present invention relates to a drug carrier combination, a drug composition, its use, a preparation method and a method of use thereof, and in particular to a drug carrier combination that can effectively release drugs at surgical sites.

In the current field of drug release technology, one of the main research directions is to achieve the expected drug release effect through the design of drug carriers. In the prior art, most materials such as proteins, amino acids and biopolymers are used to manufacture drug carriers. Among them, biopolymers are more commonly used materials. Biopolymers must have biocompatibility and biodegradability. "Biocompatibility" means that the material is compatible with individual organisms without immune rejection or pathological changes, and it will not cause or cause cardiovascular disease during use. Embolism, toxic reaction, allergic reaction, tissue destruction and carcinogenesis, etc. "Biodegradability" means that when a material is implanted or used in an organism, the material will undergo hydrolysis or oxidation in the environment of the organism. The phenomenon that causes the material to disintegrate or decompose into other products, and the products after the material disintegration or decomposition can be further decomposed through the basic metabolism of the organism and discharged from the body. Biopolymer materials can be divided into natural polymer materials and synthetic polymer materials. The common natural polymer materials are chitosan, alginate, chitin, and collage. , Hyaluronic Acid and other materials.

On the other hand, in orthopedic surgery, drug release is also an important issue. For example, in artificial joint replacement surgery, the probability of postoperative infection is about 2~3%. The biggest risk of postoperative infection is the deep infection of the operation. If it is not handled properly, it will require multiple operations or long-term antibiotics. treatment. In order to reduce the risk of inflammation caused by deep infection, there is currently a method to add antibiotics to the implanted bone filling material, and then release the antibiotic through the implanted bone filling material to the part where deep infection may occur.

However, the release of antibiotics through the implanted bone filling material to reduce the risk of inflammation caused by deep infections will cause another problem. When antibiotics are added to the bone filling material, the durability of the bone filling material is significantly reduced, which may lead to the recovery of the late implantation. There is a risk of swaying and displacement when the implant is inserted. In order to solve the problem that the durability of the bone filling material decreases after antibiotics are added, another alternative method is to use traditional injections to apply antibiotics. Usually, antibiotics are injected into the patient's wrist vein and then delivered to the affected area through the systemic blood circulation. This method prevents the antibiotics injected into the patient's body from being completely and effectively delivered to the affected area.

The purpose of the present invention is to solve the above-mentioned problems and provide a drug carrier combination comprising a first mixed material and a second mixed material. The first mixed material includes 300 to 1200 parts by weight of a hydrophilic polymer material, 300 to 1200 parts by weight of tricalcium phosphate, and 100 to 600 parts by weight of a water-soluble dispersant. The second mixed material includes 500 to 3,600 parts by weight of a moisturizing material and 400 to 730 parts by weight of a divalent cation salt, and the moisturizing material has high biocompatibility, high water content and degradability.

In the drug carrier combination as described above, the tricalcium phosphate may be α-phase-tricalcium phosphate or β-phase-tricalcium phosphate.

The pharmaceutical carrier combination as described above, the water-soluble dispersant is selected from the group consisting of methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose.

The drug carrier combination as described above, the moisturizing material is selected from the group consisting of hyaluronic acid, collagen, gelatin and polydextrose.

In the drug carrier combination as described above, the divalent cation salt is selected from the group consisting of calcium chloride, calcium carbonate, barium chloride, potassium chloride and magnesium chloride.

In order to achieve the above and other objectives, the present invention provides a drug carrier combination for preparing anti-inflammatory and antibiotic drugs, which comprises the above-mentioned drug carrier combination.

In order to achieve the above and other objectives, the present invention provides a method for preparing a drug carrier combination, which comprises the following steps: (a) 300 to 1200 parts by weight of hydrophilic polymer material, 300 to 1200 parts by weight of tricalcium phosphate, and 100 to 600 parts by weight of the water-soluble dispersant are mixed to form a first mixed material; and (b) 500 to 3600 parts by weight of the moisturizing material and 400 to 730 parts by weight of the divalent cation salt are mixed to form a second mixed material , The moisturizing material has high biocompatibility, high moisture content and degradability.

In order to achieve the above and other objectives, the present invention provides a method of using a drug carrier combination, which includes the following steps: (a) providing the first mixed material of the above drug carrier combination; (b) combining the drug component with the first mixed material; A mixed material is mixed in an aqueous solution to form a precursor mixture; (c) a second mixed material of the above-mentioned drug carrier combination is provided; and (d) the second mixed material and the precursor mixture are mixed to form a drug combination.

In order to achieve the above and other objectives, the present invention provides a pharmaceutical composition, which comprises the above-mentioned pharmaceutical carrier combination and pharmaceutical ingredients.

The pharmaceutical composition as described above, the pharmaceutical component may be an anti-inflammatory component or an antibiotic, and the anti-inflammatory component is selected from Adalimumab, Certolizumab, Etanercept, Golimumab (Golimumab), Abatacept (Abatacept), Tocilizumab (Tocilizumab), Rituximab (Rituximab) and Infliximab (Infliximab). Gentamicin, Vancomycin, Mezlocillin, Cloxacillin, Meticillin, Cephalothin, Lincomycin, Lincomycin, and more Colistin E (Polymyxin E), Bacitracin (Bacitracin), and Fusidic Acid (Fusidic Acid).

Through the above-mentioned drug carrier combination, drug composition, its use, its preparation method and its use method, the effect of effectively releasing the drug at the surgical site can be achieved, and the conventional method of applying antibiotics to the patient's body by injection can be solved. In the method, the problem that the drug cannot be effectively delivered to the affected part of the patient.

In order to fully understand the purpose, features and effects of the present invention, the following specific embodiments are used to illustrate the present invention in detail with the accompanying drawings. The description is as follows:

Preparation method of the drug carrier combination: In this embodiment, the drug carrier combination is composed of a first mixed material and a second mixed material, and is prepared by the following method.

First, perform the steps of preparing the first mixed material in the drug carrier combination: providing 300 to 1200 parts by weight of hydrophilic polymer material, 300 to 1200 parts by weight of tricalcium phosphate, and 100 to 600 parts by weight of water-soluble dispersant , The above weight parts of hydrophilic polymer material, tricalcium phosphate and water-soluble dispersant are dissolved in water and mixed. In this step, the uniform mixing of the hydrophilic polymer material and tricalcium phosphate makes hydrogen bonds between each other, and through the hydrogen bonding to produce a network structure, the aforementioned water-soluble dispersant can promote the hydrophilic polymer material and The tricalcium phosphate is mixed evenly. The above-mentioned hydrophilic polymer material, tricalcium phosphate, and water-soluble dispersant are mixed to form the first mixed material, which will be referred to as agent A in the following description. After agent A is made, if agent A is to be stored more stably, agent A can also be made into a dry batt block material by a drying process, but agent A can also be stored in the original solution form instead of This is limited.

Next, proceed to the step of preparing the second mixed material in the drug carrier combination: providing 500 to 3600 parts by weight of the moisturizing material and 400 to 730 parts by weight of the divalent cation salt, the moisturizing material has high biocompatibility, high Water content and degradability, the above weight parts of the moisturizing material and divalent cation salts are dissolved in water and mixed. In this embodiment, the moisturizing material can also be directly dissolved in the divalent cation salts In solution.

Through the above steps, the first mixed material and the second mixed material composing the drug carrier combination can be made. The method for the drug carrier combination to carry the drug will be described later.

In this embodiment, the hydrophilic polymer material can be selected from sodium alginate (Sodium Alginate), propylene glycol alginate (Propylene glycol alginate, PGA), chitin (Chitin) and chitosan (Chitosan). However, in other embodiments, a hydrophilic polymer material having similar properties to the hydrophilic polymer material in the aforementioned group can also be selected, and is not limited to this embodiment. The weight part of the hydrophilic polymer material can be 300, 400, 500, 600, 700, 800, 900, 1000, 1100 or 1200, but the weight part of the hydrophilic polymer material is not limited to the above specific value.

In this embodiment, the tricalcium phosphate may be α-Tricalcium phosphate or β-Tricalcium phosphate. The weight part of the tricalcium phosphate can be 300, 400, 500, 600, 700, 800, 900, 1000, 1100 or 1200, but the weight part of the tricalcium phosphate is not limited to the above-mentioned specific value.

In this embodiment, the water-soluble dispersant is selected from the group consisting of Methyl cellulose, Ethylcellulose, Carboxymethylcellulose, Hydroxyethyl cellulose, and hydroxyethyl cellulose. Hydroxypropyl Methylcellulose (Hydroxypropyl Methylcellulose), but in other embodiments, water-soluble dispersants with similar properties to the water-soluble dispersants in the foregoing group can also be selected, instead of using this embodiment Is limited. The weight part of the water-soluble dispersant can be 100, 200, 300, 400, 500 or 600, but the weight part of the water-soluble dispersant is not limited to the above-mentioned specific value.

In this embodiment, the moisturizing material is selected from the group consisting of hyaluronic acid, collagen, gelatin and dextran, but in other embodiments, it can also be selected from the group consisting of The moisturizing materials in the group have moisturizing materials with similar properties, and are not limited to this embodiment. The weight of the moisturizing material can be 500, 600, 800, 1000, 1200, 1500, 1600, 1700, 1900, 2100, 2300, 2500, 2700, 2900, 3100, 3300, 3500 or 3600, but the weight of the moisturizing material The parts are not limited to the above-mentioned specific values.

In this embodiment, the divalent cation salt is selected from calcium chloride (Calcium chloride), calcium carbonate (Calcium carbonate), Barium chloride (Barium chloride), Potassium chloride (Potassium chloride) and Magnesium chloride (Magnesium chloride) However, in other embodiments, divalent cation salts having similar properties to the divalent cation salts in the foregoing group can also be selected, and this embodiment is not limited to this embodiment. The weight part of the divalent cation salt can be 400, 450, 500, 550, 600, 650, 700 or 730, but the weight part of the divalent cation salt is not limited to the above-mentioned specific value.

Preparation of the drug carrier sample 1-3: In this embodiment, the A and B agents of the drug carrier sample 1-3 are prepared according to the above-mentioned method for preparing the drug carrier combination. The specific preparation process is as follows. In the following description, sample 1 is taken as an example to illustrate the preparation process of the drug carrier sample. The preparation process of drug carrier samples 2 and 3 is the same as that of sample 1, the difference is only the composition ratio of A and B used in the preparation process Different, and the composition ratio of the A and B agents used in the preparation of the drug carrier samples 1-3 will be disclosed in the following table.

First, the steps of preparing agent A of sample 1 are carried out: the weight parts of sodium alginate, tricalcium phosphate and methyl cellulose used as a dispersant as listed in Table 1 below are dissolved in water and mixed.

單位：重量份 Table 1: The weight of each component of the A agent of the drug carrier samples 1-3

Unit: parts by weight

Next, proceed to the steps of preparing agent B of sample 1: provide the weight parts of hyaluronic acid and calcium chloride listed in Table 2 below (in the form of a calcium chloride solution with a volume percentage of 3%) and mix them. Dissolve hyaluronic acid in calcium chloride solution.

單位：重量份 Table 2: The weight of each component of agent B of drug carrier samples 1-3

Unit: parts by weight

Finally, when the A and B agents of the prepared sample 1 are mixed and mixed uniformly, the sample 1 in a colloidal state will be formed. The preparation process of samples 2 and 3 is the same as the preparation process of sample 1 described above, so it will not be repeated.

Refer to Figure 1. Figure 1 shows the appearance of the drug carrier sample 1 in a colloidal state in the contents of the syringe. The drug carrier sample 1 is milky white gel. The appearance of the drug carrier samples 2 and 3 is also the same as the appearance of the drug carrier sample 1. the same.

Refer to Figure 2. Figure 2 shows the microscopic particle shape of the colloidal drug carrier sample 1 observed with an inverted microscope (ECLIPSE Ts2, NIKON) at a magnification of 10 times the eyepiece X 20 times the objective lens, as can be seen from Figure 2 , The particles in the drug carrier sample 1 are uniformly dispersed.

Biocompatibility test of drug carrier:

First, prepare colloidal drug carrier samples 1-3 using the aforementioned preparation method, and prepare four 6-well plates at the same time, and inject 2ml of NIH/3T3 cell culture medium into the three holes of each 6-well plate (culture with DMEM medium, NIH/3T3 cell concentration is 1×10 ⁵ cells/ml) as the cell test sample. Then, add drug carrier sample 1 to the three cell test samples in the first 6-well plate as experimental group 1, drug carrier sample 1 The volume ratio of the cell culture medium to each cell test sample is 1:100, and the drug carrier sample 1 is added to the first 6-well plate in the second 6-well plate and the third 6-well plate. Drug carrier samples 2 and 3 were added as experimental group 2 and experimental group 3 respectively, and no drug carrier sample was added to the fourth 6-well plate as a control group. Finally, put the 6-well plates of the experimental group 1-3 and the control group into a cell culture incubator, culture at 37°C for 48 hours, and at the 24th hour and at the 48th hour after the culture, from the experimental group 1 -3 and the control group, 100μl of the cell test samples were taken out of the three cell test samples and used tetramethylthiazol salt solution (MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5- Diphenyltetrazolium bromide) was subjected to the MTT test. Based on the results of the MTT test, the average cell survival rate of the experimental group 1-3 and the control group was calculated.

Figure 3 shows the cell survival rate results of the drug carrier biocompatibility test. It can be seen from Figure 3 that the experimental group 1-3 with the drug carrier sample 1-3 added after 24 hours of culture, the experimental group 1-3 Compared with the control group, the number of cells increased, and because the cell concentration in the cell sap of the experimental group 1-3 increased after 24 hours of culture, the cell survival environment in the cell sap was deteriorated, so after 48 hours After culturing, the number of cells in the cell fluid of the experimental group 1-3 decreased compared with the number of cells cultured for 24 hours, but the number of cells in the experimental group 1-3 was higher than that of the control group. It can be seen that this example The drug carrier of has high biocompatibility and is not biologically toxic, and the drug carrier of this embodiment has the effect of promoting cell growth.

Pharmaceutical composition preparation method: In this embodiment, a pharmaceutical composition comprising the aforementioned pharmaceutical carrier combination and pharmaceutical ingredients is further provided, and the pharmaceutical composition is prepared by the following method.

First, prepare a first mixed material, namely agent A, according to the aforementioned preparation method of the drug carrier combination, and then provide 30 to 300 parts by weight of the drug component to be used, and uniformly mix the agent A and the drug component in an aqueous solution to form a The precursor mixture; then, a second mixture material, that is, agent B, is prepared according to the aforementioned pharmaceutical carrier combination preparation method; finally, the precursor mixture is mixed with agent B to form a pharmaceutical composition. Since the hydrophilic polymer material and tricalcium phosphate in agent A form a network structure through hydrogen bonding, the drug ingredients can be dispersed and entangled in the network structure, and then the divalent cation salt in agent B The divalent cations provided by the class undergo a cross-linking reaction with the aforementioned network structure (this cross-linking reaction is formed by ionic bonding between a hydrophilic polymer material and a divalent cation) to effectively coat the drug. Through the above-mentioned method of combining the drug component and the drug carrier, the drug carrier can carry the drug and finally be released in the human body.

In this embodiment, in order to enable the drug carrier to coat the drug component more effectively, agent A is mixed and reacted with the drug component first, and then mixed and reacted with agent B. However, in other embodiments It is also possible to choose to mix and react the A and B agents with the pharmaceutical ingredients according to the requirements of the manufacturing process, and is not limited to this embodiment.

In this embodiment, the drug component may be an anti-inflammatory component or an antibiotic, and the anti-inflammatory component is selected from the group consisting of adalimumab, certolizumab, etanercept, golimumab, abatacept, and tromethamine. The group consisting of beadzumab, rituximab and infliximab; the antibiotic is selected from the group consisting of gentamicin, vancomycin, mezlocillin, cloxacillin, methicillin, cephalothin, lincomycin It is a group consisting of polymyxin, polymyxin E, bacitracin and fusidic acid. However, in other embodiments, it is also possible to select pharmaceutical ingredients with similar properties to the pharmaceutical ingredients in the foregoing group, and is not limited to this embodiment. The weight parts of the pharmaceutical ingredients can be 30, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280 or 300, and the preferred weight parts range is 80-200, but Not limited to this.

Drug release rate test of pharmaceutical composition:

First, a total of 3ml of the A and B solution (the weight ratio is sodium alginate: tricalcium phosphate: methyl cellulose: hyaluronic acid: calcium chloride = 36: 36: 15: 80: 20) and 50 mg The gentamycin in the mixture is mixed to prepare a sample of a pharmaceutical composition that can be used as an anti-inflammatory and antibacterial drug, and the sample of the pharmaceutical composition is put into a dialysis bag.

Next, prepare a 500ml beaker, pour 300ml of phosphate buffered saline (PBS) solution, place the dialysis bag containing the sample of the pharmaceutical composition in the PBS solution, and place the beaker containing the dialysis bag and the PBS solution Slightly shake it at 37°C to allow the drug components in the dialysis bag to be released in the PBS solution.

Finally, the beaker containing the dialysis bag and the PBS solution was slightly shaken. When the following time points passed, 3ml of the PBS solution was taken out of the PBS solution in the beaker and used for high performance liquid chromatography (HPLC) The concentration of gentamicin in the PBS solution is analyzed, that is, the content of the drug component released from the dialysis bag is detected. And, when 3 ml of PBS solution is taken out from the PBS solution in the beaker at each time period, 3 ml of fresh PBS solution is added to the beaker at the same time. The time points for taking out the PBS solution are as follows: 15 minutes, 30 minutes, 45 minutes, 30 minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 150 minutes, 180 minutes, 1 day, and 2 days.

Figure 4 shows the drug release rate of the pharmaceutical composition. It can be seen from Figure 4 that from about 15 minutes to about 180 minutes, the concentration of gentamicin in the PBS solution is quite consistent until the One day later, the concentration of gentamicin in the PBS solution was significantly increased. Therefore, the pharmaceutical composition in this embodiment can prolong the release time and residence time of the drug component in the human body. Therefore, when the drug carrier is contained When the pharmaceutical composition is applied to the human body (for example, applied to the patient’s surgical affected area), it can more effectively exert the effect of the drug and can effectively deliver the drug to the affected area, thereby solving the problem of applying antibiotics to the affected area by injection. In the method in the patient's body, the drug cannot be effectively delivered to the affected part of the patient. The pharmaceutical composition does not affect the integration and recovery of the patient's surrounding area or the prosthesis and bone tissue implanted in the patient's body, so as to achieve higher Human safety.

In addition, the pharmaceutical composition of this embodiment can be directly applied to the patient's affected part of orthopedic surgery, or the pharmaceutical composition can be applied to implantable medical devices, implanted prostheses, and implants used in orthopedic surgery. The surface of metal implant materials and related orthopedic implantable fixed medical equipment. The method of applying the pharmaceutical composition to the above-mentioned medical device may be by immersing the above-mentioned medical device coated with the pharmaceutical composition in a 1.0% to 3.0% aqueous solution of a divalent cation salt (such as calcium chloride) to strengthen The cross-linking strength of the drug carrier and the drug component.

The above-mentioned drug carrier penetrates the network structure formed by the hydrophilic polymer material and tricalcium phosphate, so that the drug components can be dispersed and entangled in the network structure, and then by the divalent cation salt in the B agent The provided divalent cations undergo cross-linking reaction with the aforementioned network structure, thereby effectively covering the drug. On the other hand, because the moisturizing material of the drug carrier is biodegradable and the other components of the drug carrier also have Biocompatibility, therefore, the drug carrier can be degraded and excreted from the human body within a certain period of time without affecting human health. At the same time, the pharmaceutical composition with the drug component carried by the drug carrier can prolong the release time and residence time of the drug component in the human body, increase the action time of the drug in the human body, and solve the problem of applying antibiotics to the patient's body by injection. In the method, the problem that the drug cannot be effectively delivered to the affected part of the patient, the pharmaceutical composition does not affect the integration and recovery of the patient's affected part or the implanted prosthesis and bone tissue in the patient's body, thereby achieving high human safety .

The present invention has been disclosed above in a preferred embodiment, but those skilled in the art should understand that the embodiment is only used to describe the present invention and should not be construed as limiting the scope of the present invention. It should be noted that all changes and substitutions equivalent to the embodiment should be included in the scope of the present invention. Therefore, the protection scope of the present invention should be defined by the scope of the patent application.

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Figure 1 is a schematic diagram of the appearance of a drug carrier sample in a colloidal state in the contents of the syringe. Figure 2 is a schematic diagram of the microscopic particle shape of a colloidal drug carrier sample. Figure 3 is a graph showing the cell survival rate of the drug carrier biocompatibility test. Figure 4 is a graph showing the results of the drug release rate of the pharmaceutical composition.

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Claims (11)

A drug carrier combination comprising: a first mixed material, comprising: 300 to 1200 parts by weight of hydrophilic polymer material; 300 to 1200 parts by weight of tricalcium phosphate; and 100 to 600 parts by weight of water-soluble dispersant; and A second mixed material, comprising: 500 to 3600 parts by weight of a moisturizing material with high cell compatibility, high moisture content and degradability; and 400 to 730 parts by weight of divalent cation salts. The drug carrier combination according to claim 1, wherein the hydrophilic polymer material is selected from the group consisting of sodium alginate, propylene glycol alginate, chitin and chitosan. The drug carrier combination according to claim 1, wherein the tricalcium phosphate may be α-phase-tricalcium phosphate or β-phase-tricalcium phosphate. The pharmaceutical carrier combination according to claim 1, wherein the water-soluble dispersant is selected from the group consisting of methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose The group. The drug carrier combination according to claim 1, wherein the moisturizing material is selected from the group consisting of hyaluronic acid, collagen, gelatin and polydextrose. The drug carrier combination according to claim 1, wherein the divalent cation salt is selected from the group consisting of calcium chloride, calcium carbonate, barium chloride, potassium chloride and magnesium chloride. A drug carrier combination is used for preparing an anti-inflammatory or antibiotic drug, and the drug carrier combination includes the drug carrier combination according to any one of claims 1 to 6. A method for preparing a drug carrier combination comprising the following steps: (a) mixing 300 to 1200 parts by weight of hydrophilic polymer material, 300 to 1200 parts by weight of tricalcium phosphate and 100 to 600 parts by weight of water-soluble dispersant Forming a first mixed material; and (b) mixing 500 to 3600 parts by weight of the moisturizing material and 400 to 730 parts by weight of the divalent cation salt to form a second mixed material, which has high biocompatibility, High moisture content and degradability. A treatment method before use of a drug carrier combination, which comprises the following steps: (a) providing a first mixed material of the drug carrier combination according to any one of claims 1 to 6; (b) combining a drug component with the drug carrier The first mixed material is mixed and reacted in an aqueous solution to form a precursor mixture; (c) providing a second mixed material of the drug carrier combination according to any one of claims 1 to 6; and (d) the second The mixed material and the precursor mixed liquid are mixed and reacted to form a pharmaceutical composition. A pharmaceutical composition, comprising: the pharmaceutical carrier combination according to any one of claims 1 to 6; and pharmaceutical ingredients. The pharmaceutical composition according to claim 10, wherein the pharmaceutical ingredient can be an anti-inflammatory ingredient or an antibiotic, and the anti-inflammatory ingredient is selected from the group consisting of adalimumab, certuzumab, and etanercept The group consisting of Gentamicin, Golimumab, Abatacept, Tocilizumab, Rituximab and Infliximab. The antibiotic is selected from the group consisting of gentamicin, vancomycin, mezlocillin, and A group consisting of oxacillin, methicillin, cephalothin, lincomycin, polymyxin E, bacitracin and fusidic acid.

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