WO2007013600A1

WO2007013600A1 - Neutron capture preparation and use thereof

Info

Publication number: WO2007013600A1
Application number: PCT/JP2006/315007
Authority: WO
Inventors: Hironobu Yanagie; Masazumi Eriguchi; Ryohei Nishimura; Syushi Higashi; Tetsuya Kajiyama
Original assignee: Hironobu Yanagie; Masazumi Eriguchi; Ryohei Nishimura; Syushi Higashi; Tetsuya Kajiyama
Priority date: 2005-07-29
Filing date: 2006-07-28
Publication date: 2007-02-01
Also published as: JP4990137B2; JPWO2007013600A1

Abstract

In order to improve the safety of neutron capture therapy, a neutron capture preparation is provided which can be accumulated in a tumor cell at a good level. A boron compound is used as a neutron-capturing agent. A W/O/W-type emulsion is formed which is composed of an inner aqueous phase containing the boron compound, an oily phase and an outer aqueous phase, and the emulsion can be used as the neutron capture preparation. Examples of the boron compound include borocaptate (BSH) and p-boronophenylalanin.

Description

Specification

Neutron capture agent and its use

Technical field

[0001] The present invention relates to a neutron capture preparation containing a boronic compound and use thereof.

Background art

[0002] Liver cancer is a cancer that develops due to hepatitis virus, cirrhosis, and the like, and is currently regarded as a cause of death after lung cancer and stomach cancer. In particular, it is difficult to select an effective treatment method. Therefore, improvement of the treatment method is being studied.

[0003] Reasons why it is difficult to select a treatment method for liver cancer include the following reasons. For example, surgical excision is known as a general treatment method for cancer, but in the case of liver cancer, due to cancer status (for example, multiple liver cancer, giant liver cancer) and decreased liver function due to cirrhosis, Excision is limited, and only about 15% of all liver cancer patients are actually excised. Even if resection is performed, there is a problem that the risk of recurrence always remains due to the nature of liver cancer that develops due to cirrhosis. Furthermore, as a method other than surgical excision, for example, hepatic artery embolization, ethanol injection method, necrosis therapy by microphone mouth wave, etc. are known. For these therapies, for example, cancer progression status, patient age The conditions that can be treated are limited depending on sex, etc.

[0004] Currently, arterial injection therapy in which an anticancer agent is selectively administered to tumor cells is relatively widely adopted as a method for treating liver cancer. This is a method in which an anticancer drug is directly injected into an artery through a catheter, and the anticancer drug is administered to a target site. According to this method, for example, compared with systemic chemotherapy in which an anticancer agent is administered intravenously, there is an advantage that problems such as diffusion of the anticancer agent into normal cells and associated side effects can be reduced. On the other hand, in order to improve the therapeutic effect, it is necessary to accumulate the anticancer drug on the target site and retain it. For this reason, with regard to arterial injection therapy, improvement of the drug form of the injected anticancer drug has been carried out in order to realize accumulation of the anticancer drug (for example, Patent Document 1). However, intra-arterial chemotherapy has a therapeutic effect that depends on the type of anticancer drug (efficacy), the type of cancer and the adaptability of the anticancer drug to the patient, and the stage of the patient. Even if certain accumulation is ensured, there remains a problem that, for example, further development of anti-cancer drugs suitable for the type of cancer and the patient will be forced.

[0005] On the other hand, research on boron neutron capture therapy (BNCT) is underway as a cancer treatment method with excellent therapeutic effects. In this therapy, a boron compound is administered, boron is accumulated in the target tumor cells, and thermal neutrons are irradiated to it. Boron and neutrons undergo a nuclear reaction (boron neutron capture reaction) to generate a particles and Li particles (recoil lithium nuclei) with excellent cell destructive power, which destroy tumor cells. Both α particles and Li particles have a range of 10 m or less, and can selectively destroy one cell in which boron is incorporated.

[0006] Unlike the above-described chemotherapy, such boron neutron capture therapy is a very useful treatment method because its effect is not affected by the type of anticancer agent or the like. However, α particles and Li particles are excellent in cell destructive power, so that a therapeutic effect can be expected. On the other hand, if boron compounds are not reliably accumulated in target tumor cells, normal cells may be destroyed. For this reason, in recent years, borocaptate (BSH), p-boronophenylalanin, etc. have been reported as boron compounds that easily accumulate in tumor cells (Non-patent Document 2). .

[0007] However, in the actual clinical medicine field, the boron neutron capture therapy to which the boron neutron capture therapy has been applied is still limited to, for example, brain tumors, skin cancers, and the like. This is presumably because the accumulation of boron has not reached the desired level. The polonic compound is usually administered to tumor cells via an artery in the form of an emulsion mixed with an intravenous contrast agent alone or in an emulsion mixed with an oil-based contrast medium (for example, riviol). However, although the accumulation of tumor cells has been improved by using BSH or the like as described above, since the emulsion-powered boron compound is released after administration, there is a concern about the effect on normal cells.

In addition, since the accumulated boron compound is not sufficiently taken up by the tumor cells, the boron concentration in the tumor cells may not be improved, and the tumor cells may not be sufficiently destroyed.

[0008] Therefore, in order to more safely apply boron neutron capture therapy to other tumor cells, particularly tumor cells of liver cancer for which it is difficult to select a treatment method, for example, boron for tumor cells. Further increases the concentration of boron and increases the boron concentration in tumor cells It is considered necessary.

Patent Document 1: JP-A-10-158152

Non-patent literature l: Shushi Higashi, M.D., Ph.D. et al. Cancer March 15, 1995, Volume 75, No. 6 Circulation 104, 1746-1748, 2001

Non-Patent Document 2: Yanagie Hironobu et al. British Journal of Cancer, 3 (4): 522-526,199 1

Disclosure of the invention

Problems to be solved by the invention

[0009] Therefore, an object of the present invention is to provide a neutron capture preparation that is excellent in selective accumulation in veg tumor cells that enhances the safety of neutron capture therapy.

Means for solving the problem

[0010] In order to achieve the above object, the neutron capture formulation of the present invention is a neutron capture formulation comprising a multiphase emulsion, wherein the multiphase emulsion contains an inner aqueous phase, an oil phase and an outer phase containing a neutron capture agent. It is a wZoZw type emulsion which is a water phase force, and the neutron scavenger is a boron compound.

[0011] Further, the present invention is a raw material of the neutron capture preparation of the present invention, which is a wZo type emulsion having an inner water phase and an oil phase force containing a neutron capture agent, and the neutron capture agent is a boron compound. It is characterized by.

The invention's effect

[0012] Thus, the neutron capture formulation of the present invention takes the form of a wZoZw type emulsion consisting of an inner aqueous phase, an oil phase, and an outer aqueous phase containing a boron compound as a neutron capture agent. Boron compounds can be included in the emulsion without flowing out, and boron compounds can be efficiently accumulated and deposited on tumor cells. Since selective accumulation in tumor cells is possible in this way, for example, even when a neutron capture agent is administered via blood, diffusion is prevented, and diffusion to other tissues or normal tissues is prevented. Impact will be reduced. In addition, since boron accumulates and deposits more reliably on the target tumor cells, the absolute value of the boron concentration in the tumor cells is set higher than in the conventional method, thereby improving the therapeutic effect. You can also go up. Therefore, according to the neutron capture preparation of the present invention, it can be applied to a tumor tissue to which neutron capture therapy has not been applied so far, and an excellent therapeutic effect can also be realized. In particular, since it was difficult to select a treatment method for liver cancer, the present invention has made it possible to apply neutron capture therapy with an excellent therapeutic effect. It can be said that it is useful.

Brief Description of Drawings

FIG. 1 is a schematic view of a wZoZw type emulsion in an example of the present invention.

FIG. 2 is a graph showing the particle size distribution of WZOZW type emulsion in the examples of the present invention. (A) shows the results of Example 1-1, and (b) shows the results of Example 12.

FIG. 3 is a photograph of WZOZW type emulsion in an example of the present invention. (A) shows the result of Example 11 and (b) shows the result of Example 12.

FIG. 4 is a photograph of a mixture in a comparative example.

[Fig. 5] Fig. 5 is an image photograph showing the result of soft-line imaging in the example of the present invention.

FIG. 6 is an image photograph showing the result of optical microscope observation in the example of the present invention.

FIG. 7 is an image photograph showing the result of optical microscope observation in a comparative example.

[FIG. 8] FIG. 8 is an electron micrograph of a tumor tissue in an example of the present invention, (a) is a result of a tumor to which WZOZW type emulsion is infused, and (b) is a Lipiodol of a comparative example. It is the result of a tumor infused with mix emulsion.

[FIG. 9] FIG. 9 is an electron micrograph of a tumor into which a boron solution of a comparative example was infused (c).

FIG. 10 is an electron micrograph of the tumor tissue over time in an example of the present invention (arterial injection of WZOZW type emulsion) and a comparative example (arterial injection of Lipiodol mix emulsion).

BEST MODE FOR CARRYING OUT THE INVENTION

[0014] As described above, the neutron capture formulation of the present invention is a neutron capture formulation having a multiphase emulsion force, and includes an inner aqueous phase, an oil phase, and an outer aqueous phase containing the multiphase emulsion force neutron capture agent. WZOZW type emulsion, characterized in that the neutron scavenger is a boron compound. The wZoZw type is a general type of emulsion. It is an abbreviation for “water in oil in water type emulsion”, which is an oil (O) droplet particle force with water (W) droplet particles confined inside and double dispersed in water (W). Means emulsion.

[0015] The WZOZW type emulsion can be represented, for example, in FIG. FIG. 1 is a schematic diagram showing an example of the configuration of a W / oZw type emulsion. In wZoZw type emulsion 1, an aqueous phase (inner aqueous phase) 10 containing a neutron scavenger is dispersed in an oil phase 11 as a dispersion medium, and an oil phase 11 having an inner aqueous phase 10 inside is further dispersed. It is dispersed in the outer water phase 12 which is a dispersion medium. In the present invention, hereinafter, the inner aqueous phase (water droplets) containing the neutron scavenger is also referred to as inner aqueous phase particles, and the oil phase (oil droplets) containing this is also referred to as wZoZw type emulsion particles. In addition

FIG. 1 is merely a schematic diagram, and the present invention is not limited to the number of particles, the particle size, and the like in the emulsion of FIG.

[0016] The wZoZw type emulsion in the present invention is a monodisperse emulsion (uniform droplet particles).

) Is preferable. The monodispersed emulsion usually means an emulsion in which droplet particles are uniformly dispersed, and the emulsions other than the monodispersed emulsion are generally called polydispersed emulsions. In the present invention, the ratio of the wZoZw type emulsion particles (the oil phase particles dispersed in the outer aqueous phase) is not particularly limited. For example, among the W ZOZW type emulsion particles, the average particle size is 75%. WZoZw type emulsion particle force having a particle size of from 150% to 150% It is preferable to satisfy 50% by volume or more of all wZoZw type emulsion particles, and more preferably 80% by volume or more. The particle size distribution of wZo / w emulsion particles can be determined by a conventionally known method, and can be measured by, for example, a laser diffraction / scattering type particle size distribution meter (hereinafter the same).

[0017] The WZOZW type emulsion substantially includes, for example, WZOZW type emulsion particles having a particle size of 50% or less of the average particle size, and wZoZw type emulsion particles having a particle size of 200% or more of the average particle size. It is preferably not included. The wZoZw type emulsion particles having a particle size of 75% force 150% of the average particle size is preferably 80% by volume or more of all wZoZw type emulsion particles, more preferably 80% by volume or more. The The wZoZw type emulsion particles having a particle size of 50% or less of the average particle size and the wZoZw type emulsion particles having a particle size of 200% or more of the average particle size are, for example, In the range which does not impair the effect of the present invention.

[0018] The average particle diameter of the WZOZW-type emulsion particles (oil phase particles) is not particularly limited! The lower limit is, for example, preferably 30 μm or more, more preferably 40 μm, and even more preferably. The upper limit is, for example, 500 μm or less, preferably 350 μm or less, more preferably 300 μm or less, and further preferably 200 μm or less. Specifically, it is in the range of ί, f row ί, 30 to 350 μm, preferably ί 30 to 300 μm, more preferably ί 20 to 200 μm. These particle sizes are at least the particle sizes before administration.

[0019] The inner water phase particles dispersed in the WZOZW type emulsion particles (oil phase particles) are preferably monodisperse emulsion (uniform droplet particles). For example, among the inner water phase particles, Inner water phase particle force having a particle size of 75% to 150% of the average particle size is preferably 50% by volume or more, more preferably 80% by volume or more of the total inner water phase particles.

[0020] The WZOZW type emulsion particles are, for example, inner water phase particles having a particle size of 50% or less of the average particle size (average particle size of the inner water phase particles), particle size of 200% or more of the average particle size. It is preferable that the inner aqueous phase particles are substantially not contained. Further, the inner water phase particle force having a particle diameter of 75% to 150% of the average particle diameter is preferably 80% by volume or more of the total inner water phase particle, more preferably 80% by volume or more. The inner water phase particles having a particle diameter of 50% or less of the average particle diameter and the inner water phase particles having a particle diameter of 200% or more of the average particle diameter are, for example, within a range not impairing the effects of the present invention. May be included.

[0021] The average pore size of the inner aqueous phase particles dispersed in the oil phase is, for example, 200 μm or less, preferably 0.5 to: LO / z m. Further, the maximum particle size of the inner aqueous phase particles is, for example, 400 or less, preferably 200 m or less. These particle sizes are at least the particle sizes before administration.

[0022] In the WZOZW type emulsion, the volume ratio of the inner aqueous phase to the outer aqueous phase is not particularly limited, but is, for example, in the range of 1:10 to 1: 0.1, preferably 1: 5 to 1: It is in the range of 1. The volume ratio of the inner water phase to the oil phase is not particularly limited, but is, for example, in the range of 1: 9 to 1: 0: 1, preferably in the range of 1: 9 to 1: 0.2, and more preferably. Is in the range of 1: 9 to 1: 0. By adjusting the volume ratio in this way, for example, the viscosity of the emulsion can be freely adjusted, and more excellent deposition properties can be realized. Also, control the sustained release rate of boron compounds You can also These volume ratios can be appropriately changed according to, for example, the type of water phase or oil phase, the nature of the cancer tissue, and the like.

[0023] In the present invention, the inner aqueous phase may be an aqueous solution containing a neutron scavenger. Examples of the neutron scavenger include boron compounds, but the type is not particularly limited, but water-soluble boron compounds are preferred, for example, borocaptate, p-boronopheralanine (p -boronophenylalanin) and the like, preferably BSH. If the compound contains a large number of boron atoms in one molecule such as BSH (12 boron atoms), the amount of alpha generated per molecule of boron will increase, so boron compound Even if the concentrations of the two are the same, the absolute value of the boron concentration can be further improved, and a sufficient effect can be obtained even when the amount of boron compound contained in the inner aqueous phase is small. These compounds may be used alone or in combination of two or more.

[0024] The content of the boron compound in the inner aqueous phase is not particularly limited, and the type of boron compound (for example, the number of boron atoms per molecule of the boron compound, the solubility of the compound), the boron compound is added. It can be appropriately determined according to the type of aqueous solvent to be administered, the site and size of the tumor tissue to be administered. Specifically, in the case of BSH, it is, for example, about 0.9 mol Zl or less than 0.9 mol Zl because of solubility.

[0025] The content of boron in the entire WZOZW type emulsion is not only the content of boron compound in the inner aqueous phase (the content of boron). For example, the inner aqueous phase dispersed in the oil phase It can be determined comprehensively depending on the amount of particles, the amount of oil phase particles dispersed in the outer aqueous phase, and the like.

[0026] The inner aqueous phase may appropriately contain an additive in addition to the boron compound. Examples of the additive include compounds that are substantially harmless to the human body. Sodium salts such as sodium chloride sodium, sodium citrate, sodium salicylate, sodium hydrogen carbonate, sodium dextran sulfate, sodium chloride calcium, Examples include various salts such as calcium salts such as calcium dalconate; various sugars such as glucose and ratatose; glycerin, D-manntol and amino acids.

[0027] The inner aqueous phase has an osmotic pressure in the range of, for example, about 0.01 to 7 OMPa, preferably 0.1 to 5 MPa, more preferably 0.1 to 3.5 MPa. Tumor tissue types, It can be determined appropriately according to the site, size, and the like. When the inner aqueous phase particles of the wZoZw type emulsion in the present invention are further expanded in the body, for example, a value exceeding the osmotic pressure of physiological saline, preferably 1.1 to 5 times the osmotic pressure of physiological saline (0 75-3. Adjust to about 5MPa). Thereby, after the neutron capture preparation of the present invention is infused into the blood, the water in the blood moves to the inner aqueous phase particles, so that the aqueous phase particles expand in the blood vessel. In the case where expansion is not necessary, for example, if the osmotic pressure of physiological saline that is the same as that of blood is set, the particle size can be maintained as it is. The osmotic pressure of the inner aqueous phase can be adjusted by, for example, the types and amounts of boron compounds and various additives. In the present invention, the osmotic pressure of physiological saline is based on the value at about 37 ° C.

[0028] The oil phase in the present invention preferably contains, for example, fats and oils, and further contains a surfactant. The fats and oils are not particularly limited as long as they are pharmacologically acceptable, and examples thereof include soybean oil, olive oil, sesame oil, camellia oil, rapeseed oil, corn oil, peanut oil, menji oil, and yodo oil. For example, strong jord oil.

[0029] The surfactant is not particularly limited as long as it is pharmacologically acceptable, and a commercially available product can be used. Specific examples include lipophilic surfactants such as polyoxyethylene hydrogenated castor oil, especially 40 mol of polyoxyethylene hydrogenated castor oil (eg, trade name HCO-40, Nikko). Chemicals, etc.) is preferable because it can prepare a WZOZW type emulsion having high stability and excellent stability at a lower concentration. In addition, tetraglycerin condensed ricinoleic acid ester (for example, trade name CR-310, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.), decaglycerin condensed ricinoleic acid ester (for example, trade name CR-500, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.), etc. A polyglycerin condensed ricinoleic acid ester surfactant may be used. The addition amount of the surfactant is not particularly limited, and can be appropriately set according to, for example, the type of fats and oils, the type of surfactant, the volume ratio of the inner aqueous phase and the outer aqueous phase, For example, 0.1 to 20% by weight, preferably 0.5 to: L0% by weight.

[0030] The oil phase may further contain other additives such as boron compound, anticancer agent (eg, lipophilic anticancer agent), lecithin, cholesterol, vitamin E and the like. In addition, the content of these additives is not particularly limited, and the types of oils and surfactants and tumors are not limited. It can be appropriately determined according to the site of the tumor tissue.

[0031] The outer aqueous phase in the present invention is not particularly limited as long as it is a pharmacologically acceptable aqueous solution, for example, and an aqueous solution of salts, saccharides and the like can be used. Examples of salts, saccharides, and other additives include those similar to the aforementioned inner aqueous phase. The osmotic pressure as described later can be adjusted by the concentration of these salts, saccharides and the like.

[0032] The outer aqueous phase may contain other components, for example, and may contain a surfactant (for example, a hydrophilic surfactant) as necessary. The surfactant is not particularly limited as long as it is substantially harmless to the human body. For example, polyoxyethylene hydrogenated castor oil, block polymer type nonionic surfactant (trade name Pluronic F68, trade name Kusama 188, manufactured by Midori Cross Co., Ltd.), lysolecithin, bile acid, polyglycerin ester (PGCR) and the like can be used. Of these, polyoxyethylene hydrogenated castor oil is preferred. Particularly, polyoxyethylene hydrogenated castor oil with 60 mol of ethylene oxide added (for example, trade name HCO-60, manufactured by Nikko Chemicals Co., Ltd.) is safe for living organisms. This is preferable because a WZOZW emulsion having excellent stability at a higher and lower concentration can be prepared.

[0033] The outer aqueous phase has an osmotic pressure in the range of, for example, about 0.01-7. OMPa, preferably 0.1-5 MPa, more preferably 0.1-3.5 MPa. The method for adjusting the osmotic pressure and the like can be performed in the same manner as the above-described inner aqueous phase.

[0034] In the WZOZW type emulsion in the present invention, the osmotic pressure of the inner aqueous phase and the osmotic pressure of the outer aqueous phase are set to a value equal to or higher than the osmotic pressure of the outer aqueous phase, and the osmotic pressures of the inner aqueous phase and the outer aqueous phase in the obtained wZoZw type emulsion are A value exceeding the osmotic pressure of physiological saline is preferable. Specifically, the osmotic pressure of the inner and outer aqueous phases of wZoZw type emulsion is preferably 1.1 to 5 times (0.75 to 3.5 MPa) of the osmotic pressure of physiological saline, for example. . This makes it possible to obtain a WZOZW type emulsion formulation with better deposition properties.

[0035] Further, since the WZOZW type emulsion is composed of an inner water phase, an oil phase, and an outer water phase that are separated from each other, for example, a drug for supplementing neutron capture therapy in any one or each phase, You may contain the anticancer agent for a synergistic effect. Thereby, the therapeutic effect can be further improved. In this case, it is preferable to use a hydrophilic drug for the aqueous phase and a lipophilic drug for the oil phase. Next, the method for producing the neutron capture preparation of the present invention will be described, but the present invention is not limited to the following method.

[0037] First, an inner water phase containing the neutron scavenger as described above is dispersed in an oil phase to form a WZO emulsion (water in oil type emulsion). The WZO type emulsion can be used as a raw material for the WZOZW type emulsion of the present invention.

[0038] The dispersion method is not particularly limited, and examples thereof include known emulsification methods such as stirring, homogenizer, and ultrasonic emulsifier. In particular, since a wZo type emulsion having excellent monodispersibility can be obtained, membrane emulsification in which the boron-containing compound-containing aqueous solution serving as the inner aqueous phase is dispersed in an oil phase as a dispersion medium through a porous membrane. The method is preferred. Specifically, the boron-containing aqueous solution is introduced into the oil phase through the pores of the porous membrane, and the boron-containing aqueous solution is dispersed in the oil phase. When dispersing the boron-containing aqueous solution, it is preferable to apply pressure to the oil phase and disperse it (press-fit dispersion).

[0039] According to such a membrane emulsification method, for example, the addition amount of the surfactant can be further reduced while maintaining the stability of the emulsion. In addition, according to the membrane emulsification method, for example, small inner water phase particles having a particle size of about 0.5 to about LO / zm can be formed, and the particle size can be easily controlled. Furthermore, since it does not generate heat during emulsification, it is a useful production method even for heat-sensitive compositions.

[0040] The porous membrane is not particularly limited, but it is preferable to use a porous glass membrane. As the porous glass membrane, a conventionally known one can be used, for example, microphase separation of glass. What was manufactured using is preferable. Specifically, CaO-BO-SiO-AlO-based porous glass disclosed in Japanese Patent No. 1504002, Patent No. 1518989

2 3 2 2 3

And CaO—B O—SiO—Al O—NaO disclosed in US Pat. No. 4,657,875.

2 3 2 2 3 2 porous glass, CaO— B O —SiO—Al O—NaO—MgO porous glass, Ca

2 3 2 2 3 2

Examples thereof include O—B 2 O 3 —SiO—ZrO-based porous glass. Of these porous glass membranes

2 3 2 2

In particular, for example, in the relative cumulative pore distribution curve, the value force obtained by dividing the pore diameter when the pore volume accounts for 10% of the total by the pore diameter when the pore volume accounts for 90% of the total. It is preferable to use a microporous membrane within the range of 1 to 1.5. Such a membrane is extremely suitable for the membrane emulsification method since the pores are particularly uniform. Such porous As the glassy glass film, for example, a trade name SPG film made by SPG Technone, a trade name SPG filter kit, etc. can be used. The porous membrane is preferably a hydrophobic porous membrane because it allows the aqueous phase to pass through the oil phase.

[0041] The pore size of the porous membrane is not particularly limited! However, it can be appropriately determined according to the desired particle size of the WZO emulsion particles (inner water phase particles) as described above. In order to form a monodisperse emulsion, those having uniform pore diameter and uniform pores are preferable. The relationship between the pore size (Dml) of the porous membrane and the particle size (Dpi) of the inner aqueous phase particles to be formed is not particularly limited, but for example, DplZDml = about 3 to 4 is preferable. By using such a porous membrane, inner water phase particles of various particle sizes can be formed, and in particular, fine particles (for example, a minimum of 0.5 μm or more, preferably 1 μm or more). Suitable for forming.

[0042] In addition, the pressure conditions during the press-fitting, for example, can be appropriately determined according to the internal aqueous phase and oil phase of the yarn且成like, for _{example, Pc> 2 7 cos Θ Zr} ( however, Pc is the pressure, γ is the interfacial tension, Θ is the contact angle, and r is the pore diameter of the porous membrane.

[0043] In addition to using the porous membrane as described above, a boron compound-containing aqueous solution serving as the inner aqueous phase is dropped by using a syringe or the like to the oil phase as a dispersion medium. It may be allowed. In this case, depending on the desired particle size of the WZO emulsion particles, the diameter of the opening at the front end of the syringe, the syringe force, the pressure when extruding the boron compound-containing aqueous solution, the volume of one drop, etc. are appropriately selected. Just decide.

[0044] The method of adding the surfactant to the oil phase is not particularly limited. For example, the oil layer is adjusted in advance to a predetermined surfactant concentration (for example, 0.1 to 10% by weight), and is stable. A WZO type emulsion may be formed, and a surfactant may be added to the obtained WZO type emulsion so that the total amount of the surfactant becomes a predetermined concentration (for example, 20% by weight or less). Thereby, the obtained WZO emulsion particles (aqueous particles) can be effectively expanded. Further, when not expanding, the concentration of the surfactant at the time of obtaining the wZo type emulsion may be maintained as it is. Thus, for example, the size of the wZo type emulsion particles can be arbitrarily controlled by adding the surfactant.

[0045] Subsequently, by dispersing the obtained WZO emulsion in the outer water phase, WZ Forms ozw type emulsion. In this way, the neutron capture preparation of the present invention can be produced.

[0046] The dispersion method is not particularly limited, and is the same as the formation of the WZO emulsion described above, and a membrane in which the wZo emulsion is press-fitted and dispersed in the outer aqueous phase as a dispersion medium through a porous membrane. An emulsification method is preferred. As the porous film, the porous glass film is preferably the same as described above, as described above. Similarly, a syringe or the like can also be used.

[0047] The pore size of the porous membrane is not particularly limited, but can be appropriately determined according to the desired particle size of the WZOZW type emulsion particles (oil phase particles) as described above. Further, in order to form a monodisperse emulsion, a porous membrane having a uniform pore size and no unevenness is preferred. The relationship between the pore size (Dm2) of the porous membrane and the particle size (Dp2) of the oil phase particles to be formed is not particularly limited. For example, Dp2ZDm2 = about 3 to 4 is preferable. By using such a porous membrane, it is possible to form oil phase particles having various particle sizes. For example, it is suitable for forming particles having a particle size of about 10 111 to 120 111 (preferably 10 to 80 111). The Further, since the oil phase including the inner aqueous phase is passed through the outer aqueous phase, a hydrophilic porous membrane is preferred.

[0048] In the neutron capture preparation of the present invention, the osmotic pressure of the inner aqueous phase and the outer aqueous phase affects the function of the neutron capture agent, the volume ratio of each phase, and the like. In this way, the particle size and packing ratio of WZOZW type emulsion particles can be controlled. The filling rate is the ratio of the wZoZw type emulsion particles to the wZoZw type emulsion!

[0049] (1) When the osmotic pressure of the inner aqueous phase and the outer aqueous phase is adjusted to be equal to the osmotic pressure of physiological saline, for example, the particle size is substantially maintained even after intraarterial injection into the body. can do. in this case

The volume ratio of the inner water phase to the oil phase is, for example, about 1: 9 to 1: 0.5, and the volume ratio of the inner water phase to the outer water phase is, for example, about 1:10 to 1: 2. Yes, the filling rate is, for example, 60% by volume or less.

[0050] (2) When the osmotic pressure of the inner aqueous phase and the outer aqueous phase is made equal and the osmotic pressure is adjusted to a value exceeding the osmotic pressure of physiological saline, The outer water phase is replaced with blood As a result, a difference in osmotic pressure occurs between the inner water phase and the water in the blood moves to the inner water phase so that the osmotic pressure becomes equal. For this reason, wZoZw-type emulsion particles can be expanded in blood vessels.

[0051] (3) When membrane emulsification is performed under conditions in which the osmotic pressure of the inner aqueous phase is higher than that of the outer aqueous phase, water moves from the outer aqueous phase to the inner aqueous phase due to the osmotic pressure difference. In addition, the volume ratio of the inner aqueous phase to the outer aqueous phase is increased, and wZ * Zw type emulsion particles are obtained with a high packing ratio.

[0052] If the osmotic pressure of the inner aqueous phase and the outer aqueous phase is adjusted to be equal to the osmotic pressure of physiological saline when the movement of water stops, the particle size of wZoZw-type emulsion particles after infusion Does not change. On the other hand, if the osmotic pressure of the inner and outer aqueous phases is designed to be higher than the osmotic pressure of physiological saline when the movement of water stops, wZoZw type emulsion particles in the blood vessel after arterial injection Expands.

[0053] Further, using such behavior (for example, the above (3)), a WZOZ w-type emulsion can be formed as described below.

[0054] Normally, when a monodispersed WZOZW type emulsion is formed by a membrane emulsification method, for example, by sufficiently circulating an outer aqueous phase, the generated wZoZw type emulsion particles are formed on the membrane surface of the porous glass membrane. Detachment is desirable. For example, it is preferable that the wZoZw type emulsion is detached from the film surface with a relatively low filling rate. On the other hand, it is preferable that the neutron capture preparation such as wZ ozw type emulsion has a relatively high filling rate in order to achieve better deposition properties. Therefore, in order to satisfy both the purpose of production and the effect of the product, for example, a relatively low filling rate (e.g. 60 volume

%)) WZoZw type emulsion, and after forming the emulsion, the water in the outer water phase is transferred to the inner water phase using the osmotic pressure difference to expand the wZoZw type emulsion particles. It is preferable to change the ratio (for example, 60% by volume or more, preferably 60 to 80% by volume).

Next, the neutron capture preparation having WZOZW type emulsion force of the present invention can be used for neutron capture therapy using a boron compound. As described above, in conventional neutron capture therapy, it was difficult to sufficiently accumulate boron compounds in tumor tissue (tumor cells). For example, α particles generated by thermal neutron irradiation, Jumping lithium nucleus is positive There was a problem of attacking normal cells and normal tissues. For this reason, although neutron capture therapy can destroy tumor cells and tumor tissue, it has limited the application sites and patients because of its effect on normal cells. However, according to the neutron capture preparation comprising the wZoZw type emulsion of the present invention, boron compounds can be selectively accumulated and deposited in the target tumor tissue and tumor cells. The target tumor tissue and tumor cells can be destroyed while avoiding the influence on cells. Thus, since the influence on normal cells and the like can be avoided, if the neutron capture preparation of the present invention is used, the target range to which neutron capture therapy can be applied can be expanded. Therefore, if the neutron capture preparation of the present invention is used, it is not particularly limited. For example, it can be applied to hypervascular tumors (liver tumor, brain tumor, ovarian tumor, breast cancer, kidney cancer, etc.), It is useful for the treatment of liver tumors because of its excellent accumulation and deposition properties.

[0056] The method of administration of the neutron capture preparation of the present invention into the body is not particularly limited, and examples thereof include submucosal local administration and intraarterial administration. In particular, it is preferable to administer the catheter directly to the affected area by an intraarterial injection method in which a catheter is inserted transarterially and the target substance (neutron capture preparation of the present invention) is administered to the target organ. In the case where the target organ is the liver, for example, the administration route may be a hepatic artery branched from the right femoral artery.

[0057] Further, the administration mode of the neutron capture preparation of the present invention is not particularly limited, and the W ZOZW type emulsion in the present invention may be administered as it is, or administered together with other replacement fluids (eg, glucose, amino acids, etc.). May be. Further, the dose of the neutron capture preparation of the present invention is not particularly limited. For example, the type and amount of boron compound contained in the neutron capture preparation (amount of polone), the site and size of the tumor tissue, It can be determined appropriately according to the age and sex of the patient. In general, the ratio of boron per lg of tumor cells is, for example, in the range of 10-30 gZg (wet), preferably in the range of 15-30 g / g (wet).

[0058] Further, the method of irradiation with thermal neutrons or epithermal neutrons is not limited, and can be appropriately determined based on conventionally known methods and conditions.

Example 1

[0059] A WZOZW type emulsion including a boron compound was produced.

[0060] (Example 1 1) 525 mg of BSH (manufactured by KATCHEM), which is a neutron scavenger, was dissolved in 3 ml of ratatose (trade name ratatoose-hydrate, 20%, manufactured by Nacalai Testa), and this solution was used as the inner aqueous phase material. Also, 4.5 ml of sword oil (trade name Ribiodol) plus 0.5 ml of polyoxyethylene hydrogenated castor oil (trade name HCO40, manufactured by Nikko Chemicals) with ethylene oxide (40 mol) Was an oil phase material. Then, 0.4 weight ⁰ / oNaCl 7.5ml, acidified ethylene added (60mol) polyoxyethylene hydrogenated castor oil (trade name HCO60, manufactured by Nikko Chemical Co., Ltd.) 0.5ml The outer water phase material was used.

[0061] First, the inner aqueous phase material is dispersed in the oil phase material through a hydrophobic porous glass membrane having a pore size of 5 m (hereinafter referred to as "first porous membrane"). Formed emulsion. Further, the obtained WZO type emulsion is dispersed in the outer water phase material through a hydrophilic porous glass membrane (hereinafter referred to as “second porous membrane”) having a pore diameter of 20 m to form a WZO type ZW type emulsion. did. As the porous glass membrane, a trade name SPG filter kit of SPG Techno Co., Ltd. was used.

[0062] (Example 1 2)

In the same manner as in Example 1-1, the inner aqueous phase material was dispersed in the oil phase material through the first porous membrane (pore diameter 5 m) to form a WZO type emulsion. Then, instead of the second porous membrane, a syringe was used, and the obtained W / O type emulsion was dropped onto the outer aqueous phase material to form a WZOZW type emulsion. The diameter of the syringe tip was about 500 m (22 gauge), and WZO type emulsion was dropped while stirring the outer aqueous phase material with a stirrer under the condition of 300 mZl drop. A W / O / W type emulsion was formed in the same manner as in Example 1 except for these conditions.

[0063] (Comparative Example 1)

After mixing the same inner aqueous phase material as in Example 1 and 5 ml of sodo oil (trade name Ribiodol) by the bombing method, this mixture was further added by 0.4 weight. / Carried in 8 ml of oNaCl and mixed in the same manner by the poving method to obtain emulsion (Libiodol-Boron Mix Emulsion, hereinafter also called “Lipiodol Mix Emulsion”! /).

[0064] For the WZOZW type emulsion of the obtained example, the particle size distribution was measured using a laser diffraction Z scattering type particle size distribution meter (trade name: SALD-2000, manufactured by Shimadzu Corporation). It was. The results are shown in the graph in Fig. 2. In Fig. 2, (a) shows the particle size distribution of Example 1-1 (b) and (b) shows the particle size distribution (Y axis: relative particle amount (q3 / Δ logx), X axis: particle size m) of Example 12. Show. In addition, a photograph of the WZOZW type emulsion of the example is shown in FIG. 3, and a photograph of the Lipiodo hox emulsion of the comparative example is shown in FIG. In FIG. 3, (a) is a photograph of Example 1-1, and (b) is a photograph of Example 1-2.

[0065] The WZOZW type emulsion of Example 1-1 has an average particle size force of about 33. of the WZOZW type emulsion particles, and a particle size of about 75 to 150% of the average particle size (about 25 to 50.25 / zm), which is about 88.9% of all particles. Further, the WZOZW type emulsion of Example 1-2 has an average particle size of WZOZW type emulsion particles of about 321.4 μm and an average particle size S of 188.9 μm to 535.3 μm. Harmful damage ij resultant force About 99.3% of all particles, ratio force that particles with particle size of 75% to 150% of average particle size (about 241 to 482 .: m) about 75. It was 5%. From the graph of Fig. 2 and the results of Fig. 3 and Fig. 4, the comparison example did not provide uniform emulsion, whereas in Examples 1 1 and 1 2 W / O / It can be seen that W-type emulsion was obtained. The WZOZW type emulsion of Example 1-1 was stored at 4 ° C., and as a result, the uniformity of the particle size was maintained even after about 1 month of preparation power. Example 2

[0066] The WZOZW emulsion produced in Example 1 was confirmed to be deposited on a liver tumor.

[0067] (Preparation of liver tumor model)

A 12-week-old Japanese white rabbit (female, 2.5 to 3 kg) was subjected to midline laparotomy, and tumor cells (VX-2 rabbit rabbit squamous cell carcinoma cells) were directly injected into the left lobe of the liver. A 10 mm diameter liver tumor was formed 10-14 days after tumor cell transplantation.

[0068] (Articulation of WZOZW type emulsion)

The above-mentioned rabbit that had developed a liver tumor was subjected to midline laparotomy, the intrinsic hepatic artery was identified and exposed, and then the gastroduodenal artery was half-opened and an elastor tube was inserted. Then, the WZOZW type emulsion (4 ml) of Example 1 was injected through the tube (BSH 75 mgZkg). The common hepatic artery was clipped during the infusion of the emulsion. [0069] (Measurement of boron concentration)

The rabbits were sacrificed 24 hours after the infusion of the emulsion, liver tumors and blood were collected, and their boron concentrations were measured. The boron concentration was measured by ICP-MAS spectroscopy based on a conventional method. In addition, the same test was carried out for the Lipiodol mix emulsion of Comparative Example 1 and an emulsion-free bottle was used as a control. Table 1 shows the results of boron concentrations in liver tumors, and Table 2 shows the results of blood boron concentrations.

[0070] [Table 1]

(Liver tumor)

Types of emulsions Particle size Polon concentration

(μm) (μg / g wet) Example 1 1 1

W / 0 / W type emulsion about 3 3. 5 1 7. 8 5 Example 1 1 2

W / 0 / W Emulsion About 3 2 1. 4 1 2. 7 7 Comparative Example 1

Lipiodol Mix Emulsion ― 1.7 5 Con 卜 Ronore ― 0

[0071] [Table 2]

(Blood)

Types of emulsions Particle size Boron concentration

(μm) (β 1 g wet) Example 1 1 1

W / 0 / W type emulsion about 3 3.5 5 6.0 Example 1 1 2

w / o / w emulsion approximately 3 2 1 .4 2. 1 Comparative Example 1

Lipiodol mix emulsion ― 2.2

As shown in the above Table 1 (liver tumor), the emulsion of the comparative example showed an extremely low polone concentration 24 hours after administration, whereas With WZOZW type emulsions of this type, boron compounds are selectively accumulated in liver tumors even 24 hours after administration. I understand. In addition, as shown in Table 2 (blood), since the boron concentration in the blood is low, the boron compound does not stay in the blood in the embodiment of the embodiment.

It is clear that it has accumulated in liver tumors. As described above, according to the neutron capture preparation having wZoZw-type emulsion force of the present invention, boron can be deposited on the target tumor tissue, so that it is possible to realize destruction of only the tumor tissue very efficiently.

Example 3

[0073] Using the wZoZw type emulsion of Example 1 1 and the wZoZw type emulsion of Example 1 2, the deposition of BSH on the liver tumor after 1 day, 3 days, and 7 days after Example 2 was performed. This was confirmed (Examples 3-1 and 3-2). Further, as comparative examples, Lipiodol mix emulsion of Comparative Example 1 (Comparative Example 3-1) and the boron solution prepared in Example 1 (the inner aqueous phase material) (Comparative Example 3-2) were used. used.

[0074] (1) Change in boron concentration over time after infusion of emulsion

The BSH concentrations in tumor tissue, normal tissue, and blood were measured by ICP-MAS spectroscopy 1 day, 3 days, and 7 days after the arterial injection of WZOZW type emulsion in Example 1-1. Example 3—1). These results are shown in Table 3 below.

[0075] [Table 3] Types of emulsions Polon concentration g / g we t 1 1 ί ； s u e

Tumor tissue Normal tissue Blood Example 1 1 1

w / o / w¾ emulsion 1 day later 1 4 1. 8 6 1 1. 2

7 days later 2 8 8 5 0 0. 2 Comparative Example 1

L i p i o d o l Mix emulsion 1 day later 5 8 .0 1 4 .8 0 .4

After 7 days, as shown in Table 3 above, compared to the comparative example, according to Example 3-1, the boron concentration in the tumor tissue was sufficiently retained even after 7 days. I was able to keep. Specifically, after 7 days, the BSH concentration in the tumor tissue of Comparative Example 3-1 decreased to 9.0. Example 3-1 showed a concentration approximately 3.2 times higher. Furthermore, in the normal tissue, Example 3-1 was able to reduce the BSH concentration in the tissue to 1Z4 than Comparative Example 3-1. From this result, According to the WZOZW type emulsion of the example, it is possible to efficiently accumulate and deposit BSH in the tumor tissue, and also suppress the accumulation and deposition in the normal tissue and reduce the influence on the normal tissue it can.

[0077] (2) Confirmation of WZOZW-type emulsion accumulation by soft-line photography

One day, three days, and seven days after the arterial injection, soft tissue imaging was performed on tumor tissue and normal tissue, and accumulation of WZOZW type emulsion in each tissue was confirmed. The same confirmation was made for Comparative Example 3-1. The results are shown in FIG. Fig. 5 is an image photograph showing the results of soft wire imaging. In the figure, "W / 0 / W emulsion" represents the W / O / W emulsion of Example 3-1, and "Lipiodol mix" The Lipiodol mixture of Comparative Example 3-1 is shown, and “day” indicates the number of days after arterial injection (the same applies to other drawings).

[0078] According to soft-line imaging, the presence of lipidol in the tissue can be confirmed. As shown in Fig. 5, in the tissue administered with the wZoZw type emulsion of Example, the deposition of ribiodol contained in the wZoZw type emulsion was confirmed even 7 days after the infusion.

. Therefore, it can be said that only the WZOZW type emulsion of the example markedly shows accumulation in the tumor tissue in light of the BSH concentration data obtained by ICP-MAS spectroscopy in (1).

[0079] (3) Confirmation of WZOZW-type emulsion accumulation by optical microscope observation

One day, three days, and seven days after the arterial injection, soft tissue imaging was performed on tumor tissue and normal tissue, and accumulation of WZOZW type emulsion in each tissue was confirmed. The same confirmation was made for Comparative Example 3-1. The result of Example 3-1 is shown in Fig. 6, and the result of Comparative example 3-1 is shown in Fig. 7. Both figures are image photographs taken with an optical microscope. In both figures, the “X value” indicates the magnification of the microscope (the same applies to the other figures).

[0080] As shown in both figures, accumulation was confirmed in both emulsions of the example and the comparative example. However, in the comparative example, as shown in FIG. 7, the accumulation of oil droplets having a very large diameter was observed, and the sizes were not uniform. In contrast, it was confirmed that the wZoZw type emulsion of the example was accumulated around the tumor with small and uniform oil droplets rich in blood vessels. [0081] (4) Confirmation of WZOZW-type emulsion accumulation by electron microscope observation The tumor tissue and normal tissue one day after the arterial injection (4 ml) were observed with an electron microscope to confirm the accumulation of WZOZW-type emulsion in each tissue. . The same confirmation was performed for the Lipiodo Hose emulsion of Comparative Example 3-1 and the boron solution of Comparative Example 3-2. The results of Example 3-1 are shown in FIG. 8 (a), the results of Comparative Example 3-1 are shown in FIG. 8 (b), and the results of Comparative Example 3-2 are shown in FIG. These figures are electron micrographs. In FIG. 9, “BS H solution” indicates the boron solution of Comparative Example 3-2.

[0082] Fig. 10 shows electron microscopic analysis of liver tumor cells 1 day, 3 days and 7 days after arterial injection using the WZOZW type emulsion of the example or the Lipiodol mix emulsion of Comparative Example 3-1. A mirror photo is shown.

[0083] As shown in Fig. 8 (a), as a result of the infusion of the emulsion of the example, vesicles that were thought to be lipidol oil droplets, which are constituents of the WZOZW type emulsion, were confirmed. On the other hand, in Comparative Examples 3-1 and 3-2, the formation of such cells was unobservable (Fig. 8 (b), Fig. 9). In addition, according to the emulsion of the example, the uptake of ribiodol was confirmed even after 7 days, and the accumulation thereof was around the tumor cells as compared with Comparative Example 3-1 in which Lipiodol mixed emulsion was infused. There was a tendency to accumulate.

Industrial applicability

[0084] As described above, according to the neutron capture preparation of the present invention, boron compound is included in the emulsion without flowing out, and boron compound is efficiently accumulated and deposited on tumor cells. Is possible. For this reason, for example, even when a neutron capture preparation is administered via blood, the influence on other tissues and normal tissues is reduced. Therefore, it can be said that application to the tumor tissue to which neutron capture therapy has not been applied so far is possible by using the neutron capture preparation of the present invention. In particular, since it is difficult to select a treatment method for liver cancer, it is extremely useful in clinical medicine that a neutron capture therapy having an excellent therapeutic effect can be realized by the present invention.

Claims

The scope of the claims

[1] A neutron capture formulation comprising multiphase emulsion,

The multiphase emulsion force is a wZoZw type emulsion comprising an inner water phase, an oil phase and an outer water phase containing a neutron scavenger,

A neutron capture preparation wherein the neutron capture agent is a boron compound.

[2] The neutron capture preparation according to claim 1, wherein the wZoZw type emulsion is a monodisperse emulsion.

[3] The inner water phase is dispersed in the oil phase, and the oil phase containing the inner water phase is dispersed in the outer water phase, thereby forming a wZoZw type emulsion, 2. The neutrality according to claim 1, wherein among the oil phase particles dispersed in a phase, the oil phase particles having a particle diameter of 75% to 150% of the average pore diameter are 50% by volume or more of the total oil phase particles. Child capture formulation.

[4] The inner water phase is dispersed in the oil phase, and the oil phase containing the inner water phase is dispersed in the outer water phase, thereby forming a wZoZw type emulsion, and the outer water phase The neutron capture preparation according to claim 1, wherein an average particle size of the oil phase particles dispersed in the particle is 30 m or more.

[5] The neutron capture preparation according to claim 1, wherein an average particle diameter of the oil phase particles dispersed in the outer aqueous phase is in a range of 30 to 500 μm.

[6] The inner aqueous phase is dispersed in the oil phase, and the oil phase containing the inner aqueous phase is dispersed in the outer aqueous phase, thereby forming a wZoZw type emulsion. The neutron capture preparation according to claim 1, wherein an average pore size of the dispersed inner water phase particles is in a range of 200 m or less.

[7] The neutron capture preparation according to claim 1, wherein the boronic compound is a water-soluble boronic compound.

[8] The neutron-capturing preparation according to claim 7, comprising at least one of the water-soluble boron compound power borocapitite and P-boronov-lualanine.

[9] The neutron-trapping preparation according to claim 1, wherein the oil phase is an oil phase containing fats and oils and a surfactant.

[10] The neutron-trapping preparation according to claim 9, wherein the surfactant is polyoxyethylene hydrogenated castor oil.

[11] A raw material for the neutron capture preparation according to claim 1,

A raw material comprising a wZo type emulsion comprising an inner water phase and an oil phase containing a neutron scavenger, wherein the neutron scavenger is a boron compound.

[12] Neutron capture therapy using a neutron capture formulation,

The neutron capture preparation is the neutron capture preparation according to claim 1, wherein the neutron capture preparation is administered into a body, the neutron capture preparation is accumulated in a target cell, and the target cell is destroyed by neutron irradiation. Capture therapy.

[13] The neutron capture therapy according to claim 12, which is a neutron capture therapy for tumor cells

[14] The neutron capture therapy according to claim 13, wherein the tumor cells are tumor cells rich in blood vessels.

15. The neutron capture therapy according to claim 13, wherein the tumor cells are liver tumor cells.

[16] The neutron capture therapy according to claim 12, wherein the neutron capture preparation is administered to an artery.