KR100314405B1 - Pharmaceutical Bead Manufacturing Device and Manufacturing Method - Google Patents

Abstract

The present invention relates to a device for producing a large amount of drug beads containing a drug that is unstable to heat, such as antibiotics, and a method for manufacturing drug beads using the device, to compensate for the disadvantages of the conventional bead manufacturing method The process of mixing and shaping pharmaceuticals, medical cement and liquid monomers at low temperatures extends the solidification time by more than 24 hours, giving ample time for the production of large quantities of beads. The same diameter does not cause the phase separation of powder and liquid even when the viscosity of the mixture is high, and the spherical mold made of plastic allows the product to be easily separated from the pressure roller so that it can be used without washing the pressure roller. It characterized by a method of producing beads continuously.

Description

Device and Method for preparing drug bead formulations

The present invention relates to a pharmaceutical bead manufacturing apparatus and a manufacturing method, and more particularly, to prevent the deterioration of quality or the decrease in productivity in the manufacturing process of pharmaceutical beads, such as antibiotics, while enabling the continuous production of bead products Continuous manufacturing method and apparatus.

Beads containing antibiotics are very meaningful in reducing the adverse effects on the whole body and increasing their therapeutic effects by ensuring that long-term delivery of antibiotics effective for the treatment of acute and chronic osteomyelitis and all infections of the musculoskeletal system directly to the lesion.

For example, chronic osteomyelitis and periarticular prosthetic infections were previously known to be caused by acute osteomyelitis, but now patients with chronic osteomyelitis due to increased traffic accidents and industrial accidents or subsequent sequelae of open fractures The trend is increasing (Journal of Orthopedic Surgery, 24: 549-556, 1989). For the treatment of this, the treatment is mainly performed by systemic therapy of antibiotics, but the frequency of recurrence after treatment is very high, It is resistant to treatment due to the abuse of antibiotics, and is one of the difficult diseases to be cured in the orthopedic field due to increased resistance to antibiotics, systemic toxicity and side effects with long-term use. Many treatment methods have been proposed to solve this osteomyelitis, among which osteosporation has long been used as a surgical method for surgically removing the necrosis of the infected bone. At this time, by filling the lung space generated by the beads containing antibiotics can serve to fill the pores and to prevent the recurrence by the medicinal effect of the antibiotic continuously released from the beads.

Septopal (E. Merch), an antibiotic bead for this purpose, is a high-temperature (150 ℃ -160 ℃) of powder mixed with antibiotic gentamicin and cement-based polymethylmethacrylate (PMMA). The method of melt-molding and injection-molding in a mold is used. This method has the advantage of making beads with a diameter of 4mm or 7mm easily, but the antibiotics are exposed to high temperatures in the manufacturing process, which reduces the titer of antibiotics and has the weakness of decomposition products. Not a suitable way to make beads.

Table 1 below shows that the antibiotic titer decreases and decomposition products are formed under high temperature storage conditions.

TABLE 1

Reduction of antibiotic titer and formation of degradation products at 25 ° C and 60min storage at 150 ° C

As another method of preparing the antibiotic beads, Korean Patent Application No. 94-1632 and Japanese Patent No. 259452 homogeneously mix the antibiotic with medical cement (polymethyl methacrylate), and then add a liquid monomer (methyl methacrylate) to the mixture. Monomers are mixed and cured into beads of appropriate size, and then threaded to provide a method for producing beads. This method maintains the titer of the antibiotic by working at room temperature, but is not suitable for producing large quantities of beads because the time it takes for the powder mixture and liquid monomer to fully react and solidify is within 10 minutes.

In addition, Arthur B. Flick (Clinical Orthopaedics and Related Research, 223, 282-286, 1987) also used a disposable syringe with a Teflon-coated stick on cold rolled steel to inject and solidify the mixture directly. Shows how to separate the beads. However, in this method, the mixture is injected directly into the molding machine through a disposable syringe. If the fluid is not good due to the high viscosity of the mixture, the injection is difficult due to the small nozzle diameter of the syringe, or the pressure applied to the nozzle of the syringe. As a result of phase separation between the mixed powder of the antibiotic and the medical cement and the liquid monomer in a state where the medical cement and the liquid monomer are not completely reacted, properties such as hardness and dissolution rate of the beads may vary depending on the injection time. In addition, since the mixture of antibiotic, medical cement and liquid monomer is directly injected into the mold, the beads do not fall well from the pressure roller after the mixture is completely solidified. It is inconvenient to produce the product continuously because of the process.

The present invention has been made to solve the above-described problems, the object of the present invention is to provide a cooling unit for cooling a mixture of medicines, medical cement and liquid monomer, a conveying portion bent at the lower end of the cooling portion and formed in a pipe shape, and the conveying portion. A cold injection device comprising a nozzle extending to mold the mixture to a certain diameter, a freezing unit surrounding the outer shape of the nozzle, a cutter for cutting the mixture to be positioned below the end of the nozzle, and a cut mixture; A bead forming apparatus comprising a container for forming a mold, a spherical mold formed by a plurality of opposing hemispherical molds, a roller for feeding each hemispherical mold, and a press roller for pressing the transferred mold on both sides, Method for preparing pharmaceutical beads using a mixture of pharmaceuticals and monomers from medical cements and liquids. In particular, the cutter is rotated about an axis to cut the mixture from the nozzle into pellets of a certain length, the mold is made of plastic, and the oil is coated to make it easy to separate the beads from the mold. And And the pressure roller is provided with a plurality of symmetrically formed, to rotate in the opposite direction to compress the mold and the medical cement is polymethyl methacrylate, methyl methacrylate-methyl acrylate copolymer, poly [ Methyl methacrylate-co-styrene] copolymers are characterized by mixing one or more of them.

The present invention is a conventional bead manufacturing method of the pharmaceutical beads manufacturing apparatus and the mixture of pharmaceutical and medical cement and liquid monomer kneading high viscosity and fluidity is not good injection, or the mixture is not separated from the mold after the mixture is solidified A method of manufacturing the mold in a roller form to enable continuous production of the product, while preventing functional defects of the product from causing a decrease in quality or productivity in the manufacturing process of the pharmaceutical beads; It is for providing the device.

1 is a schematic view showing a cold injection portion and a bead molding portion of the drug beads manufacturing apparatus for producing a mixture in pellet form according to an embodiment of the present invention,

2, 3 and 4 are explanatory views illustrating a process of separating the mold from the molded beads using a plastic mold for molding the spherical beads, respectively, according to the present invention.

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

1: Cooling injection device 2: Bead molding device

10: pharmaceutical powder, medical cement and liquid monomer mixture

11: transfer unit 20: cooling unit

21: Frozen 22: Nozzle

23: rotating shaft 30: cutting machine

40: mixture in pellet form 50: globular template

51: hemispherical mold 52: iron core groove

53: half sphere groove 62: mixture container

70: medical core 90: bead

Rl: pressure roller R2: feed roller 1

R3: Feed Roller 2

In one aspect, the present invention provides a cooling unit for cooling a mixture of pharmaceuticals, medical cement and liquid monomers; A conveying part bent at the lower end of the cooling part and formed to have a pipe shape; A nozzle extending to the conveying portion to mold the mixture to a predetermined diameter; A freezing unit provided surrounding the outer shape of the nozzle; A container for storing the mixture cut in the cooling injection device and the cooling injection device comprising a cutter positioned under the end of the nozzle to cut the mixture; Globular mold formed by a plurality of opposing hemispherical molds; A roller for conveying each hemispherical mold; Provided is a bead manufacturing apparatus, characterized in that consisting of a bead molding device consisting of a pressure roller for pressing the transferred mold on both sides.

In another aspect, the present invention is to put a mixture of medicines, medical cement and methyl methacrylate in the cooling unit, lowering the conveying unit and the extended nozzle to a certain temperature through the freezing unit to freeze the mixture, and then molded to a certain size by a cutter, Provided is a method for producing a pharmaceutical bead characterized in that the pharmaceutical beads are produced by supplying a spherical mold and applying pressure with a pressure roller.

Hereinafter, preferred embodiments of the present invention will be described with reference to the accompanying drawings.

FIG. 1 is an explanatory view showing a cold injection device 1 and a bead forming device 2 for making a pellet-like mixture in the present invention, illustrating the method and apparatus used in the manufacturing process. First, medicines, especially antibiotics, medical cement and liquid monomers are mixed at a low temperature, and then the mixture is transferred by the transfer part 11, and the cylinder is large and long enough to have a diameter of about the final bead diameter as shown in the upper left of the figure. After passing through the recessed nozzle 22 and injecting it into the shape of a cylinder, the cutter 30 cuts the mixture into a constant length so as to have the same volume as the final bead volume, thereby making the mixture 40 in pellet form. During the transfer, the temperature is maintained at 0 ° C. by the cooling unit 20 to delay the solidification of the mixture. In the nozzle 22 part, the temperature is maintained at −20 ° C. by the freezing unit 21 to suppress the reaction of the mixture as much as possible. It is configured to. When the temperature of the pellet-form mixture 40 is increased to 0 ° C., it is possible to reshape into a desired shape, so that it is used for a roller-shaped mold prepared in advance. When the temperature of the mixture is 0 ° C, the solidification time is longer than 1 hour, especially when the temperature of the mixture is lowered to -20 ° C, so that the solidification time is extended by 24 hours or more. There are advantages that can be placed, and the titer per bead of the prepared antibiotic represented 80% to 120% relative to the initial value, thereby maintaining the titer of the antibiotic. In addition, the beads prepared by this method were well injected even when the viscosity of the liquid monomer was small due to the high viscosity, and the pressure applied to the nozzle was small so that the phase separation of the powder and the liquid did not occur.

In describing the method and apparatus for continuously producing beads using a mold, a conventional manufacturing method is a long rectangular mold, in which several hemispherical flaws are made in a straight line, which are connected by iron cores of 15, 30 or more units. When manufacturing the mold, each mold had to be different in length, and the number of nozzles of the injection molding machine had to be changed according to the number of hemispherical flaws made in the mold, which caused a problem of making several nozzles. In order to eliminate the problems of the conventional manufacturing method, two pressure rollers (Rl) having several hemispherical grooves are rotated in opposite directions on both sides, and a spherical mold 50 and a medical iron core (between) are disposed therebetween. The device is designed so that 70 is simultaneously supplied through the feed rollers R2 and R3, and the pellet mixture 40 is continuously supplied from the container 60 with the freezing section 21 and compression molded in the pressure roller. It enables continuous bead production. At this time, the pressure roller Rl serves to pressurize the mixture to be formed into a bead shape, and the spherical mold 50 serves to maintain the bead shape while the mixture is solidified. The final product produced through this device is solidified at room temperature in the form of a globular mold (50) surrounding the beads, and then packaged to go to the finished product, and cut into 15, 30 or more units. Not only can it be packaged in roll form and can be cut to the desired length at the site where the beads are used, so there is no need to make several molds depending on the number of beads connected. Beads prepared in this way can be used after peeling off the outer packaging and peeling the globular mold 50 when using the product.

2, 3 and 4 illustrate a method for easily separating beads from a spherical mold made of a plastic material such as polypropylene resin in the present invention, the existing bead manufacturing method is antibiotic and medical cement And by injecting the mixture of liquid monomer directly into the mold, the mixture was solidified in the mold and the mold was not reusable during the solidification time, so that several molds had to be made. Also, the solidified beads were separated from the mold after the mixture was solidified. It was not easy to do, and there was a problem in continuous mass production because the mixture remained in the mold and could not be reused without washing.

The present invention uses a method of solidifying in a spherical mold 50 of plastic material, in order to eliminate the problems of the existing manufacturing method, by pouring the beads and the mold 50 together from the mold after the mixture is solidified This allows for continuous use without cleaning the mold. In addition, since the globular mold 50 itself surrounds the beads, there is an advantage in helping to maintain a sterile state during packaging. The spherical mold 50 can be easily separated from the beads when the product is used, and has an advantage of being more easily separated by coating with an oily material, in particular, silicone oil.

The above-described mold 50 is made of a plastic resin, and in particular, the polypropylene resin does not react with a mixture of antibiotics, medical cement and liquid monomers, and when it is made thin, it can be bent well and maintain the original mold form well. Suitable for making molds. In addition, as shown in Figure 4 by making a groove (51) that can enter the medical iron core in the mold (50) to be able to produce beads connected to the medical iron core.

The present invention configured as described above does not wash the mold by separating the beads and the mold together after the mixture is solidified using a method of solidifying the mixture in a thin mold made of plastic as described above in the apparatus and method for manufacturing a pharmaceutical bead. Continuous use is possible without. In addition, since the globular mold itself surrounds the beads, there is an advantage in helping to maintain sterility even when packaging. This thin mold can be easily removed from the beads when the product is in use, and can be easily separated by pre-coating with oily material, especially silicone oil.

Claims (6)

In the manufacturing apparatus of pharmaceutical beads, It has an inverted internal structure, a rotor for mixing the injected bead component materials is located perpendicular to the center portion, and the mixture 10 in which the component materials are mixed is discharged vertically downward by a tube connected to an opening formed at the bottom thereof. Cooling unit 20 provided with a cooling function for the internal mixture; The connection pipe of the lower end of the cooling unit 20 is bent and formed in a pipe shape and conveys the mixture 10 by the rotation of a single blade or a double blade screw installed in the inner hollow center, and a cooling means is provided on the outer surface. Transfer unit 11; It extends in a pipe form from the discharge side end of the conveying portion 11, the inner diameter is smaller than the inner diameter of the conveying portion 11 and is the same as the diameter dimension of the bead to be manufactured, the outer side is provided with a freezing means 21, A rotary cutting blade is installed at one point 23 around the nozzle for discharging the mixture 10, and a cutter 30 for cutting the extruded mixture 10 into chips 40 of a predetermined size is provided. A cooling injection device 22; It is to receive and store the mixture chip 40 of the predetermined size discharged in the state cut from the cooling injection device 22 and to distribute one by one to the outlet of the predetermined size formed in the lower portion and the freezing means 21 around the outer wall. Provided dispenser 60; A pair of spherical molds 50 including a plurality of opposing hemispherical molds, rollers R2 and R3 for transporting the molds 50 including the hemispherical molds, and the spherical molds 50 from both sides Apparatus for producing a drug beads, characterized in that consisting of a bead forming device consisting of a pressing roller (R1) for pressing to form a bead of a predetermined shape in the mold. 2. The apparatus of claim 1, wherein the rotary shaft of the rotary cutter (30) is positioned below the nozzle end to cut the mixture from the nozzle into pellets of a predetermined length. The apparatus of claim 1, wherein the globular mold (50) is formed with an iron core groove connecting each hemispherical groove. 2. The apparatus of claim 1, wherein the globular mold is made of a flexible plastic material and coated with an oily material to promote detachment of the beads from the mold. A method of manufacturing a drug bead using the drug bead manufacturing apparatus according to any one of claims 1 to 4, Putting a mixture containing a pharmacologically active substance, medical cement as a binder, and methyl methacrylate as a liquid monomer component in a predetermined ratio into the cooling unit 20 maintained at 0 ° C., and mixing the mixture; Transferring the mixed mixture (10) to the conveying unit (11) through a connecting tube below the cooling unit (20) and pushing the mixture (10) toward the injection device (22) while further mixing the mixture (10) by a scruw; Injecting the mixture (10) through a nozzle while freezing at -20 ° C by a freezing means (21); Continuously cutting the mixture (10) into pellet-shaped chips (40) of predetermined size by a two-blade rotary cutting blade installed outside the outlet of the nozzle while injecting the mixture (10) through the nozzle; And Pellet-shaped chips 40 of a predetermined size that are continuously cut are accommodated in the distributor 60 where the freezing is maintained at -20 ° C and discharged one by one to be stored one by one in the lower spherical mold, and then press roller A method of producing a pharmaceutical bead, comprising the step of providing a pharmaceutical package having a spherical shape of the mold in a packaged state by press molding. The method of claim 5, wherein the medical cement is selected from the group consisting of polymethyl methacrylate, methyl methacrylate-methyl acrylate copolymer, poly [methyl methacrylate-co-styrene] copolymer and mixtures thereof Method for producing a pharmaceutical beads, characterized in that.