JPS6059204B2 - Method for producing sustained release complex - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a sustained release complex containing a physiologically active substance.

More specifically, the present invention utilizes an interfacial precipitation method in water using a [(W/0)/W] type composite emulsion to form microspheres with a diameter of 0.1 to 5000 μm containing a physiologically active substance. The present invention relates to a method of producing a sustained release composite. The development and establishment of techniques for producing microspheres is becoming increasingly important in fields such as medicine and chemistry. That is,
For example, if it were possible to synthesize microspheres that contain an anticancer drug and have sustained release properties, it would be possible to directly introduce the microspheres into the cancer-affected area using an injection method without undergoing surgery on cancer patients, or indirectly by injecting them into blood vessels. This makes it possible to introduce it directly into the cancerous area. Physiologically active substances, including anticancer drugs, are generally susceptible to a drop in titer when exposed to heat or radiation, but the inventors have found that when treated at low temperatures below 0°C, the drop in titer can be almost ignored. I found out the results of my research.

Therefore, the present invention was completed based on this fact. That is, the present invention polymerizes a hydrophobic, low-temperature vitrifying vinyl polymerizable monomer that can be polymerized at a low temperature of 0° C. or lower by irradiating it with light or ionizing radiation in the presence of a physiologically active substance. This is one of its characteristics. The configuration of the present invention will be explained below.

According to the present invention, one or more physiologically active substances as the core material of microspheres are dissolved in a buffer solution having an appropriate pH, and then one or more hydrophobic low-temperature vitrifying substances are dissolved. Vinyl J polymerizable monomer is added and mechanically stirred to form a (W/0) type emulsion, and this (W/0) type emulsion is then used as a protective colloid containing a water-soluble polymer. Add to the aqueous solution and stir thoroughly by mechanical stirring [(W/0)/W]6
A composite emulsion of Rin is prepared, and this system is irradiated with light or ionizing radiation at a temperature of 0° C. or lower to polymerize a hydrophobic vitrifying vinyl polymerizable monomer, and then this system is heated.
0.1 to 5,000 PTr1 containing a physiologically active substance by appropriately performing operations such as depressurization, cooling, freeze drying, etc.
, a microsphere-like sustained release composite is produced.

In carrying out the present invention, 0.01 to 2 parts of a hydrophobic low-temperature vitrification vinyl polymerizable monomer is added to 1 part by weight of a buffer or aqueous solution of a suitable pH containing 0.01 to 2 parts of a physiologically active substance.
．． An aqueous solution containing 5 to 1 parts by weight and 0.05 to 1% by weight of a water-soluble polymer is used in an amount of 4 to 10 parts by weight.

The hydrophobic low-temperature vitrifying vinyl polymerizable monomer used in the present invention is a monomer that does not crystallize and exhibits a supercooled state at a temperature below 0°C if the temperature is higher than the glass transition temperature, and the glass transition temperature Monomers that have a maximum initial polymerization rate in the polymerization temperature range of 50°C or lower, including the following monomers: hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl methacrylate. , hydroxypropyl acrylate, hydroxybutyl methacrylate, hydroxybutyl acrylate, glycol dimethacrylate, triethylene glycol dimethacrylate, polyethylene glycol #200 dimethacrylate, polyethylene glycol #400 dimethacrylate, polyethylene glycol #600 dimethacrylate, Diethylene glycol diacrylate, diethylene glycol dimethacrylate, triethylene glycol diacrylate, polyethylene glycol #200 diacrylate. polyethylene glycol #400 diacrylate, polyethylene glycol #600 diacrylate, trimethylolpropane trimethacrylate, trimethylolethane trimethacrylate, trimethylolpropane triacrylate, trimethylolethane triacrylate, glycidyl methacrylate, etc.

The water-soluble polymers used in the present invention include synthetic polymers such as polyvinyl alcohol, polyacrylic acid, and polyhydroxyethyl acrylate, as well as gelatine, gum arabic,
Examples include dextran, protein, protein, cellulose, polysaccharide, carboxypolymethylene, and the like.

Furthermore, the physiologically active substances that can be used in the present invention include bleomycin hydrochloride, mitomycin C1 carbazylquinone, lomustine, ifosfamide, thioinosine, cytarpine, fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil, cytotein, chlorambutyl, dipromochloride, Mannitol, thioteba, cyclophosphamide, acetylurin, noradrenaline, serotonin, kallikrene, gastrin, secretin, adrenaline, insulin, glucagon, no-β-methazone,
Indomethacin ACTHl growth hormone, gonadotropin, oxytocin, vasopressin, thyroxine, Himaru hormone, follicle hormone, progestin, adrenocortical hormone, prostaglandin, antihistamine, antihypertensive agent, vasodilator, vascular reinforcing agent, stomachic digestion agents, intestinal regulators, contraceptives, disinfectants for the skin, agents for parasitic skin diseases, anti-inflammatory agents, vitamin preparations, various enzyme preparations, vaccines, antiprotozoal agents,
Interferon inducer, anthelmintic, fish disease drug, pesticide, auxin gibberellin, sidekinin, abscisic acid,
Examples include insect pheromones.

The means for polymerizing the vinyl polymerizable monomer employed in the present invention is light or ionizing radiation.

The radiation source is not limited to α, β, γ, electron beam, neutron beam, etc., but gamma rays from CO3O are preferable. The radiation is administered at a dose rate of 1 x 1 f' to 1 x 1 σ roentgen/hour, with a total dose of 1 x 1 σ to 1 x 10 7 roentgen, preferably 1 x σ
~l×1σ roentgen/hour dose rate total dose 1×103
It is preferable to irradiate in the range of 5×1 Cf' roentgen. Irradiation with light or ionizing radiation: -120°C to 0°C
It is preferable to carry out within the range of . The microsphere-like sustained-release composite produced by the method of the present invention described above has a physiologically active substance as a core substance coated with a hydrophobic polymer, and a surface portion of which is further coated with a water-soluble polymer. Since the microspheres are protected, the elution of physiologically active substances from the microspheres can be sustained for a long time. Furthermore, it is possible to incorporate 90% or more of the physiologically active substance used into the sustained release complex. The present invention will be specifically explained below using Examples.

In addition, the elution test of physiologically active substances from sustained release complexes was conducted by U.
3 using a phosphate buffer with a pH of 7.2 according to SPX■
I went with rC. Example 1 Adriamycin 50Tn9 was dissolved in phosphate buffer (pH 7.
2) A W/0 suspension liquid was prepared by dissolving the mixture in 0.3 ml and adding 0.5 ml of diethylene glycol dimethacrylate and mechanical stirring.

To create a microsphere emulsion made of this W/0 suspension and to protect it, 10 ml of a 1% polyvinyl alcohol aqueous solution was added,
A quick mechanical stir was applied. And [(W/0)/W
After producing an emulsion consisting of microspheres, the ampoule containing the emulsion solution was cooled to a temperature of -78C (dry ice + methanol). In this state, CO('. γ rays from the radiation source are 5×1CPr
Microspheres of 80-130 μm containing adriamycin were synthesized by irradiation with 211r at a dose rate of ad/Hr. The elution behavior of adriamycin from this microsphere is shown in FIG. 1a. Examples 2 to 4 In Example 1, trimethylolpropane trimethacrylate (Example 2), neopentyl glycol dimethacrylate (Example 3), and glycidyl methacrylate (Example 4) were used instead of diethylene glycol dimethacrylate to form microspheres. An ear-shaped sustained release complex was synthesized.

The elution behavior of adriamycin from this microsphere is shown in FIG. That is, B, c and d in FIG. 1 indicate the elution behavior of Examples 2, 3 and 4, respectively. Example 5 Mitomycin C2Om9 was added to phosphate buffer (PH7.2) 0
．． 0.2 mt of triethylene glycol dimethacrylate and 0.15 mt of hydroxyhexyl methacrylate were added thereto, and a W/0 suspension liquid was prepared by mechanical stirring.

In this suspension, a 0.5% albumin aqueous solution (
PH7.2) was added to produce an emulsion consisting of [(W/0)/W] microspheres with rapid mechanical stirring, and after freezing at -78°C, at this temperature, cobalt-60 was added. γ-rays of 0.8 Mrad were irradiated. The elution behavior of mitomycin C from microspheres having a diameter of 40-60 μm is shown in FIG. 1e.

[Brief explanation of the drawing]

Figure 3 is a graph showing the elution behavior of a physiologically active substance from the microsphere-like sustained release composite prepared according to the present invention.

Claims (1)

[Claims] 1. After dissolving one or more physiologically active substances in a pH-adjusted buffer, and then adding one or more polymerizable hydrophobic low-temperature vitrification vinyl polymerizable monomers. A primary emulsification step in which a vinyl polymerizable monomer emulsion containing an aqueous solution containing a physiologically active substance is prepared by stirring well by mechanical operation; an aqueous solution containing a water-soluble polymer as a protective colloid is added to the emulsion, and then mechanical A physiological process consisting of a secondary emulsification process in which a secondary emulsion is prepared by stirring well by operation, and a process in which the secondary emulsion is irradiated with light or ionizing radiation at a temperature of 0°C or less to polymerize a vinyl polymerizable monomer. A method for producing a microsphere-like sustained release complex containing an active substance.