JPS58213708A - Preparation of molded bar drug having prolonged effect - Google Patents

Abstract

PURPOSE:The titled drug capable of being directly inserted and applied to the affected part, obtained by pulverizing polyglycollic acid or a glycollic acid- lactic acid copolymer, deaerating and drying it under reduced pressure, blending it with a drug, preheating the blend, feeding it to a mold at constant temperature under pressure, molding it. CONSTITUTION:Polyglycollic acid or a glycollic acid-lactic acid copolymer having >=80wt% polyglycollic acid is pulverized, deaerate and dried at 100-200 deg.C under 5-10mm.Hg reduced pressure for 2-3hr, low-volatile components in the polymer are completely volatilized. 100pts.wt. above-mentioned polymer is mixed with 20-40pts.wt. drug (e.g., carcinostatic agent such as 5-fluorouracil, etc.), preheated, fed to a mold kept at 195-235 deg.C, and molded into a needle-like material having 1.5mm. diameter and about 3cm length. The strength of the molded drug is raised by the deaeration treatment, and low-boiling organic impurities and air will not get into the body.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides polyglycolic acid or polyglycolic acid
The present invention relates to a method for producing a sustained-release molded drug based on a glycolic acid-lactic acid copolymer containing 0% or more. More specifically, the present invention relates to a method for mixing a drug with these polyglyfuric acids and molding the mixture into a rod-shaped sustained-release 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 anti-convulsants are molded into tablets, pellets, or capsules using bioabsorbable polymeric materials as a base material to continuously supply drugs 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 by directly inserting a needle into the affected area without damaging the affected area or its surroundings, as one of the administration forms. The method of the present invention is a manufacturing method thereof, in which bioabsorbable aliphatic polyester such as lactic acid is added to polyglycolic acid or glycolic acid.
This is a method for producing a sustained-release molded drug in the form of a rod, using polyglycolic acids copolymerized to a weight ratio of 0 or less as a drug base material.

Polyglycolic acid, which is usually used for medical molding, has a melting point of 218-220°C and a decomposition temperature of 260°C, and a polyglycolic acid copolymer containing 20% of lactic acid has a melting point of 182-185"O and a decomposition temperature of 260°C. It is a solid polymer having physical properties of about 257 to 260°C.

When polyglycolic acid is formed into surgical sutures, it is usually spun at 240 to 250°C. Since polyglycolic acids have a relatively narrow range between their melting point and decomposition temperature and have a high melt viscosity, they not only require strict conditions for molding, but also produce molded products that are hard and brittle.

Therefore, there are naturally limitations to its use.In the present invention, polyglycolic acid and its copolymer are used as a base material for a molding agent formed into a rod-shaped body. It takes advantage of strength.

When a drug is mixed with polyglycolic acids and formed into a rod-shaped body, other polymers such as cellulose, which are known as bioabsorbable polymeric materials, are usually used, which makes it easier to administer the drug by pricking into the affected area of the body. Although it is easy, it has drawbacks such as its brittleness and the possibility of breaking, especially when the diameter is small.

Usually, polyglycolic acids are obtained in bulk or molten form by bulk or solution polymerization.

This is crushed and used for molding, but the polymer contains low-boiling volatiles such as trace amounts of solvent during polymerization and unreacted products and by-products of the monomer glycolide.
If this is directly melted in a heating bath and molded into a mold,
Low-boiling substances that cannot be removed from the special mold become bubbles and remain as cavities (voids) in the molded product. If a rod-shaped molded product forms a nest, it becomes more susceptible to breakage (not only that, but what is even more important in the case of molded drugs is that when the molded product is inserted into a living body, the low-boiling organic impurities that form the nest will break). When taking a bath or storing molded chemicals, the air trapped in the nest enters the body.

The present inventors solved the above problems and at the same time conducted extensive research into a method for molding polyglyfuric acids as a sustained-release molded drug without reducing its medicinal properties when used as a molding base material for drugs such as polyglyfuric acids. , which has completed the method of the present invention.

That is, in the method of the present invention, before molding, a polymer of polyglycolic acids is pulverized, this is pretreated by drying and degassing under reduced pressure, and then a drug powder is mixed and heated, and then a constant By press-fitting in a mold that is maintained at a constant temperature, a rod-shaped product with high strength and almost no cavities is created.
Moreover, it is a method for producing a rod-shaped sustained-release molded drug in which drug components are uniformly distributed without PS.

In the method of the present invention, the rod-shaped drug is a drug having a decomposition temperature higher than the bath 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, and is formed into a rod-shaped body that can be inserted into a living body.

The rod-shaped body is a so-called needle-shaped body with a diameter of 1.5 dragons or less and a length of 6 harmonies or more with a pointed tip, or a plate-shaped object with a constant thickness of about 2 dragons or more is made into a rod shape. It is a rod-shaped body that is cut into a length of about 1 cm and inserted into the body using a plunger, but needle-shaped molded bodies are used because of the ease of molding using a mold and the convenience of administration. is preferred and the method of the invention is particularly suitable for this production.

In order to obtain an acicular molded product, the mixed powder deaerated by pretreatment is melted and compressed into a mold having a plurality of acicular molds that are maintained at a predetermined temperature in advance. The molding equipment is a pot-type transfer molding machine equipped with a cooling device, or a pre-treated mixed powder is preformed into a pellet shape, which is then continuously molded using an injection molding machine using a method similar to transfer molding. It can also be molded, but the drug content,
It is necessary to change the molding time settings as appropriate depending on the physical properties of the polymer and the shape of the needle-shaped body. Deterioration is more likely to occur. In the case of needle-shaped molding, the polymer is melted in a heating bath, press-fitted into the mold, and then rapidly cooled to around 100 to 160° C., so that the molded product does not break when taken out and can be easily peeled off. Therefore, in the present invention, it is preferable to use a press molding machine that can freely cool the mold or that can be rapidly cooled instantly, and that has a pot for melting the powder and presses the molten material into the mold. A simple press molding device with a pressure-resistant mold is sufficient, and it is preferable to carry out the process in batches using this.

Method t1 of the present invention When carrying out the process using a press molding machine, it may be carried out in the following manner, for example.

The finely powdered monocopolymer is prepared at a predetermined temperature between 100 and 200'0, for example, the copolymer with lactic acid is preferably heated at a temperature of tL<100 to 1.
40°C1 polyglycolic acid polymer is 120-180°C
So, under reduced pressure, preferably 5 to 10 mmH,! The powder was subjected to degassing and fluidized drying for 2 to 6 hours using a vacuum dryer under the pressure of i' to completely degas the low volatile matter contained in the heavy metal powder, replacing it with an inert gas, and sealing it. Also, the chemicals to be mixed are powdered and, if necessary, dried under reduced pressure at 40 to 60 degrees Celsius to remove moisture and sealed in the presence of an inert gas. 70% of the drug is added to the polymer powder
% or less and mix thoroughly. 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 molding is not performed immediately after pretreatment and mixing, a preheating step may be provided if necessary to complete heating, and the mixture is introduced into a press mold pot preset at a predetermined temperature between 195 and 265°C.

If the temperature before introduction is too low, it will take too much time for melting during molding, and if it is too high, the drug may decompose, which is not preferable. The molding temperature after being placed in the mold pot is maintained at a predetermined temperature. If the temperature is lower than the predetermined temperature, the polymer may not be completely bathed, causing phase separation from the drug and making it easier to form cavities. . In addition, if molding is performed at a temperature higher than the specified temperature, not only will the drug decompose, but even if the polymer is pretreated, air bubbles will form and there will be a tendency to form cavities. When the temperature is 195 to 210°C, the temperature is preferably 195 to 210°C.

The mixed powder introduced into the mold bond will normally melt if it is held at this temperature for 1 to 5 minutes, depending on the amount, so the inside of the mold will immediately become distorted under a pressure of 20 to 300 kvcd. Li, it is attached to the formwork and can be taken out from 100"C
After cooling rapidly to about 130'0, it is desirable to release the mold and take out the molded product. After taking out the molded product at 100'O or more, the molded product is sterilized and stored in a sealed state in the presence of an inert gas.

In the method of the present invention, in the case of polyglycolic acid polymers, modified polymers such as 7-cetylated polymers can also be used.

Example: Finely powdered to a particle size of 150μ or less, intrinsic viscosity 07 [Fenono L 10 M-1 part and Triku pR Phenol 7]
Parts by weight of polyglycolic acid 28I (measured at 30±0.1°C in a mixed bath medium at a concentration of 05%) was degassed and fluidized for 3 hours at 180°C under a pressure of 5 to 10 imHg using a vacuum dryer. After that, the container was sealed with nitrogen gas. On the other hand, 5FU (5-fluorouracil) crystals were powdered and 11 was heated to 5 to 10 m at 40 to 60°C using a vacuum dryer.
After degassing and fluidized drying for 6 hours under a pressure of 1H19, nitrogen/'7
The container was sealed and replaced with gas.

The above polyglycolic acid and 5F'U were completely mixed using a sample mixer to prepare a polyglycolic acid mixed powder containing 5FU30X, and the 4I was mixed with 100
Preheat at ~120℃ for 5 minutes or more. This preheated T-mixed powder is then closed with bolts into a two-part press mold in which 20 needle-shaped molds with a length of 4 cm and a diameter of 1.5 cm are carved, and the powder is heated at 225 to 265 degrees. The pot part KS in the mold was held by C. After keeping at this temperature for 1 to 2 minutes, the powder in the pot will begin to melt in the bath.1 After this is confirmed, 150
Pressure was applied from the hot part into the needle mold at a pressure of ~200 kg/d. After cooling for 60 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 cooled in air. If the mold is opened by loosening the bolts at a temperature below 100°C, the molded product in the mold can be easily ejected from the mold, and there is no cracking. After scraping off the ri, 20 acicular molded products of polyglycolic acid containing 30% 5FU, each having a length of 4 cm, were observed under a microscope, but almost no voids were observed in the molded products. In addition, the compressive strength of this acicular molded product over a length of 1 crn in the good book direction is 800 g on average.
It weighed 1 kg, and was inserted into the abdomen of a rat (σ) for about 2 cm, but it did not break.

Patent applicant: Mitsui Toatsu Chemical Co., Ltd. Procedural amendment (voluntary) June 1982
July 10th, Commissioner of the Japan Patent Office Shima 1) Haruki Tono 1 Indication of the case Date of June 1982 Patent application 2 Name of the invention Process for manufacturing a rod-shaped sustained release molded drug 3 Relationship with the amended person case Patent Applicant Address: 3-2-5 Kasumigaseki, Chiyoda-ku, Tokyo Column 5 of "Detailed Description of the Invention" of the Specification, Contents of Amendment Line (2) Page 9 of the Specification, 2nd line from the bottom and the first line ~ Insert the following sentence between.

[The rod-shaped drug thus obtained is administered locally using an auxiliary device such as an i-contact or a plunger, but in this case, po-1-nog-1-nocholic acids are more effective than polylactic acids. Since the sustained release time is somewhat fast, if necessary, the sustained release time of the drug can be adjusted as appropriate by post-treatment such as coating the molded product by immersing it in molten polylactic acid or a polylactic acid solution dissolved in a solvent such as methylene chloride. You can also use it after adjusting it. "that's all

Claims (1)

[Scope of Claims] 1. A method for producing a sustained-release molded drug based on polyglycolic acid or a glycolic acid-lactic acid copolymer containing 80% by weight or more of polyglycolic acid, - Make the lactic acid copolymer into a fine powder, dry it at 100-200°C under reduced pressure, mix it with the drug, preheat it if necessary, and heat it to 195-200°C.
Method 2 for producing a rod-shaped sustained-release molded drug, characterized in that the drug is introduced into a mold maintained at 5°C and molded, and the rod-shaped drug is shaped into a needle that can be inserted into a living body The method according to claim 1, which is a product. 3. The method according to claim 1, wherein the drug to be mixed is an anticancer drug having a decomposition temperature of 250° C. or higher. 4. Perform molding using a press molder,
A method according to claim 1. 4. After press-fitting into the mold of the breath molding machine and completing molding, 100
5. The method of claim 4, wherein the mold is rapidly cooled at ~130°C.