JPS5933214A - Carcinostatic agent formed to microsphere and its preparation - Google Patents

Abstract

PURPOSE:To prepare the titled carcinostatic agent containing homogeneously mixed 1-n-hexylcarbamoyl-5-fluorouracil and polylactic acid, having excellent slow-releasing effect, and suitable for the local application, by dissolving the above components in methylene chloride, and adding the solution to an aqueous solution of gelatin having a specific pH under stirring. CONSTITUTION:A polylactic acid selected from poly-D,L-lactic acid and a copolymer of glycolic acid and >=50% of lactic acid, is dissolved together with <=40wt%, preferably about 10wt% of 1-n-hexylcarbamoyl-5-fluorouracil (HCFU) in methylene chloride at room temperature (the concentration of the polylactic acid is preferably 1-10%). The methylene chloride solution is added to an aqueous solution of gelatin (having a gelatin concentration of 0.3-5%) adjusted to 3.0-6.0pH preferably 4.0-5.0pH with dilute hydrochloric acid, under stirring. The mixture is heated slowly to evaporate methylene glycol and obtain white microspheres having a particle diameter of 10-300mu and consisting of a homogeneous mixture of HCFU and polylactic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION Preparation of 5-fluorouracil in microspheres 1. Regarding sustained-release anticancer agent and method for producing the same. The copolymer and 1-1-hegisyl-rubamoyl-5-fluorouran are homogeneously dissolved in a solid solution, forming granules with a diameter of 1.
Microspheres with a diameter of 0 to 300μ
Sphere) Structure of microsphere control gun cutting, 11
-n-hexol-rubamoyl-5-fluorouracil (
Hereinafter, I- (abbreviated as CFU) is a mask compound of the anticancer drug 5-fluorouracil (hereinafter abbreviated as 5-FU) (15 FU is one of the anti-metabolite anticancer drugs that has pharmacological effects. Although it is known as an excellent drug, it has a short metabolic half-life, is highly toxic, and has the drawbacks of causing gastrointestinal disorders, especially in vivo.

In order to improve these drawbacks, HCFU was recently developed as an anticancer drug.

HCFU has already been established as an anticancer agent with excellent anticancer activity, duration of blood concentration, and low toxicity. i,
It cannot be said that the suppression of gastrointestinal side effects is necessarily zero when given continuously.On the other hand, as a recent anticancer therapy, localized anticancer drugs are administered only to the vicinity of the cancerous area and are directed to normal cells. Preventing side effects 11. At the same time, a dosing method using excipients such as resin in consideration of the sustainability of the medicinal effect,
Research on drug forms is also being actively conducted. 1 Continuously apply the active ingredient ht a! only around the cancer affected area over a long period of time. II. A so-called sustained-release local administration method for delivering a cancer drug is known as C1, for example, an anticancer drug is placed in a capsule, or a tablet or pellet is formed and administered around the local area of the cancer-affected area. A method of embedding an anticancer drug into a polymer +) Jt membrane by coacervasion, or a method of embedding the anticancer drug in a polymer + Jt membrane using coacervasion, or dissolving the polymer and the drug using the same solvent to form a homogeneous solid solution at the molecular level. The precipitated microsphere-formed drug is injected into the muscles or blood vessels around the local area, and the capillaries around the local area are embolized with nuclear capsules or spheres to deliver the drug only to the occluded local blood vessels. Examples include methods that utilize leaching.

When an anticancer drug formulated in microcapsules or microspheres such as 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 need to have a certain sustained release effect, and for that purpose, microspheres encapsulated outside a certain diameter have a uniform coating and are difficult to release into microspheres. The polymer material used as the agent is preferably a bioabsorbable polymer material, but ethyl cellulose, polyvinyl alcohol, etc. are usually used in the preparation of microspheres. Polyglycolic acid and polylactic acid are bioabsorbable polymers, but they have physical property limitations such as polyglycolic acid having a high melting temperature and melt viscosity, and polylactic acid having a low glass transition temperature and high melt viscosity. It is said that uniform microspheres are essential for these bioabsorbable polymers.

For this reason, there are very few examples of microcapsules and microspheres (usually microspheres are also called microgrills) using polyglycolic acid or its 11-mer compound and polylactic acid or its copolymer; Publication No. 54-55717 describes -40 using polylactic acid.
-10 (there is a description that it is carried out under ultra-low temperature conditions of 1°C).

In the above publication, when manufacturing microcapsules at a low temperature of -40 to -1()0°C, the core feed to be encapsulated is insoluble, such as toluene, and polylactic acid is dissolved in a solvent with a low freezing point. When manufacturing trench microspheres by dispersing core material O.1 fine particles using It is manufactured by adding a phase separator such as polyhydric alcohol, which is a non-solvent to the solvent, into a solution 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 microencapsulation can produce a uniform coating! Although it is said that d-microspheres are better in terms of a constant sustained drug release effect, the drug must be completely dissolved in order to form microspheres. 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 that there was one.

While the present inventors were actively investigating microspheres in HCFU microsphere preparations, we surprisingly found that HCFU
Polylactic acid has good compatibility with its copolymer, and the two are homogeneously mixed by solid solution, and when formulated into microsphere granules, it can be used as an anticancer agent with a sustained release effect. In addition, there was no need to carry out the process at ultra-low temperatures or pre-treatment for ultrafine granulation of 11 CF U, and by combining a constant solvent and a specific phase separation agent. , there is no aggregation of microspheres at all,
! 1. ! Uniform II with an average particle diameter of about 200 μm or more is optimal when used in an embolic state in blood vessels around cancerous areas.
It was also found that microspheres of CI"U" could be obtained. The present invention provides a formulated II CF U anticancer agent and a method for producing the same.
-D%L-Lactic acid is a copolymer of lactic acid and glycolic acid with 50% or more of lactic acid, and has an intrinsic viscosity of 0.5 to 1.5 (30±0% in a mixed solvent of 10 parts by weight of phenol and 7 parts by weight of trichlorophenol). Polymers having a concentration (measured at a concentration of 0.5 at 0.1°C) are preferred.

The microspheres made of polylactic acids and HCFU of the present invention can be produced as follows.

Polylactic acids and powdered 11CF'U40 at room temperature
A weight of less than 10% by weight, preferably about 10% by weight, is added to methylene chloride until completely dissolved. It is preferable to use polylactic acids at a dilute concentration of about 1 to 10 parts relative to JM methylene. Apart from this, 0.3 to 5 qb of gelatin
An aqueous gelatin solution is prepared by adjusting the aqueous solution to a P II of 3.0 to 6.0, preferably 4.0 to 5.0, with dilute hydrochloric acid. A gelatin aqueous solution with PI (6,9 or higher) is not preferable because HCFU will be hydrolyzed when a methylene chloride solution is added.If the pH is below 1 PH3, uniform microspheres cannot be obtained.In this acidic gelatin aqueous solution, HcF'
A methylene chloride solution in which U and polylactic acids are dissolved is added under stirring and the temperature is slowly raised to 30 to 60°C, so that the methylene chloride in the solution emulsified in a micellar form evaporates while foaming. If heated for several hours, methylene chloride will be completely removed by evaporation, so remove the upper layer of fruit, filter and separate, 1) Wash and remove remaining gelatin with warm water of Ha ~ 5, and dry in vacuum. , white 71 cross-spheres with a particle size of 10-3 ooμ are obtained, and no methylene chloride remains in the microspheres.

HCF U-containing microspheres flj obtained in this way
IJ cancer agent is made of a biopolymer base of polylactic acids and II C
Ii'U is homogeneously mixed in the form of granules and has a certain sustained release property.

An F1 embodiment is shown below.

Example Intrinsic viscosity value Cη] = o, a: Bo IJ having the following:
D L-lactic acid [phenol/trichlorophenol = 1
After dissolving 1.8I in 40 g of methylene chloride with stirring, 1-n-hexylcarbamoyl-rasyl (IICFU) was dissolved in 40 g of methylene chloride. ) I: Mitsurol "J O,29" manufactured by Mitsui Toatsu Kagaku ■ was added to the solution to completely dissolve nf to obtain a transparent homogeneous solution.

Separately, 2 g of acid-treated gelatin (manufactured by Miyagi Kagaku Hat Co., Ltd., jelly strength 250 μm) was added to 1989 water and dissolved by heating at 50°C to prepare a 1-1 aqueous solution. After cooling to room temperature, PIT was adjusted to 4.5 with J'M acid.

The gelatin aqueous solution was transferred to a 500 ml beaker, the methylene chloride solution was added thereto, stirred and emulsified at 300 rpm for 5 minutes using a 5 ctn paddle-shaped stirring blade, and then methylene chloride was added while gradually heating from the outside. was evaporated, and the internal temperature reached 50° C. in about 30 minutes, and microsphere formation was completed when it was confirmed that the methylene chloride odor had completely disappeared. After removing some aggregates in the upper layer, it was filtered and washed with warm water of pH 4.5, and then air-dried at 50°C to obtain 1.6 g of white spherical microspheres with a particle size of 30 to 200μ. The elemental analysis values are as shown in Table 9. : 1. Uniformly containing 3% HCFU. As a result of the chlorine analysis, the content of methylene chloride was not found to be less than 8.3%.
I (section) N (%) F (section) elemental analysis value '
i9,94 5,84 1.53 0.69 Test Example IT CI” U powder was dissolved in P II 6 physiological saline (N
After dissolving in aClO, Q section) and leaving it for a day and night,
This saline solution decomposed into CI” U or 5-FU [
The IV spectrum was measured and it was confirmed that the absorbance and concentration were proportional.
: 270 nm) ■ 7
0.135■ 14
0.28, (f's) 21,
0.426■ 28
0,551■ 35 0
, 68 II CI" obtained in Example using
50 mg of microspheres containing U9-3%
me in physiological saline and directly on each measurement day.
The UV spectrum was measured immediately after me sampling and the results shown in the table below were obtained.6 Days] 4
6 7 8 II 15 20 elution 5-FU (p
pm) 7.5 19 22 24 26 31 3
6 38 Elution rate (%) 4 10 12 13 1
a 17 1ta From Table 20, it was confirmed that the +1 CF U anticancer drug formulated in the microspheres obtained in the example had a long-term sustained release effect.
Patent 111 violation≦! r1 person Mitsui Toatsu Chemical Co., Ltd.

Claims (2)

[Claims] (1) An anticancer agent formulated into microspheres made of a homogeneous mixture of I-n-hexylcarbamoyl-5-fluorouracil and polylactic acid or a copolymer thereof. , (2) A solution of -n-hexylcarbamoyl-5-fluorouranordopolylactic acid or its copolymer dissolved in methylene chloride is added to an aqueous gelatin solution maintained at pH 3 to 6 with a stirring knife; A method for producing an anticancer agent formulated into microspheres made of 1-n-hexylcarbamoyl-5-fluorouracil and polylactic acid or a copolymer thereof.