KR20020041927A - Beeds containing combined antibiotic and the method of making the same - Google Patents

Abstract

PURPOSE: A process of preparing a complex antibiotic bead as a bone cement bead containing two or more antibiotics is provided. Whereby, the bead product has an increased treatment effect by improving an elution rate of an antibiotic. CONSTITUTION: Two or more antibiotic powers are mixed with bone cement powder and each antibiotic powder is kneaded with a liquid monomer. The kneaded material is poured into a mold and then injected and each injection molded product is formed into a bead. The antibiotic is cefazolin sodium and tobramycin sulfate.

Description

Beads containing combined antibiotic and the method of making the same

The present invention relates to complex antibiotic beads and methods for their preparation. More specifically, the present invention is powdered polymethyl methacrylate resin (also called acrylic resin, powdered polymethyl methacrylate resin is polymethyl methacrylate, poly (methyl methacrylate-methyl acrylate) -air A complex antibiotic bead comprising two or more antibiotics in a bone cement comprising coalesced and poly (methylmethacrylate-co-styrene) -copolymers currently used in the clinic) and liquid methylmethacrylate. The present invention relates to a complex antibiotic bead and a method for preparing the same, wherein each of the antibiotics is limited in a separate area within the beads so as not to react chemically with each other in the beads.

Bone cement beads containing antibiotics (hereinafter referred to as antibiotic beads) reduce the side effects of systemic administration by ensuring that antibiotics, which are effective for the treatment of chronic osteomyelitis and musculoskeletal infections, are delivered directly to the site of infection. To increase it.

The main cause of chronic osteomyelitis and infections around joint prostheses was previously known as acute osteomyelitis, but now patients with chronic osteomyelitis are also increasing due to open fractures due to increased traffic accidents and industrial accidents. Systemic administration of antibiotics is the primary treatment for osteomyelitis, but this treatment is frequently associated with drug resistance due to antibiotic misuse and abuse before the patient's visit, and increases antibiotic resistance and systemic toxicity due to long-term administration of the drug. Due to the side effects of orthopedic surgery is known as one of the diseases that are difficult to cure. Another suitable treatment for osteomyelitis is shunting tissue removal, which is known as the main treatment, especially osteoctomy. The site of osteomyelitis is often found in the lower part of the body, in particular, it is known that the treatment of osteopatomy of the lower part of the body is very difficult because it involves much more tissue damage than other body parts. To address this, after primary surgery to surgically remove bones from infection, a second treatment is to deliver antibiotics directly to the site of infection over a long period of time by inserting a local antibiotic delivery system into the cavities caused by curettage. Combination therapy combined with is known to have a lot of success. Examples of topical antibiotic delivery systems include antibiotic-containing beads (antibiotic impregnated polymethylmethacrylate beads), implantable antibiotic pumps, continuous irrigation catheter, and the like. Of these, antibiotic transfer pumps for implantation and continuous irrigation catheters have the advantage of increasing the concentration of antibiotics at the site of infection to increase the therapeutic effect compared to systemic administration of antibiotics, while surgical applications for transplantation in clinical applications Disadvantages such as required have also been raised.

In the case of antibiotic beads, the use period was known in 1969 and has been made and used by doctors in the operating room for a long time in the orthopedic field. Antibiotic beads are used in the form of beads by mixing antibiotic powder with bone cement composition. The antibiotic beads were mixed with powdered polymethylmethacrylate-based resin polymers or copolymers with an antibiotic powder, mixed with an appropriate amount of prepolymer as a liquid methylmethacrylate monomer or resin, and then obtained an atherosclerosis. A dough phase having this possible degree of viscosity is prepared by hand or by molding into a certain shape and size using a mold injection machine. After a certain period of time, the hardness becomes cement beads, and the antibiotics in the beads are initially eluted at a very high concentration, showing a bactericidal effect. However, the dissolution of antibiotics has a disadvantage in that it decreases below a concentration that can effectively treat infection over time. Currently, commercially available antibiotic beads are known as Septopal, which contains one gentamicin. Manufactured by E. Merck and sold in Europe. On the other hand, in many surgical sites, orthopedic surgeons are randomly selected and mixed with cement to manufacture manually. Thus, the type and content of antibiotics used or the size of the beads are not standardized.

The amount of antibiotic eluted from the beads is a very important factor in determining the drug's efficacy. In particular, the type and content of the antibiotics discussed above, the size of the beads, the type and type of the cement used, or whether the antibiotic dissolution control factors are used in the beads determine the amount and the dissolution of the antibiotic. The amount of eluting antibiotics should be at a concentration higher than the minimum inhibitory concentration (MIC) value for at least osteomyelitis or other concomitant strains at the site of infection, and the duration of the dissolution is about 4 to 6 with secondary removal. Ideally, the course will progress slowly during the week. Thus, techniques for controlling the dissolution of antibiotics from antibiotic beads are very useful for increasing the utility of antibiotic beads. However, the aspect of antibiotic dissolution has been overlooked until now because antibiotic beads prepared in the operating room have not been standardized even in the size of the beads and the antibiotic content that actually affect the dissolution of the antibiotic.

In particular, in the case of beads prescribed in combination with various antibiotics, the dissolution rate is lowered due to the chemical interaction between the antibiotics. Prior art US Pat. No. 5,641,514 relates to a method for preparing beads by combining various antibiotics, and the drug treatment effect is excellent due to the synergistic action of antibiotics, but the dissolution rate is reduced due to the interaction between drugs.

In the case of the antibiotics, tobramycin sulfate and cefazoline sodium salt, each is well soluble in water, but when mixed together and put into water, they react chemically with each other at high concentrations to form white precipitates, which are insoluble in water. In the prior art, two antibiotics of tobramycin sulfate and cefazoline sodium salt are homogeneously mixed together in the beads so that the two antibiotics are present at high concentrations in the water at the contact point when the beads enter the body and come into contact with moisture. As a result, chemical reactions with each other form precipitates, which do not dissolve easily, and possibly also block small pores where moisture can enter the beads, thereby reducing the dissolution rate.

An object of the present invention is to provide a complex antibiotic beads and a method for producing the same comprising two or more antibiotics to improve the dissolution rate of the antibiotic to have a more certain therapeutic effect.

1 is a comparative view of the dissolution rate of antibiotic beads prepared by the method of Example 1.

Figure 2 is a comparison of the dissolution rate of antibiotic beads prepared by the method of Example 2.

Figure 3 is a comparison of the dissolution rate of antibiotic beads prepared by the method of Example 3.

Figure 4 is a comparison of the dissolution rate of antibiotic beads prepared by the method of Comparative Example 1.

The composite antibiotic beads according to the present invention, in the composite antibiotic beads comprising two or more antibiotics in a bone cement comprising powdered polymethyl methacrylate resin and liquid methyl methacrylate, the antibiotic chemically in the beads The antibiotics are characterized in that they are configured to be distributed in a separate area in the beads so as not to react with each other.

Method for producing a complex antibiotic beads according to the present invention comprises the steps of producing a complex antibiotic beads comprising two or more antibiotics, mixing two or more antibiotic powders and bone cement powder separately; Mixing and kneading a liquid monomer into each powder mixture; Injecting each of the atherosclerosis into a mold having a shape that can be combined into one bead; And molding each of the injection moldings into one bead.

Hereinafter, specific embodiments of the present invention will be described in detail.

In the composite antibiotic beads according to the present invention, in the composite antibiotic beads comprising two or more antibiotics in a bone cement comprising powdered polymethyl methacrylate-based resin polymer or copolymer and liquid methyl methacrylate, It is characterized in that each of the antibiotics is configured to be limitedly distributed in a separate region in the beads so as not to react chemically with each other.

In particular, the cefazoline sodium salt and tobramycin sulfate may be used as the antibiotic.

The complex antibiotic beads according to the present invention are configured such that each of the antibiotics having a chemical interaction among the complex prescribed antibiotics, vancomycin, tobramycin or cefazoline is limited in a separate area in the beads so that the parts in contact with each other are minimized. The antibiotic dissolution rate was improved to have a more certain therapeutic effect.

Method for producing a complex antibiotic beads according to the present invention comprises the steps of producing a complex antibiotic beads comprising two or more antibiotics, mixing two or more antibiotic powders and bone cement powder separately; Mixing and kneading a liquid monomer into each powder mixture; Injecting each of the atherosclerosis into a mold having a shape that can be combined into one bead; And molding the respective injection-molded materials into one bead.

In particular, the cephazoline sodium salt and tobramycin sulfate may be used as the antibiotic. In the process of mixing the composite antibiotic beads with the bone cement powder and the antibiotic powder, two antibiotics that react chemically with each other, namely, tobramycin sulfate and cefazoline sodium salt, are separately mixed with the bone cement powder, and a liquid monomer is added to each powder mixture. After mixing and kneading, each bamboo block is injected into hemispheres, and then each hemisphere injection is formed by integrating and molding into one bead. By separating and molding two antibiotics with chemical interactions, each of the antibiotics is configured to be limited in a separate area within the beads, minimizing the areas where the antibiotics come in contact with each other, thereby improving the antibiotic dissolution rate and thus providing more certain therapeutic effects. It is to have.

Hereinafter, preferred embodiments and comparative examples of the present invention will be described.

The following examples are intended to illustrate the invention and should not be understood as limiting the scope of the invention.

Example 1

Method for producing complex antibiotic beads

Powder 1 and Powder 2 were sieving using a standard body according to the composition of Table 1 below, and then mixed well using a mixer. Liquid monomer was added to each powder mixture and mixed well. Each of the atherosclerotic mixtures obtained at this time was injected into a hemispherical bead mold as an injection machine, and then the molds were combined into one to form a sphere.

Powder 1 Powder 2 Vancomycin Hydrochloride 1865.28 mg 1865.28 mg Sephazoline Sodium 4584.04 mg Tobramycin Sulfate 6050.43 mg Bone Cement Powder (Poly (methylmethacrylate-co-styrene) -copolymer) 19008.00 mg 19008.00 mg Powder total 26923.71 mg 25457.33 mg Bone cement solution 11.8152 ml 11.8152 ml

1 is a comparative view of the dissolution rate of antibiotic beads prepared by the method of Example 1. A is the dissolution rate of cefazoline, B is the dissolution rate of tobramycin, and C is the dissolution rate of vancomycin.

Example 2

Preparation of Complex Antibiotic Beads

It was prepared in the same manner as in Example 1 according to the composition of Table 2.

Powder 1 Powder 2 Vancomycin Hydrochloride 1865.28 mg 1865.28 mg Sephazoline Sodium 4584.04 mg Tobramycin Sulfate 5747.90 mg Bone Cement Powder (Poly (methylmethacrylate-co-styrene) -copolymer) 19008.00 mg 19008.00 mg Powder total 26621.18 mg 25457.33 mg Bone cement solution 11.8152 ml 11.8152 ml

Figure 2 is a comparison of the dissolution rate of antibiotic beads prepared by the method of Example 2. D is the dissolution rate of cefazoline, E is the dissolution rate of tobramycin, and F is the dissolution rate of vancomycin.

Example 3

Preparation of Complex Antibiotic Beads

It was prepared in the same manner as in Example 1 according to the composition of Table 3.

Powder 1 Powder 2 Vancomycin Hydrochloride 1865.28 mg 1865.28 mg Sephazoline Sodium 4584.04 mg Tobramycin Sulfate 5768.55 mg Bone Cement Powder (Poly (methylmethacrylate-co-styrene) -copolymer) 19008.00 mg 19008.00 mg Powder total 26641.83 mg 25457.33 mg Bone cement solution 11.8152 ml 11.8152 ml

Figure 3 is a comparison of the dissolution rate of antibiotic beads prepared by the method of Example 3. G is the dissolution rate of cefazoline, H is the dissolution rate of tobramycin, and I is the dissolution rate of vancomycin.

Comparative Example 1

Preparation of Complex Antibiotic Beads

Composite antibiotic beads were prepared by the method described in US Pat. No. 5,641,514 as follows. Powder 1 was sieving using a standard according to the composition shown in Table 4, and then mixed well using a mixer. The liquid monomer was added to the powder mixture and mixed well. The mixture of the porcelain obtained at this time was inject | poured into the bead metal mold | die by injection molding, and it solidified as it was.

powder Vancomycin Hydrochloride 3730.57 mg Sephazoline Sodium 4584.04 mg Tobramycin Sulfate 6050.43 mg Bone Cement Powder (Poly (methylmethacrylate-co-styrene) -copolymer) 38016.00 mg Powder total 52381.03 mg Bone cement solution 23.6304 ml

Figure 4 is a comparison of the dissolution rate of antibiotic beads prepared by the method of Comparative Example 1. J is the dissolution rate of cefazoline, K is the dissolution rate of tobramycin, and L is the dissolution rate of vancomycin.

As a result of the synthesis of the results of Figures 1 to 4, the antibiotic beads of Examples 1 to 3 prepared by the method for producing a complex antibiotic beads according to the present invention in the dissolution rate compared to the antibiotic beads of Comparative Example 1 prepared by the prior art Overall improvement, and the rate of elution decreased more slowly. Therefore, it was confirmed that the composite antibiotic beads, which are configured to have a limited distribution of each of the antibiotics in the divided areas in the beads, so that the antibiotics do not chemically react with each other in the beads, are more advantageous in dissolution rate than the conventional antibiotic beads.

Therefore, according to the present invention, there is an effect of providing a complex antibiotic beads and a method for preparing the same, comprising two or more antibiotics, which prevents chemical reactions between antibiotics, improves the dissolution rate of antibiotics, and has a more certain therapeutic effect.

Claims (4)

In a composite antibiotic bead comprising two or more antibiotics in a bone cement comprising powdered polymethyl methacrylate resin and liquid methyl methacrylate, Complex antibiotic beads, characterized in that each of the antibiotics is configured to be limited in a separate area in the beads so that the antibiotics do not chemically react with each other in the beads. The method of claim 1, Combination antibiotic beads, characterized in that the antibiotic is in particular cefazoline sodium salt and tobramycin sulfate. In the method for producing a complex antibiotic beads comprising two or more antibiotics, Mixing at least two antibiotic powders separately with bone cement powder; Mixing and kneading a liquid monomer into each powder mixture; Injecting each of the atherosclerosis into a mold having a shape that can be combined into one bead; And The method of manufacturing a complex antibiotic beads, characterized in that consisting of; step of incorporating each of the injection molding into one bead. The method of claim 3, wherein The method of producing a complex antibiotic beads, characterized in that the antibiotic is in particular cefazoline sodium salt and tobramycin sulfate.