Medical composition, hemostatic agent, and applicator

Abstract

To provide a medical composition and a hemostatic agent excellent in both hemostatic properties and retention properties with time, and to provide a sprayer capable of satisfactorily spraying the medical composition or the hemostatic agent.SOLUTION: Provided are a medical composition and a hemostatic agent which are powders containing polyacrylic acid and polyvinylpyrrolidone, and a sprayer which sprays the medical composition on a surface of a lumen of a digestive tract. A sprayer includes a main body and a catheter, the main body including an accommodating portion that accommodates air from outside a body and is capable of spraying the air by pressurizing the accommodated air, a container that accommodates a medical composition, and at least two check valves, the catheter including a connecting portion that is connected to the container and through which the medical composition flows, the sprayer being capable of spraying the medical composition from an end portion of the catheter to a surface of a lumen of a gastrointestinal tract by spraying the air by the accommodating portion.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to medical compositions, hemostatic agents, and applicators. [Background technology]

[0002] In the medical field, endoscopic diagnosis and treatment using endoscopes are widely performed. In endoscopic diagnosis and treatment, for example, treatment such as resection of lesions in the digestive tract is performed using treatment instruments. For example, for early-stage gastric cancer, colon cancer, etc., endoscopic submucosal dissection (ESD), endoscopic mucosal resection (EMR), etc., which are procedures that use an endoscope to remove cancer tissue on the mucosal surface, are commonly performed.

[0003] In recent years, because postoperative bleeding and perforation can occur at the excision site of the mucosal layer, such as the ulcer base, it has been considered desirable to protect the ulcer base by suturing with clips, etc. Another approach has been to spray a medical adhesive to protect the mucosal layer, including the ulcer base.

[0004] A medical two-component reactive adhesive made of a mixed powder containing an aldehyde glucan powder and a partially carboxylated poly-L-lysine powder is known as a medical adhesive that is used on mucous membranes or the like after removal of a lesion by endoscopic treatment, surgery, or the like, and adheres to an adherend such as an organ until the wound heals (Patent Document 1).Patent Document 1 describes that the medical two-component reactive adhesive can be applied to a wound or the like by spraying, and can be used as a hemostatic agent. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 2019-092645 Summary of the Invention [Problem to be solved by the invention]

[0006] When hemostasis is achieved by spraying a hemostatic agent on the gastrointestinal mucosa that has been bleeding due to treatment such as endoscopic diagnosis or endoscopic therapy, it is desirable for the powder-spreading type hemostatic agent to have both excellent hemostatic properties, which allow for good hemostasis at the bleeding site, and excellent retention properties, which allow the hemostatic agent to remain at the bleeding site for an appropriate period of time without being dissolved or decomposed by body fluids, etc.

[0007] The present disclosure has been made in light of the above. The problem that one embodiment of the present disclosure aims to solve is to provide a medical composition and a hemostatic agent that are excellent in both hemostatic properties and retention over time, as well as a sprayer that can effectively spray the medical composition or the hemostatic agent. [Means for solving the problem]

[0008] Specific means for solving the problems include the following aspects. <1> A medical composition to be applied to the surface of the digestive tract lumen of a living body, the medical composition being a powder containing polyacrylic acid and polyvinylpyrrolidone. <2> The powder contains a polyacrylic acid powder and a polyvinylpyrrolidone powder. <1> The medical composition described in <3> It is made up of polyacrylic acid powder particles attached to the surface of polyvinylpyrrolidone powder particles. <1> or <2> The medical composition described in <4> Granules containing polyacrylic acid powder and polyvinylpyrrolidone powder. <1> ~ <3> 10. The medical composition according to claim 9, wherein the composition is a pharmaceutical composition. <5> The granules have a volume distribution average particle size D50 of 50 μm to 500 μm. <4> The medical composition described in <6> The polyacrylic acid and polyvinylpyrrolidone are contained in a mass ratio of 1:10 to 10:1. <1> ~ <5> 10. The medical composition according to claim 9, wherein the composition is a pharmaceutical composition. <7> The total content of polyacrylic acid and polyvinylpyrrolidone is 10% by mass to 100% by mass based on the total mass of the medical composition. <1> ~ <6> 10. The medical composition according to claim 9, wherein the composition is a pharmaceutical composition. <8> It is a hemostatic agent <1> ~ <7> 10. The medical composition according to claim 9, wherein the composition is a pharmaceutical composition. <9> <1> ~ <7> A hemostatic agent comprising the medical composition described in any one of the above. <10> <1> ~ <8> or the medical composition according to any one of <9> a sprayer for spraying the hemostatic agent described in the above onto the surface of the lumen of the digestive tract, the sprayer comprising a main body and a catheter, the main body having a storage section that stores air from outside the body and is capable of spraying the air by pressurizing the stored air, a container that stores the medical composition, and at least two check valves, the catheter being connected to the container and having a connecting section through which the medical composition flows, and the sprayer being capable of spraying the medical composition onto the surface of the lumen of the digestive tract from the end of the catheter by spraying air using the storage section. <11> At least one of the check valves has a function of being biased in a closing direction under normal pressure and opening under pressure. <10> The dispenser according to claim 1. <12> At least one of the check valves is a duckbill type check valve <10> or <11> The dispenser according to claim 1. <13> The main body has a connecting part that connects the storage part and the container, and the connecting part has at least one duckbill type check valve. <10> ~ <12> 10. The dispenser according to claim 9, wherein the diffuser is a <14> The container is a spherical structure containing an elastic resin that can pressurize air by squeezing. <10> ~ <13> 10. The dispenser according to claim 9, wherein the diffuser is a <15> The catheter has an inner diameter of 0.5 mm to 2.5 mm and is located at the distal end of the body. <10> ~ <14> 10. The dispenser according to claim 9, wherein the diffuser is a <16> The catheter has at least two flow paths: a flow path through which the medical composition flows and a flow path through which water flows. <10> ~ <15> 10. The dispenser according to claim 9, wherein the diffuser is a [Effects of the Invention]

[0009] According to one embodiment of the present disclosure, there are provided a medical composition and a hemostatic agent that are excellent in both hemostatic properties and retention over time, and a sprayer that can effectively spray the medical composition or the hemostatic agent. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 is a photograph of the powder of the medical composition taken with an electron microscope (specifically, a scanning electron microscope, SEM). [Figure 2] FIG. 2 is an explanatory diagram illustrating an example of a dispenser. [Figure 3] FIG. 3 is an explanatory diagram illustrating another example of the dispenser. [Figure 4] FIG. 4 is a graph showing the particle size distribution of Carbopol 971P on a volume basis, where the bar graph shows the frequency distribution (left scale) and the line graph shows the cumulative distribution (right scale). [Figure 5] FIG. 5 is a graph showing the particle size distribution of PVP K90 on a volume basis, where the bar graph shows the frequency distribution (left scale) and the line graph shows the cumulative distribution (right scale). [Figure 6] FIG. 6 is a graph showing the volumetric particle size distribution of the medical composition obtained in Example 2, where the bar graph shows the frequency distribution (left scale) and the line graph shows the cumulative distribution (right scale). DETAILED DESCRIPTION OF THE INVENTION

[0011] Hereinafter, embodiments of the present disclosure will be described. The present disclosure is not limited to the following embodiments, and can be implemented with appropriate modifications within the scope of the object of the present disclosure. In the present disclosure, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the upper and lower limits. In the numerical ranges described in stages in the present disclosure, the upper or lower limit described in a certain numerical range may be replaced with the upper or lower limit of another numerical range described in stages. Furthermore, in the numerical ranges described in the present disclosure, the upper or lower limit described in a certain numerical range may be replaced with a value shown in the examples. In the present disclosure, when a plurality of substances corresponding to each component are present in the composition, the amount of each component in the composition means the total amount of the plurality of substances present in the composition, unless otherwise specified. In the present disclosure, a combination of two or more preferred aspects or embodiments is a more preferred aspect or embodiment. In this disclosure, "mass%" and "wt%" are synonymous, and "parts by mass" and "parts by weight" are synonymous. In this disclosure, "%" indicating the amount of a component is based on mass unless otherwise specified. In the present disclosure, "powder" includes "powder" and "granules." In this disclosure, "granules" refers to particles formed from particles in a powder and consisting of particles larger than the primary particles of the powder (including secondary particles and granules consisting of multiple primary particles). In this disclosure, normal pressure means standard atmospheric pressure at 25°C.

[0012] In the present disclosure, the weight average molecular weight (Mw) is a value measured by the GPC method. Specifically, the molecular weight was measured using a gel permeation chromatography (GPC) analyzer equipped with columns of TSKgel GMHxL, TSKgel G4000HxL, or TSKgel G2000HxL (all trade names manufactured by Tosoh Corporation), using THF (tetrahydrofuran) as a solvent and a differential refractometer, and converted using polystyrene as a standard substance.

[0013] In this disclosure, "particle size" means the average particle size unless otherwise specified. In the present disclosure, the average particle size is the volume distribution average particle size D50, and is a value measured by the following method. The powder particles to be measured were measured using a laser diffraction / scattering particle size distribution analyzer (LMS-3000 (Malvern Instruments)) in the spray-type dry measurement mode, and the particle size distribution was quantified under the conditions of a measurement range of 0.10 μm to 3500.00 μm and a compressed air pressure of 0.1 MPa.

[0014] The medical composition, hemostatic agent, and sprayer according to the present disclosure will be described in detail below.

[0015] (Medical composition) A medical composition (hereinafter also referred to as medical composition) that is one embodiment of the present disclosure is a medical composition to be applied to the surface of the digestive tract lumen of a living body, and is a powder containing polyacrylic acid and polyvinylpyrrolidone.

[0016] Hemostatic agents of the type that are sprinkled as powder on bleeding sites in the gastrointestinal mucosa are desired to have both excellent hemostatic properties, which allow for effective hemostasis, and excellent retention over time, which allows the hemostatic agent to remain at the bleeding site without being decomposed by moisture or the like. The present inventors have discovered that a medical composition that is a powder containing polyacrylic acid and polyvinylpyrrolidone can be applied to the surface of the digestive tract lumen of a living body, and is a medical composition that has both excellent hemostatic properties and long-term retention properties. Although the detailed mechanism is unknown, the inventors speculate that after polyacrylic acid and polyvinylpyrrolidone become aqueous solutions due to the water contained in blood, mucous membranes, etc., or water supplied, they form hydrogen bonds with each other to form a gel that is suitable as a hemostatic agent for internal use, resulting in a hemostatic agent with excellent hemostatic properties and retention over time. Furthermore, a powder containing polyacrylic acid and polyvinylpyrrolidone, or a gel produced from these, is a chemically stable resin, and is also excellent as a hemostatic agent in that it is extremely safe.

[0017] The medical composition is preferably applied to the surface of the lumen of the digestive tract of a living body using an endoscope. The medical composition can also be applied to targets other than the surface of the lumen of the digestive tract of a living body. For example, the medical composition can be applied to any area, mainly inside the body, such as a wound in laparoscopic surgery using a rigid endoscope or open surgery.

[0018] The medical composition may be a powder containing polyacrylic acid and polyvinylpyrrolidone, regardless of the method of powder synthesis. Polyacrylic acid may also contain polymethacrylic acid, which is sometimes called a carboxyvinyl polymer. Furthermore, it may contain structural units derived from monomers other than acrylic acid, as long as the effects of the medical composition are not impaired. Furthermore, a portion of the polyacrylic acid may form a salt, such as sodium or calcium. Furthermore, the polyacrylic acid may be chemically crosslinked within the molecule. Therefore, carboxyvinyl polymer can be used as the polyacrylic acid. The polyacrylic acid and polyvinylpyrrolidone may each be one type or multiple types, and any combination is acceptable.

[0019] Polyacrylic acid is a polymer obtained by polymerizing acrylic acid. Polyvinylpyrrolidone is typically a polymer obtained by polymerizing N-vinyl-2-pyrrolidone. It may contain structural units derived from monomers other than N-vinyl-2-pyrrolidone, provided that the effectiveness of the medical composition is not impaired. Specifically, it may be a copolymer of polyvinylpyrrolidone and vinyl acetate. Furthermore, polyvinylpyrrolidone may be chemically crosslinked within the molecule.

[0020] In the medical composition, the polyacrylic acid and polyvinylpyrrolidone are preferably contained in a mass ratio of 1:10 to 10:1, more preferably 1:3 to 2:1. When the medical composition contains polyacrylic acid and polyvinylpyrrolidone in this range, when the medical composition is applied to the surface of the gastrointestinal lumen of a living body, the medical composition has excellent hemostatic properties when applied to a bleeding site, and also forms a gel that remains appropriately at the application site due to the moisture on the surface of the gastrointestinal lumen of a living body, resulting in excellent retention over time, and is therefore preferable because it has both excellent hemostatic properties and excellent retention over time.

[0021] In the medical composition, the total content of polyacrylic acid and polyvinylpyrrolidone is preferably 10% by mass to 100% by mass based on the total mass of the medical composition. The medical composition may consist of polyacrylic acid and polyvinylpyrrolidone, and may or may not contain other ingredients. In the medical composition, the total content of polyacrylic acid and polyvinylpyrrolidone is more preferably 50% by mass to 100% by mass. When the medical composition contains polyacrylic acid and polyvinylpyrrolidone in this range, when the medical composition is applied to the surface of the digestive tract lumen of a living body, the composition has excellent hemostatic properties when applied to a bleeding site, and the moisture on the surface of the digestive tract lumen of a living body causes the composition to become a gel that remains appropriately at the application site, resulting in excellent retention over time, and is therefore preferred because it has both excellent hemostatic properties and excellent retention over time.

[0022] In the medical composition, any component other than polyacrylic acid and polyvinylpyrrolidone may be used as long as it does not significantly impair the functionality of the medical composition. Examples include drugs for bleeding sites, components such as hyaluronic acid that improve compatibility with the body, and colorants that improve the identification of the application site. The powder component may also contain less than 20% water. The medical composition may contain water during the secondary particle production process described below. In such cases, the medical composition may contain less than 20% water based on the total mass of the medical composition.

[0023] In addition, when the medical composition is referred to as having excellent hemostatic properties, it means that when the medical composition is sprayed on the bleeding site, hemostasis is achieved within a certain period of time, such as 10 minutes, although this will depend on the state of the bleeding. Furthermore, when the medical composition is said to have excellent retention properties over time, it means that, for example, when the medical composition is sprayed on a bleeding site, the medical composition continues to adhere to the sprayed site for a certain period of time, such as several hours to several days or more, although this will depend on the condition of the site where the medical composition is sprayed.

[0024] The method for producing the powder containing polyacrylic acid and polyvinylpyrrolidone is not limited. The powder containing polyacrylic acid and polyvinylpyrrolidone preferably has an average particle size in the range of 10.0 μm to 1000 μm, more preferably in the range of 50.0 μm to 500 μm. A powder having an average particle size of 50.0 μm or more is preferable because it is easy to handle and, for example, when sprayed using an endoscope, the scattering of the powder is limited, preventing the endoscopic field from becoming cloudy. On the other hand, a powder having an average particle size of less than 500 μm is preferable because it prevents clogging of catheters and the like used when spraying using an endoscope.

[0025] As a method for adjusting the average particle size of the powder containing polyacrylic acid and polyvinylpyrrolidone, a known method can be used. For example, the average particle size can be adjusted by granulating the raw material.

[0026] The powder containing polyacrylic acid and polyvinylpyrrolidone preferably contains a polyacrylic acid powder and a polyvinylpyrrolidone powder. The polyacrylic acid powder and the polyvinylpyrrolidone powder may each be powders. By mixing these powders, a powder containing polyacrylic acid and polyvinylpyrrolidone can be obtained. There are no particular limitations on the uniformity of the mixing, and mixing using a known mixer may be used. The polyacrylic acid powder and the polyvinylpyrrolidone powder may each contain one type or multiple types, and any combination is acceptable.

[0027] The polyacrylic acid powder can be used without any limitation as long as it is a powder. For example, one having a weight average molecular weight (Mw) of 5,000 or more is preferably used, and 40,000 or more or intramolecularly crosslinked polyacrylic acid is more preferred. Furthermore, for example, one having an average particle size of 1 μm to 200 μm is preferably used, and 1 μm to 10 μm is more preferred.

[0028] Any polyvinylpyrrolidone powder can be used without limitation as long as it is a powder. For example, one having a weight average molecular weight (Mw) of 5,000 to 3,500,000 is preferably used, and 300,000 to 2,000,000 is more preferably used. Furthermore, for example, one having an average particle size of 10 μm to 200 μm is preferably used, and 100 μm to 200 μm is more preferably used.

[0029] The average particle size of the primary particles in the polyacrylic acid powder and the average particle size of the primary particles in the polyvinylpyrrolidone powder can be used without any limitation, and the two may have approximately the same average particle size, or one may have a larger average particle size than the other.

[0030] The average particle size of the primary particles in the polyacrylic acid powder and the average particle size of the primary particles in the polyvinylpyrrolidone powder may be adjusted before use. The average particle size can be adjusted by reducing the particle size of each primary particle, increasing the particle size, adjusting the particle size distribution, or the like. As a method for adjusting the average particle size, a known method can be adopted. For example, the primary particles in the polyacrylic acid powder may be previously subjected to a process for increasing the particle size by granulation, and the primary particles in the polyvinylpyrrolidone powder may be previously subjected to a process for decreasing the particle size by stirring or the like, and then these may be mixed to prepare a powder containing polyacrylic acid and polyvinylpyrrolidone.

[0031] The polyacrylic acid powder and polyvinylpyrrolidone powder may be, for example, commercially available powders, such as Carbopol 971P from Lubrizol and Hiviswako 104 from Fujifilm Wako Co., Ltd., and the polyvinylpyrrolidone powder may be, for example, Kollidon F90EVO from BASF and Plasdon K90 from Ashland.

[0032] The average particle size of the granulated secondary particle powder may be adjusted by granulating the polyacrylic acid powder and the polyvinylpyrrolidone powder as raw materials. As a method for adjusting the average particle size of the secondary particle powder, a known method can be adopted. For example, the average particle size of the secondary particle powder can be adjusted by granulating the polyacrylic acid powder and the polyvinylpyrrolidone powder as raw materials by, for example, fluidized bed granulation.

[0033] The powder containing polyacrylic acid and polyvinylpyrrolidone preferably has polyacrylic acid powder particles attached to the surfaces of polyvinylpyrrolidone powder particles. In this case, the average particle size of the primary particles of the polyvinylpyrrolidone powder is preferably larger than the average particle size of the primary particles of the polyacrylic acid powder. For example, a powder of polyvinylpyrrolidone primary particles having an average particle size of 50 μm to 150 μm and a powder of polyacrylic acid primary particles having an average particle size of 0.5 μm to 10 μm can be used as raw materials. The powder containing polyacrylic acid and polyvinylpyrrolidone may include secondary particles formed by, for example, multiple primary particles of polyacrylic acid powder attached to one primary particle of polyvinylpyrrolidone powder.

[0034] The method for producing a powder of secondary particles in which primary particles of polyacrylic acid powder adhere to the surfaces of primary particles of polyvinylpyrrolidone powder is not limited, but for example, a powder in which particles of polyacrylic acid powder adhere to the surfaces of particles of polyvinylpyrrolidone powder can be prepared by adding water to polyacrylic acid powder and polyvinylpyrrolidone powder as raw materials and performing fluidized bed granulation. Both the polyacrylic acid powder and the polyvinylpyrrolidone powder are water-soluble, and can be easily mixed together by using water, for example, to form a powder in which the polyacrylic acid powder particles adhere to the surfaces of the polyvinylpyrrolidone powder particles. Furthermore, the average particle size of the secondary particle powder can be adjusted by adjusting the amounts of the raw materials, i.e., the polyacrylic acid powder, the polyvinylpyrrolidone powder, and the water, and adjusting the granulation process, such as adjusting the timing of adding water and the granulation speed.

[0035] By adjusting the average particle size of the secondary particles of the powder, which is formed by polyacrylic acid powder particles adhering to the surfaces of polyvinylpyrrolidone powder particles, the occurrence of the following problems can be suppressed: For example, when a medical composition, which is a powder containing polyacrylic acid and polyvinylpyrrolidone, is sprayed onto the surface of the lumen of the digestive tract, it is possible to suppress clouding of the endoscopic field of view due to scattering of the powder, and it is possible to suppress clogging of a catheter when the medical composition is delivered to the spraying site.

[0036] As shown in FIG. 1, in a photograph 10 taken by an electron microscope (scanning electron microscope, SEM) of the powder of the medical composition, the powder in which polyacrylic acid particles 12 adhere to the surfaces of polyvinylpyrrolidone powder particles 11 is a powder in which polyacrylic acid particles 12 are bound to polyvinylpyrrolidone powder particles 11. In photograph 10, the powder of the medical composition contains many fine polyacrylic acid particles 12 bound to the polyvinylpyrrolidone powder particles 11, resulting in a finely uneven surface. Furthermore, the powder in which polyacrylic acid particles 12 adhere to the surfaces of polyvinylpyrrolidone powder particles 11 has an average particle size of 100 μm to 200 μm. The powder shown in FIG. 1 was prepared by adding water to polyacrylic acid powder and polyvinylpyrrolidone powder and performing fluidized bed granulation.

[0037] The powder containing polyacrylic acid and polyvinylpyrrolidone is preferably a granule containing a powder of polyacrylic acid and a powder of polyvinylpyrrolidone. The granule may be any granule containing a powder of polyacrylic acid and a powder of polyvinylpyrrolidone, or may be granulated from these powders.

[0038] The average particle size of the granules is preferably 50 μm to 500 μm, more preferably 100 μm to 300 μm.The particle size distribution of the granules is preferably unimodal. It is preferable that the average particle size of the granules is within the above range, because this prevents the endoscopic field from becoming cloudy when the medical composition, which is a powder containing polyacrylic acid and polyvinylpyrrolidone, is sprayed onto the surface of the lumen of the digestive tract, and also prevents problems from occurring when the medical composition is transported to the spraying site, such as preventing catheter clogging. Furthermore, since it is easy to control the state of the powder when forming the granules, for example by adjusting the average particle size, it is possible to prepare a powder that is suitable for the type of sprayer used to spray the medical composition.

[0039] There are no particular limitations on the method for preparing granules containing polyacrylic acid powder and polyvinylpyrrolidone powder, but they can be prepared, for example, by granulating the polyacrylic acid powder and polyvinylpyrrolidone powder. Both the polyacrylic acid powder and the polyvinylpyrrolidone powder are water-soluble, and they can be easily bound together to form granules, for example, by using water. Furthermore, the particle size distribution, average particle size, specific surface area, etc. of the secondary particle granules can be adjusted by adjusting the amounts of the raw materials (polyacrylic acid powder, polyvinylpyrrolidone powder, and water), the timing of water addition, the granulation speed, and other adjustments to the granulation process.

[0040] The secondary particles preferably have a large specific surface area and are bulky. A large specific surface area facilitates contact with water, which can lead to rapid dissolution after spraying. Furthermore, bulkiness makes it difficult for particles to be compacted by vibration during transportation, and can be expected to allow storage in a state that is easy to spray.

[0041] Granules containing polyacrylic acid powder and polyvinylpyrrolidone powder are preferably formed by polyacrylic acid powder particles adhering to the surface of polyvinylpyrrolidone powder particles. For example, secondary particle granules can be obtained by adding water to polyvinylpyrrolidone powder having an average primary particle size of 50 μm to 150 μm and polyacrylic acid powder having an average primary particle size of 0.5 μm to 10 μm and performing fluidized bed granulation. The powder shown in FIG. 1 is a granule formed by polyacrylic acid powder particles adhering to the surface of polyvinylpyrrolidone powder particles.

[0042] The method for producing the medical composition is not particularly limited, but a preferred example is the granulation method using polyacrylic acid powder, polyvinylpyrrolidone powder, and water, as described above. The water used in this case preferably contains a colorant or other component. Granules made using water containing a colorant or other component, when applied to a bleeding site, can color the area where the granules are applied, making the area more noticeable.

[0043] Any dye that does not cause adverse effects when used inside the body can be used as the colorant. Furthermore, since the colorant is sprayed inside the body, a color that is conspicuous when sprayed, such as blue, green, or red, is preferred. Specifically, for example, food dyes, dyes commonly sprayed in dyeing methods during endoscopic examination or endoscopic treatment, etc. can be used.

[0044] Specific examples of food coloring include tar dyes such as Fast Green FCF (Green No. 3), Brilliant Blue FCF (Blue No. 1), and Indigo Carmine (Blue No. 2). Specific examples of dyes commonly sprayed in dye methods during endoscopic examination or endoscopic treatment include indigo carmine, crystal violet (pyoktanin), and methylene blue. Depending on the procedure used in endoscopic examination or endoscopic treatment, Lugol's and toluidine blue, which are used in the esophagus, are also used. Fluorescein and acridine orange, which are used in fluorescence methods, can also be used. In addition, the water used in this case may contain water-soluble chemicals in addition to the colorant.

[0045] These colorants can be used during the production of the medical composition. Alternatively, the medical composition can be colored by, for example, separately spraying the medical composition and water containing the colorant. For example, if the medical composition is in the form of granules, the granules easily absorb the water containing the colorant, so even colorants that fade over a relatively short period of time can be used. Furthermore, since the procedure can be performed without changing the colorant, for example, coloring of the medical composition and the lesion can be performed without changing the catheter, which is preferable. In this case, for example, a catheter with two flow paths can be used.

[0046] The medical composition is preferably a hemostatic agent. That is, the medical composition is preferably one that is applied to a bleeding site on the surface of the lumen of the digestive tract of a living body. The medical composition is preferably applied as a hemostatic agent to a bleeding site on the surface of the lumen of the digestive tract of a living body in a treatment using an endoscope.

[0047] The medical composition serving as a hemostatic agent may contain ingredients other than polyacrylic acid and polyvinylpyrrolidone, such as drugs effective in stopping hemostasis, or drugs effective in healing the lesion when the site of hemostasis is a lesion.

[0048] (hemostatic agent) One embodiment of the present disclosure is a hemostatic agent comprising a medical composition. The hemostatic agent can stop bleeding at a bleeding site by applying the hemostatic agent to the surface of the lumen of the digestive tract of a living body. The medical composition is preferably sprayed at the bleeding site by a conventional hemostatic agent spraying method using an endoscope.

[0049] The hemostatic agent can be applied to the surface of the digestive tract lumen of a living body using a catheter inserted through the forceps port of an endoscope. When the hemostatic agent is sprayed alone, it gels with moisture at the bleeding site, resulting in a hemostatic agent with excellent hemostatic properties and retention over time. Alternatively, the hemostatic agent may be sprayed together with water to be applied to the bleeding site. In this case, the water may contain a colorant or the like.

[0050] The hemostatic agent may contain ingredients other than polyacrylic acid and polyvinylpyrrolidone. Examples include drugs that are effective in stopping bleeding, and drugs that are effective in healing lesions when the site of bleeding is a lesion. Specific examples include epinephrine and prednisolone.

[0051] (spreader) A sprayer (hereinafter referred to as sprayer) according to one embodiment of the present disclosure is a sprayer for spraying a medical composition or a hemostatic agent onto the surface of the lumen of the digestive tract, and comprises a main body and a catheter. The main body has a storage section that stores air from outside the body and is capable of spraying the air by pressurizing the stored air, a container that stores the medical composition, and at least two check valves. The catheter has a connection section that connects to the container and through which the medical composition flows. By spraying air from the storage section, the medical composition can be sprayed onto the surface of the lumen of the digestive tract from the end of the catheter.

[0052] To apply powder to affected areas in the digestive tract via an endoscope, a spray device is required to deliver the powder through a tube such as a catheter. However, when considering the reuse of the device, contamination after use and gelation due to contact with moisture of particles remaining in the catheter are unavoidable, which may prevent safe and normal spraying when reused. Therefore, it is preferable to use a disposable spray device. Furthermore, a simple configuration with limited functions as a disposable device is preferable from a medical economic perspective. The sprayer is equipped with at least two check valves and can manually spray the medical composition onto the surface of the lumen of the digestive tract. For example, because the medical composition can be manually sprayed, the amount, timing, and speed of spraying of the medical composition can be precisely controlled. Furthermore, the sprayer has an air storage section that can spray air by manually applying pressure, and air intake is automatic, so there is no need for a spray can containing liquefied gas or compressed gas, electricity to operate the air intake mechanism, etc. Therefore, the entire sprayer is disposable, can be made inexpensive, there is no risk of infection, etc., and it is preferable from a medical economic perspective.

[0053] The sprayer also has at least two check valves. By combining two check valves, the medical composition can be sprayed without suctioning air through the catheter. Not suctioning air through the catheter prevents the sprayed medical composition from flowing back or absorbing moisture from the body, thereby preventing the catheter from clogging with the medical composition and the medical composition in the container from gelling due to moisture.

[0054] 2, sprayer 20, which is an example of a sprayer, includes a main body 21 and a catheter 22. Main body 21 has a storage section 23, a container 24, and two check valves, check valve 25a and check valve 25b. The catheter 22 has a connector 27a at one end. The catheter 22 is connected to the container 24 by the connector 27a and via a connector 27b provided at the end of the connecting portion 26a of the container 24. The other end of the catheter 22 is placed inside the body via the forceps port of the endoscope, and is capable of spraying the medical composition to the area to be sprayed. A medical composition 28 is contained within the container 24 . Furthermore, storage unit 23 is connected to container 24 via check valve 25a. Check valve 25a is provided in connecting unit 26b that connects storage unit 23 and container 24. Check valve 25b is attached to storage unit 23. Connecting units 26a and 26b have flow paths formed therein, which are specifically tubes.

[0055] The main body has at least two check valves. At least one of the check valves is preferably biased in a closing direction under normal pressure and opens under pressure. Of the two check valves, the other check valve is preferably biased in a closing direction under pressure and opens under normal pressure.

[0056] By having the main body have a combination of at least two check valves with different functions, the sprayer can spray the medical composition by applying pressure, and by stopping the pressure, air can be prevented from being drawn through the catheter. Specifically, by combining at least two check valves with different functions, the sprayer can spray the medical composition by applying pressure, and by stopping the pressure, air can be prevented from being drawn through the catheter. This prevents air from being drawn through the catheter, thereby preventing the sprayed medical composition from flowing back and absorbing moisture from the body, and preventing the catheter from clogging with the medical composition and the medical composition in the container from gelling due to moisture.

[0057] At least one of the check valves is preferably a duckbill check valve. A duckbill check valve is a check valve that is reliably biased in the closing direction at normal pressure and opens when pressurized. A specific example is the PP duckbill mini check valve (model number FK212601) manufactured by Isis Corporation. By providing at least one of the at least two check valves in the dispenser as a duckbill check valve, it is possible to more reliably suppress the intake of air from the catheter.

[0058] The storage unit and the container are connected by a connecting part. The connecting part connecting the storage unit and the container is preferably provided with at least one check valve. The connecting part is preferably provided with at least one check valve that opens when pressurized and closes under pressure other than pressurized, such as negative pressure or normal pressure. Any check valve mechanism can be used as long as it has this function, but it is preferable that the check valve provided in the connecting part be, for example, a duckbill type check valve, as this allows for more reliable control of flow.

[0059] 2, in dispenser 20, which is an example of a dispenser, connecting portion 26b is provided with check valve 25a. Check valve 25a is a duckbill type check valve.

[0060] The storage section is preferably a spherical structure containing an elastic resin that can pressurize air by squeezing. By using a spherical structure containing an elastic resin, the storage section can be squeezed, for example, manually, and air can be sprayed into the container by squeezing the storage section. The storage section preferably includes at least one check valve. By including the check valve in the storage section, when compression is stopped, air is automatically drawn into the storage section from the outside via the check valve.

[0061] The storage unit preferably includes at least one check valve that closes when pressurized and opens under pressure other than pressurized conditions, such as negative pressure or normal pressure. Any check valve with this function can be used. For example, the check valve included in the storage unit is preferably a diaphragm-type check valve.

[0062] 2, in sprayer 20, which is an example of a sprayer, storage section 23 is provided with check valve 25b. Check valve 25b is a diaphragm-type check valve.

[0063] As described above, the main body of the sprayer is provided with at least two check valves with different functions, located opposite the catheter relative to the container, thereby suppressing air intake from the catheter and enabling the medical composition to be sprayed in an efficient manner.

[0064] The catheter preferably has an inner diameter of 0.5 mm to 2.5 mm and is disposed at the distal end of the main body. The inner diameter is more preferably 1.0 mm to 2.0 mm. When the inner diameter of the catheter is 0.5 mm or more, the medical composition can be smoothly dispersed, and when the inner diameter is 2.5 mm or less, the catheter can be inserted into the forceps opening through which a treatment tool is passed in a normal endoscope.

[0065] Furthermore, the distal end of the main body where the catheter is disposed is preferably the end of the main body opposite the housing portion, i.e., the catheter and the housing portion are preferably disposed on opposite sides of the main body. This allows the medical composition to be efficiently circulated through the flow path of the catheter when the storage section is squeezed. Note that the catheter and storage section may be arranged in a manner other than being opposite each other. Because the catheter is inserted into the endoscope forceps port, the catheter and storage section may be arranged at an angle of, for example, 90° so as not to interfere with endoscopic operation.

[0066] As shown in FIG. 2, dispenser 20, which is an example of a dispenser, has a catheter 22 connected to one distal end of a main body 21 via a connecting portion 26a, and has a housing portion 23 at the distal end on the opposite side. This allows the medical composition 28 to be efficiently dispersed from the flow path of the catheter 22 when the storage section 23 is squeezed.

[0067] The catheter preferably has at least two flow paths: one through which the medical composition flows and one through which water flows. This allows water to be sprayed onto the sprayed medical composition when the medical composition is sprayed onto the surface of the digestive tract lumen of a living organism. The sprayed medical composition can gel due to moisture in the mucous membrane, moisture from bleeding blood, etc., but in some cases, spraying water can cause gelation more quickly. Furthermore, as described above, the medical composition can be colored by spraying water containing a dye.

[0068] The operation of the sprayer will now be described. As shown in Figure 2, a medical composition 28 is placed in advance in a container 24 of a sprayer 20, which is an example of a sprayer. Then, a catheter 22 is inserted through the forceps port of the endoscope and placed in the lumen of the digestive tract of a living body to spray the medical composition. One end of the catheter 22 is an outlet for the medical composition. When spraying the medical composition 28, the storage section 23 is usually squeezed manually. This applies pressure to the storage section 23, and the air stored in the storage section 23 passes through the connecting section 26b and the check valve 25a and is sprayed into the container 24. In Figure 2, arrows indicate the flow of air, and indicate that air flows in only one direction at each check valve. When air is injected into the container 24, the medical composition 28 travels through the connecting portion 26a, the connector 27b, the connector 27a, and the flow path within the catheter 22 in that order, and the medical composition 28 is sprayed from one end of the catheter 22.

[0069] Next, squeezing of storage section 23 is stopped and the pressure is released, so that check valves 25a and 25b work together to create a negative pressure only in the area on the storage section 23 side from check valve 25a, and outside air is drawn in through check valve 25b. This eliminates the negative pressure in storage section 23, and air is stored in storage section 23.

[0070] By repeating this series of steps, the medical composition 28 can be continuously dispersed.

[0071] As in the sprayer 20, the check valve 25b may be disposed at any position on the housing portion 23 side of the check valve 25a in the connecting portion 26b.

[0072] As shown in Figure 3, in dispenser 30, an example of a dispenser, check valve 25b is located at one end of connecting portion 26c, which branches into three directions. Container 24 operates, for example, like a rubber bulb in a dropper, with air intake through check valve 25b and air ejection through check valve 25a. In Figure 3, arrows indicate the air flow, and each check valve allows air to flow in only one direction.

[0073] The medical composition and sprayer can be distributed as a medical composition-containing sprayer, with the medical composition contained in the sprayer container. One medical composition-containing sprayer can be used per procedure. The medical composition-containing sprayer is disposable, has no risk of infection, is highly safe, and does not require electricity, compressed spray cans, etc., making it less expensive and preferable from a medical economic perspective. [Example]

[0074] The present disclosure will be described in further detail below based on examples. The materials, amounts used, ratios, processing details, processing procedures, etc. shown in the following examples can be changed as appropriate without departing from the spirit of the present disclosure. Therefore, the scope of the present disclosure should not be construed as being limited by the following examples. In the following, unless otherwise specified, "parts" and "%" are by mass. In addition, "Carbopol" is a registered trademark. In the following, the mention that "Carbopol" is a registered trademark will be omitted.

[0075] Examples 1 to 12 The materials shown in Table 1 were mixed and charged into a fluidized bed granulator (FL-LABO manufactured by Freund Corporation) to a final weight of 250 g. Next, pure water was sprayed onto the powder in the powder portion at an intake temperature of 70°C, an intake air volume of 0.3 m3 / min, a spray rate of approximately 4 mL / min, and a spray pressure of 0.18 MPa, followed by granulation. The mixture was then dried under reduced pressure at 40°C for 10 hours in a vacuum dryer to obtain granulated material. The average particle size was controlled by controlling the granulation time during which water was gradually added. All of the granulated products were in the form of granules, and the results of measuring the average particle size (volume distribution average particle size D50 shown above) are shown in Table 1.

[0076] The units of the compositions shown in Table 1 are mass % based on the total mass of the medical composition. In Table 1, blank cells indicate that the compound was not included. Details of the materials shown in Table 1 are as follows.

[0077] Carbopol 971P: Cross-linked polyacrylic acid powder, manufactured by Lubrizol, particle size 2.6 μm Polyacrylic acid 1,000,000: Polyacrylic acid powder, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., molecular weight 1,000,000, particle size 2.0 μm PVP K90: Polyacrylic acid powder, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., molecular weight 360,000, particle size 165 μm PVP K30: Polyacrylic acid powder, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., molecular weight 40,000, particle size 50 μm. Poly(1-vinylpyrrolidone-co-vinyl acetate): Powder of copolymer of vinyl acetate and polyvinylpyrrolidone, Ashkand Plasdone S-630, molecular weight 20,000, particle size 40 μm Blue No. 1: Tokyo Chemical Industry Co., Ltd. Sodium hyaluronate: Sigma Aldrich, molecular weight 100,000, particle size 10 μm

[0078] The particle size distribution of the medical composition, which is the granulated product obtained in Example 2, was measured. As shown in Figures 4 and 5, compared with the particle size distribution and average particle size of Carbopol 971P, a material for the medical composition (Figure 4), and the particle size distribution and average particle size of PVP K90, a material for the medical composition (Figure 5), as shown in Figure 6, the medical composition, which is the granulated product obtained in Example 2, was a granule with a larger particle size than each material, had a unimodal particle size distribution, and had a relatively uniform particle size.

[0079] (evaluation) The medical compositions obtained in Examples 1 to 12 were subjected to the following tests.

[0080] <Clogged catheter> A catheter tube made of PTFE (polytetrafluoroethylene) with an inner diameter of 1.0 mm and an outer diameter of 1.5 mm was connected to the dispenser shown in FIG. 2, and the solution was dispensed. -Evaluation criteria- 10 g of each example was sprayed, and if the powder was sprayed to the end without clogging, it was judged that there was no clogging, and if spraying could not be completed halfway, it was judged that there was clogging. If there is a blockage, the user will have to stop work unexpectedly, which is inappropriate. Therefore, cases without blockages were judged to be pass.

[0081] <Difficulty in spreading when spraying> If powder is scattered inside the digestive tract, the powder may scatter inside the tract, clouding the field of view under the endoscope and interfering with the user's work. For this reason, the following evaluation was carried out. 5 ml of the medical composition was sealed in a transparent centrifuge tube bottle (Violamo Centrifuge Tube II 15 mL, obtained from AS ONE Corporation), and the floating of the powder in the tube when vigorously stirred by hand was visually and organoleptically evaluated. In the following evaluation, 4 and 5 were considered to be pass, and 1 to 3 were considered to be fail. -Evaluation criteria- 5: No powder scattering is observed immediately after stirring 4: A small amount of powder was scattered immediately after stirring, but no powder scattering was observed within 5 seconds. 3: Immediately after stirring, powder was scattered, but after 5 seconds, only a small amount of powder was scattered. 2: Immediately after stirring, powder was scattered, to the point that the inside of the tube was no longer transparent. After 5 seconds, only a small amount of powder was scattered. 1: Immediately after stirring, powder is scattered, to the point that the inside of the tube is no longer transparent. After 5 seconds, a large amount of powder continues to be scattered.

[0082] <Hemostasis> The pig's abdomen was opened, and a bleeding wound measuring 6 mm in diameter and 2 mm deep was created in the liver using a biopsy trephine. 0.5 g of the medical composition was applied to cover the bleeding wound, forming a film, and the wound was then compressed with gauze moistened with saline. The condition of the bleeding wound was visually observed 1 minute, 2 minutes, 5 minutes, and 10 minutes after application of the medical composition, and evaluated and summarized based on the following evaluation criteria. In the following evaluation, a score of 3 to 5 was considered to indicate good hemostasis. A score of 1 or 2 was considered to be unsatisfactory. -Evaluation criteria- 5: Observation of the bleeding wound after 1 minute confirmed that hemostasis had been achieved. 4: When the bleeding wound was observed after 1 minute, it was found that bleeding had not stopped. However, when the bleeding wound was observed after 2 minutes, it was confirmed that bleeding had stopped. 3: When the condition of the bleeding wound was observed after 2 minutes, it was found that hemostasis had not been achieved, but when the condition of the bleeding wound was observed after 5 minutes, it was confirmed that hemostasis had been achieved. 2: Observation of the bleeding wound after 5 minutes showed that hemostasis had not been achieved, but observation of the bleeding wound after 10 minutes confirmed that hemostasis had been achieved. 1: Even after 10 minutes of observation of the bleeding wound, bleeding had not stopped.

[0083] <Retention over time> 0.5 g of the medical composition was applied to an area of ​​2 cm diameter on a collagen casing (manufactured by Nippi) that had been swollen with saline, and saline was gently poured on top of the composition to gel the medical composition. The medical composition attached to the collagen casing was left to stand in 100 ml of physiological saline, and the sheet was removed over time. The collagen casing was visually inspected for any remaining medical composition, and a score was assigned according to the following visual evaluation. A higher score is preferable, and a score of 3 or higher was deemed practical. A score of 1 or 2 was deemed unacceptable. -Evaluation criteria- 5: The medical composition remained for 3 days or more. 4: Within 1 day or more but less than 3 days, the medical composition no longer remained attached to the casing. 3: Within 8 hours or more and less than 1 day, no medical composition remained attached to the casing. 2: Within 1 hour or more and less than 8 hours, no medical composition remained attached to the casing. 1: In a short time of less than 1 hour, none of the medical composition remained attached to the casing.

[0084] [Table 1]

[0085] (Comparative Examples 1 to 3) Granulated materials were obtained using the materials shown in Table 2 in the same manner as in the example. The granulated product became granules in Comparative Example 2, but did not become granules in Comparative Example 1. The results of measuring the average particle size (volume distribution average particle size D50 shown above) are shown in Table 2.

[0086] [Table 2]

[0087] (Reference Examples 1 and 2) Granules were obtained using the materials shown in Table 3 in the same manner as in Example 1, except that the granulation method was changed. In Reference Example 1, the granulation method was to continuously provide excess moisture, thereby obtaining powder with a large average particle size. In Reference Example 2, as a granulation method, PVP K90 was first ground in a mortar to reduce the average particle size, and then granulated in the same manner as in the Examples, thereby obtaining a powder with a lower average particle size than that of the Examples.

[0088] [Table 3]

[0089] It was demonstrated that the medical compositions shown in the Examples and Reference Examples are medical compositions that are excellent in both hemostatic properties and retention over time. Furthermore, it has been demonstrated that the medical compositions shown in the examples are less likely to clog catheters and less likely to diffuse when sprayed, and when sprayed using an endoscope, they suppress clouding of the endoscopic field of view. [Explanation of symbols]

[0090] 10 Photos 11 Polyvinylpyrrolidone powder particles 12 Polyacrylic acid powder particles 20, 30 Spreader 21 Main Unit 22 Catheter 23 Storage unit 24 Container 25a, 25b check valve 26a, 26b, 26c connection part 27a, 27b connectors

Claims

1. A medical composition to be applied to the surface of the digestive tract lumen of a living body, comprising: A medical composition which is a powder containing polyacrylic acid and polyvinylpyrrolidone.

2. 2. The medical composition according to claim 1, wherein the powder comprises a powder of the polyacrylic acid and a powder of the polyvinylpyrrolidone.

3. 2. The medical composition according to claim 1, wherein the powder is formed by adhering particles contained in the polyacrylic acid powder to the surfaces of particles contained in the polyvinylpyrrolidone powder.

4. 2. The medical composition according to claim 1, wherein the powder is a granule containing the polyacrylic acid powder and the polyvinylpyrrolidone powder.

5. 5. The medical composition according to claim 4, wherein the granules have a volume distribution mean particle size D50 of 50 μm to 500 μm.

6. 2. The medical composition according to claim 1, wherein the polyacrylic acid and the polyvinylpyrrolidone are contained in a mass ratio of 1:10 to 10:

1.

7. 2. The medical composition according to claim 1, wherein the total content of said polyacrylic acid and said polyvinylpyrrolidone is 10% by mass to 100% by mass based on the total mass of said medical composition.

8. The medical composition according to claim 1, which is a hemostatic agent.

9. A hemostatic agent comprising the medical composition according to any one of claims 1 to 7.

10. A sprayer for spraying the medical composition according to any one of claims 1 to 8 or the hemostatic agent according to claim 9 onto the surface of the lumen of the digestive tract, A main body and a catheter are provided. the main body has a storage section that stores air from outside the body and is capable of spraying the stored air by pressurizing the air, a container that stores the medical composition, and at least two check valves; the catheter has a connection part that is connected to the container and through which the medical composition flows; A sprayer capable of spraying the medical composition onto the surface of the digestive tract lumen from the end of the catheter by spraying the air from the container.

11. 11. The dispenser according to claim 10, wherein at least one of the check valves has a function of biasing the valve in a closing direction under normal pressure and opening under pressure.

12. 11. The dispenser of claim 10, wherein at least one of the check valves is a duckbill-style check valve.

13. the main body includes a connecting portion that connects the storage portion and the container, 11. The dispenser of claim 10, further comprising at least one duckbill check valve in said connection.

14. The dispenser according to claim 10, wherein the container is a spherical structure containing an elastic resin capable of compressing the air by squeezing.

15. 11. The dispenser of claim 10, wherein the catheter has an inner diameter of 0.5 mm to 2.5 mm and is disposed at the distal end of the body.

16. The dispenser according to claim 10, wherein the catheter has at least two flow paths: a flow path through which the medical composition flows and a flow path through which water flows.

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