JPS58216117A - Preparation of rod-shaped slow-releasing formed drug - Google Patents

Abstract

PURPOSE:To prepare the titled drug which can be thrusted directly into the diseased part and is resistant to break, by adding a drug to polylactic acid or a lactic acid-glycolic acid copolymer, mixing the composition under melting, removing the low-boiling components under reduced pressure, and molding the mixture in a mold. CONSTITUTION:A drug is added to a polylactic acid or a lactic acid-glycolic acid copolymer containing >=30wt% of polylactic acid, and mixed in an inert gas stream under heating and melting at 220-240 deg.C. At an arbitrary stage, the low-boiling volatile components in the polymer are removed under reduced pressure. The degassed mixture is molded preferably by compression molding to obtain a rod-shaped product such as a needle. After the completion of molding, the mold is preferably quenched to 5-10 deg.C, and the needle is released from the mold. The drug is e.g. a carcinostatic agent having a decomposition point of >=250 deg.C (e.g. 5-fluorouracil), etc. Since the formed product is free from voids because of the degassing process, it is resistant to break, and prevents the intrusion of low-boiling components and air into the body.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a sustained-release molded drug based on polylactic acid or a lactic acid copolymer containing 30% or more of polylactic acid. More specifically, the present invention relates to a method of mixing a drug with polylactic acid or polylactic acids prepared by copolymerizing lactic acid with glycolic acid having a content of 70% by weight or less based on the lactic acid, and molding the mixture into a rod-shaped body as a sustained-release molded drug.

Aliphatic polyesters such as polylactic acid, polyglycolic acid, and their copolymers are bioabsorbable and hydrolyzable polymers, and their properties are used to process them into medical sutures, etc. ing.

In addition, in the recent medical field, drugs with strong side effects such as anticancer drugs are made into tablets made of bioabsorbable polymeric materials.
``There is also active research into administration methods that continuously supply drugs over a long period of time by forming them into Ishipe-1/Normal or capsule shapes.''
(be.

Non-applicant wo - [, One of the forms of throwing is injury to the affected area and its surroundings - IL7. We have previously provided a new sustained-release molded drug that can be directly inserted into the affected area in the form of a needle. This is a method for producing a sustained-release molded drug.

Polylactic acid, which is usually used for medical molding, has a melting point of 58-60°C and a decomposition temperature of about 265°C.
1-71 acid co-compound 11 has a melting point of 53 to 54°C and a decomposition temperature of about 24'i 5' (3, 1-71 acid copolymerization containing 70% by weight of glycolic acid). The product is an amorphous thermal caustic polymer having physical properties of a melting point of 165 to 145"0 and a decomposition temperature of about 258"0. Polymers have a low melting temperature but a high decomposition temperature (σ), so when used for bulk molding of lumps, it is much easier to mold than polyglycolic acid, but it is usually not obtained as a crystalline product. Since there is no powder, if you try to use it for molding in powder form,
Polylactic acids have a low glass transition temperature (buildability), making it difficult to make them into fine powder, and their melts are viscous, making it difficult to form medical moldings using polylactic acids. There were restrictions.

In the present invention, polylactic acid and its copolymer containing a small amount (at least 60%) of polylactic acid are used as a base material for a molding agent to be molded into a rod-shaped body, and a bioabsorbable polymer material is used as a base material. This takes advantage of the strength and flexibility of lactic acid and its copolymers.

As mentioned above, since it is difficult to make the polylactic acids used in the present invention into a fine powder, a crystal or powdered drug is mixed with the polymer in the form of lumps or chips, and the mixture is then molded into a rod-like body as a molding agent. However, a molded article having a uniform drug composition cannot be obtained. In addition, the polymer obtained by cutting ordinary lumps into chips contains low-boiling volatile components that are used in 1-coating and are unreacted. If this is heated and melted as it is and subjected to mold molding, the low boiling point substances will not be able to escape from the mold during molding and will become bubbles, forming cavities (voids) in the molded product.
What remains? If a molded rod-shaped product forms a nest, it is often prone to breakage when the molded drug is administered and inserted.More importantly, in the case of a molded drug, if the molded product is inserted into the cow's body, it may form a nest. Volatile components, which are low boiling point impurities, may be eluted into the body, or during storage of molded drugs,
The air held in the nest enters the body.

The present inventors have solved the above problems and at the same time developed a method V in which polylactic acids are used as the molding base 4A of a drug to form a sustained-release molded drug without reducing its medicinal component. As a result of intensive study, the method of the present invention was completed.

That is, in the method of the present invention, polylactic acid or polylactic acid is added at 60% by weight.
In the method for producing a sustained-release molded drug using the lactic acid-glycolic acid copolymer containing the above, (5) the drug-added polylactic acid or copolymer is added to 220 to 24
The drug is mixed by heating and melting to 0"0, and at this time, the pressure is reduced at any time to degas the low boiling point substances in the polymer, and the thus obtained drug-containing polylactic acid or copolymer is In this method, a preformed product is preheated if necessary to a temperature below the melting point of the preformed product, and then introduced into a mold and molded.

In the method of the present invention, the rod-shaped body forming agent means a temperature higher than the temperature carried out in the preforming step of the present invention, that is, preferably 250 °C.
A drug having a decomposition temperature of °C or higher, for example, a known anticancer agent such as 5-fluorouracil or mitomycin, is added to 100 parts by weight of polylactic acid and contains 70 parts by weight or less, preferably 20 to 40 parts by weight, and is injected into the living body. It is molded into a rod-shaped body that can be inserted. As a rod-shaped body, the diameter is 1.
1 crn, which is a so-called needle-shaped product with a pointed tip that is about 5 am or less and a length of about 3 cm or more, or a plate-shaped product that has a constant thickness of about 2 dragons or more and is cut into a rod shape.
A rod-shaped body (6) with a length of about A molded article with f L <, the method of the present invention is particularly suitable for this production.

To mold a sword-shaped product from a pre-flffi molded product mixed with a drug, the preform in the form of nitrogen or pellets is heated to a predetermined temperature and then compressed in a needle-shaped mold. Force 1 that can be press-fitted into the molded area that only needs to be molded
Even if you use a normal 1-type transfer molding machine or injection molding machine that has a pressure-resistant full mold setting that can connect a group-bo/p,
J: However, it is necessary to change the settings during the molding 110 as appropriate depending on the content of the drug in the preform, the physical properties of the polymer, and the shape of the rod. Is compression molding using an injection molding machine or the like a melting process? in-tome +
1; '1 The time is long (and the chemical deteriorates easily).In addition, in the case of cylindrical molding, it is better to melt the polymer in a heating bath and then quickly cool it after press-fitting into the mold, making it easier to peel off the molded product. So,
It is preferable to carry out the process in a hatch using a press molding machine whose mold can be freely removed or which can instantly cool the mold.

When carrying out the method of the present invention using a press molding machine,
For example, it may be implemented as follows.

The monopolymerized product is prepared in the form of chips or pellets, preferably kept under reduced pressure at room temperature and pre-degassed, and after adding a predetermined amount of dried drug thereto, it is placed in a closed container with ventilation holes. 220 to 240 while stirring in an inert gas stream.
Melt by heating at °C. At that time, if necessary, for a short time under high-speed stirring, usually for 2 to 5 minutes 5 to 10i + mH#
The low boiling point volatiles in the polymer are degassed at a pressure of . If the degassing time is long, the chemical will sublimate due to the degassing at high temperatures.

The temperature during deaeration and melting of the polymer is 220 to 240°C, and below 220"C, deaeration will not be completed completely.
Furthermore, uniform distribution of the drug into the molten polymer can be obtained.

In addition, if the temperature exceeds 2 4 ()'0, the chemical will sublimate or decompose and will not be launched.After degassing, inert gas is introduced to return the inside of the container to normal pressure, and moisture and oxygen from the outside are removed from the container. It is preferable to prevent the liquid from flowing inside and to take it out quickly after melting.

In this way, the drug is uniformly mixed, and the degassed polymerization melt is taken out as an iffi polymer, cooled, and cut into chips or pellets for compression molding. A. However, in order to shorten the molding time and suppress the sublimation of the drug, it is necessary to heat it before molding, and do not perform subsequent molding after preforming.
・If necessary, a preheating process is provided if necessary. The heating temperature preheated at the time of introduction before molding is a temperature below the melting point of the preform, preferably about 10° C. lower than the melting point of the bath. When using a lactic acid copolymer containing 40% by weight or less of polylactic acid or polyglycolic acid, heat the lactic acid copolymer containing 50 to 70% by weight of polyglycolic acid at about 50 to 55°C. Time to use! Heat to a temperature of about 80 to 120℃.
) is desirable. The mold temperature during molding is preferably 10 to 20°C or higher than the melting point of the preform. When using a polymer, the temperature is about 65P-80℃, and when using a lactic acid copolymer containing 50 to 70% by weight of polyglyco/L acid, it is about 11 [
] to 150°C is preferable.

It is preferable that the mold pot of the press molder be preheated to the molding temperature in advance.As soon as the heated preform is introduced into the mold pot, it will start melting, so the mold pot will be 20 to 300 kg/c++ immediately after bath melting! If you have a mold that can be easily removed after molding, you can put it in ice water for a short time to quickly cool it, then cool it in air and then take it out. In the method of the invention, it is preferable to perform rapid cooling to 5 to 100°C, so it is preferable to use a mold equipped with a cooling device that can instantaneously cool down to this temperature. (10) After taking out the molded product 1 molding 11! ! It can be sterilized and used inactive.

Example Intrinsic viscosity 0.6 [: 3 in a mixed solvent of Noenol (10 parts by weight) and Tric I-IrJ phenol (7ill parts)
0: + 0.1-(IJ, concentration ['1.5 i at j6
65g of polylactic acid (chips) and 51-"
Mix 15.1% of U (5-fluorouracil) powder, put it in a 300 ml Separanol cylindrical HNOS, degas it for 5 minutes in a room under reduced pressure of 5 to 10 mmH, and then degas it with argon gas. Replaced.

When the flask was heated at 231 J to 24 D-0 for 5 minutes, the polymer began to melt in the bath, so 11.1 to 2 Or, p, m
Stir for 5 minutes at a rotational speed of
The mixture was stirred for 5 minutes using Or and pom.

Stop the people of Fulgonkas, 100-200r, p,
The average weight was 380 gr when measured over a length of m(11) 1 ca.

After degassing for 2 minutes by reducing the pressure to 5 to 10 gmH, 9 while stirring, the stirring was stopped, and the contents were poured into the hat from the 0 flask to return to normal pressure by flowing an argon gas stream. After cooling to around 100°C, cut into chips to obtain preformed product 45 of polylactic acid-5FU composition.
I got g. Weighed out 4g of it and preheated it at 50 to 55°C for 20 minutes or more.Meanwhile, a mold part carved to mold 20 needles with a length of 4cIn and a diameter of 1.51m and a pot part were prepared. , closed with two molded bolts, 70
'C heating to L? , = 0 Then, put the preheated preform into the pot part of the mold, and immediately after melting, the temperature was reduced to 200 to 9/c.
It was press-fitted from the pot section into the mold section at a pressure of d.

After letting it stand for 2-3 minutes, rapidly cool the mold for 1-2 minutes for 5-10 minutes.
After cooling to ℃, the temperature was returned to room temperature, the bolts were loosened to open the mold, and the molded product was taken out from the mold.

After scraping off the firmness, 20 5FU30X-containing polylactic acid I-shaped molded products each having a length of 4 cm were obtained. This needle-shaped molded product was observed under a microscope, but no voids were observed. The compressive strength of this molded product in the longitudinal direction is (12) Patent applicant: Sangatsu Toatsu Chemical Co., Ltd. (15)

Claims (1)

[Claims] 1. Polylactic acid or polylactic acid to which a drug has been added is used in a method for producing a sustained-release molded drug based on a lactic acid-glycolic acid copolymer containing 30% by weight or more of polylactic acid. Alternatively, the copolymer is heated and melted at 220 to 240°C and the drug is mixed, and at this time, low-boiling volatile components in polylactic acid or the copolymer are degassed, and the drug thus obtained is contained. A rod-shaped product characterized in that a preformed product of polylactic acid or a copolymer thereof is preheated if necessary to a temperature below the melting point of the preformed product, and then introduced into a mold and molded. A method for producing a sustained-release molded drug. 2. The method according to claim 1, wherein the rod-shaped drug is a needle-shaped product that can be inserted into a living body. 6. 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. (1) 4. The method according to claim 1, wherein the rod-shaped body is molded using a press molder. 5. After completing the mold forming with the press molder, press the mold 5 to 1
6. The method according to claim 4, in which the polylactic acid or copolymer added with the drug is heated and melted in an inert gas stream. Method.