JPH0233007B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a sustained-release molded drug based on polyglycolic acid or a glycolic acid-lactic acid copolymer containing 80% or more of polyglycolic acid. More specifically, the present invention relates to a method for mixing a drug with these polyglycolic acids and molding the mixture into a needle-like body as a sustained-release molded drug.

Polyglycolic acid, polylactic acid, and the like are bioabsorbable and hydrolyzable polymers, and their properties are utilized to process them into medical sutures and the like.

In addition, in the recent medical field, drugs with strong side effects such as anticancer drugs are formed into tablets, pellets, or capsules using bioabsorbable polymeric materials as a base material to continuously supply the drug over a long period of time. Research on administration methods is also active.

The present applicant has previously provided a new sustained-release molded drug that can be administered directly to an affected area in the form of acupuncture without damaging the affected area or its surroundings. The method of the present invention is a manufacturing method for the production of needle-like bodies using polyglycolic acid or polyglycolic acids obtained by copolymerizing glycolic acid with bioabsorbable aliphatic polyester such as lactic acid in an amount of 20% by weight or less as a drug base material. A method for producing a release-molded drug.

Polyglycolic acid, which is usually used for medical molding, has a melting point of 218-220℃, a decomposition temperature of 260℃,
Further, a polyglycolic acid copolymer containing 20% by weight of lactic acid is a solid polymer having physical properties such as a melting point of 182 to 185°C and a decomposition temperature of about 257 to 260°C. When polyglycolic acid is formed into surgical sutures etc.
Spun at 240-250℃. Polyglycolic acids have a relatively narrow range between their melting point and decomposition temperature and have a high melt viscosity, so not only do they require strict conditions for molding, but the molded products are hard and brittle. Therefore, its use was naturally limited.

In the present invention, polyglycolic acid and a copolymer thereof are used as a base material for a molding agent formed into a needle-like body, and the strength of polyglycolic acid and a copolymer thereof is utilized.

When a drug is mixed with polyglycolic acids and formed into a needle-like body, it is usually easier to administer the needle to the affected area of the body than when using other polymers such as cellulose, which are known as bioabsorbable polymer materials. It is easy to use, but on the other hand, due to its brittleness, it has disadvantages such as breaking when handling the molded product or inserting the molded medicine into the needle, especially when the diameter is reduced and the length is 3 cm or more. There is.

Usually, polyglycolic acids are obtained in bulk or molten form by bulk or solution polymerization, and are crushed and used for molding, but the polymer contains trace amounts of solvent and monomers during polymerization. Contains low-boiling volatiles such as unreacted products and by-products of cricolide. When this is heated and melted as it is and subjected to mold molding, the low boiling point substances cannot be removed from the mold during molding, and the low boiling point substances become bubbles and remain as cavities (voids) in the molded product. If a nest is formed in a needle-like object, it will not only become more susceptible to breakage, but what is even more important in the case of a molded drug is that when the molded product is inserted into a living body, the low-boiling organic impurities that form the nest will be removed. Air elutes into the body, or air trapped in nests enters the body while the molded drug is being stored.

The present inventors have solved the above-mentioned problems and at the same time have worked diligently to develop a method for molding polyglycolic acids as a sustained-release molded drug without reducing its medicinal ingredients when polyglycolic acids are used as a molding base material for the drug. As a result of the study, the method of the present invention was completed.

That is, in the method of the present invention, before molding, a polymer of polyglycolic acids is pulverized, and this is pretreated by drying and degassing under reduced pressure, after which the drug powder is mixed and heated, and then the powder is heated at a constant temperature. By press-fitting in a mold that is maintained at a constant temperature, the needle-shaped body has almost no cavities and is strong, and the drug component is uniformly distributed without loss of drug ingredients, resulting in a sustained-release needle-shaped body. This is a method for producing a molded drug.

In the method of the present invention, the needle-shaped drug is a drug having a decomposition temperature higher than the melting point of the polyglycolic acid as a base material, such as a powder of a known anticancer agent such as 5-fluorouracil or mitomycin. 70 parts by weight or less, preferably 20 to 40 parts by weight,
It is shaped into a needle-like body that can be inserted into a living body. The needle-shaped body has a diameter of about 1.5 mm or less and a length of about 3 cm or more and has a sharp tip.A needle-shaped molded body is preferable from the viewpoint of ease of molding using a mold and convenient administration method. , the method of the present invention is particularly suitable for this production.

In order to obtain a needle-shaped molded product, the mixed powder deaerated by pretreatment is melted and press-fitted into a mold having a plurality of needle-shaped molds that are maintained at a predetermined temperature and then compression molded. The molding equipment is a pot-type transfer molding machine equipped with a cooling device, or an injection molding machine that preforms the pretreated mixed powder into a pellet shape and continuously molds it using a method similar to transfer molding. Molding is also possible, but it is necessary to change the molding time settings as appropriate depending on the drug content, physical properties of the polymer, and shape of the needle, and in some cases, an injection molding machine may be used. If the molding process is carried out in a timely manner, the melt residence time will be longer and the chemical will be more likely to deteriorate. In the case of needle-shaped molding, it is better to heat and melt the polymer, press it into the mold, and then rapidly cool it to around 100 to 130°C, so that the molded product will not break when taken out and peeling will be easier.

Therefore, in the present invention, it is preferable to use a press molding machine whose mold can be freely removed or whose mold can be rapidly cooled, and a pressure-resistant molding machine that has a pot for melting the powder and can press the molten material into the mold. A press molding device with a simple mold is sufficient, and it is preferable to carry out batch molding using this.

When the method of the present invention is carried out in batches using a press molding machine, it may be carried out, for example, as follows.

The finely powdered polymer is heated at a predetermined temperature between 100 and 200°C, for example, the copolymer with lactic acid is preferably heated at a temperature of 100 to 200°C.
140℃, polyglycolic acid polymer at 120-180℃,
Subjected to degassing fluidized drying for 2 to 3 hours using a vacuum dryer under reduced pressure, preferably at a pressure of 5 to 10 mmHg,
Completely deaerate the low volatile matter contained in the powder polymer, replace with inert gas, and seal. The chemicals to be mixed are also powdered and, if necessary, dried under reduced pressure at 40 to 60°C to remove water and the like, and sealed in the presence of an inert gas. Up to 70% of the drug is added to the thus pretreated polymer powder and thoroughly mixed.

Next, these mixed powders are subjected to mold compression molding, but in order to shorten the molding time and suppress the decomposition and sublimation of the drug, they must be heated to around 100°C before being subjected to molding. Therefore, if the material is not molded immediately after pretreatment and mixing, a preheating step is provided if necessary, and the material is heated and introduced into a press mold pot preset at a predetermined temperature between 195 and 235.degree. If the temperature before introduction is low, it will take too long to melt during molding.
Further, if the temperature is too high, the drug may be decomposed, which is not preferable. The molding temperature after introduction into the mold pot is maintained at a predetermined temperature; if the temperature is lower than the predetermined temperature, the polymer will not be completely dissolved and will phase separate from the drug, making it easy to form cavities.

Furthermore, if molding is performed at a temperature higher than a predetermined temperature, not only will the drug decompose, but also air bubbles will tend to form even if the polymer is pretreated. 220-230℃ when using polyglycolic acid
It is preferable to mold with 195 ~ 195 when using a glycolic acid-lactic acid copolymer containing 20% polylactic acid.
210°C is preferred.

The mixed powder introduced into the mold pot will usually melt if held at this temperature for 1 to 5 minutes, depending on the amount, so immediately press it into the mold at a pressure of 20 to 300 kg/cm ² and leave it standing. Take it out later. At that time, especially needle-like molded products with small diameters, when taken out after air cooling, cracks or distortions may occur, or they may stick to the mold and be difficult to take out, so they must be press-fitted into the mold and molded. After that, if the mold can be easily removed, it is preferable to put it into ice water and rapidly cool it to about 100 to 130°C, then release the mold and take out the molded product. If the temperature is 100°C or higher, even if the mold is immersed in ice water, water will not seep through the mold for a short period of time, and the physical properties of the molded product will not be affected. After taking out the molded product, sterilize it.
Store tightly closed in the presence of inert gas.

The drug thus obtained in the form of a needle-shaped body is administered directly to the local area, but at that time, polyglycolic acids have a slightly faster sustained drug release time than polylactic acid, so if necessary, for example, a molten drug may be used. It is also possible to use the molded product after adjusting the sustained release time of the drug as appropriate by post-treatment such as coating the molded product by immersing it in a polylactic acid solution dissolved in a solvent such as polylactic acid or methylene chloride.

In the method of the present invention, in the case of a polyglycolic acid polymer, a modified polymer such as acetylated polymer can also be used.

Example 28 g of polyglycolic acid with an intrinsic viscosity of 0.7 (measured at 30 ± 0.1°C and a concentration of 0.5% in a mixed solvent of 10 parts by weight of phenol and 7 parts by weight of trichlorophenol), which had been pulverized to a particle size of 150μ or less, was dried in a vacuum dryer. 180 using
After degassing and fluidized drying at a temperature of 5 to 10 mmHg for 3 hours, the mixture was sealed in a container purged with nitrogen gas.

Meanwhile, 12g of 5FU (5-fluorouracil) crystals were powdered and heated to 40-60°C using a vacuum dryer.
After degassing and fluidized drying for 3 hours under a pressure of 5 to 10 mmHg, the mixture was sealed in a container purged with nitrogen gas.

Completely mix the above polyglycolic acid and 5FU using a sample mixer to prepare a polyglycolic acid mixed powder containing 30% 5FU, and add 4g of it.
Preheated at 100-120°C for 5 minutes or more. This preheated mixed powder was used to mold 20 needle-shaped molds with a length of 4 cm and a diameter of 1.5 mm.
The two-piece press mold in which the book was engraved was closed with bolts, and the material was introduced into the pot section of the mold, which was maintained at 225 to 230 degrees Celsius. After maintaining this temperature for 1 to 2 minutes and confirming that the powder in the pot had begun to melt, the powder was press-fitted from the pot into the needle mold at a pressure of 150 to 200 kg/cm ² . After standing still for 30 seconds, the mold was placed in ice water and rapidly cooled to 100 to 130°C in 30 seconds to 1 minute, then taken out from the ice water and air cooled. When the mold was opened by loosening the bolts at a temperature below 100°C, the molded product in the mold could be easily removed from the mold, and there were no cracks. After scraping off the burrs, the resulting 20 4 cm long polyglycolic acid acicular moldings containing 30% 5FU were observed under a microscope, but almost no voids were observed in the moldings. The compressive strength of this needle-shaped molded product over a length of 1 cm in the longitudinal direction was 800 g to 1 kg on average, and it did not break when it was inserted into the abdomen of a rat for about 2 cm.

Comparative Example 28 g of polyglycolic acid with an intrinsic viscosity of 0.7 (measured at 30 ± 0.1°C and a concentration of 0.5% in a mixed solvent of 10 parts by weight of phenol and 7 parts by weight of trichlorophenol), which has been pulverized to a particle size of 150μ or less, was dried in a vacuum dryer. 180 using
After degassing and fluidized drying at a temperature of 5 to 10 mmHg for 3 hours, the mixture was sealed in a container purged with nitrogen gas.

Meanwhile, 12g of 5FU (5-fluorouracil) crystals were powdered and heated to 40-60°C using a vacuum dryer.
After degassing and fluidized drying for 3 hours under a pressure of 5 to 10 mmHg, the mixture was sealed in a container purged with nitrogen gas.

Completely mix the above polyglycolic acid and 5FU using a sample mixer to prepare a polyglycolic acid mixed powder containing 30% 5FU, and add 4g of it.
Preheated at 100-120°C for 5 minutes or more. This preheated mixed powder was used to mold 20 needle-shaped molds with a length of 4 cm and a diameter of 1.5 mm.
The two-piece press mold in which the book was engraved was closed with bolts, and the material was introduced into the pot section of the mold, which was maintained at 225 to 230 degrees Celsius. After maintaining this temperature for 1 to 2 minutes and confirming that the powder in the pot had begun to melt, the powder was press-fitted from the pot into the needle mold at a pressure of 150 to 200 kg/cm ² . After standing still for 30 seconds, remove the mold.
Air cooled to 100-130°C. When the mold was opened by loosening the bolts at a temperature below 100℃ and the molded product in the mold was taken out of the mold, the mold and molded product adhered well and remained in perfect shape, making it difficult to separate from the mold. There were many needles, and only 4 out of 20 polyglycolic acid needle-like molded products containing 30% 5FU with a length of 4 cm were obtained.

Claims (1)

[Claims] 1 Polyglycolic acid or polyglycolic acid
In a method for producing a sustained-release molded drug based on a glycolic acid-lactic acid copolymer containing 80% by weight or more, polyglycolic acid or a glycolic acid-lactic acid copolymer is made into a fine powder and heated at 100 to 200°C. After degassing and drying under reduced pressure, the chemicals are mixed, heated, and introduced into the mold of a press molder maintained at 195-235℃, and after completion of molding, the mold is heated to 100-130℃. 1. A method for producing a needle-like sustained-release molded drug, the method comprising rapidly cooling the drug.