JPS6048485B2 - Method for producing sustained release complex containing bleomycin hydrochloride - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to sustained release complexes containing pleomycin hydrochloride.

In order for a drug to effectively exert its effects, it must reach the diseased tissue site; when administered orally, it is absorbed from the gastrointestinal tract and reaches the diseased tissue via the blood; Because the effects are not only local but systemic, side effects are often a problem.

Furthermore, much larger doses of drug must be administered than are needed in the diseased tissue. In the case of conventional cancer drugs, oral administration or direct administration into the blood is used, and in order to maintain drug efficacy, multiple administrations are required, resulting in more side effects than destruction of diseased tissue. The current situation is that

Therefore, there is a need for a drug that can be directly administered to diseased tissues, releases medicinal substances continuously over a certain period of time, reduces side effects, and has excellent medicinal efficacy.

The present invention was developed in response to such demands.

Regulation of water-soluble collagen was published in 13871/1971.
No. 44-1175 and No. 46-15033.

Collagen has low immune activity and no inflammatory properties, so it is an excellent biocompatible material and can be replaced by bioassembly. A method for sustained release of pilocarpine hydrochloride, an eye drop, using this collagen (Japanese Patent Application Laid-Open No. 50-42025
(No.), or a method for sustained release of insulin, a hypoglycemic drug (Japanese Patent Application Laid-open No. 102827/1983), has been developed. However, these conventional sustained-release drugs have a problem that should be improved in that their efficacy lasts only for several hours. The sustained-release composite made of cross-linked collagen in which pleomycin hydrochloride is supported on collagen produced according to the present invention has a long duration of efficacy of 20 days or more. According to the invention, 1 part by weight of methanol contains 0.01 parts by weight of pleomycin hydrochloride o, ol-m and one or more supercooling vitrifying monomers.
Dissolve 10 parts by weight of collagen, and add collagen i to this mixture.
A sustained-release complex containing pleomycin hydrochloride is produced by adding 1 to 1 tumor volume and irradiating it with ionizing radiation at a temperature of -40°C or lower.

The present invention takes advantage of the fact that bleomycin hydrochloride and a supercooling vitrifying monomer are both dissolved in methanol, and adsorbs bleomycin hydrochloride and the monomer into collagen, and irradiates the collagen with electrogenic radiation.

In the present invention, after pleomycin hydrochloride and a vitrifying monomer are permeated into the inside of collagen using methanol as a medium, the crosslinking density of collagen can be arbitrarily adjusted by changing the type and concentration of the vitrifying monomer, but It is necessary to control the experimental conditions so that the crosslinking density is at a level that does not reduce the affinity between the living body and the fluorine.

Generally, pharmaceuticals tend to decrease in titer when exposed to radiation, but in the low temperature range of the irradiation temperature of −40° C. or lower in the present invention, there is no necessity for a decrease in titer. The week-cooling vitrifying monomer used in the present invention does not crystallize at low temperatures, but easily becomes a stable supercooled state, rapidly increasing its viscosity with each temperature, and, for example, at the glass transition point, it becomes a glass state or a crystalline state. It reaches a high viscosity of 10”° poise, which can be described as a solid state.The advantages of this vitrifying monomer are 1.
Because it polymerizes at low temperatures and with small doses, pleomycin hydrochloride is hardly damaged or deactivated by heat or radiation. 2. The supercooled state is advantageous for producing sustained release composites of various shapes by casting or mold polymerization.

For example, since it has a high viscosity and a high polymerization rate, it can be polymerized and fixed as a film on the inner wall of a plastic tube without clogging or sagging. In addition, it is possible to absorb particles without causing adhesion or aggregation between particles. It can be polymerized into cells or fine particles. The vitrifying monomers used in the present invention are one or more monomers belonging to the following group 1 [A] that do not crystallize even at low temperatures and are in a stable supercooled state; Mixing ratio of 3 with a monomer of group [A] that does not have cooling properties
There are monomers of group [B] that impart supercooling properties to the entire mixed monomer when mixed at 0% to 5%.

[Group A]; Hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl methacrylate, hydroxypropyl acrylate, hydroxybutyl methacrylate, hydro1xybutyl acrylate, hydroxypentyl methacrylate, hydroxypentyl acrylate, hydroxyhexyl methacrylate, hydroxyhexyl acrylate, hydroxy Heptyl methacrylate, hydroxyheptyl acrylate, glycidyl methacrylate, glycidyl acrylate, diethylene glycol dimethacrylate diacrylate, tetraethylene glycol dimethacrylate diacrylate, polyethylene glycol methacrylate diacrylate, ethylene glycol dimethacrylate diacrylate, propylene glycol dimethacrylate diacrylate Acrylate, dipropylene glycol dimethacrylate diacrylate, polypropylene glycol dimethacrylate diacrylate, butylene glycol methacrylate diacrylate, hexanediol dimethacrylate diacrylate, hexanediol dimethacrylate diacrylate, heptanediol dimethacrylate diacrylate, methacrylate triacrylate, diethylaminoethyl methacrylate, diethylaminobutyl methacrylate, dimethylaminoethyl methacrylate, dimethylaminobutyl methacrylate, benzyl methacrylate,
Examples include methoxypolyethylene glycol methacrylate acrylate, ethoxypolyethylene glycol methacrylate acrylate, methoxypropane glycol methacrylate acrylate, and ethoxypropylene glycol methacrylate acrylate.

[B] Group: Vinyl acetate, vinyl propionate, vinyl oxate, methyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate, propyl methacrylate, propyl acrylate, butyl methacrylate, butyl acrylate, pentyl methacrylate,
Pentyl acrylate, hexyl methacrylate, hexyl acrylate, lauryl methacrylate, lauryl acrylate, stearyl methacrylate, stearyl acrylate, styrene, vinyltoluene, sulfonated styrene, acrylic acid, methacrylic acid, aminostyrene, vinylpyrrolidone, acrylamide, methacrylamide, methylene bis Acrylamide, methylol acrylamide, acrylonitrile, methacrylonitrile, diallyl phthalate, itaconic acid, maleic anhydride, diallyl isophthalate, diallyl succinate, diacyl itaconate, divinylbenzene, triallyl cyanurate,
etc. are exemplified. The radiation sources employed in carrying out the present invention include visible ultraviolet light from a low-pressure or high-pressure mercury lamp, sunlight, light from a photon factory, X-rays, gamma rays,
It may be beta rays, electron beams, alpha rays, mixed radiation from chemical reactors, gamma rays from spent fuels or fusion products.

It is desirable to keep the irradiation dose as low as possible, as large doses will deactivate cells or organelles during the fixation process.
To cure the monomer 100%, irradiation of 1×1 square radius or more is required. Therefore, for ionizing radiation, the dose rate is 1
×10'～1×ICPR/time 1×10”～5×1(P
R) Preferably, an irradiation dose of 1 x 1 (1' to 1 x 1σR) is required. When the cross-linked collagen of the present invention is inserted into a living body, it gradually releases pleomycin hydrochloride and maintains its medicinal efficacy. Collagen is characterized by being dissolved or taken into the body at the same time.

This will be explained below using examples. Example 1-5, Comparative Example 1 0.03 parts by weight of pleomycin hydrochloride and 0.01 parts by weight of diethylene glycyl dimethacrylate in 1 part by weight of methanol.
After adding and mixing 1 part by weight, this was mixed with 1 part by weight of water-soluble powdered collagen. Pleomycin hydrochloride and diethylene glycol dimethacrylate were poured into the heel area and further penetrated into the inside of the collagen using methanol as a medium while mechanically stirring.

After that, the temperature of dry ice and methanol (-78℃)
Below, under reduced pressure (10-°77!771 Hg), γ-rays from CO were irradiated for 5 hours at a dose rate of 1 × 1 IR/Hr. After irradiation, cross-linked collagen containing pleomycin hydrochloride was irradiated at room temperature. It was dried under reduced pressure.The elution of pleomycin hydrochloride from the obtained powdered crosslinked collagen was carried out using USPhamac.
Using a tester based on OpiesXlX, pH 6. O
O Distilled water 1.000TrL1) Temperature 3TC) 100rp
This was done at a rotational speed of m. The results are shown in Table 1.
Example 6 In Examples 1-5, powdered crosslinked collagen was prepared using 0.10 parts by weight of trimethylolpropane trimethacrylate instead of diethylene glycol dimethacrylate.

The amount of pleomycin hydrochloride eluted from this prepared collagen was 26% after 10 days, 46% after 20 days, and 58% after 30 days.

Example 7 Strontium-89 was used instead of DCO in Example 6.
β-rays were irradiated at a total dose of 6×1 Rad at −78°C.

The elution amount of pleomycin hydrochloride was almost the same as in Example 6. Example 8 In Example 6, powdered crosslinked collagen was prepared by adding 0.10 parts by weight of hydroxyethyl methacrylate and tetramethylolmethanetetramethacrylate in a composition ratio of 1:1 instead of trimethylolpropane trimethacrylate.

Claims (1)

[Claims] 1. After dissolving and mixing pleomycin hydrochloride, one or more supercooling vitrifying polymerizable monomers, and collagen in methanol, irradiation with ionizing radiation at a temperature of -40°C or lower A method for producing a sustained release complex containing pleomycin hydrochloride, comprising: 2. The mixing ratio of methanol, pleomycin hydrochloride, and vitrifying polymerizable monomer is 1:0.01 to 10: in parts by weight.
1-10. The method according to claim 1.