Carrier for DDS and method for producing the same

Abstract

To provide a technology that enables enhanced sustainability of drug release in a carrier for DDS.SOLUTION: The carrier for DDS (drug delivery system) comprises a tubular substance that carries a drug within an internal space, and a plug part that seals the opening of the internal space and includes a polymer material.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a support for DDS and a method for producing the same. [Background technology]

[0002] Drug delivery systems (DDS) have been actively researched as a technology for continuously delivering the minimum amount of drug required at the required time and to the required location. For example, Patent Document 1 discloses a DDS carrier in which a drug is supported on tubular apatite crystals. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2014 / 045534 Summary of the Invention [Problem to be solved by the invention]

[0004] However, to increase the sustained release of a drug from a DDS carrier, it is necessary to slow down the release rate of the drug. The technology described in Patent Document 1 could not control the release rate of the drug from the openings in the apatite crystals, and therefore could not increase the sustained release of the drug.

[0005] The present invention has been made in view of the above circumstances, and one of its exemplary purposes is to provide a technique that enables the sustained release of a drug from a DDS carrier to be increased. [Means for solving the problem]

[0006] In order to solve the above problems, a DDS carrier according to one embodiment of the present invention comprises a tubular substance that carries a drug in its internal space, and a plug that closes the opening of the internal space and contains a polymeric material.

[0007] According to this embodiment, the sustained release of the drug from the DDS carrier can be increased.

[0008] The polymeric material may include organic polymers forming a cross-linked structure.

[0009] The DDS support may further comprise a poor solvent for the polymer material held in the internal space.

[0010] The plug may be gel-like or porous.

[0011] The plug may be biocompatible.

[0012] Another aspect of the present invention is a method for producing a DDS carrier, which includes a tube preparation step of preparing a tubular substance carrying a drug in its internal space, and a production step of bringing a polymer solution containing an organic polymer into contact with an ionic solution containing ions that cause the organic polymer to form a crosslinked structure in the internal space, thereby producing an organic polymer that has formed a crosslinked structure.

[0013] According to this embodiment, the sustained release of the drug from the DDS carrier can be increased.

[0014] The ions may be multivalent cations.

[0015] The organic polymer may be alginic acid and the ions may be divalent calcium ions.

[0016] The polymer solution may further contain a phosphate, and in the production step, the ionic solution and the polymer solution may be brought into contact with each other to produce calcium phosphate together with the organic polymer that forms a crosslinked structure.

[0017] Another aspect of the present invention is a method for producing a DDS carrier, which includes a tube preparation step of preparing a tubular substance carrying a drug in its internal space, and a precipitation step of bringing a polymer solution, in which an organic polymer is dissolved in a good solvent, into contact with a poor solvent for the organic polymer in the internal space, thereby precipitating the organic polymer.

[0018] According to this embodiment, the sustained release of the drug from the DDS carrier can be increased.

[0019] The solubility of the poor solvent for the organic polymer may be 1 / 25 or less of the solubility of the good solvent, which makes it possible to more easily precipitate the organic polymer in the precipitation step.

[0020] Any combination of the above components and any transformation of the present invention into a method, device, system, etc. are also valid aspects of the present invention. [Effects of the Invention]

[0021] According to the present invention, a technique can be provided that enables the sustained release of a drug from a DDS carrier to be increased. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 is a diagram schematically showing a support for DDS according to one embodiment of the present invention. [Figure 2] FIG. 1 is a diagram illustrating the flow of a method for producing a DDS support according to one embodiment of the present invention. [Figure 3] 1 is a diagram for explaining the state of reaction between an ionic solution and a polymer solution. FIG. [Figure 4] FIG. 10 is a diagram showing the results of measuring absorbance for tube samples according to Example 2 and Comparative Example 1. [Figure 5] FIG. 10 is a diagram showing the results of observing the behavior of calcium chloride solutions in tube samples according to Example 3 and Comparative Example 2. [Figure 6]FIG. 10 is a diagram showing the results of recording the distance traveled by a colored calcium chloride solution every second for tube samples according to Example 3 and Comparative Example 2. [Figure 7] FIG. 1 is a diagram illustrating a method for producing a DDS support according to one embodiment of the present invention. [Figure 8] 1 is a diagram for explaining the state of reaction between a polymer solution and a poor solvent. FIG. [Figure 9] FIG. 10 is a diagram showing the results of measuring absorbance for tube samples according to Example 4 and Comparative Example 3. [Figure 10] FIG. 10 is a diagram showing the results of observing the behavior of calcium chloride solutions in tube samples according to Example 5 and Comparative Example 4. [Figure 11] FIG. 10 is a diagram showing the results of recording the distance traveled by a colored calcium chloride solution every second for tube samples according to Example 5 and Comparative Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0023] (background) The use of DDS can reduce the amount of drugs used and side effects, and DDS has been actively studied. Among these, DDS carriers have been devised that support drugs in tubular inorganic crystals or organic polymer microtubes or nanotubes, and gradually release the drugs from these tubular materials.

[0024] To increase the sustained release of a drug from a DDS carrier in which a drug is loaded in a tubular substance, it is necessary to slow down the drug release rate. To increase the sustained release, it is necessary to reduce the diameter of the release hole in the opening of the tubular substance. However, with a tubular substance, reducing the inner diameter results in a decrease in the amount of drug loaded in each tube, which poses a problem of reduced sustained drug efficacy. In the case of a tubular substance, it is effective to plug the opening with some kind of substance to form a relatively small opening diameter.

[0025] However, there is no established technology for individually plugging drug-loaded microtubes or nanotubes, leaving pores through which the drug can pass while retaining the drug content. For example, one method has been investigated in which drug-loaded microtubes or nanotubes are immersed in a solution containing a biodegradable polymer, and then the solvent is removed by heating. However, there are problems with this method, such as the risk of deterioration of the loaded drug due to heating and the aggregation of microtubes or nanotubes loaded with multiple drugs.

[0026] For example, Reference 1 describes a decrease in the absorption spectrum area (Figure 1) and an increase in the minimum inhibitory concentration (MIC) (Figure 3) when the drug is heated at 100°C or 121°C. Reference 2 also describes that nanotubes aggregate when complexed with organic matter, resulting in a deterioration of their properties, and that drying at 60°C causes nanotube aggregation.

[0027] (References) 1.MK Hsieh, CL Shyu, JW Liao, CA Franje, YJ Huang, SK Chang, PY Shih, CC Chou. "Correlation analysis of heat stability of veterinary antibiotics by structural degradation, changes in antimicrobial activity and genotoxicity." Veterinarni Medicina, vol.56, no.6, 2011, pp. 274-285. 2.MJ Saif, HM Asif, M. Naveedj. "PROPERTIES AND MODIFICATION METHODS OF HALLOYSITE NANOTUBES: A STATE-OF-THE- ART REVIEW." Chil. Chem. Soc., vol.63, no.3 2018, pp.4109-4125

[0028] (Embodiment) Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. In the description of the drawings, the same elements are given the same reference numerals, and duplicated explanations will be omitted as appropriate. Furthermore, the configurations described below are examples and do not limit the scope of the present invention in any way.

[0029] 1 is a diagram schematically illustrating a DDS carrier 1 according to one embodiment of the present invention. As shown in FIG. 1, the DDS carrier 1 according to this embodiment mainly comprises a tubular substance 10, a drug 20, and a stopper portion 30.

[0030] The tubular material 10 has a tubular shape, and is specifically a hollow microtube or nanotube that extends in one direction. The tubular material 10 carries a drug 20 in its internal space 12.

[0031] 1, the outer and inner edge portions of the tubular material 10 are circular when viewed in the direction of length L, but this is not limited thereto and the shape may be polygonal, such as triangular, rectangular, or hexagonal. Regarding the size of the tubular material 10, for example, the length L may be 0.001 mm to 500 mm, the inner diameter d1 may be 0.1 μm to 1000 μm, and the outer diameter d2 may be 1 to 2000 μm.

[0032] The tubular substance 10 according to this embodiment may be, for example, a material that is stable against water, and specifically may be inorganic materials such as chlorapatite, hydroxyapatite, inorganic glass, silicon dioxide, titanium dioxide, aluminum oxide, zirconium oxide, boron nitride, aluminum nitride, and iron oxide-silica composites, metal materials such as cobalt alloys, and organic polymers such as polyethylene, polystyrene, polymethyl methacrylate, cellulose, cellulose derivatives, polyethylene terephthalate, maltose, diphenylaniline, and polyvinylpyrrolidone, or a composite of a combination of these.

[0033] A poor solvent for the polymer material that constitutes the plug 30 may be held in the internal space 12 of the tubular material 10. The poor solvent may be, for example, ethanol, methanol, 1-propanol, 1-butanol, etc. In this case, it is preferable that the tubular material 10 is stable against the poor solvent.

[0034] The stopper 30 comprises a polymeric material and blocks the opening 14a of the internal space 12 of the tubular substance 10. Specifically, the stopper 30 is formed near or inside the opening 14a so as to prevent or inhibit the release of the drug 20 carried in the internal space 12 from being released from the opening 14a. The stopper 30 does not need to completely block the opening 14a, and a gap may be formed between the inner surface of the tubular substance 10 and the stopper 30, or within the stopper 30 itself. In this case, the stopper 30 may be configured to allow the drug 20 to pass through the gap.

[0035] The stopper 30 is preferably made of a material that is less harmful to the living body and has biocompatibility and biodegradability when using the DDS carrier 1. Specifically, the stopper 30 is preferably made of a polymer material that is used as a biomaterial. Examples of the polymer material may include polycaprolactone (PCL), polylactic acid, glycolic acid, polytrimethylene carbonate, polyethylene glycol copolymer, dioxanone-lactide copolymer, etc.

[0036] The polymer material constituting the plug 30 may include an organic polymer that forms a cross-linked structure. This organic polymer causes chemical cross-linking and may be, for example, alginic acid. In this case, the polymer material may include, for example, calcium alginate, in which alginic acid forms a cross-linked structure with calcium.

[0037] The plug 30 may be gel-like or porous. In this case, at least a portion of the drug 20 may diffuse inside the plug 30. The rate at which the drug 20 diffuses can be varied greatly depending on, for example, the concentration and structure of the gel-like substance of the plug 30. The plug 30 may also contain inorganic nanoparticles and microparticles.

[0038] Furthermore, the plug 30 may contain an inorganic material in addition to the polymer material. The inorganic material may be, for example, needle-shaped calcium phosphate. Specifically, the plug 30 may be made of a mixture of calcium alginate and calcium phosphate. This makes the plug 30 more mechanically strong than when the plug 30 is made of calcium alginate alone.

[0039] 1 shows the stopper 30 only on the side of the opening 14a, but a stopper may also be formed on the side of the other opening 14b, thereby preventing the drug 20 from being released from both openings 14a and 14b.

[0040] (Manufacturing method 1) A method for producing a DDS support according to one embodiment of the present invention will be described with reference to Fig. 2. Fig. 2 is a diagram for explaining the flow of a method for producing a DDS support according to one embodiment of the present invention. The method for producing a DDS support according to this embodiment includes a tube preparation step, a solution preparation step, an injection step, and a generation step.

[0041] In the tube preparation step, a tubular substance carrying a drug in its internal space is prepared. For example, as shown in Fig. 2(a), the above-mentioned tubular substance 10 is made to carry a drug 20, and the tubular substance 10 carrying the drug 20 in its internal space 12 is prepared.

[0042] In this case, the tubular material 10 may have a size that allows the solvent to be drawn into the internal space by capillary action. The size of the tubular material 10 is preferably, for example, a length L of 0.001 mm to 500 mm, an inner diameter d1 of 0.1 μm to 1000 μm, and an outer diameter d2 of 1 to 2000 μm.

[0043] In the solution preparation step, a polymer solution containing an organic polymer and an ion solution containing ions that cause the organic polymer to form a crosslinked structure are prepared.

[0044] Polymer solutions are prepared by dissolving organic polymer raw materials in various solvents. For example, polymer solutions can be prepared by dissolving organic polymers in pure water. In this case, the organic polymer may be any water-soluble organic polymer, such as an alginate or alginic acid ester, and more specifically, may be sodium alginate, potassium alginate, ammonium alginate, or propylene glycol alginate.

[0045] The higher the concentration of alginate or alginate ester in the polymer solution, the stronger the mechanical strength of the stoppers generated in the generation step described below, and the narrower the region in the interior space 12 of the tubular material 10 where the stoppers are generated. On the other hand, the lower the concentration of alginate or alginate ester in the polymer solution, the wider the region in the interior space 12 of the tubular material 10 where the stoppers are generated, and the weaker the mechanical strength of the stoppers generated.

[0046] The polymer solution may contain a phosphate dissolved therein in addition to the alginate or alginate ester, and may also contain inorganic particles in addition to the alginate or alginate ester.

[0047] The ionic solution is a solution containing various ions, and the ions contained in the ionic solution are preferably polyvalent cations, particularly divalent calcium ions. Note that the type of ions contained in the ionic solution is not limited to calcium, and may be monovalent ions, divalent ions such as Sr and Br, or trivalent ions such as Al.

[0048] The ionic solution may be, for example, an aqueous calcium solution prepared by dissolving a calcium salt in pure water. The calcium salt used to prepare the aqueous calcium solution is not particularly limited as long as it has high solubility in water, and may be, for example, calcium chloride, calcium iodide, calcium nitrate, calcium acetate, etc.

[0049] In the injection step, an ionic solution containing ions that cause the organic polymer to form a cross-linked structure is injected into the internal space 12 of the tubular material 10. In this embodiment, as shown in FIG. 2(a), the ionic solution is injected into the internal space 12 from one opening 14a. For example, the opening 14a of the tubular material 10 may be brought into contact with the ionic solution, and the ionic solution may be injected into the internal space 12 of the tubular material 10 by capillary action utilizing the shape of the tubular material 10. As a result, the ionic solution 31 is held in the internal space 12, as shown in FIG. 2(b).

[0050] In the formation step, the polymer solution and the ionic solution 31 are brought into contact with each other in the internal space 12 of the tubular material 10 to form an organic polymer that has formed a crosslinked structure. Specifically, the polymer solution is brought into contact with the ionic solution 31 that has been injected into the internal space 12, and a polymer material containing an organic polymer that has formed a crosslinked structure is precipitated. For example, the opening 14a of the tubular material 10 is brought into contact with the polymer solution 32, and the polymer solution 32 is injected into the internal space 12 through the opening 14a. At this time, the organic polymer contained in the polymer solution 32 reacts immediately with the functional groups for crosslinking in contact with the ions in the ionic solution 31 near or inside the opening 14a of the tubular material 10, forming a crosslinked structure.

[0051] The reaction between the ionic solution 31 and the polymer solution 32 will be described with reference to FIG. 3(a). When the ionic solution 31 and the polymer solution 32 come into contact with each other as shown in FIG. 3(a), a polymer material 36 that forms a plug is precipitated at the interface between the ionic solution 31 and the polymer solution 32 as shown in FIG. 3(b). This polymer material 36 is produced near or inside the opening 14a in the internal space 12 of the tubular substance 10. As a result, a plug 34 made of the polymer material that blocks the opening 14a is formed as shown in FIG. 2(c).

[0052] When the polymer solution 32 contains an organic polymer, ionic cross-linking between alginic acids caused by the carboxyl groups and ions of alginic acid causes localized deposition of a water-insoluble metal alginate gel. In this case, the ionic cross-linking reaction occurs rapidly, especially with calcium ions, which are divalent ions, and the plug is formed as a gel or porous substance. The drug 20 present within the gel substance is in a state where it can diffuse, but the rate of diffusion can vary greatly depending on the concentration and structure of the gel.

[0053] According to the manufacturing method of the DDS carrier of this embodiment, the size and shape of the plug 34 can be adjusted to control the drug release rate depending on the application. For example, when the DDS carrier is used for dentures in dental treatment, the size of the plug 34 may be adjusted so that the drug is released over a period of about one week. Furthermore, when the DDS carrier is used for cancer treatment, the size of the plug 34 may be adjusted so that the drug is released slowly.

[0054] If the polymer solution 32 contains calcium phosphate in addition to alginic acid or an alginate ester, calcium phosphate can be precipitated simultaneously with the precipitation of calcium alginate when the polymer solution 32 and the ionic solution 31 come into contact with each other. In this case, the plug 34 produced contains a mixture of calcium alginate and calcium phosphate, and is therefore mechanically stronger than when it contains only calcium alginate.

[0055] According to the manufacturing method of the DDS carrier of this embodiment, a stopper portion 34 can be formed in the internal space 12 of the tubular substance 10. This suppresses the release of the drug from the DDS carrier 1, and can increase the sustainability of the drug release from the DDS carrier 1.

[0056] Furthermore, the method for producing a DDS carrier according to this embodiment does not require heating, which may lead to deterioration of the drug 20 or aggregation of the tubular material 10. Therefore, the method for producing a DDS carrier according to this embodiment makes it possible to individually and selectively embolize the tubular material 10 while suppressing deterioration of the drug and aggregation of the tubular material 10.

[0057] (Example 1: Embolization of glass tube with calcium alginate gel) In Example 1, a borosilicate glass tube was used as the tubular material. Furthermore, in order to understand the sustained release effect of the drug held in the internal space of the tube, a tube sample was prepared in which the dye methylene blue (Methylene Blue / MB) was held instead of the drug, and the embolization effect was evaluated. The method for preparing the tube sample according to Example 1 will now be described in detail.

[0058] First, calcium chloride was dissolved in pure water to prepare a calcium chloride solution with a concentration of 1 mol / L. 0.5 mg of MB was added to 10 ml of the calcium chloride solution to color it. The tip of a borosilicate glass tube with an outer diameter of 1000 μm, an inner diameter of 800 μm, and a length of 25 mm was placed in contact with the colored calcium chloride solution, and the colored calcium chloride solution was injected into the interior space of the borosilicate glass tube through capillary action.

[0059] Next, 99 g of pure water and 1 g of sodium alginate powder (Kimica Co., Ltd., Kimica Algin I-5) were prepared, and while vigorously stirring the pure water, the sodium alginate powder was gradually added to the pure water to prepare a sodium alginate solution with a concentration of 1 wt %.

[0060] The tip of a 10 mm borosilicate glass tube filled with calcium chloride solution was inserted into the prepared sodium alginate solution, and the tube was held in this position for 10 seconds, allowing the sodium alginate solution to be injected into the internal space of the tube by hydrostatic pressure.

[0061] Ten seconds after the sodium alginate solution began to be injected into the tube's internal space, the tube was removed from the sodium alginate solution. After wiping off any droplets on the tube's exterior wall with an ethanol-soaked paper towel, the tube was left standing horizontally for 30 minutes. Within the tube's internal space, alginate ions and calcium ions reacted rapidly near the boundary between the calcium chloride solution injected first and the aqueous sodium alginate solution injected later. As a result, a water-insoluble calcium alginate gel with an ionically cross-linked structure precipitated within the tube's internal space. This calcium alginate gel constituted the plug that sealed the borosilicate glass tube.

[0062] Example 2: Embolization of glass tube with a complex of calcium alginate gel and calcium phosphate Example 2 shows an example of forming a plug reinforced with calcium alginate gel and a calcium phosphate composite. In Example 2, a tube sample was prepared in the same manner as in Example 1, except that dipotassium hydrogen phosphate was used as the phosphate salt to generate calcium phosphate. The method for preparing the tube sample according to Example 2 will be specifically described below.

[0063] First, calcium chloride solution was poured into a borosilicate glass tube in the same manner as in Example 1. Next, 49 g of pure water and 1 g of sodium alginate powder (Kimica Co., Ltd., Kimica Algin IL-6M) were prepared, and the sodium alginate powder was gradually added to the pure water while vigorously stirring to prepare a sodium alginate solution with a concentration of 2 wt%. 10 g of dipotassium hydrogen phosphate was dissolved in this sodium alginate solution to prepare a phosphoric acid-containing sodium alginate solution.

[0064] The tip of a 10 mm borosilicate glass tube containing calcium chloride solution was inserted into the prepared phosphate-containing sodium alginate solution, and the tube was held in this position for 10 seconds, allowing the phosphate-containing sodium alginate solution to be injected into the internal space of the borosilicate glass tube by hydrostatic pressure.

[0065] Ten seconds after inserting the borosilicate glass tube into the phosphate-containing sodium alginate solution, the tube was removed from the solution. Liquid droplets on the outer wall of the borosilicate glass tube were wiped off with an ethanol-soaked paper towel, and the borosilicate glass tube was then left in a horizontal position for 30 minutes. In the interior space of the borosilicate glass tube, alginate ions and calcium ions reacted near the boundary between the calcium chloride solution injected first and the phosphate-containing sodium alginate aqueous solution injected later. As a result, a water-insoluble calcium alginate gel and a water-insoluble calcium phosphate complex formed by the reaction of phosphate ions and calcium ions were produced. This complex formed a plug that sealed the borosilicate glass tube. The tube with this complex plug formed was designated the tube sample of Example 2.

[0066] (Comparative Example 1) In Comparative Example 1, calcium chloride was dissolved in pure water to prepare a calcium chloride solution with a concentration of 1 mol / L. 0.5 mg of MB was added to 10 mL of the calcium chloride solution to color it. The tip of a borosilicate glass tube with an outer diameter of 1000 μm, an inner diameter of 800 μm, and a length of 25 mm was brought into contact with the colored calcium chloride solution, and the colored calcium chloride solution was injected into the interior space of the borosilicate glass tube by capillary action, yielding a tube sample according to Comparative Example 1.

[0067] (Verification 1) In Verification 1, we demonstrate that the formation of a stopper made of an ionically cross-linked organic polymer gel suppresses the release of a drug held in the internal space of a borosilicate glass tube. Below, we explain the verification of the suppression of drug release by the stopper.

[0068] Approximately 5 mm of the tip of each of the tube samples according to Example 2 and Comparative Example 1 was immersed in 2 ml of pure water. One minute after the start of immersion, the tube sample was removed from the pure water. The liquid after the tube sample was removed was the liquid in which the immersion time was 1 minute.

[0069] The removed tube sample was immersed in another 2 ml of pure water. After 4 minutes had passed since the start of immersion, the tube sample was removed from the pure water. The liquid after which the tube sample was removed was designated as the liquid with a 4-minute immersion time. In this way, the tube sample was immersed in pure water for a total of 5 minutes. Using the same procedure, the tube sample was immersed in pure water for 10, 30, and 60 minutes.

[0070] The solution obtained by immersing the tube sample described above was measured using a JASCO UV-visible spectrophotometer in the range of 500 nm to 800 nm using the single-beam method to determine the absorbance at around 670 nm, which is due to MB. MB diffuses from the internal space of the tube sample into the pure water, and the magnitude of light absorption at around 670 nm increases or decreases depending on the amount of MB contained in the solution. The absorbance at wavelengths of 500 nm and 800 nm was considered to be 0, and the integrated value of the spectrum, from which the background was subtracted, was determined to be the absorbance at 670 nm, which is due to MB.

[0071] For Example 2 and Comparative Example 1, measurements were taken on three tube samples each, and the average value was used as the absorbance. The absorbance was integrated to determine the relative amount of MB released over time by immersion. The start time was set to 0 minutes, and the absorbance was set to 0. The integrated absorbance values, which indicate the amount of MB released, were calculated for immersion times of 1 minute, 5 minutes, 10 minutes, 30 minutes, and 60 minutes.

[0072] Fig. 4 shows the absorbance measurement results for Example 2 and Comparative Example 1. In Fig. 4, the horizontal axis represents the immersion time (minutes), and the vertical axis represents the integrated absorbance value. As shown in Fig. 4, in Comparative Example 1, a large increase in absorbance occurred within 1 minute due to the release of MB, and the absorbance value then became approximately constant. This is thought to be because most of the MB in the internal space of the borosilicate glass tube was released into the liquid within 1 minute, and then the MB concentrations in the internal space of the tube and in the liquid became approximately equal.

[0073] On the other hand, in Example 2, the release of the drug did not progress after 60 minutes of immersion, and the rapid release of MB was suppressed as in Comparative Example 1. Therefore, it was confirmed that the stopper made of a complex of calcium alginate gel and calcium phosphate is effective in the sustained release of the drug carried in the tube sample.

[0074] (Example 3: Embolization of chlorapatite tube) In Example 3, the method of Example 2 was applied to a chlorapatite tube, and a calcium chloride solution colored with MB was injected into the inner space of the chlorapatite tube, and one end of the chlorapatite tube was plugged to prepare a tube sample. The preparation method of the tube sample according to Example 3 will be specifically described below.

[0075] First, calcium chloride was dissolved in pure water to prepare a calcium chloride solution with a concentration of 1 mol / L. 0.5 mg of MB was added to 10 ml of the calcium chloride solution to color it. The tip of a chlorapatite tube with an outer diameter of approximately 200 μm, an inner diameter of approximately 80 μm, and a length of approximately 2500 μm was brought into contact with the colored calcium chloride solution, and the colored calcium chloride solution was injected into the internal space of the chlorapatite tube by capillary action.

[0076] 99 g of pure water and 1 g of sodium alginate powder (Kimica Co., Ltd., Kimica Algin I-5) were prepared, and the sodium alginate powder was gradually added to the pure water while vigorously stirring to prepare a sodium alginate solution with a concentration of 1 wt%. In Example 3, dipotassium hydrogen phosphate was added in addition to sodium alginate.

[0077] The tip of a 10 mm chlorapatite tube into which calcium chloride solution containing MB had been injected was inserted into the prepared sodium alginate solution, and the tube was held in this state for 10 seconds, thereby injecting the sodium alginate solution into the internal space of the chlorapatite tube under hydrostatic pressure (atmospheric pressure).

[0078] Ten seconds after inserting the chlorapatite tube into the sodium alginate solution, the tube was removed from the sodium alginate solution. Droplets on the outer wall of the chlorapatite tube were wiped off with a paper towel soaked in ethanol. In the interior space of the chlorapatite tube, near the boundary between the calcium chloride solution injected first and the phosphate-containing sodium alginate aqueous solution injected later, a water-insoluble calcium alginate gel and water-insoluble calcium phosphate complex formed an embolism near the opening of the chlorapatite tube. The calcium alginate gel was formed by the reaction of alginate ions with calcium ions, and the calcium phosphate was formed by the reaction of phosphate ions with calcium ions. The chlorapatite tube embolized with this complex was used as the tube sample of Example 3.

[0079] (Comparative Example 2: Chlorapatite tube without embolization) An ethanol solution colored with MB was injected into the internal space of a chlorapatite tube having an outer diameter of approximately 200 μm, an inner diameter of approximately 80 μm, and a length of approximately 2500 μm in the same manner as in Example 3 to prepare a tube sample according to Comparative Example 2.

[0080] (Verification 2) In Verification 2, the sustained drug release effect due to embolization was confirmed in a tube sample using a tube with a different shape and material from Verification 1. For this purpose, the tube samples according to Example 3 and Comparative Example 2 were used, and the embolization effect of Example 3 was evaluated by observing the difference in the migration behavior of the injected colored calcium chloride solution toward the open end when the tube samples were left horizontally. The details of Verification 2 will be explained in detail below.

[0081] First, the tube samples according to Example 3 and Comparative Example 2 were placed horizontally, and the open end (the end opposite the plugged end) of the tube sample according to Example 3 was fixed on carbon tape. For the tube sample according to Comparative Example 2, one end was fixed on the carbon tape. With the tube sample fixed, the behavior of the colored calcium chloride solution injected into the internal space of the tube sample was observed for 14 seconds. The observation results are shown in FIG. 5.

[0082] In Figure 5, the top two photographs show the tube sample according to Example 3, and the bottom two photographs show the tube sample according to Comparative Example 2. For each of the two photographs, the top photograph shows the state of the tube sample at the start of observation, and the bottom photograph shows the state of the tube sample 14 seconds after observation began. Furthermore, for the tube sample according to Example 3, the end on the left is the end that has been embolized, and the end on the right is the end that has not been embolized.

[0083] As shown in Fig. 5, in the tube sample according to Example 3, which had been subjected to embolization, almost no movement of the meniscus of the colored calcium chloride solution was observed (Ca Alginate plugged in Fig. 5). On the other hand, in the tube sample according to Comparative Example 2, which had not been subjected to embolization, the meniscus of the colored calcium chloride solution moved 230 µm toward the carbon tape-fixed side (left side) in 14 seconds (Non Plugged in Fig. 5).

[0084] The distance traveled by the colored calcium chloride solution was recorded every second, and the results are shown in Figure 6. In Comparative Example 2 (Non-plugged in Figure 6), the colored calcium chloride solution traveled a distance that was approximately proportional to the time, whereas in Example 3 (Ca Alginate-plugged in Figure 6), the colored calcium chloride solution barely moved.

[0085] In Comparative Example 2, the colored calcium chloride solution was pulled out by the tension of the carbon tape securing the open end, causing the liquid surface to move. In contrast, in Example 3, the movement of the colored calcium chloride solution was suppressed by the tension of the carbon tape. This is because the embolization effect suppressed the inflow of air from the embolized side, and it is clear that embolization is effective in sustained release of the drug contained in the tube.

[0086] (Manufacturing method 2) In the manufacturing method 2 of a DDS carrier, unlike the above-mentioned manufacturing method 1, a plug is formed in the tube material using a good solvent and a poor solvent for the organic polymer. The manufacturing method 2 of a DDS carrier includes a tube preparation step, a solution preparation step, an injection step, and a precipitation step.

[0087] 7 is a diagram illustrating a manufacturing method 2 for a DDS carrier. In the tube preparation step, a tubular substance 10 carrying a drug 20 in an internal space 12 is prepared, as shown in FIG. 7(a). In manufacturing method 2, a tubular substance 10 similar to that in manufacturing method 1 described above may be prepared.

[0088] In the solution preparation step, a polymer solution in which an organic polymer is dissolved in a good solvent and a poor solvent for the organic polymer are prepared.

[0089] The polymer solution is prepared by dissolving an organic polymer in various solvents. The organic polymer undergoes precipitation during the production process described below. The organic polymer is the raw material for the plug portion of the DDS carrier. Therefore, when considering its use as a DDS carrier, the organic polymer should preferably be a substance that is less harmful to the living body, biocompatible, and biodegradable, and preferably one that has been used as a biomaterial. Examples of organic polymers that can be used include polycaprolactone, polylactic acid, glycolic acid, polytrimethylene carbonate, polyethylene glycol copolymer, and dioxanone-lactide copolymer.

[0090] The good solvent is preferably a solvent that dissolves the organic polymer and is mutually miscible with the poor solvent for the organic polymer, which will be described later. Examples of the good solvent include chloroform, trifluoroethanol, methylene chloride, acetone, ethyl acetate, and methyl ethyl ketone.

[0091] A higher concentration of the organic polymer in the polymer solution facilitates the formation of mechanically stronger plugs in the precipitation step described below, but narrows the region in the interior space of the tubular material where plugs are generated.On the other hand, a lower concentration of the organic polymer in the polymer solution broadens the region in the interior space of the tubular material where plugs are generated in the precipitation step.

[0092] The poor solvent preferably does not dissolve the organic polymer used in the polymer solution and is miscible with the good solvent. For example, the poor solvent is preferably a lower alcohol with a small proportion of alkyl moieties in the molecule. Specifically, the poor solvent may be ethanol, methanol, 1-propanol, 1-butanol, or the like. The solubility of the organic polymer in the poor solvent relative to the solubility in the good solvent is 1 / 25 or less, preferably 1 / 100 or less.

[0093] In the injection step, a poor solvent for the organic polymer is injected into the internal space 12 of the tubular material 10. Specifically, as shown in FIG. 7(a), the poor solvent is injected into the internal space 12 from one opening 14a of the tubular material 10. For example, the opening 14a of the tubular material 10 may be brought into contact with the poor solvent, and the poor solvent may be injected into the internal space 12 of the tubular material 10 by hydrostatic pressure. The poor solvent injected into the tubular material 10 is drawn to the inside of the internal space 12 of the tubular material 10 by capillary action. As a result, as shown in FIG. 7(b), the poor solvent 40 is retained in the internal space 12. When the poor solvent is injected, a drug that dissolves in the poor solvent may be carried in the internal space 12 of the tubular material 10.

[0094] In the precipitation step, a poor solvent 40 for the organic polymer is brought into contact with a polymer solution 42 in the internal space 12 of the tubular material 10, thereby precipitating the organic polymer. Specifically, as shown in FIG. 7(b), a good solvent is injected into the internal space from the opening 14a into which the poor solvent 40 was injected. More specifically, the opening 14a on the side of the tubular material 10 into which the poor solvent 40 was injected may be brought into contact with the polymer solution 42, and the polymer solution may be injected into the internal space 12. This brings the polymer solution and the poor solvent 40 into contact with each other near or inside the opening 14a.

[0095] The reaction between the polymer solution and the poor solvent will be described with reference to FIG. 8. As shown in FIG. 8(a), when the polymer solution 42 and the poor solvent 40 come into contact with each other, a state in which the organic polymer cannot be locally dissolved (hereinafter also referred to as a "supersaturated state") is formed at the interface between the poor solvent 40 and the polymer solution 42. As a result, as shown in FIG. 8(b), the organic polymer 46 dissolved in the polymer solution 42 precipitates from the interface between the polymer solution 42 and the poor solvent 40. As a result, as shown in FIG. 7(c), a plug 44 made of the organic polymer is formed near the opening 14a of the tubular substance 10. Furthermore, as shown in FIG. 7(c), after the plug 44 is formed, the poor solvent 40 may remain in the internal space 12.

[0096] The stopper 44 may be formed in a gel-like or porous state, allowing the drug 20 to diffuse therein. Alternatively, the stopper 44 may be formed like a membrane. The state of the formed stopper 44 varies depending on, for example, the type and concentration of the organic polymer in the polymer solution 42. For example, the stopper 44 is more likely to become membrane-like as the concentration of the organic polymer increases, and more likely to become sponge-like as the concentration of the organic polymer decreases. The stopper 44 may contain inorganic nanoparticles or microparticles to the extent that the increase in viscosity is not hindered.

[0097] Considering the influence of a good solvent on a living body, it is preferable that no polymer solution 42 remains in the internal space 12 of the tubular material 10 after the precipitation step is completed.

[0098] According to the method for producing a DDS carrier according to Production Method 2, it becomes possible to individually and selectively plug the openings of the tubular substance 10 .

[0099] (Example 4: Confirmation of the principle using a borosilicate glass tube, embolization with a biodegradable polymer) In Example 4, a borosilicate glass tube was used as the tubular material. In addition, to measure the sustained release effect of the loaded drug, MB was loaded in the inner space of the borosilicate glass tube, and a tube sample was prepared.

[0100] In Example 4, polycaprolactone (PCL: molecular weight 80,000), a biodegradable polymer, was used as the organic polymer serving as the raw material for embolization, trifluoroethanol was used as the good solvent, and ethanol was used as the poor solvent.

[0101] First, 0.5 mg of MB was added to 7.9 g of ethanol to prepare colored ethanol. The tip of a borosilicate glass tube (outer diameter 1000 μm, inner diameter 800 μm, length 25 mm) was brought into contact with the colored ethanol, and the colored ethanol was injected into the inner space of the borosilicate glass tube by capillary action.

[0102] PCL was dissolved in trifluoroethanol, a good solvent, to prepare a PCL solution containing 30 wt% PCL. A 10 mm tip of a borosilicate glass tube filled with colored ethanol was inserted into the PCL solution and held there for 20 seconds, allowing the PCL solution to be injected into the tube's interior by hydrostatic pressure.

[0103] Twenty seconds after inserting the tip of the tube into the PCL solution, the borosilicate glass tube into which the PCL solution had been injected was removed from the PCL solution. Droplets on the outer wall of the tube were wiped off with a paper towel soaked in trifluoroethanol. The tube was then left horizontally stationary for 30 minutes. As a result, PCL precipitated near the boundary between the colored ethanol (a poor solvent for PCL) that had been first injected into the interior space of the tube and the trifluoroethanol (a good solvent for PCL) that had been injected later, plugging the opening of the borosilicate glass tube.

[0104] (Comparative Example 3: Principle verification using borosilicate glass tube, tube sample without embolization) Colored ethanol containing MB was prepared in the same manner as in Example 4. The tip of a borosilicate glass tube with an outer diameter of 1000 μm, an inner diameter of 800 μm, and a length of 25 mm was brought into contact with the colored ethanol, and the colored ethanol containing MB was injected into the internal space of the borosilicate glass tube by capillary action, to prepare a tube sample according to Comparative Example 3.

[0105] (Verification 3) In verification 3, we demonstrate that embolization suppresses the release of the drug contained in the internal space of the tube. Below, we explain the results of verifying the suppression of drug release by embolization.

[0106] Approximately 5 mm of the tip of each tube sample in Example 4 and Comparative Example 3 was immersed in 2 ml of pure water. One minute after the tube sample began to be immersed, the tube sample was removed from the liquid and placed in another 2 ml of pure water. Four minutes after the tube sample began to be immersed in the new pure water, the tube sample was removed from the liquid. The total immersion time in the resulting liquid was 5 minutes. The tube samples were immersed in the same manner for 10, 30, and 60 minutes.

[0107] The solution obtained by immersing the tube samples described above was measured using a JASCO visible-ultraviolet spectrophotometer in the wavelength range of 500 to 800 nm using the single-beam method to determine the absorbance at around 670 nm, which is attributable to MB. The amount of MB diffusing from the tube sample into the pure water increases or decreases the light absorption at around 670 nm. The absorbance at wavelengths of 500 nm and 800 nm was considered to be zero, and the integrated value of the spectrum obtained by subtracting the background from these values ​​was used as the absorbance at 670 nm, which is attributable to MB. For each of Example 4 and Comparative Example 3, three tube samples were measured, and the average value was used as the absorbance. The relative amount of MB released over time due to immersion was calculated by integrating the absorbance. The start of immersion of the tube samples was designated as (0 min), and the absorbance at this time was designated as 0. Figure 9 shows the absorbance values, indicating the amount of MB released, for immersion times of 1, 5, 10, 30, and 60 min.

[0108] In Comparative Example 3, a rapid release of MB occurred within 10 minutes of the start of immersion of the tube sample, after which an equilibrium state was reached and the integrated absorbance value remained almost constant. On the other hand, in Example 4, MB release did not progress after 60 minutes of immersion, and the rapid release of MB was suppressed. Therefore, it was confirmed that embolization with PCL is effective for the sustained release of the drug carried in the tube sample.

[0109] (Example 5: Embolization of chlorapatite tube) In Example 5, the method of Example 4 was applied to a chlorapatite tube, and an ethanol solution colored with MB was loaded onto the tube, and one end of the chlorapatite tube was plugged to prepare a tube sample. The method for preparing the tube sample of Example 5 will be specifically described below.

[0110] First, 0.5 mg of MB was added to 7.9 g of ethanol to prepare colored ethanol. The tip of a chlorapatite tube with an outer diameter of approximately 200 μm, an inner diameter of approximately 80 μm, and a length of approximately 2500 μm was placed in contact with the colored ethanol, and the colored ethanol was injected into the inner space of the chlorapatite tube by capillary action.

[0111] PCL was dissolved in trifluoroethanol, a good solvent, to prepare a PCL solution containing 30 wt% PCL. The tip of a chlorapatite tube filled with colored ethanol was inserted 1 mm into the PCL solution and held in this position for 10 seconds, allowing the PCL solution to be injected into the interior space of the tube by hydrostatic pressure (atmospheric pressure).

[0112] Ten seconds after inserting the tube into the PCL solution, the tube was removed from the solution and the droplets on the outer wall of the tube were wiped off with a paper towel soaked in trifluoroethanol. In the interior space of the chlorapatite tube, PCL rapidly precipitated when the PCL solution came into contact with the colored ethanol, a poor solvent for PCL, and formed an embolism near the opening of the tube.

[0113] (Comparative Example 4: Chlorapatite tube without embolization) A tube sample according to Comparative Example 4 was prepared by injecting the ethanol solution colored with MB into a chlorapatite tube having an outer diameter of approximately 200 μm, an inner diameter of approximately 80 μm, and a length of approximately 2500 μm in the same manner as in Example 5.

[0114] (Verification 4) In Verification 4, the sustained drug release effect due to embolization was confirmed in a tube sample using a tube with a different shape and material from that in Verification 3. In Verification 4, the tube samples according to Example 5 and Comparative Example 4 were left horizontally, and the embolization effect was evaluated by observing the difference in the migration behavior of the injected colored ethanol toward the open end of the tube.

[0115] The tube samples of Example 5 and Comparative Example 4 were placed horizontally, with the open end of the tube sample of Example 5 and one end of the tube sample of Comparative Example 4 fixed to carbon tape. In this position, the behavior of the colored ethanol injected into the internal space of the tube was observed for 14 seconds. The observation results are shown in Figure 10.

[0116] In Figure 10, the top two photographs show the tube sample according to Example 5, and the bottom two photographs show the tube sample according to Comparative Example 4. For each of the two photographs, the top photograph shows the state of the tube sample at the start of observation, and the bottom photograph shows the state of the tube sample 14 seconds after observation began. Furthermore, for the tube sample according to Example 5, the end on the left is the end that has been embolized, and the end on the right is the end that has not been embolized.

[0117] In the plugged tube sample according to Example 5, almost no movement of the colored ethanol was observed (Fig. 10: PCL plugged). On the other hand, in the unplugged tube sample according to Comparative Example 4, the liquid front of the injected colored ethanol moved to the 450 μm carbon tape fixed side (left side) in 14 seconds (Fig. 10: Non-plugged).

[0118] The distance traveled by the colored calcium chloride solution was recorded every second, and the results are shown in Figure 11. It can be seen that in Comparative Example 4, the colored calcium chloride solution traveled a distance that was approximately proportional to the time, whereas in Example 5, the colored calcium chloride solution hardly moved at all.

[0119] Thus, in the tube sample of Comparative Example 4, the injected colored ethanol was pulled out by the tension of the carbon tape securing the open end, causing the liquid surface to move. In contrast, in the tube sample of Example 5, the movement of the liquid was suppressed by the tension of the carbon tape. This is thought to be because the inflow of air from the blocked side was suppressed by the embolization effect.

[0120] The present invention has been described above based on the embodiments. These embodiments are merely examples, and it will be understood by those skilled in the art that various modifications are possible in the combination of the components and treatment processes, and that such modifications are also within the scope of the present invention. [Explanation of symbols]

[0121] 1 DDS carrier, 10 tubular material, 12 internal space, 14a, 14b opening, 20 drug, 30, 34, 44 stopper, 31 ionic solution, 32 polymer solution, 36 polymer material, 40 poor solvent, 42 polymer solution, 46 organic polymer

Claims

1. a tubular material carrying a drug in its internal space; a plug portion that closes the opening of the internal space and contains a polymer material, Support for DDS.

2. The polymer material includes an organic polymer forming a cross-linked structure. The support for DDS according to claim 1 .

3. a poor solvent for the polymer material held in the internal space; The support for DDS according to claim 1 .

4. The plug is gel-like or porous. The support for DDS according to claim 1 .

5. The plug portion has biocompatibility. The support for DDS according to claim 1 .

6. a tube preparation step of preparing a tubular material carrying a drug in an internal space; a generating step of bringing a polymer solution containing an organic polymer into contact with an ionic solution containing ions that cause the organic polymer to form a crosslinked structure in the internal space, thereby generating an organic polymer having the crosslinked structure; A method for producing a support for DDS.

7. The ions are multivalent cations. A method for producing the DDS support according to claim 6.

8. the organic polymer is alginic acid; The ion is a divalent calcium ion. A method for producing the DDS support according to claim 7.

9. the polymer solution further comprises a phosphate; In the producing step, the ionic solution and the polymer solution are brought into contact with each other to produce calcium phosphate together with the organic polymer forming the crosslinked structure. A method for producing the DDS support according to claim 6.

10. a tube preparation step of preparing a tubular material carrying a drug in an internal space; a precipitation step of bringing a polymer solution in which an organic polymer is dissolved in a good solvent and a poor solvent for the organic polymer into contact with each other in the internal space to precipitate the organic polymer, A method for producing a support for DDS.

11. the solubility of the poor solvent with respect to the organic polymer is 1 / 25 or less of the solubility of the good solvent with respect to the organic polymer; A method for producing the DDS support according to claim 10.

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