JPH0363532B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 1-n-hexylcarbamoyl-5
- A sustained-release anticancer drug containing fluorouracil in microspheres and a method for producing the same. In the present invention, "an anticancer agent formulated into microspheres" refers to granular particles with a particle size of 10 to 100, in which polylactic acid or its copolymer and 1-n-hexylcarbamoyl-5-fluorouracil are homogeneously solid-solubilized.
Micro sphere with 300μ
It is an anticancer drug with a microsphere structure. 1-n-hexylcarbamoyl-5-fluorouracil (hereinafter abbreviated as HCFU) is a mask compound of the anticancer drug 5-fluorouracil (hereinafter abbreviated as 5-FU). Although 5-FU is known to have excellent pharmacological effects among anti-metabolite anticancer drugs, it has short metabolic half-life, strong toxicity, and has the drawbacks of causing gastrointestinal disorders, especially in vivo. In order to improve these drawbacks, HCFU has recently been developed as an oral anticancer drug.
HCFU already has a good reputation as an anticancer agent with excellent anticancer activity, long blood concentration, and low toxicity. However, if administered in large doses and continuously over a long period of time as an oral anticancer agent, it is difficult to suppress side effects in the digestive system. It cannot necessarily be said that it is zero. On the other hand, recent anticancer therapy involves administering locally administerable anticancer drugs only to the vicinity of the cancerous area to prevent side effects on normal cells, and at the same time using excipients such as resins to maintain drug efficacy. method and
Research on drug forms is also being actively conducted. The so-called sustained-release local administration method that continuously supplies an active ingredient amount of the anticancer drug only to the vicinity of the cancer-affected area over a long period of time is known, for example, by putting the anticancer drug in a capsule or tablet. There are two methods: embedding the molded product into a pellet form around the cancer-affected area, micro-encapsulating the anti-cancer drug with a polymer coating using coacervation, or using the same solvent as the polymer and the drug. A microsphere-formed drug that is dissolved, homogeneously dissolved and precipitated at the molecular level into microspheres is injected into the muscles or blood vessels around the local area, and is placed in the capillaries around the local area in the form of nuclear capsules or spheres. Examples include a method that utilizes the exudation of a drug only into a local blood vessel that has been embolized and occluded. When an anticancer agent formulated into microspheres such as microcapsules or microspheres is used for embolization of local and peripheral blood vessels, it is generally required to have a uniform particle size of about 200 μm or less. In addition, these microspheres must have a certain sustained release effect, and for that purpose, microspheres with a fixed particle size must have a uniform coating, and microspheres must have a uniform coating. It is necessary to formulate to have homogeneous mixing. In addition, bioabsorbable polymeric materials are preferable for the polymers used as coatings and mixed bases for forming microspheres, but ethyl cellulose, polyvinyl alcohol, etc. are usually used for microsphere formulations. . polyglycolic acid,
Polylactic acids are bioabsorbable polymers, but they have physical property limitations such as polyglycolic acid's high melting temperature and high melt viscosity, and polylactic acid's low glass transition temperature and high melt viscosity. It is said that it is difficult to obtain uniform microspheres using absorbent polymer materials. For this reason, there are very few examples of using polyglycolic acid or its copolymer and polylactic acid or its copolymer in microcapsules or crocospheres (microspheres are also called microprills); -55717 publication describes that polylactic acid is used under ultra-low temperature conditions of -40 to -100°C. In the above publication, when manufacturing microcapsules at a low temperature of -40 to -100°C, the core material to be encapsulated, such as toluene, is insoluble, and polylactic acid is dissolved using a low freezing point solvent. When dispersing core material fine particles and manufacturing microspheres, both the polymer and the atomized drug core are dissolved using a solvent such as toluene and chloroform, and the solvent is dissolved in these low-temperature solutions. It is manufactured by adding a phase separating agent such as a polyhydric alcohol, which is a non-solvent, to precipitate capsule particles or precipitate particles. Normally, in the case of anticancer drugs formulated into microspheres, the shape of the finely powdered drug particles is not uniform, so it is difficult to obtain a uniform coating with microencapsulation. However, in order to make microspheres, it is necessary to completely dissolve the drug. However, as stated in the above-mentioned publication, at ultra-low temperatures, there are very few solvents that can commonly dissolve polylactic acid or its copolymer and known anticancer agents. It seems to be hot. The present inventors have been intensively investigating microspheres in HCFU microsphere preparations, and have surprisingly found that HCFU has good compatibility with polylactic acid or its copolymer, and both can be combined by solid solution. It was found that a product that was homogeneously mixed and formulated into microspheres in the form of microsphere granules had a large sustained release effect as an anticancer agent. Moreover, it can be carried out at ultra-low temperatures and HCFU
There is no need for pre-treatment to make the particles into ultra-fine particles, and by combining a specific solvent and a specific phase separation agent, there is no aggregation of microspheres at all, making it especially suitable for use in an embolized state in blood vessels around cancer-prone areas. It was also found that uniform HCFU microspheres with an average particle size of about 200μ or less could be obtained. The present invention provides 1-n-hexylcarbamoyl-5
- Provides an HCFU anticancer agent formulated into microspheres made of a homogeneous mixture of fluorouracil and polylactic acid or a copolymer thereof, and a method for producing the same. The polylactic acid or its copolymer used in the present invention is a copolymer of poly-D, L-lactic acid, or glycolic acid containing 50% or more of lactic acid, and has an intrinsic viscosity of 0.5 to 1.5 (10 parts by weight of phenol and trichlorophenol). 7
(measured at a concentration of 0.5% by weight at 30±0.1°C in a mixed solvent) is preferred. Microspheres made of polylactic acids and HCFU of the present invention can be produced as follows. At room temperature, polylactic acids and powdered
40% by weight or less of HCFU, preferably about 10% by weight, is added to methylene chloride and completely dissolved. It is preferable to use polylactic acids at a dilute concentration of about 1 to 10% relative to methylene chloride. Apart from this, gelatin
A 0.3 to 5% aqueous gelatin solution is prepared by adjusting the pH to 3.0 to 6.0, preferably 4.0 to 5.0, with dilute hydrochloric acid. An aqueous gelatin solution with a pH of over 6.0 is unfavorable because HCFU will be hydrolyzed when a methylene chloride solution is added, and a gelatin solution with a pH of less than 30 will not yield uniform microspheres. A methylene chloride solution in which HCFU and polylactic acids were dissolved was added to this gelatin acidic aqueous solution while stirring, and the solution was stirred for 30 minutes.
When the temperature is raised to ~60°C, the methylene chloride in the emulsified micellar solution evaporates while foaming. If heated for several hours, methylene chloride will be completely removed by evaporation, so the upper layer of aggregates will be removed and over-separated.
By washing off residual gelatin with warm water of pH 4 to 5 and drying in vacuum, white microspheres with a particle size of 10 to 300μ are obtained, and no methylene chloride remains in the microspheres. . The thus obtained HCFU-containing microsphere anticancer agent has a biopolymer base of polylactic acids.
HCFU is homogeneously mixed in granular form,
It has a certain sustained release property. Examples are shown below. Example 1 Poly DL lactic acid having intrinsic viscosity [η] = 0.63 [measured at 0.5% concentration at 30°C in a mixed solvent of phenol/trichlorophenol = 10/7 (weight ratio)]
After dissolving 1.8 g in 40 g of methylene chloride with stirring, 1-n-hexylcarbamoyl-5-fluorouracil (HCFU) [manufactured by Mitsui Toatsu Chemical Co., Ltd.,
0.2 g of Miflor (trade name) was added and completely solubilized to obtain a transparent homogeneous solution. Separately, add 2 g of acid-treated gelatin [manufactured by Miyagi Chemical Co., Ltd., Jelly Strength 250 Bloom] to 198 g of water, and add 50 g of gelatin to 198 g of water.
A 1% aqueous solution was prepared by heating and dissolving at °C, and after cooling to room temperature, the pH was adjusted to 4.5 with dilute hydrochloric acid. The gelatin aqueous solution was transferred to a 500 ml beaker, the methylene chloride solution was added thereto, and the mixture was emulsified by stirring at 300 rpm for 5 minutes using a 5 cm paddle-shaped stirring blade.
The methylene chloride was evaporated while being gradually heated from the outside, and it took about 30 minutes for the internal temperature to reach 50°C. After confirming that the methylene chloride odor had completely disappeared, microsphere formation was completed. After removing some aggregates in the upper layer, the mixture was filtered and washed with warm water of PH4.5, and then air-dried at 50°C to obtain 1.6 g of white spherical microspheres with a particle size of 30 to 200 μm. The elemental analysis values of the microspheres were as shown in the table below, and they uniformly contained 9.3% HCFU. Furthermore, as a result of chlorine analysis, no methylene chloride was found to be present at all. C(%) H(%) N(%) F(%) Elemental analysis value 49.94 5.84 1.53 0.69 Example 2 L-lactic acid-glycolic acid copolymer (L-lactic acid/glycolic acid) having intrinsic viscosity [η] = 0.75 Acid=
Using 1.8 g of 95/5 mol %), 1.58 g of white spherical microspheres were obtained in the same manner as in Example 1. According to elemental analysis values (F%=0.70, N%=1.55), it contained 9.5% HCFU. Comparative Example By the same operation as in Example 1, poly DL lactic acid,
A clear homogeneous solution of methylene chloride and HCFU was obtained. Separately, prepare a 1% aqueous solution of acid-treated gelatin, and adjust the pH to 8 with 0.1N aqueous sodium hydroxide solution.
It was prepared as follows. Using these two solutions, microspheres were formed in the same manner as in Example 1. After removing some aggregates in the upper layer, filtration and pH=
After washing with warm water from Step 8, air dry at 50℃ to obtain a particle size of 30.
1.6g of white spherical microspheres of ~200μ were obtained. The degradation of HCFU was investigated by thin layer chromatography. That is, the obtained microspheres were dissolved in anhydrous methylene chloride, spotted on a silica gel plate, and developed with a benzene/acetone mixture (5/3). A weak spot with an Rf value of about 0.7 is a spot with an Rf value of about 0.7.
A strong spot was detected at 0.15. The former is
HCFU, the latter was identified as 5FU, a degradation product. On the other hand, in the microspheres prepared in Examples 1 and 2, only HCFU spots with an Rf value of about 0.7 were observed. Test example: HCFU powder in physiological saline (NaCl 0.9%) at PH6
After dissolving in HCFU and leaving it for a day and night, the eluted HCFU becomes 5-FU.
The UV spectrum of this saline was measured, and it was confirmed that the absorbance and concentration were proportional, and the following calibration curve was created.

[Table] HCFU9.3% obtained in the example using this
100 mg of the contained microspheres was put into 50 ml of physiological saline, 1 ml to 3 ml was directly sampled on each measurement day, and the UV spectrum was immediately measured to obtain the results shown in the table below.

[Table] From the table, it was confirmed that the HCFU anticancer agent formulated into the microspheres obtained in the Examples had a long-term sustained release effect.

Claims (1)

[Claims] 1. A solution of 1-n-hexylcarbamoyl-5-fluorouracil and polylactic acid or a copolymer thereof dissolved in methylene chloride is added to an aqueous gelatin solution maintained at pH 3 to 6 under stirring. 1-n-hexylcarbamoyl-5-
A method for producing an anticancer agent formulated into microspheres made of fluorouracil and polylactic acid or a copolymer thereof.