Composition for transarterial microembolization comprising sugar alcohol, and preparation method therefor

Abstract

The present invention relates to a composition for transarterial microembolization comprising a sugar alcohol, and a preparation method therefor. The composition for transarterial microembolization of the present invention can embolize even capillaries without a risk of developing resistance by using a sugar alcohol commonly used in the pharmaceutical and food fields, and thus is expected to be useful as an embolic agent.

Description

Composition for microarterial embolization containing sugar alcohols and method for preparing the same

[0001] The present invention relates to a composition for microarterial embolization comprising a sugar alcohol and a method for preparing the same.

[0002] The present invention claims priority based on Korean Patent Application No. 10-2025-0010527 filed on January 23, 2025, and all contents disclosed in the specification and drawings of said application are incorporated by reference into the present application.

[0003]

[0004] Embolization is a treatment method that uses embolizing agents to artificially block blood flow, thereby blocking blood vessels that supply nutrients or oxygen to specific lesions, killing the lesions, or locating and blocking bleeding vessels. The most commonly performed procedure is transarterial chemoembolization, which is used to treat liver cancer. Other procedures include cerebral aneurysm embolization, bronchial artery embolization, uterine artery embolization, and transarterial micro embolization (TAME).

[0005] If inflammation persists for more than 3 months, new blood vessels (neovascularization) are formed and continuously receive nutrients, oxygen, and inflammatory substances, and new nerves are distributed around these vessels, causing pain to persist and become chronic. Microarterial embolization is a treatment method that can eliminate inflammation and improve pain by blocking the neovascularization caused by inflammation.

[0006] Meanwhile, unlike transarterial chemoembolization aimed at tumor necrosis, microarterial embolization requires the use of embolization materials that can block blood vessels for as short as 2 to 3 hours or as long as 2 weeks depending on the site of inflammation to remove inflammation and then dissolve naturally. Currently, microarterial embolization utilizes microcrystalls formed when antibiotics and contrast agents are mixed.

[0007] However, using microcrystals formed when antibiotics and contrast agents are mixed presents a problem in that it entails side effects such as the development of antibiotic resistance.

[0008]

[0009] To solve the above problems, the inventors developed a new embolizing agent applicable to microarterial embolization by suspending mannitol, a type of sugar alcohol used as a drug and food additive, in a W / O emulsion formed by mixing an aqueous contrast agent, an oily contrast agent, or an oily contrast agent and an aqueous contrast agent, and completed the present invention by confirming that the developed embolizing agent can embolize even the capillaries.

[0010] Accordingly, the object of the present invention is to provide a composition for microarterial embolization comprising a sugar alcohol and a contrast agent as active ingredients.

[0011] Another objective of the present invention is to provide a method for preparing a composition for microarterial embolization.

[0012]

[0013] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below.

[0014]

[0015] To achieve the above objective, the present invention provides a composition for microarterial embolization comprising a sugar alcohol and a contrast agent as active ingredients.

[0016] In one embodiment of the present invention, the sugar alcohol may be mannitol, sorbitol, xylitol, erythritol, arabitol, maltitol, inositol, lactitol, isomalt, fucitol, or a mixture thereof, but is not limited thereto.

[0017] In another embodiment of the present invention, the sugar alcohol may have an average particle size of 1 to 300 μm, but is not limited thereto.

[0018] In another embodiment of the present invention, the sugar alcohol may have round crystalline particles, but is not limited thereto.

[0019] In another embodiment of the present invention, the sugar alcohol may be suspended in the contrast agent, but is not limited thereto.

[0020] In another embodiment of the present invention, the contrast agent may be one or more contrast agents selected from the group consisting of aqueous contrast agents and oily contrast agents, but is not limited thereto.

[0021] In another embodiment of the present invention, the aqueous contrast agent may be one or more selected from the group consisting of iopamidol, pamiray, metrizamide, diatrizoate, ioxaglate, iopentol, iomeprol, iotrolan, iohexol, iooversol, ioxilan, iopromide, iodixanol, and iobitridol, but is not limited thereto.

[0022] In another embodiment of the present invention, the oily contrast agent may be lipiodol, but is not limited thereto.

[0023] In another embodiment of the present invention, when the contrast agent is an aqueous contrast agent, the sugar alcohol may have an average particle size of 1 to 100 μm, but is not limited thereto.

[0024] In another embodiment of the present invention, the sugar alcohol may be suspended in an aqueous contrast agent at a concentration of 5 to 50% (w / v), but is not limited thereto.

[0025] In another embodiment of the present invention, when the contrast agent is an oily contrast agent, the sugar alcohol may have an average particle size of 1 to 100 μm, but is not limited thereto.

[0026] In another embodiment of the present invention, the sugar alcohol may be suspended in an oily contrast agent at a concentration of 5 to 50% (w / v), but is not limited thereto.

[0027] In another embodiment of the present invention, the composition may be an emulsion formulation formed by mixing an aqueous contrast agent and an oily contrast agent, but is not limited thereto.

[0028] In another embodiment of the present invention, the aqueous contrast agent and the oily contrast agent may be mixed in a volume ratio of 1:1 to 10, but are not limited thereto.

[0029] In another embodiment of the present invention, the aqueous contrast agent may contain a drug, but is not limited thereto.

[0030] In another embodiment of the present invention, the drug and the aqueous contrast agent may be mixed in a volume ratio of 1:1 to 10, but are not limited thereto.

[0031] In another embodiment of the present invention, the oily contrast agent may have the sugar alcohol suspended therein, but is not limited thereto.

[0032] In another embodiment of the present invention, the sugar alcohol may have an average particle size of 1 to 100 μm, but is not limited thereto.

[0033] In another embodiment of the present invention, the sugar alcohol may be suspended in an oily contrast agent at a concentration of 5 to 50% (w / v), but is not limited thereto.

[0034] In addition, the present invention provides a method for preparing a composition for microarterial embolization, comprising: (S1) a step of separating sugar alcohol particles by size using a sieve of 10 to 400 μm; and (S2) a step of mixing the sugar alcohol particles separated in step (S1) with a contrast agent.

[0035] In addition, the present invention provides a microarterial embolization use of a composition comprising a sugar alcohol and a contrast agent as active ingredients.

[0036] In addition, the present invention provides a use for preparing a preparation for microarterial embolization comprising a sugar alcohol and a contrast agent as active ingredients.

[0037] In addition, the present invention provides a microarterial embolization method comprising the step of administering a composition comprising a sugar alcohol and a contrast agent as active ingredients to an individual in need of the composition in a pharmaceutically effective amount.

[0038]

[0039] The composition for microarterial embolization of the present invention is expected to be usefully utilized as an embolizing agent because it can embolize down to the capillaries without the risk of resistance development by using sugar alcohols commonly used in the pharmaceutical and food industries.

[0040]

[0041] Figure 1 shows the design and CAD drawing of the microfluidics chip fabricated in Example 4, the fabricated chip, and the results of microscopic observation of the fabricated chip.

[0042] Figure 2 shows the results of observing the characteristics of mannitol particles and antibiotic powder under a microscope in a dry state.

[0043] Figure 3 shows the results of observing the characteristics under a microscope while mannitol particles and antibiotic powder were suspended in ethanol.

[0044] Figure 4 shows the results of observing the appearance of mannitol particles and antibiotic powder suspended on Xenetix 350 under a microscope.

[0045] Figure 5 shows the results of measuring the average size of mannitol particles by sieve size in a mannitol suspension formulation in an aqueous contrast agent.

[0046] Figure 6 shows the results of microscopic observation of the characteristics of mannitol particles according to sieve size in a mannitol suspension formulation in an aqueous contrast agent.

[0047] Figure 7 shows the results of measuring the average size of mannitol particles at different concentrations in a mannitol suspension formulation in an aqueous contrast agent.

[0048] Figure 8 shows the distribution of mannitol particle sizes by concentration in a mannitol suspension formulation in an aqueous contrast agent.

[0049] Figure 9 shows the results of measuring the average size of mannitol particles according to concentration over time in a mannitol suspension formulation in an aqueous contrast agent.

[0050] Figure 10 shows the results of observing, under a microscope, changes in the characteristics of mannitol particles over time according to concentration in a mannitol suspension formulation in an aqueous contrast agent.

[0051] Figures 11a and 11b show the results of a microfluidic chip penetration embolization test of a mannitol suspension formulation in an aqueous contrast agent.

[0052] Figure 12 shows the results of a microfluidic chip disintegration test of a mannitol suspension formulation in an aqueous contrast agent.

[0053] Figure 13 shows the results of observing the characteristics of a mannitol suspension formulation in an oily contrast agent under a microscope, the distribution of mannitol particle sizes, and the measurement of the average size.

[0054] Figure 14 shows the results of measuring the average particle size according to the concentration of mannitol particles in a mannitol suspension formulation in an oily contrast agent.

[0055] Figure 15 shows the results of measuring the average particle size of mannitol particles over time in a mannitol suspension formulation in an oily contrast agent.

[0056] Figure 16 shows the results of a microfluidic chip penetration embolization test of a mannitol suspension formulation in an oily contrast agent.

[0057] Figure 17 shows the results of microscopic observation of the dissolving tendency of mannitol particles in oily and aqueous contrast agents during a microfluidic chip disintegration test of a mannitol suspension formulation in an oily contrast agent.

[0058] Figure 18 shows the results of a microfluidic chip disintegration test of a mannitol suspension formulation in an oily contrast agent.

[0059] Figure 19 shows the results of observing layer separation over time according to the composition of mannitol suspension w / o emulsion formulations.

[0060] Figure 20 shows the results of microscopic observation of the characteristics of the mannitol suspension w / o emulsion formulation and the results of the embolization test of the mannitol suspension w / o emulsion formulation, as well as the results of microscopic observation of the inside of the microfluidic chip after embolization.

[0061] Figure 21 shows the results of a disintegration test of a mannitol suspension w / o emulsion formulation, which is the result of observing the inside of the microfluidic chip under a microscope after disintegration.

[0062] Figure 22 shows the results of a microfluidic chip disintegration test of a mannitol suspension w / o emulsion formulation.

[0063]

[0064] The inventors developed a new embolizing agent by suspending mannitol, a type of sugar alcohol used as a drug or food additive, in a W / O emulsion formed by mixing an aqueous contrast agent, an oily contrast agent, or an oily contrast agent and an aqueous contrast agent at a concentration above saturation to produce mannitol crystals, and utilizing the produced mannitol crystals for embolization. The invention was completed by confirming that the developed embolizing agent can embolize even capillaries.

[0065]

[0066] The present invention will be described in detail below.

[0067]

[0068] The present invention provides a composition for microarterial embolization comprising a sugar alcohol and a contrast agent as active ingredients.

[0069] In the present invention, "sugar alcohol" is a sugar derivative obtained by reducing the carbonyl group of a monosaccharide or starch, and is widely used in fields such as pharmaceuticals, cosmetics, food, and feed as an additive, excipient, sweetener, humectant, stabilizer, and thickener.

[0070] Including all claims below, the sugar alcohol may be mannitol, sorbitol, xylitol, erythritol, arabitol, maltitol, inositol, lactitol, isomalt, fucitol, or a mixture thereof, and according to one embodiment of the present invention, the sugar alcohol may be mannitol, but is not limited thereto.

[0071] In the present invention, "mannitol" refers to a type of sugar alcohol that exists in a free form in nature in plants such as ash trees, onions, and dried persimmons, as well as in algae, fungi, and mushrooms, and generally refers to a substance that can be used as an excipient, an analytical reagent, an osmotic diuretic, a sweetener, etc.

[0072] In all claims below, the sugar alcohol may have an average particle size of 1 to 300 µm, 1 to 200 µm, 1 to 100 µm, 1 to 80 µm, 1 to 60 µm, 1 to 50 µm, 1 to 30 µm, 1 to 25 µm, 1 to 20 µm, 1 to 15 µm, 1 to 10 µm, 1 to 5 µm, 20 to 30 µm, 20 to 60 µm, or 40 to 60 µm. According to one embodiment of the present invention, the sugar alcohol (mannitol) is filtered through a sieve of 25 µm or 50 µm, and the average particle size may be 1 to 25 µm or 1 to 50 µm, but is not limited thereto. Here, the average size of the sugar alcohol particles refers to the average size of the sugar alcohol particles before being suspended in a contrast agent.

[0073] According to one embodiment of the present invention, when the sugar alcohol particles are suspended in a contrast agent, the crystal shape of the particles may be a round crystal shape close to spherical, which is advantageous for embolization of capillaries, which are fine conduits, but is not limited thereto.

[0074] Including all claims below, since the sugar alcohol is suspended in the contrast agent, the composition may be a suspension formulation in which the sugar alcohol is suspended in the contrast agent, but is not limited thereto.

[0075] Including all claims below, the contrast agent in this specification may be one or more contrast agents selected from the group consisting of aqueous contrast agents and oily contrast agents, and may also include an emulsion formulation in which an aqueous contrast agent and an oily contrast agent are mixed.

[0076] Including all claims below, the aqueous contrast agent may be one or more selected from the group consisting of iopidol, pamiray, metrizamide, diatrizoate, ioxaglate, iopentol, iomeprol, iotrolan, iohexol, iooversol, ioxilan, iopromide, iodixanol, and iobitridol, and the oily contrast agent may be lipiodol, but is not limited thereto. According to one embodiment of the present invention, the aqueous contrast agent may be iobitridol (xenetix 350), and the oily contrast agent may be lipiodol.

[0077] In all claims below, in the present specification, where the contrast agent is an aqueous contrast agent, the sugar alcohol may have an average particle size of 1 to 100 µm, 1 to 80 µm, 1 to 60 µm, 1 to 50 µm, 1 to 30 µm, 1 to 25 µm, 1 to 20 µm, 1 to 15 µm, 1 to 10 µm, 1 to 5 µm, 20 to 30 µm, 20 to 60 µm, or 40 to 60 µm, and is not limited thereto, but preferably is filtered through a sieve of 25 µm or 50 µm size, and the average particle size may be 1 to 25 µm or 1 to 50 µm (see Example 6-1). Here, the average size of the sugar alcohol particles refers to the average size of the sugar alcohol particles before being suspended in the aqueous contrast agent.

[0078] Including all claims below, in this specification, where the contrast agent is an aqueous contrast agent, the sugar alcohol is 5 to 50% (w / v), 5 to 40% (w / v), 5 to 30% (w / v), 5 to 20% (w / v), 5 to 15% (w / v), 10 to 50% (w / v), 10 to 40% (w / v), 10 to 30% (w / v), 10 to 20% (w / v), 10 to 15% (w / v), 15 to 50% (w / v), 15 to 40% (w / v), 15 to 30% (w / v), 15 to 20% (w / v), 5% (w / v), 10% (w / v), 15% (w / v), 20% (w / v), Sugar alcohols may be suspended in an aqueous contrast agent at a concentration of 30% (w / v), 40% (w / v), or 50% (w / v), but are not limited thereto; any concentration at which the sugar alcohol suspended in the aqueous contrast agent can form crystals may be included. According to one embodiment of the present invention, the sugar alcohol may be suspended in an aqueous contrast agent at a concentration of 15% (w / v) or higher.

[0079] In all claims below, in the present specification, when the contrast agent is an oil-based contrast agent, the sugar alcohol may have an average particle size of 1 to 100 µm, 1 to 80 µm, 1 to 60 µm, 1 to 50 µm, 1 to 30 µm, 1 to 25 µm, 1 to 20 µm, 1 to 15 µm, 1 to 10 µm, 1 to 5 µm, or 20 to 30 µm, but is not limited thereto; preferably, it may be filtered through a sieve of 25 µm size, and the average particle size may be 1 to 25 µm (see Example 7). Here, the average size of the sugar alcohol particles refers to the average size of the sugar alcohol particles before being suspended in the oil-based contrast agent.

[0080] Including all claims below, in this specification, where the contrast agent is an oily contrast agent, the sugar alcohol may be suspended in the oily contrast agent at a concentration of 5 to 50% (w / v), 5 to 40% (w / v), 5 to 30% (w / v), 5 to 20% (w / v), 5 to 15% (w / v), 5 to 10% (w / v), 10 to 50% (w / v), 10 to 40% (w / v), 10 to 30% (w / v), 10 to 20% (w / v), 10 to 15% (w / v), 5% (w / v), 10% (w / v), 15% (w / v), 20% (w / v), 30% (w / v), 40% (w / v), or 50% (w / v), but is not limited thereto. In addition, according to one embodiment of the present invention, the sugar alcohol may be suspended in an oily contrast agent at a concentration of 10% (w / v).

[0081] Including all claims below, the composition may be an emulsion formulation formed by mixing an aqueous contrast agent and an oily contrast agent. Specifically, according to one embodiment of the present invention, it may be a W / O emulsion formulation formed by mixing an oily contrast agent in which mannitol is suspended as the oil phase (O phase) and an aqueous contrast agent in which a drug is mixed as the aqueous phase (W phase). The mixing of the oil phase and the aqueous phase may be achieved by connecting a syringe containing the oil phase and a syringe containing the aqueous phase to a 3-way stock and reciprocating to push the aqueous phase toward the oil phase or the oil phase toward the aqueous phase.

[0082] Including all claims below, the aqueous contrast agent and the oily contrast agent may be mixed in a volume ratio of 1:1 to 10, 1:1 to 8, 1:1 to 5, 1:1 to 3, 1:1 to 2.5, 1:1 to 2, 1:1 to 1.5, 1:2 to 4, 1:1, 1:2, 1:3, 1:4, or 1:5, and according to one embodiment of the present invention, the aqueous contrast agent and the oily contrast agent may be mixed in a volume ratio of 1:3, but are not limited thereto.

[0083] Including all claims below, the aqueous contrast agent or oily contrast agent of the emulsion formulation may each be mixed with a water-soluble or fat-soluble drug, but is not limited thereto.

[0084] Including all claims below, in the present specification, the aqueous contrast agent in the emulsion formulation may be mixed with a (water-soluble) drug, and the drug and the aqueous contrast agent may be mixed in a volume ratio of 1:1 to 10, 1:1 to 8, 1:1 to 5, 1:1 to 3, 1:1 to 2.5, 1:1 to 2, 1:1 to 1.5, 1:2 to 10, 1:2 to 8, 1:2 to 5, 1:2 to 3, 1:2 to 2.5, 1:1, 1:2, 1:3, 1:4, 1:5, 5:5, 4:6, or 3:7, and according to one embodiment of the present invention, the drug and the aqueous contrast agent may be mixed in a volume ratio of 3:7, but are not limited thereto.

[0085] The above-mentioned drug may be a local anesthetic such as bupivacaine or lidocaine, an anti-inflammatory agent such as ibuprofen, or an antibiotic such as ceftazidime, but is not limited thereto. According to one embodiment of the present invention, the above-mentioned drug may be bupivacaine.

[0086] Including all claims below, in the emulsion formulation, the oily contrast agent may have a sugar alcohol suspended therein, and the sugar alcohol is at a concentration of 5 to 50% (w / v), 5 to 40% (w / v), 5 to 30% (w / v), 5 to 20% (w / v), 5 to 15% (w / v), 5 to 10% (w / v), 10 to 50% (w / v), 10 to 40% (w / v), 10 to 30% (w / v), 10 to 20% (w / v), 10 to 15% (w / v), 5% (w / v), 10% (w / v), 15% (w / v), 20% (w / v), 30% (w / v), 40% (w / v), or 50% (w / v). It may be suspended in an oily contrast agent, and according to one embodiment of the present invention, it may be suspended in an oily contrast agent at a concentration of 10% (w / v), but is not limited thereto.

[0087] In the entirety of the following claims, the sugar alcohol may have an average particle size of 1 to 100 µm, 1 to 80 µm, 1 to 60 µm, 1 to 50 µm, 1 to 30 µm, 1 to 25 µm, 1 to 20 µm, 1 to 15 µm, 1 to 10 µm, 1 to 5 µm, or 20 to 30 µm, but is not limited thereto; preferably, it may be filtered through a sieve of 25 µm size, and the average particle size may be 1 to 25 µm. Here, the average particle size of the sugar alcohol refers to the average particle size of the sugar alcohol prior to suspension in an oily contrast agent.

[0088]

[0089] In addition, the present invention comprises (S1) a step of separating sugar alcohol particles by size using a sieve of 10 to 400 μm; and

[0090] (S2) A method for preparing a composition for microarterial embolization, comprising the step of mixing the sugar alcohol particles separated in step (S1) with a contrast agent.

[0091] Including all claims below, the sieve comprises 10 to 400 µm, 10 to 300 µm, 10 to 200 µm, 10 to 100 µm, 10 to 60 µm, 10 to 50 µm, 10 to 30 µm, 10 to 25 µm, 20 to 400 µm, 20 to 300 µm, 20 to 200 µm, 20 to 100 µm, 20 to 60 µm, 20 to 50 µm, 20 to 30 µm, 20 to 25 µm, 25 to 400 µm, 25 to 300 µm, 25 to 200 µm, 25 to 100 µm, 25 to 60 µm, 25 to 50 µm, 25 to 30 µm, 40 to 400 µm, A sieve of size 40 to 300㎛, 40 to 200㎛, 40 to 100㎛, 40 to 60㎛, 40 to 50㎛, 50 to 400㎛, 50 to 300㎛, 50 to 200㎛, 50 to 100㎛, or 50 to 60㎛ may be used, and according to one embodiment of the present invention, a sieve of size 25㎛ or 50㎛ may be used, but is not limited thereto.

[0092] In the present specification, including all claims below, the step of mixing the sugar alcohol particles and the contrast agent may involve injecting the contrast agent into the sugar alcohol particles and vortexing to suspend them, or mixing the oily contrast agent in which the sugar alcohol is suspended with the aqueous contrast agent to form an emulsion formulation.

[0093] Preferred embodiments are presented below to aid in understanding the present invention. However, the following embodiments are provided merely to facilitate a better understanding of the invention, and the scope of the invention is not limited by the following embodiments.

[0094]

[0095] [Example]

[0096] Example 1. Preparation of a Mannitol Suspension Formulation in an Aqueous Contrast Agent

[0097] Mannitol powder was placed in sieves of 25, 50, and 200 μm sizes, covered with lids, and shaken to filter out particles. An aqueous contrast agent (Xenetix 350) was injected into the mannitol powder obtained under each filtration condition, vortexed for 30 seconds, and suspended to prepare a mannitol suspension formulation in the aqueous contrast agent.

[0098]

[0099] Example 2. Preparation of a Mannitol Suspension Formulation in an Oily Contrast Agent

[0100] Mannitol powder was placed in sieves of 25, 50, and 200 μm sizes, covered with lids, and shaken to filter out particles. An oily contrast agent (Lipiodol) was injected into the mannitol powder obtained under each filtration condition, vortexed for 30 seconds, and suspended to prepare a mannitol suspension formulation in the oily contrast agent.

[0101]

[0102] Example 3. Preparation of a mannitol suspension formulation in an emulsion

[0103] Mannitol powder was placed in a 25 μm sieve, covered with a lid, and shaken to filter out particles. An oily contrast agent (Lipiodol) was injected into the obtained mannitol powder and vortexed for 30 seconds to suspend it, after which the prepared suspension was transferred to a syringe. An aqueous contrast agent (Xenetix 350) and bupivacaine were mixed in a 7:3 ratio and transferred to a syringe. The syringes containing the aqueous and oil phases were each connected to a 3-way stopcock, and during the first mixing, the aqueous phase was pushed toward the oil phase and mixed 50 times back and forth to prepare a mannitol suspension formulation in an emulsion.

[0104]

[0105] Example 4. Fabrication of a Microfluidics Chip for Verifying Embolic Potential

[0106] As shown in Fig. 1, to simulate the varying sizes of blood vessels in the body (maximum approximately 3 mm, minimum approximately 10 µm), the microfluidic chip was designed with the conduits splitting into two at specific ratios (1:1, 1:2, 1:3, 1:4) such that the thinnest part of the conduit is 10 µm. The microfluidic chip was fabricated as follows:

[0107] First, a PDMS pattern mimicking a blood vessel structure was fabricated by solidifying PDMS (polydimethylsiloxane) on a silicon wafer designed with the microfluidic chip, and the fabricated PDMS pattern was attached to a glass plate to fabricate a microfluidic chip mimicking a blood vessel structure.

[0108] The width of the conduits of the manufactured microfluidic chip is divided from a maximum of 3 mm to a minimum of 10 µm, so the fluid starts flowing from one drug inlet and passes through each conduit of different sizes from 3 mm to 10 µm individually to be discharged.

[0109] By passing the embolization formulation through a microfluidic chip, it is possible to determine how far the embolization formulation can reach even the narrowest conduits, and through this, it is possible to determine on the microfluidic chip whether embolization is possible down to the smallest microvessels in the body (diameter approximately 10 μm).

[0110]

[0111] Example 5. Comparison of sugar (mannitol) particles and antibiotic particles

[0112] Particles ranging from 20 to 200 μm were obtained from mannitol powder using a sieve. The characteristics of the mannitol powder were examined under a microscope in a dry state and dispersed in EtOH and Xenetix 350, respectively, and the characteristics of the antibiotic used in transarterial microembolization (TAME) (imipenem / cilastatin) were examined under a microscope in a dry state and dispersed in EtOH and Xenetix 350, respectively, to compare the characteristics of the mannitol powder and the antibiotic powder.

[0113] As shown in Figures 2 to 4, when mannitol particles were compared with conventional imipenem / cilastatin in powder (dry) state, dispersed in poorly soluble EtOH, and dissolved in Xenetix 350, respectively, the particle size was generally similar to that of antibiotics for TAME, as particles obtained between 20 and 200 μm using a sieve were used.

[0114] In addition, regarding particle shape, the antibiotic for TAME was an elongated crystalline form, while mannitol was a relatively round crystalline form.

[0115]

[0116] Example 6. Performance evaluation of a mannitol suspension formulation in an aqueous contrast agent as a rapid disintegration formulation

[0117] Since mannitol may dissolve or aggregate when suspended in an aqueous contrast agent, the size of mannitol particles was checked according to sieve size, concentration, and time elapsed after suspension.

[0118]

[0119] Example 6-1. Results of measuring the average size of mannitol particles according to sieve size

[0120] Mannitol powder was placed in sieves of 25, 50, and 200 μm sizes, covered with lids, and shaken to filter out particles. After obtaining particles for each filtration condition, they were mixed with an aqueous contrast agent (Xenetix 350) at a concentration of 10% (w / v) and vortexed for 30 seconds; immediately afterward, the average major axis size of the particles was measured using a microscope. For each filtration condition, the formulation was prepared three times, and each prepared formulation was sampled three times to obtain nine samples for each filtration condition. The particle size was measured directly using a microscope, and particle size data was obtained more than 100 times for each filtration condition to calculate the average major axis of the particles.

[0121] As shown in Figures 5 and 6, after suspension in an aqueous contrast agent, when the sieve size was 25 µm or less, the average length of the particle's major axis was measured to be 8.7 µm (standard deviation 6.3 µm) and the maximum value 41.3 µm; when the sieve size was 50 µm or less, the average length of the particle's major axis was measured to be 11.7 µm (standard deviation 10.9 µm) and the maximum value 62.0 µm; when the sieve size was 200 µm or less, the average length of the particle's major axis was measured to be 19.4 µm (standard deviation 18.4 µm) and the maximum value 117.1 µm; and for the control group (not filtered by sieve), the average length of the particle's major axis was measured to be 20.1 µm (standard deviation 18.0 µm) and the maximum value 102.2 µm.

[0122] Since the diameter of human capillaries is about 10 µm, it appears that all four of the above cases can block the capillaries, and it was predicted that the conditions with sieve sizes of 25 µm and 50 µm or less, corresponding to an average particle size of about 10 µm, would be the most effective as embolic agents.

[0123]

[0124] Example 6-2. Measurement results of average mannitol particle size and particle size distribution at different concentrations

[0125] Mannitol powder was placed in a 25 μm sieve, covered with a lid, and shaken to filter out the particles. The obtained particles were mixed with an aqueous contrast agent (Xenetix 350) at concentrations of 7.5, 10, 12.5, 15, and 20% (w / v) and vortexed for 30 seconds. Immediately after mixing, the average major axis size of each particle was measured using a microscope. For each concentration, the formulation was prepared three times, and each prepared formulation was sampled three times to obtain nine samples for each concentration. The particle size was measured directly using a microscope, and particle size data was obtained more than 100 times for each concentration to calculate the average major axis of the particles.

[0126] As shown in Fig. 7, regarding particle sizes according to mannitol concentration after suspension with aqueous contrast agent, the average particle major axis length was measured to be 15.8 μm (standard deviation 11.4 μm) and the maximum value 67.6 μm for 7.5%; 11.7 μm (standard deviation 10.9 μm) and the maximum value 62.0 μm for 10%; 10.7 μm (standard deviation 8.2 μm) and the maximum value 64.5 μm for 12.5%; 10.0 μm (standard deviation 9.9 μm) and the maximum value 58.4 μm for 15%; and 11.1 μm (standard deviation 9.6 μm) and the maximum value for 20% It was measured at 55.5 µm.

[0127] As shown in Figure 8, regarding the particle size distribution by mannitol concentration, it can be seen that the distribution of small particles of 5 μm or less is smaller at lower concentrations. Accordingly, it was confirmed that as the concentration decreases, most of the small particles dissolve in the aqueous contrast agent, and the average particle size increases.

[0128]

[0129] Example 6-3. Results of measuring the average size of mannitol particles over time

[0130] Mannitol (sieve: 50 µm) particles were mixed with an aqueous contrast agent (Xenetix 350) at concentrations of 10, 12.5, 15, and 20% (w / v) and vortexed for 30 seconds. The major axis size of the particles was measured using a microscope immediately after mixing and over time. For each concentration, the formulation was prepared three times, and each prepared formulation was sampled three times to obtain nine samples for each concentration. The particle size was measured directly using a microscope, and particle size data was obtained more than 100 times over time for each concentration to calculate the average major axis of the particles.

[0131] As shown in Figure 9, the average size of mannitol particles was measured over time. When the mannitol concentration was 10%, the size was measured as 11.7 µm immediately after suspension and 16.7 µm after 1 hour; when the mannitol concentration was 12.5%, the size was measured as 8.3 µm immediately after suspension and 9.9 µm after 1 hour; when the mannitol concentration was 15%, the size was measured as 8.8 µm immediately after suspension and 9.0 µm after 1 hour; and when the mannitol concentration was 20%, the size was measured as 8.9 µm immediately after suspension and 8.0 µm after 1 hour.

[0132] As a result of observing changes in particle characteristics over time, as shown in Figure 10, it was confirmed that when the mannitol concentration was 15% or higher, the mannitol particles were sufficiently saturated in the aqueous contrast agent, and there was no change in particle size. When the mannitol concentration was 12.5% ​​or lower, it was confirmed that the mannitol was not sufficiently saturated in the aqueous contrast agent, so small mannitol particles dissolved, and the average particle size increased over time. From the above results, it was determined that when performing TAME using an aqueous contrast agent, dissolving the mannitol particles at a concentration of 15% or higher is suitable for maintaining performance.

[0133]

[0134] Example 6-4. Embolization / Disintegration Test of Mannitol Suspension Formulation in an Aqueous Contrast Agent on a Microfluidics Chip

[0135] The microfluidic chip penetration embolization / disintegration test was conducted as follows.

[0136] Embolization test: A mannitol suspension formulation in an aqueous contrast agent (sieve: 25 μm, mannitol concentration 15%, average particle size 8.8 μm) is placed in a syringe and injected into a microfluidic chip through a microcatheter at a rate of 0.04 mL / min using a syringe pump, and observed under a microscope.

[0137] Disintegration test: Fill a syringe with 0.9% NaCl solution (physiological saline) and inject it into the microfluidic chip through a microcatheter at a rate of 0.04 mL / min using a syringe pump, and observe under a microscope.

[0138] As shown in Figs. 11a, 11b, and 12, the embolization / disintegration test results showed that mannitol was more effective than imipenem in blocking the thin portions of the microfluidic chip pattern branches. This was due to the fact that the crystal shape of the mannitol particles is relatively spherical and contains a large amount of relatively small crystals of 5 μm or less, and it was determined that mannitol particles are more suitable than imipenem for blocking fine conduits.

[0139] However, the water solubility of imipenem particles was 5 mg / mL and the water solubility of mannitol particles was 213 mg / mL; since mannitol has higher water solubility, the disintegration time for mannitol tended to be about twice as fast as that of imipenem, and microscopic observation confirmed that the solubility of imipenem and mannitol in Xenetix 350 was about 0.5% or less and 4~5%, respectively.

[0140]

[0141] Example 7. Performance evaluation of a mannitol suspension formulation in an oily contrast agent as a rapid disintegration formulation

[0142] Example 7-1. Measurement Results of Average Size and Distribution of Mannitol Particles in Oily Contrast Agents

[0143] Mannitol powder was placed in a 25 μm sieve, covered with a lid, and shaken to filter out the particles. After obtaining the filtered particles, they were mixed with an oily contrast agent (Lipiodol) at a concentration of 10% (w / v) and vortexed for 30 seconds; immediately after mixing, the average major axis size of the particles was measured using a microscope. Mannitol suspension formulations in the oily contrast agent were prepared three times, and each prepared formulation was sampled three times to obtain nine samples. The particle size was measured directly using a microscope, and particle size data was obtained more than 100 times to calculate the average major axis of the particles.

[0144] As shown in Figure 13, the average particle size is 10.8 µm, and the distribution is 14.9% in 0–5 µm, 35.1% in 5–10 µm, 41.2% in 10–20 µm, 8.8% in 20–30 µm, and 0% in 30 µm or more.

[0145]

[0146] Example 7-2. Results of measuring average particle size according to mannitol particle concentration in oily contrast agent

[0147] Mannitol powder was placed in a 25 μm sieve, covered with a lid, and shaken to filter out the particles. After obtaining the particles, they were mixed with an oily contrast agent (Lipiodol) at concentrations of 5%, 10%, and 15% (w / v). Immediately after mixing by vortexing for 30 seconds, the average major axis size of the particles was measured using a microscope. The formulation was prepared three times for each concentration, and each prepared formulation was sampled three times to obtain nine samples for each concentration. The particle size was measured directly using a microscope, and particle size data was obtained more than 100 times for each concentration to calculate the average major axis of the particles.

[0148] As shown in Fig. 14, the size of mannitol particles in the oily contrast agent was measured to be 11.4 μm at a concentration of 5%, 10.8 μm at 10%, and 12.1 μm at 15%. From this, it was found that mannitol particles do not dissolve in the oily contrast agent, so there is no change in particle size according to concentration.

[0149]

[0150] Example 7-3. Results of measuring the average particle size of mannitol particles in an oily contrast agent over time

[0151] Mannitol powder was placed in a 25 μm sieve, covered with a lid, and shaken to filter out the particles. Mannitol particles were mixed with an oily contrast agent (Lipiodol) at a concentration of 10% (w / v), and the average major axis size of the particles was measured immediately after mixing, after 1 hour, and after 1.5 hours. Mannitol suspension formulations in the oily contrast agent were prepared three times, and each prepared formulation was sampled three times to obtain nine samples. The particle size was measured directly using a microscope, and particle size data was obtained more than 100 times to calculate the average major axis of the particles.

[0152] As shown in Figure 15, the size of mannitol particles in the oily contrast agent was measured to be 10.8 μm immediately after mixing, 11.2 μm after 1 hour, and 10.7 μm after 1.5 hours. Similar to the results of measuring the average particle size according to mannitol particle concentration, it was found that there was no change in the size of mannitol particles over time because the mannitol particles did not dissolve in the oily contrast agent.

[0153]

[0154] Example 7-4. Results of embolization / disintegration tests on a microfluidics chip for a mannitol suspension formulation in an oily contrast agent

[0155] The microfluidic chip penetration embolization / disintegration test was conducted as follows.

[0156] Embolization test: A mannitol suspension formulation in an oily contrast agent (sieve: 25 µm, mannitol concentration 10%) is placed in a syringe and injected into a microfluidic chip through a microcatheter at a rate of 0.04 mL / min using a syringe pump, and observed under a microscope.

[0157] Disintegration test: Fill a syringe with 0.9% NaCl solution (physiological saline) and inject it into the microfluidic chip through a microcatheter at a rate of 0.04 mL / min using a syringe pump, and observe under a microscope.

[0158] As shown in Figure 16, the embolization test results confirmed that blockage occurred up to the thinnest duct (about 10 μm). Additionally, due to the hydrophobic nature of the microfluidic chip, blockage occurred faster when Lipiodol was used as the solvent compared to when Xenetix 350 was used.

[0159] Microscopic observation results, as shown in Figures 17 and 18, confirmed that Lipiodol blocks the contact between the mannitol particles and the disintegration solution to some extent, and as a result, the disintegration rate was delayed by more than twice compared to Xenetix 350.

[0160] From the above results, it was found that there was no significant difference in disintegration rate compared to the antibiotic (imipenem) TAME formulation.

[0161] However, compared to imipenem, which is slowly penetrated, it was confirmed that mannitol suspended in Lipiodol does not disintegrate until Lipiodol prevents contact with the disintegration solution, and then dissolves rapidly when the mannitol comes into direct contact with the disintegration solution.

[0162]

[0163] Example 8. Performance evaluation of a mannitol suspension W / O emulsion formulation as a rapid disintegration formulation

[0164] Example 8-1. Optimization of Emulsion Composition (Emulsion Stability According to Ratio of Aqueous Contrast Agent and Bupivacaine)

[0165] The densities of the aqueous contrast agent (Xenetix 350), oil contrast agent (Lipiodol), and Bupivacaine were measured using a D4 densimeter. The densities of Bupivacaine and the aqueous contrast agent were measured after mixing them at ratios of 5:5, 4:6, and 3:7, respectively. The aqueous phase (W phase), prepared by mixing Bupivacaine and the aqueous contrast agent in a specific ratio, and the oil phase (O phase), prepared by suspending mannitol powder (sieve: 25 µm) in Lipiodol at a concentration of 10% (w / v), were each placed in syringes. A mannitol suspension W / O emulsion formulation was prepared by mixing 50 times back and forth using a 3-way stopcock at a ratio of W:O = 1:3. The characteristics of the prepared formulation were examined under a microscope, and the degree of emulsion stabilization was confirmed by visual observation immediately after preparation, after 30 minutes, and after 2 hours.

[0166] The density measurement results for each composition are shown in Table 1. When bupivacaine and aqueous contrast agent were mixed in a 3:7 ratio, the density was 1.2896 g / cm³. 3 The density of mannitol suspended in Lipiodol at a concentration of 10% (w / v), 1.2920 g / cm³ 3 The difference with was the smallest.

[0167] Separation density (g / cm³) 3 )Xenetix 3501.4017Lipiodol1.280610% Mannitol in Lipiodol1.2920Bupivacaine1.0270Bupivacaine: 71.2896

[0168]

[0169] As shown in Figure 19, visual observation of the emulsion's layer separation over time confirmed that the layer separation occurred latest in the emulsion mixed with the drug and aqueous contrast agent in a 3:7 ratio, resulting in the smallest difference in density between the W phase and the O phase.

[0170] Under the condition where the drug:aqueous contrast agent = 3:7 phase separation occurred latest, the concentration of the drug (drug content) in the emulsion formulation was calculated to be 0.375 mg / mL.

[0171]

[0172] Example 8-2. Results of embolization / disintegration tests on a microfluidics chip for a mannitol suspension formulation in an emulsion

[0173] The microfluidic chip penetration embolization / disintegration test was conducted as follows.

[0174] Embolization test: Place a mannitol W / O emulsion formulation (W:O=1:3, drug:aqueous contrast agent=3:7) into a syringe and inject it into a microfluidic chip through a microcatheter at a rate of 0.04 mL / min using a syringe pump, and observe under a microscope.

[0175] Disintegration test: Fill a syringe with 0.9% NaCl solution (physiological saline) and inject it into the microfluidic chip through a microcatheter at a rate of 0.04 mL / min using a syringe pump, and observe under a microscope.

[0176] As shown in Figure 20, the embolization test results of the mannitol suspension formulation in the emulsion confirmed that although the mannitol particles could not be fully stacked throughout the entire conduit due to the different phases of the emulsion, they could block the conduit overall and cause embolization.

[0177] As shown in Figure 21, the disintegration test results of the mannitol suspension formulation in the emulsion confirmed that after disintegration, Lipiodol remained in some places within the conduit, but the mannitol dissolved overall and the conduit was completely cleared.

[0178] As shown in Figure 22, when comparing the disintegration ability with the antibiotic (imipenem) TAME, it was confirmed that the oily contrast agent delayed contact with the disintegration solution, and the time taken to penetrate to the finest duct was about 10% later compared to the antibiotic TAME formulation.

[0179]

[0180] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0181]

[0182] The composition for microarterial embolization of the present invention has industrial applicability as it can be usefully utilized as an embolizing agent, as it uses a sugar alcohol commonly used in the pharmaceutical and food industries to embolize even the capillaries without the risk of resistance development.

Claims

A composition for microarterial embolization comprising a sugar alcohol and a contrast agent as active ingredients. In paragraph 1, A composition for microarterial embolization, wherein the sugar alcohol is mannitol, sorbitol, xylitol, erythritol, arabitol, maltitol, inositol, lactitol, isomalt, fucitol, or a mixture thereof. In paragraph 1, A composition for microarterial embolization, characterized in that the above sugar alcohol has an average particle size of 1 to 300 μm. In paragraph 1, A composition for microarterial embolization, wherein the above sugar alcohol is characterized by having round crystalline particles. In paragraph 1, A composition for microarterial embolization characterized in that the above sugar alcohol is suspended in the above contrast agent. In paragraph 1, A composition for microarterial embolization, characterized in that the contrast agent is one or more contrast agents selected from the group consisting of aqueous contrast agents and oily contrast agents. In paragraph 6, A composition for microarterial embolization, characterized in that the above aqueous contrast agent is one or more selected from the group consisting of iopamidol, pamiray, metrizamide, diatrizoate, ioxaglate, iopentol, iomeprol, iotrolan, iohexol, iooversol, ioxilan, iopromide, iodixanol, and iobitridol. In paragraph 6, A composition for microarterial embolization characterized in that the above oily contrast agent is lipiodol. In paragraph 1, In the case where the above contrast agent is an aqueous contrast agent, A composition for microarterial embolization, characterized in that the above sugar alcohol has an average particle size of 1 to 100 μm. In Paragraph 9, A composition for microarterial embolization, characterized in that the above sugar alcohol is suspended in an aqueous contrast agent at a concentration of 5 to 50% (w / v). In paragraph 1, In the case where the above contrast agent is an oil-based contrast agent, A composition for microarterial embolization, characterized in that the above sugar alcohol has an average particle size of 1 to 100 μm. In Paragraph 11, A composition for microarterial embolization, characterized in that the above sugar alcohol is suspended in an oily contrast agent at a concentration of 5 to 50% (w / v). In paragraph 1, A composition for microarterial embolization, characterized in that the above composition is an emulsion formulation formed by mixing an aqueous contrast agent and an oil contrast agent. In Paragraph 13, A composition for microarterial embolization characterized by the above aqueous contrast agent and oil contrast agent being mixed in a volume ratio of 1:1 to 10. In Paragraph 13, A composition for microarterial embolization characterized in that the above aqueous contrast agent is mixed with a drug. In paragraph 15, A composition for microarterial embolization characterized by the above-mentioned drug and aqueous contrast agent being mixed in a volume ratio of 1:1 to 10. In Paragraph 13, A composition for microarterial embolization, characterized in that the above oily contrast agent has the above sugar alcohol suspended therein. In Paragraph 17, A composition for microarterial embolization, characterized in that the above sugar alcohol has an average particle size of 1 to 100 μm. In Paragraph 17, A composition for microarterial embolization, characterized in that the above sugar alcohol is suspended in an oily contrast agent at a concentration of 5 to 50% (w / v). (S1) A step of separating sugar alcohol particles by size using a sieve of 10 to 400 μm; and (S2) A method for preparing a composition for microarterial embolization, comprising the step of mixing the sugar alcohol particles separated in step (S1) with a contrast agent. Microarterial embolization use of a composition comprising a sugar alcohol and a contrast agent as an active ingredient. Use for preparing a preparation for microarterial embolization comprising a sugar alcohol; and a contrast agent as an active ingredient. A method for microarterial embolization comprising the step of administering a composition containing a sugar alcohol and a contrast agent as active ingredients to an individual in need of the composition in a pharmaceutically effective amount.

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