JP2023090691A - cell preparation - Google Patents

Abstract

To develop a cell preparation that is highly safe and an administration system thereof, in which not only liquid volume of cell suspension to be administered but the number of cells can be controlled by devising an installation method of a tube used in infusion administration of the cell preparation.SOLUTION: Provided is a cell preparation used in administration into a living body at a flow rate of 1.5 mL/min or less. The cell preparation is used with a combination of a container for storing the cell preparation and a tube for connecting a needle for administration into the living body. The tube has an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including a connection portion with the needle.SELECTED DRAWING: Figure 1

Description

TECHNICAL FIELD The present invention relates to cell preparations that can be administered intravenously even at low speeds.

In recent years, research and development of cell preparations used for treatment have been actively promoted, and many of them have come to be used in clinical practice. Typical administration methods of cell preparations include intravascular drip administration and local administration in a carrier-supported state. Among them, drip administration is widely used as a method of administering cell preparations because of its low invasiveness and simple operation. As a method of intravenous administration of cell preparations, it is common to hang a container containing cell preparations on an infusion stand, connect a blood transfusion tube to the container, and control the flow rate at a constant rate using an infusion pump or roller clamp. is. Since currently used drip infusion administration of cell preparations is intended for adults, the administration rate is set at 3 to 5 mL/min or higher (for example, Non-Patent Document 1).

On the other hand, in the case of children, a flow rate of about 1 mL/min, which is slower than that for adults, is recommended for infusion administration (Non-Patent Document 2), and it is necessary to set a flow rate of about 1 mL/min for cell preparations.

Temcell® HS order package insert, JCR Pharma Co., Ltd., January 2017 Guideline for Anesthetics and Anesthesia-Related Drugs 3rd Edition 4th Revision, VII Infusion/Electrolyte Solution, Japanese Society of Anesthesiologists, September 5, 2019

In the development of a cell preparation for children, the present inventors set the flow rate of the cell preparation to 1 mL / min and actually performed a simulation by experiment of infusion administration, and determined the amount of liquid to be dropped and the number of cells. Measured over time. As a result, it was found that although the amount of the dropped liquid itself was constant and was the same as the set value, the number of cells in the liquid fluctuated greatly up and down. Specifically, the number of cells that flow into the blood vessel per unit time rises to a level equivalent to the flow rate of administration to an adult at a certain timing, and drops at a very low flow rate at another timing. We faced an unexpected problem that the actual number of cells injected into the blood vessel could not be controlled.

The present inventors have made intensive studies to solve the above problems, and surprisingly, by adding a specific device to the tube used for drip administration, at a low flow rate of 1.5 mL / min or less Also, it was found that infusion administration can be performed while maintaining not only the liquid volume but also the cell number at the set value. That is, according to this specification, the following inventions are provided.

(1) A cell preparation that is instilled into the body at a flow rate of 1.5 mL/min or less from a container suspended on an infusion stand through a tube and a needle connected to the downstream end of the tube, the tube comprising: A cell preparation using a first tube having an inner diameter of 2.3 mm or less in a section extending at least 20 cm from a connecting portion with a needle.
(2) A second tube having an inner diameter of 2.4 mm or more is further connected to the upstream side of the first tube, and the upstream end of the second tube is placed at a position higher than the downstream end. The cell preparation according to (1), characterized in that
(3) The cell preparation according to (2), wherein the installation angle of the second tube is not less than 70° with respect to the horizontal plane.
(4) The cell preparation according to (2), wherein the second tube is installed substantially perpendicular to the horizontal plane.
(5) Any one of (2) to (4), wherein the downstream end of the first tube is installed at a position higher than the connecting portion between the first tube and the second tube. cell preparations.
(6) The cell preparation according to any one of (1) to (5), which is administered by controlling the flow rate using an infusion pump.
(7) The cell preparation according to any one of (1) to (6), wherein the subject is under 15 years of age.
(8) The cell preparation according to any one of (1) to (6), wherein the body weight of the administration subject is 50 kg or less.
(9) Any of (1) to (8), wherein the cell preparation is administered by infusion into a blood vessel through a tube from a container suspended on an infusion stand at a flow rate of 1.5 mL/min or less. A cell preparation with a label, a package insert or an instruction manual that describes the means described above, or means related or equivalent thereto.
(10) The cell preparation according to (9), wherein the means is to use a tube with an inner diameter of 2.3 mm or less and/or to install the tube during drip administration.

[1] A cell preparation used for internal administration at a flow rate of 1.5 mL/min or less, which is used in combination with a container for containing the cell preparation and a tube connecting the needle for internal administration, The cell preparation, wherein the tube has an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including the connecting portion with the needle.
[2] The cell preparation of [1], wherein the subject for internal administration is under 15 years old.
[3] The cell preparation of [1] or [2], wherein the body weight of the subject for the internal administration is 50 kg or less.
[4] The cell preparation according to any one of [1] to [3], which is attached with a label, a package insert or an instruction manual describing the method of administration into the body.
[5] The cell preparation according to any one of [1] to [4], wherein the inner diameter of the tube at the second end is larger than the inner diameter of the tube at the first end.
[6] The cell preparation according to any one of [1] to [5], wherein the tube is composed of two or more tubes connected to each other.
[7] The cell preparation of [6], wherein the two or more tubes are connected by a tube connector.
[8] The cell preparation according to [7], wherein the tube connector is positioned lower than the second end.
[9] The cell preparation according to [7] or [8], wherein the tube connector is positioned lower than the first end.
[10] The cell preparation according to any one of [1] to [9], wherein the tube having the second end is arranged at 90°±20° to the horizontal plane.
[11] The cell preparation according to any one of [1] to [10], wherein the tube having the first end has a folded portion.
[12] The cell preparation according to any one of [1] to [11], wherein the tube has a flow rate control section.
[13] The cell preparation of [12], wherein the flow rate control unit includes an infusion pump or a syringe pump.
[14] A device for administering a liquid formulation, in which a needle for internal administration, a channel, and a container for containing a liquid formulation are connected in that order, wherein the needle is connected to a first end of the channel. , the container is connected to a second end of the channel, the channel has an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including the first end, and the liquid formulation The above device configured to be administered to the body through a needle at a flow rate of 1.5 mL/min or less.
[15] The device according to [14], wherein the liquid formulation contains cells and/or microparticles having a sedimentation velocity of 0.50 μm/s to 50 μm/s.
[16] The device of [14] or [15], wherein the liquid formulation is a cell formulation.
[17] The device according to [15] or [16], wherein the fine particles have a diameter of 5 μm to 30 μm.
[18] The apparatus of any of [14] to [17], wherein the inner diameter of the channel at the second end is greater than the inner diameter of the channel at the first end.
[19] The apparatus according to any one of [14] to [18], wherein the flow path is composed of two or more flow paths that are connected to each other.
[20] The device according to [19], wherein the two or more channels are connected by a channel connecting portion.
[21] The device according to [20], wherein the flow path connecting portion is arranged at a position lower than the second end.
[22] The device according to [20] or [21], wherein the flow path connecting portion is arranged at a position lower than the first end.
[23] The apparatus of any one of [14] to [22], wherein the channel having the second end is arranged at 90°±20° to the horizontal plane.
[24] The apparatus according to any one of [14] to [23], wherein the channel having the first end has a fold.
[25] The device according to any one of [14] to [24], wherein the channel has a flow rate control section.
[26] The device of [25], wherein the flow rate control unit includes an infusion pump or a syringe pump.
[27] A cell preparation administration kit comprising a tube, wherein the tube is used in combination with a needle for internal administration and a container for containing the cell preparation, and the needle is attached to a first end of the tube. wherein the container is connected to a second end of the tube, the tube having an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including the first end, and the cell preparation is flowed at a flow rate of 1 The above kit, which is administered to the body at 5 mL/min or less.
[28] The kit of [27], wherein the tube is a tube having both a first end and a second end.

The present invention makes it possible to provide cell preparations that are safe and highly effective even for subjects such as children whose administration rate is limited.

FIG. 4 is a diagram showing a method of placing a cell preparation according to one embodiment of the present invention; FIG. 4 is a schematic diagram of the installation angles of the tubes in Examples 1 to 3. FIG. FIG. 10 is a schematic diagram of the installation angle of the tube in Examples 4 to 8. FIG. FIG. 10 is a schematic diagram regarding the installation angle of the tube in Comparative Examples 1 and 2. FIG. 4 shows the cell concentration of the cell suspension collected in Example 1. FIG. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). The cell concentration of the cell suspension collected in Example 2 is shown. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). The cell concentration of the cell suspension collected in Example 3 is shown. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). The cell concentration of the cell suspension collected in Example 4 is shown. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). The cell concentration of the cell suspension collected in Example 5 is shown. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). The cell concentration of the cell suspension collected in Example 6 is shown. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). The cell concentration of the cell suspension collected in Example 7 is shown. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). FIG. 10 shows the cell concentration of the cell suspension collected in Example 8. FIG. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). The cell concentration of the cell suspension collected in Comparative Example 1 is shown. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). The cell concentration of the cell suspension collected in Comparative Example 2 is shown. A horizontal line drawn in the graph indicates the concentration of the cell suspension in the container (that is, before dropping). 1 is a schematic diagram showing an exemplary configuration of a device of the invention; FIG.

[1] Description of Terms FIG. 1 shows an installation method of one embodiment of the cell preparation of the present invention. In this embodiment, the cell preparation flows from the container suspended on the drip stand through the tube connected to the container, and is discharged from the needle connected to the tip of the tube.

As used herein, the terms upstream and downstream of the tube are defined according to the direction of flow of the cell preparation during administration, and the "upstream side" of the tube refers to the side into which the cell preparation flows, that is, the container side. show. The “downstream side” of the tube refers to the side from which the cell preparation is discharged, ie, the needle side.

In some embodiments, as shown in FIG. 14, in a channel (e.g., tube) that connects a container for containing a cell formulation and a needle for internal administration, the end connected to the needle (i.e., the downstream end) ) is called the first end, and the end connected to the container (that is, the upstream end) is called the second end.

[2] Cell preparation A “cell preparation” as used herein is a composition containing cells, preferably a pharmaceutical composition. A cell preparation may consist of a cell suspension. A "cell suspension" as used herein includes medically and/or pharmaceutically acceptable cells and a medically and/or pharmaceutically acceptable agent.

Cell types are not particularly limited as long as they are medically and/or pharmaceutically acceptable cells. GS cells, which are pluripotent stem cells derived from testis, EG cells derived from fetal primordial germ cells, Muse cells derived from bone marrow, etc.), somatic stem cells (bone marrow, adipose tissue, dental pulp, placenta, egg membrane, umbilical cord blood) , Mesenchymal stem cells derived from amniotic membrane, chorion, etc., neural stem cells, etc.), leukocytes, monocytes, granulocytes, lymphocytes (T cells, B cells, NK cells, etc.), megakaryocytes, macrophages, nerve cells, myocardium cells, myocardial progenitor cells, hepatocytes, hepatic progenitor cells, α cells, β cells, γ cells, fibroblasts, chondrocytes, corneal cells, vascular endothelial cells, vascular endothelial progenitor cells, pericytes, and the like. may be a gene-introduced form or a form in which the target gene or the like on the genome is knocked down.

The cells used in the present invention are typically of human origin, and include, for example, rodents such as mice, rats and hamsters; primates such as gorillas, chimpanzees and marmosets; It may be derived from livestock such as horses, sheep and goats, or mammals such as pets.

Diseases to which cell preparations are applied are not particularly limited, and include immune-related diseases, ischemic diseases, lower limb ischemia, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, neurological diseases, and graft-versus-host disease. (GVHD), inflammatory bowel disease, Crohn's disease, ulcerative colitis, radiation enteritis, systemic lupus erythematosus, lupus erythematosus, connective tissue disease, stroke, cerebral infarction, intracerebral hematoma, cerebrovascular palsy, brain tumor, cirrhosis, atopic Dermatitis, multiple sclerosis, psoriasis, epidermolysis bullosa, diabetes, mycosis fungoides (Alibert-Bazin syndrome), scleroderma, diseases caused by degeneration and/or inflammation of connective tissue such as cartilage, articular cartilage defects, Meniscal injury, elastic osteochondrosis, atrophic osteonecrosis, knee osteoarthritis, inflammatory arthritis, rheumatoid arthritis, eye disease, angiogenesis-related disease, ischemic heart disease, coronary heart disease, hereditary muscle Disease, Hereditary blood disease, Hereditary neurological disease, Myocardial infarction, Angina pectoris, Heart failure, Cardiomyopathy, Valvular disease, Wound, Epithelial injury, Fibrosis, Pulmonary disease, Muscular dystrophy, Spinal muscular atrophy, Chronic pancreatitis, Chronic It can be used as a therapeutic agent for diseases selected from nephritis and cancer. In addition, when the purpose of use is blood transfusion or hematopoietic stem cell transplantation, it is not included in the cell preparation of the present invention. In other words, the cell preparation of the present invention is not used for the main purpose of blood cell replenishment. The cell preparation of the present invention is used, for example, in regeneration, cell therapy, gene therapy, such as immune cell therapy, cell replacement therapy, and ex vivo gene therapy.

The medically and/or pharmaceutically acceptable agent is not particularly limited as long as it can maintain cells in a form that can be used as a medicine and can be administered to animals such as humans. The medically and/or pharmaceutically acceptable agent may be mixed with the cell medicinal preparation at the stage of manufacturing as a pharmaceutical preparation, or may be mixed with the cell medicinal preparation at the stage of administering the cell medicinal preparation to a patient or subject. may be mixed with The medically and/or pharmaceutically acceptable drug is not particularly limited, but examples thereof include physiological saline, electrolyte solution, Ringer's solution, high calorie infusion, glucose solution, water for injection, amino acid electrolytes, and the like. In addition, the medically and/or pharmaceutically acceptable agents may optionally contain salts, vitamins, amino acids, polysaccharides, dimethylsulfoxide, buffers, albumin, media, cell cryoprotectants, and the like. . It may also contain immunosuppressive agents, antibiotics, albumin preparations, vitamin preparations, anti-inflammatory agents, etc., which are ingredients having medicamental activity.

Examples of the salts include alkali metal salts such as lithium, sodium, and potassium; alkaline earth metal salts such as calcium, barium, and magnesium; salts of aluminum, zinc, copper, iron, and the like; ammonium salts; tetraethylammonium, tetrabutyl quaternary ammonium salts such as ammonium, methyltributylammonium, cetyltrimethylammonium, benzylmethylhexyldecylammonium, and choline; organic amines such as pyridine, triethylamine, diisopropylamine, ethanolamine, diolamine, tromethamine, meglumine, procaine, and chloroprocaine; Salt; includes, but is not limited to, salts with amino acids such as glycine, alanine, and valine.

Examples of the vitamins include, but are not limited to, folic acid, niacinamide, pyridoxine hydrochloride, biotin, calcium D-pantothenate, riboflavin, vitamin B12, thiamine, vitamin A, and vitamin E.

The amino acids include all essential amino acids (L-tryptophan, L-leucine, L-lysine, L-phenylalanine, L-isoleucine, L-threonine, L-histidine, L-methionine, and L-valine), all non-essential amino acids (L-alanine, L-arginine, L-asparagine, L-aspartic acid, glycine, L-glutamine, L-glutamic acid, L-cysteine, L-serine, L-tyrosine, L-proline), etc. can include, but are not limited to, natural amino acids such as L-cystine.

Examples of the polysaccharides include water-insoluble polysaccharides such as cellulose, chitin and chitosan, and hyaluronic acid, gellan gum, deacylated gellan gum, rhamzan gum, diutan gum, xanthan gum, carrageenan, xanthan gum, hexuronic acid, and fucoidan. , pectin, pectic acid, pectinic acid, heparan sulfate, heparin, heparitin sulfate, keratosulfate, chondroitin sulfate, dermatan sulfate, rhamnan sulfate, alginic acid and salts thereof, but are limited to these. not.

The medium is not particularly limited as long as it is composed of a component composition that allows cells to survive and is composed of a component composition that can be administered to animals such as humans. Examples include BME medium and BGJb. Medium, CMRL1066 medium, Glasgow MEM medium, Improved MEM Zinc Option medium, IMDM medium (Iscove's Modified Dulbecco's Medium), Medium 199 medium, Eagle MEM medium, αMEM medium, DMEM medium (Dulbecco's Mo defined Eagle's Medium ), Ham F10 medium, Ham F12 medium, RPMI 1640 medium, Fischer's medium, and mixed medium thereof (e.g., DMEM/F12 medium (Dulbecco's Modified Eagle's Medium/Nutrient Mixture F-12 Ham)), CHO-S-SFM II (Life Technologies Japan Co., Ltd.), Hybridoma-SFM (Life Technologies Japan Co., Ltd.), eRDF Dry Powdered Media (Life Technologies Japan Co., Ltd.), UltraCULTURETM (BioWhittaker), UltraDOMATM (BioWhittaker), UltraCHOTM (manufactured by BioWhittaker), UltraMDCK™ (BioWhittaker) and the like. For example, media such as STEMPRO (registered trademark) hESC SFM (Life Technologies Japan Co., Ltd.), mTeSR1 (Veritas), and TeSR2 (Veritas) can be used.

The cell cryoprotectant is not particularly limited, but examples include CP-1 (manufactured by Kyokuto Pharmaceutical Co., Ltd.), BAMBANKER (manufactured by Lymphotech), and STEM-CELLBANKER (manufactured by Nippon Zenyaku Kogyo Co., Ltd.). , ReproCryo RM (manufactured by Reprocell), CryoNovo (manufactured by Akron Biotechnology), MSC Freezing Solution (manufactured by Biological Industries), CryoStor (manufactured by HemaCare) and the like.

Examples of the antibiotic include sulfa preparations, penicillin, pheneticillin, methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, ampicillin, amoxicillin, cyclacillin, carbenicillin, ticarcillin, piperacillin, azlocillin, mekzlocillin, mecilinum, anzinocillin, Cephalosporins and their derivatives, oxolinic acid, amifloxacin, temafloxacin, nalidixic acid, pyromidic acid, ciprofloxacin, cinoxacin, norfloxacin, perfloxacin, rosaxacin, ofloxacin, enoxacin, pipemidic acid, sulbactam, clavulinic acid, β-bromopenicillanic acid, β-chloropenicillanic acid, 6-acetylmethylene-penicillanic acid, cefoxazole, sultanpicillin, adynocillin and sulbactam formaldehyde-foedrate esters, tazobactam, aztreonam, sulfazetin, isosulfazetin, norcadicine, m-carboxyphenyl, Examples include, but are not limited to, methyl phenylacetamidophosphonate, chlortetracycline, oxytetracycline, tetracycline, demeclocycline, doxycycline, metacycline, and minocycline.

Examples of the anti-inflammatory agent include, but are not limited to, 5-aminosalicylic acid preparations, steroid preparations, immunosuppressants, biological preparations, and the like. Examples of the above 5-aminosalicylic acid preparations include salazosulfapyridine and mesalazine, but are not limited thereto. Examples of the above steroid preparations include, but are not limited to, cortisone, prednisolone, methylprednisolone, and the like.

In addition, the cell preparation may contain various additives such as emulsifiers, dispersants, buffers, preservatives, wetting agents, antioxidants to increase storage stability, isotonicity, absorption and/or viscosity. , a chelating agent, a thickener, a gelling agent, a pH adjuster, and the like.

Examples of the thickener include, but are not limited to, hydroxyethyl starch, dextran, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, and the like. The concentration of the thickening agent depends on the selected thickening agent, but can be arbitrarily set within a concentration range that achieves the desired viscosity while being safe when administered to a patient or subject.

The viscosity of the cell suspension is not particularly limited, but if the viscosity is too high, drip administration cannot be performed appropriately. For example, the viscosity at the temperature conditions at the time of administration when measured using a rotary viscometer TV-20 (manufactured by Toki Sangyo Co., Ltd.) at a rotation speed of 10 rpm is preferably 35 mPa·sec or less, more preferably 30 mPa·sec or less. , Still more preferably 25 mPa·sec or less, for example, 24 mPa·sec or less, 21 mPa·sec or less, 20 mPa·sec or less, 19 mPa·sec or less, 16 mPa·sec or less, 15 mPa·sec or less, 14 mPa·sec or less, 11 mPa·sec or less 10 mPa·sec or less, 9 mPa·sec or less, 8 mPa·sec or less, 7 mPa·sec or less, 6 mPa·sec or less, 5 mPa·sec or less, 4 mPa·sec or less, 3 mPa·sec or less, 2.5 mPa·sec or less, or It is 2 mPa·sec or less.

If the cell concentration (cells/mL) of the cell preparation is too high, the cells may clog blood vessels, lungs, etc., and the osmotic pressure of the cell preparation may become too high, which may affect the body of the patient or subject. burden may be high. On the other hand, if the cell concentration is too low, it will take a long time to administer the amount of cells that can obtain a therapeutic effect, and during that time the quality of the cell preparation will deteriorate and the patient or subject will have to spend a lot of time. This may lead to the burden of longer Therefore, the preferred cell concentration is not particularly limited because it is appropriately set in consideration of these, for example, 1 × 10 ⁴ cells / mL or more, 2 × 10 ⁴ cells / mL or more, 3 × 10 ⁴ cells / mL or more, 4×10 ⁴ cells/mL or more, 5×10 ⁴ cells/mL or more, 6×10 ⁴ cells/mL or more, 7×10 ⁴ cells/mL or more, 8×10 ⁴ cells/mL or more, 9×10 ⁴ cells /mL or more, 1×10 ⁵ cells/mL or more, 2×10 ⁵ cells/mL or more, 3×10 ⁵ cells/mL or more, 4×10 ⁵ cells/mL or more, 5×10 ⁵ cells/mL or more, 6 ×10 ⁵ cells/mL or more, 7 × 10 ⁵ cells/mL or more, 8 × 10 ⁵ cells/mL or more, 9 × 10 ⁵ cells/mL or more, 1 × 10 ⁶ cells/mL or more, 1.5 × 10 ⁶ cells/mL or more, 2×10 ⁶ cells/mL or more, and 1×10 ⁹ cells/mL or less, 9×10 ⁸ cells/mL or less, 8×10 ⁸ cells/mL or less, 7×10 ⁸ cells/mL or less /mL or less, 6×10 ⁸ cells/mL or less, 5×10 ⁸ cells/mL or less, 4×10 ⁸ cells/mL or less, 3×10 ⁸ cells/mL or less, 2×10 ⁸ cells/mL or less, 1 ×10 ⁸ cells/mL or less, 9 × 10 ⁷ cells/mL or less, 8 × 10 ⁷ cells/mL or less, 7 × 10 7 cells/mL or less, 6 × 10 ⁷ cells/mL or less, 5 × 10 ⁷ cells/ ^mL or less mL or less, 4×10 ⁷ cells/mL or less, 3×10 ⁷ cells/mL or less, 2×10 ⁷ cells/mL or less, 1×10 ⁷ cells/mL or less, 9×10 ⁶ cells/mL or less, 8× 10 ⁶ cells/mL or less, 7×10 ⁶ cells/mL or less, 6×10 ⁶ cells/mL or less, 5×10 ⁶ cells/mL or less, 4×10 ⁶ cells/mL or less, 3×10 ⁶ cells/mL 2.5×10 ⁶ cells/mL or less, 2×10 ⁶ cells/mL or less. In addition to the above, it can be appropriately determined depending on the dosage form, purpose of use, age, body weight, symptoms, etc. of the patient or test subject.

The cell preparation of the present invention is administered to a patient or subject by the administration method described below. Although the route of administration to a subject (patient or subject) for internal administration is not particularly limited, for example, subcutaneous injection, intralymph node injection, intravenous injection, intraarterial injection, intraperitoneal injection, intrapleural injection, direct local injection It can be an injection or the like. Among them, intravascular administration of a patient or subject, that is, intravenous injection or intraarterial injection is preferred, and intravenous injection is more preferred.

The present invention provides a cell preparation for use in the method for administering a cell preparation described later, that is, a cell preparation for use in the body at a flow rate of 1.5 mL/min or less, and a container for containing the cell preparation. and a cell preparation used in combination with a tube connecting the needle for internal administration, wherein the tube has an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including the connection with the needle.

The administration method using the cell preparation of the present invention (e.g., the rate of administration described later, the characteristics of tubes used in combination, etc.) may be described in the label attached to the cell preparation, package insert, or instruction manual. .

The administration method of the cell preparation of the present invention is described in detail below.
The container used for providing the cell preparation of the present invention is not particularly limited as long as the cells in the cell preparation can survive. For example, the cell preparation of the present invention may be provided in a state of being filled in a container different from the container used in the administration method described below, or in a state of being filled in a container that can be used in the administration method described below. may be provided in From the point of view of sanitation and ease of operation, it is preferable to use the same container that was used when the cell preparation was provided for the administration method described below. However, if frozen, it may be administered after thawing, or if necessary, it may be administered after diluting with physiological saline, Ringer's solution, or the like.

[3] Method for administering a cell preparation In the present invention, a cell preparation is transferred from a container for containing the cell preparation (e.g., a container suspended from an infusion stand) to a tube and the downstream end of the tube (first (end) to the subject of internal administration (patient or subject). The tube has an inner diameter of 2.3 mm or less in a section from the connection with the needle (first end) to at least 20 cm toward the upstream side (that is, a section of at least 20 cm including the connection with the needle). Use the first tube.

The first tube is not particularly limited as long as it has an inner diameter of 2.3 mm or less in a section from the connecting part with the needle to at least 20 cm, but from the viewpoint of more accurately maintaining the number of cells to be administered, Preferably 2.2 mm or less, 2.1 mm or less, 2.0 mm or less, 1.9 mm or less, 1.8 mm or less, 1.7 mm or less, 1.6 mm or less, 1.5 mm or less, 1.4 mm or less, 1.3 mm 1.2 mm or less, 1.15 mm or less, 1.1 mm or less, and 1.0 mm or less. In addition, if the inner diameter of the tube is too small, cells may clog the tube. 0.8 mm or more, 0.9 mm or more, or 1.0 mm or more.

The container is not particularly limited as long as it allows the cells in the cell preparation to survive and is connectable to a tube or the like for internal administration. For example, various containers for infusion preparations (drip containers) that are commonly used in the relevant field and other containers capable of containing liquid preparations (for example, syringes, etc.) can be used. Examples of drip containers include cryopreservation bags (manufactured by Corning), flow bag F-100 (manufactured by Nipro), flow bag F-050 (manufactured by Nipro), safemic TPN bag (manufactured by JMS). ), Hikarik IVH bag (manufactured by Terumo Corporation) and the like can be used. The material of the container is not particularly limited. For example, any material may be used as long as it is a material that will be described later for tubes and flow paths.

The method of connecting the container and the tube is not particularly limited as long as the cell preparation in the container is properly transferred into the tube. It can be connected by sticking a needle. Alternatively, the container and the tube may be joined by welding using an aseptic joining machine or the like, or may be connected using a connector, a stopcock, or the like. The connection means between the container and the tube may be attached to the container, attached to the tube, or provided independently therefrom.

An IV stand or the like can be used to hold the container. The drip stand is not particularly limited, and any form can be used as long as the container containing the cell preparation can be suspended and the preferred installation conditions for the tube of the present invention can be achieved. can be Considering the operability of medical personnel and the safety of patients and subjects, it is preferable to use an infusion stand that is manufactured and sold for the purpose of use during infusion administration.

The type and material of the needle are not particularly limited as long as they are commonly used in the relevant field. can be determined as appropriate. As for the shape of the needle, for example, a winged needle, an indwelling needle, or an infusion needle can be used, but an indwelling needle is preferable when a certain amount of administration time is required. If the gauge of the needle is too large, the patient or test subject tends to feel pain when the needle is inserted. Specifically, Surfow indwelling needle SR-OT2419C (24G, 19mm, manufactured by Terumo), Nipro Safeletcas 09-046 (22G, 32mm, manufactured by Nipro), Nipro Safeletcas PU 09-081 (24G, 19mm) ), and Angiocut Plus 382412 (24G, 19mm, manufactured by JMS).

The method of connecting the tube and the needle is not particularly limited. For example, the tube and/or the needle may be connected via a connector attached thereto, or via a three-way stopcock. Alternatively, a commercially available tube with a needle connected in advance to the tip of the tube can be used.

The first tube (tube having a first end) in the present specification is not particularly limited as long as it has an inner diameter of 2.3 mm or less and can be used for intravenous drip administration. However, for example, extension tube JV-NDH1100FL (tube length 100 cm, inner diameter 1.0 mm, manufactured by JMS), extension tube JV-ETP2100FL (tube length 100 cm, inner diameter 2.0 mm, manufactured by JMS), extension tube 66- 767 (tube length 100 cm, inner diameter 1.5 mm, manufactured by Nipro), Safide extension tube SF-ET1020L22 (tube length 100 cm, inner diameter 1.1 mm, manufactured by Terumo), top extension tube X2-WL100 (tube inner diameter 2.0 mm , tube length 100 cm, manufactured by Top Co.) and the like.

Although the material of the first tube is not particularly limited, it may be, for example, a soft material, a hard material, or a combination thereof. The material of the portion that contacts the cell preparation is not particularly limited as long as the passing cell preparation is not harmful to the administration subject. Specifically, for example, polytetrafluoroethylene, ethylene-tetrafluoroethylene copolymer, fluorine-based resins such as perfluoroalkoxy fluorine resins, polyvinyl chloride, polybutadiene, polyethylene, olefin-based resins such as polypropylene, styrene-isoprene- Styrene copolymer, styrene-butadiene-styrene copolymer, acrylonitrile-butadiene-styrene copolymer, polyester, polyamide, polyether nylon resin, olefin resin, ethylene-vinyl acetate copolymer, thermoplastic elastomer, natural rubber, polyolefin , various natural or synthetic resins such as polycarbonate, nylon elastomer, polyurethane, silicone, silicone rubber, glass, metal such as stainless steel, titanium alloy, aluminum alloy, or mixtures thereof It is also possible to use

The configuration of the section of at least 20 cm including the connection with the needle is not particularly limited. For example, it may be composed of one tube, or may be composed of two or more tubes. The tubing used in this section may be tubing having an inside diameter within the above ranges throughout its entirety, and only for the above sections having inside diameters within the above ranges and other parts having inside diameters outside the above ranges. It may be a tube. The length of this section is not particularly limited. For example, it can be 50 cm or more, 80 cm or more, 90 cm or more, 100 cm or more, 110 cm or more, 120 cm or more, 130 cm or more, 140 cm or more, or 150 cm or more.

The tube length of the first tube is not particularly limited. If this section is composed of one tube, the tube length of the first tube is not particularly limited as long as it is 20 cm or longer. If the tube length of the first tube is too short, the movement of the patient or subject is restricted. 130 cm or more, 140 cm or more, and 150 cm or more. Although the upper limit is not particularly limited, it is, for example, 250 cm, 200 cm, 190 cm, 180 cm, 170 cm, 160 cm, and 150 cm.

In the present invention, the object of the present invention can be achieved by using only the first tube as the tube (in this case, the first tube has both a first end and a second end). , a container is connected to the second end of the first tube), and a second tube having an inner diameter of 2.4 mm or more (a tube having a second end) is connected to the upstream side of the first tube. good too. In general, most commercially available infusion sets and blood transfusion sets used for infusion in this field have an inner diameter corresponding to that of the second tube. In addition, commercially available infusion sets and blood transfusion sets come with bottle needles and drip cylinders (chambers) for connecting to drip containers in advance, clamps for adjusting the drip rate, tube diameters, and pressure resistance of tubes. In the present invention, the administration system for cell preparations can be constructed more simply by using not only the first tube but also the second tube. In addition, the drip speed can be easily controlled.

At this time, the tube connecting portion is arranged at a position lower than the second end, and the upstream end (second end) of the second tube is installed at a position higher than the downstream end. is preferred, especially if an infusion pump is not used. On the other hand, the position of the downstream end (first end) of the first tube is not particularly limited. It may be at a position higher than or lower than the connecting portion (tube connecting portion), or at the same height. In the present invention, by using the first tube, even if the downstream end (first end) of the first tube is positioned higher than the connecting portion (tube connecting portion) with the second tube. Even if it is installed, it is possible to administer the set number of cells without allowing the cells in the formulation to stay in the tube. In that case, the method of the present invention is excellent in that it is not necessary to restrict the posture and movement of the patient or subject during administration because the length and position of the tube from the drip container to the needle can be given a margin. ing.

The internal shape of the tube is not particularly limited. For example, it may be circular, elliptical, substantially circular, fan-shaped, substantially fan-shaped, polygonal, or a combination thereof. If the internal shape is other than circular, the inner diameter of the tube refers to the diameter of the largest inscribed circle. The outer and inner shape of the tube may change along the way.

The inner diameter of the second tube is not particularly limited as long as it is 2.4 mm or more and is connectable to both the container containing the cell suspension and the first tube. For example, 10.0 mm or less, 9.9 mm or less, 9.8 mm or less, 9.7 mm or less, 9.6 mm or less, 9.5 mm or less, 9.4 mm or less, 9.3 mm or less, 9.2 mm or less, 9.1 mm Below, 9.0 mm or less, 8.9 mm or less, 8.8 mm or less, 8.7 mm or less, 8.6 mm or less, 8.5 mm or less, 8.4 mm or less, 8.3 mm or less, 8.2 mm or less, 8.1 mm 8.0 mm or less, 7.0 mm or less, 6.0 mm or less, 5.0 mm or less, 4.5 mm or less, 4.0 mm or less, 3.9 mm or less, 3.8 mm or less, 3.7 mm or less, 3.6 mm 3.5 mm or less, 3.4 mm or less, 3.3 mm or less, 3.2 mm or less, 3.15 mm or less, 3.1 mm or less, 3.0 mm or less, 2.9 mm or less, 2.8 mm or less, 2.7 mm 2.6 mm or less, preferably 2.5 mm or less, 2.5 mm or more, 2.6 mm or more, 2.7 mm or more, 2.8 mm or more, 2.9 mm or more, 3.0 mm or more, 3.1 mm or more, 3 0.15 mm or more, 3.2 mm or more, 3.3 mm or more, 3.4 mm or more, 3.5 mm or more are preferable.

The inner diameter of the tube at the second end on the container side may be within the range described above. For example, the inner diameter of the second tube may be outside the range described above in sections other than the second end. Alternatively, only the first tube may be used in the method and the second end of the first tube may be within the range described above. Alternatively, even if the second end of the tube is outside the above range, the present invention also includes the case where it can be connected to the container by using a device that connects the second end and the container. .

The second tube and the first tube may be connected via another tube, or may be directly connected. The connection may be a connection via a tube connection. In this case, the inner diameter of the tube changes discontinuously at the connection.

If the tube is composed of two or more tubes connected to each other, the number is not particularly limited. For example, 2 or more, 3 or more, 4 or more tubes can be connected. The inner diameters of the tubes other than the first tube are not particularly limited. Multiple tubes may have the same inner diameter, or all tubes may have different inner diameters. Moreover, when using several tubes, each connection mode is not specifically limited. For example, all or part of the connection may be made by a tube connection and the inner diameter may change discontinuously, or no tube connection may be used and the inner diameter may change continuously throughout the tube. The tube may be branched.

In the present specification, the connection method at the connecting portion of the first tube and the second tube is not particularly limited, but for example, connection via a connector attached to the tube, connection via a three-way stopcock, FF Connection via a connector such as a connector, connection by welding using an aseptic jointer or the like, and the like can be mentioned. Further, they may be integrally formed so as to substantially satisfy the inner diameters corresponding to the first tube and the second tube of the present invention.

As the second tube in the present specification, there is no problem in using any tube as long as it has an inner diameter of 2.4 mm or more and can be used for drip administration, and is not particularly limited. - U300L (manufactured by Terumo), TI-J350P terfusion infusion set (manufactured by Terumo), TI-PU300L infusion set for terfusion pump (manufactured by Terumo), blood transfusion set JB-U13L (manufactured by JMS), blood transfusion set JBP -U33L (manufactured by JMS), blood transfusion set TF-4A1Z (manufactured by Nipro), infusion set ECO ISE-200 Z (manufactured by Nipro), and the like.

Although the material of the second tube is not particularly limited, it may be, for example, a soft material, a hard material, or a combination thereof. The material of the portion that contacts the cell preparation is not particularly limited as long as the passing cell preparation is not harmful to the administration subject. Specifically, for example, polytetrafluoroethylene, ethylene-tetrafluoroethylene copolymer, fluorine-based resins such as perfluoroalkoxy fluorine resins, polyvinyl chloride, polybutadiene, polyethylene, olefin-based resins such as polypropylene, styrene-isoprene- Styrene copolymer, styrene-butadiene-styrene copolymer, acrylonitrile-butadiene-styrene copolymer, polyester, polyamide, polyether nylon resin, olefin resin, ethylene-vinyl acetate copolymer, thermoplastic elastomer, natural rubber, polyolefin , various natural or synthetic resins such as polycarbonate, nylon elastomer, polyurethane, silicone, silicone rubber, glass, metal such as stainless steel, titanium alloy, aluminum alloy, or mixtures thereof It is also possible to use Also, the materials of the first tube and the second tube may be the same or different.

The method of administering the cell preparation in the present invention is limited as long as it is a method in which the flow rate is controlled to 1.5 mL/min or less and the cell preparation can be administered into the patient's or subject's body through a needle connected to the downstream end of the tube. For example, although not required, the tube preferably includes a flow rate regulator. Specifically, for example, a clamp is attached to the tube as a flow rate control unit, and the clamp is adjusted to control the flow rate while administering by gravity; and a method of administering while controlling the flow rate by connecting a tube to a container containing the cell preparation set in a syringe liquid delivery means such as a syringe pump. Multiple flow rate controls may be included, eg, two or more clamps and/or two or more infusion pumps may be used, or a combination of clamps and infusion pumps.

The position of the flow rate adjusting section is not particularly limited. For example, the first tube and/or the second tube may have a flow control portion, and the tube connection may have a flow control portion.

The infusion pump is not particularly limited as long as it is commonly used in the field, but examples include Terfusion infusion pump TE-161S (manufactured by Terumo Corporation), Terfusion infusion pump TE-261 (manufactured by Terumo Corporation), Safetech infusion pump 2 FP-N17 (manufactured by Nipro), Curesense infusion pump IP-100 (manufactured by JMS) and the like can be mentioned.

The size of the installation angle of the tube having the second end (e.g., the second tube) (corresponding to the angle described for the second tube in FIGS. 2-1 and 2-2 and the angle α in FIG. 14) Although the height is not particularly limited, it is preferable to set the installation angle so that the tube connecting portion is arranged at a position lower than the upstream end (second end). Specifically, for example, it is preferable that the installation angle of the tube having the second end is not less than 70° with respect to the horizontal plane. Here, the installation angle of the tube having the second end is not less than 70° with respect to the horizontal plane means that the installation angle in 80% or more of the entire tube having the second end is not less than 70°. say. Although the ratio of the sections in which the installation angle is not less than 70° is not limited as long as it is 80% or more, it is preferably 85% or more, more preferably 90% or more. Moreover, the installation angle is more preferably not less than 80°, more preferably not less than 85°, and more preferably substantially vertical. The installation angle can be, for example, an angle in the range of 90°±20°, 90°±15°, 90°±10°, 90°±5°. Substantially perpendicular refers to angles in the range of 90°±5°. More preferably, the angle may be in the range of, for example, 90°±4°, 90°±3°, 90°±2°, and 90°±1°. On the other hand, when the first tube is connected to a tube having a second end, the installation angle of the first tube is not limited, and as described above, the downstream end of the first tube is connected to the second end. The object of the present invention can be achieved not only at a higher position than the connection with the tube, but also in the case of a high upslope at that angle.

The configuration of the section installed at the installation angle described above is not particularly limited. For example, it may be composed of only the second tube, may be composed of only the first tube, or may be composed of two or more tubes (for example, both the first tube and the second tube). may For example, part of the first tube and/or all or part of the tube connecting the first tube and the second tube may constitute this section.

The length of the section is not particularly limited. 30 cm or more, 40 cm or more, 50 cm or more, 70 cm or more, 90 cm or more, 100 cm or more, 110 cm or more, 115 cm or more, 120 cm or more, 130 cm or more, 140 cm or more, 145 cm or more.

Moreover, when a part of 1st tube comprises this area, the length is not specifically limited. For example, it may be 1 cm or more, 2 cm or more, 3 cm or more, 4 cm or more, 5 cm or more. It may be 9 cm or less, 7 cm or less, or 6 cm or less.

The tube length of the second tube is not particularly limited. When the section is composed only of the second tube, the tube length of the second tube may be any length as long as the above installation angle can be satisfied. If the second tube is too long and the above installation angle is satisfied, the installation position of the container will be too high and the operability of the medical staff will be reduced. , 220 cm or less, 210 cm or less, 200 cm or less, 190 cm or less, 180 cm or less, 170 cm or less, 160 cm or less, 150 cm or less. If the length is too short, movement of the patient or subject will be restricted. 120 cm or more, 130 cm or more, 140 cm or more, and 145 cm or more.

A tube connection may be positioned lower than the first end. If a portion of the tube is positioned lower than the first end, the tube will have one or more folds (FIG. 14; curves in FIGS. 2-1 and 2-2). In this case, the tube having the first end preferably has one or more folds.

The size of the angle at the folded portion (folded angle: angle β in FIG. 14) is not particularly limited. For example, it can be 70° or less, 60° or less, 50° or less, 40° or less, 30° or less, 25° or less, 20° or less, 15° or less, 10° or less, 5° or less, or 0°. . The folding angle may be fixed, or may be configured to be variable within a certain width.

If the fold has a downwardly convex shape, downstream of the fold, the tube faces upward. This upward slope (the angle shown in relation to the curve in FIGS. 2-1 and 2-2) is not particularly limited. For example, the upward slope is 20° or more, 30° or more, 40° or more, 50° or more, 60° or more, 65° or more, 70° or more, 75° or more, 80° or more, 85° or more, or 90° be able to.

The position of the folded portion (curved portion) is not particularly limited. For example, a cuff may be included at any location on the first tube (the tube having the first end). The position is not particularly limited as long as it is downstream of the section installed at the installation angle described above. For example, it may have a turn-back part immediately after the above-mentioned section, or it may be provided at a certain distance downstream from the above-mentioned section.

The distance between the above section and the folded portion is not particularly limited. For example, it may be 1 cm or more, 2 cm or more, 3 cm or more, 4 cm or more, 5 cm or more. It may be 9 cm or less, 7 cm or less, or 6 cm or less. In addition, the distance between the folded portion and the first end is, for example, 20 cm or more, 50 cm or more, 80 cm or more, 90 cm or more, 95 cm or more, 100 cm or more, 110 cm or more, 115 cm or more, 120 cm or more, 130 cm or more, 140 cm or more, It can be 145 cm or more and 150 cm or more.

The shape of the folded portion is not particularly limited. For example, it may be V-shaped or U-shaped. Also, the folded portion may include a section in which the tube is horizontal.

The tube may include stops. The stopping part is a part that temporarily interrupts the movement of the cell preparation in the tube or stops it at the end of administration. The configuration of the stopping portion is not particularly limited. For example, stopping means based on constriction such as a clamp and stopping means based on a partition such as a cock may be used.

The tube may also include a flow rate indicator. By including the flow rate display section, the flow rate of the cell preparation can be easily grasped. The configuration of the flow velocity display section is not particularly limited. For example, means for visualizing the flow state, such as a drip tube, and means for converting the flow velocity into a numerical value, such as a flow velocity display screen of an infusion pump, may be used.

The tube can include a degassing section. The degassing section is a section for discharging air and air bubbles in the cell preparation. The configuration of the degassing section is not particularly limited. For example, a drip tube, an air vent filter, and the like can be mentioned.

The number of each part mentioned above is not particularly limited. One or more of each may be included. Also, the position of each part is not particularly limited. For example, the tube with the first end may have it, the tube with the second end may have it, or all the tubes may have it.

Also, one device may function as a plurality of units. For example, a cock such as a three-way stopcock can function both as a stopping part and as a tube connecting part. Any device that can be used as a flow rate regulator can also generally be used as a stop.

The flow rate for administering the cell preparation is appropriately determined according to the purpose of use and the age, body weight, body weight, etc. of the person (patient or subject) to whom the cell preparation is to be administered, and is not particularly limited, but the flow rate is too slow. In some cases, it takes a long time to administer the cell preparation, which may cause deterioration of the quality of the cell preparation. It is preferably 0.9 mL/min or more and 1.0 mL/min or more. Also, the flow rate is not particularly limited as long as it is 1.5 mL/min or less. It can be 0 mL/min or less.

Patient or subject age and weight:
Patients or subjects for whom the administration method of the present specification is performed are assumed to be patients or subjects who need to be administered cell preparations at a slower flow rate than adults because their bodies are smaller than those of adults. The age of the target patient or test subject is not limited, but includes, for example, 18 years old or younger, 17 years old or younger, 16 years old or younger, 15 years old or younger, and 14 years old or younger. Similarly, the body weight of the target patient or subject is not limited, but the lighter the body weight, the slower the flow rate administration may be required. be done.

The cell preparation of the present invention is a cell preparation that is instilled into the body through a tube from a container for containing the cell preparation (for example, a container suspended from an infusion stand) at a flow rate of 1.5 mL/min or less. A label, package insert, or instruction manual that describes the administration and the means of administration of the present invention, or a means capable of obtaining an effect related or equivalent thereto, can be attached.

The effect related to or equivalent to the administration means of the present invention is that, when the cell preparation is administered by infusion at a flow rate of 1.5 mL/min or less, the infusion can be performed while maintaining not only the flow rate but also the cell count at the set value. Show effect. More specifically, it shows the effect that the average deviation rate of the cell suspension administered by drip infusion is within ±10%. The average deviation rate can be calculated by the method described in Examples. The average deviation rate achieved is within ±10%, within ±9%, within ±8%, within ±7%, within ±6%, within ±5%, within ±4%, within ±3%, within ±2 %, within ±1.5%, within ±1%.

It is preferable that the administration means of the present invention uses at least a combination of tubes with an inner diameter of 2.3 mm or less, and/or is a tube installation condition during drip infusion.

The details of the tube to be used and the installation conditions of the tube include the conditions described in the method for administering the cell preparation in [3] above, but similar or related means or effects equivalent to the present invention are used. It is not particularly limited as long as it is a condition that can be obtained.

[4] A device for administering a liquid formulation The present invention is a device for administering a liquid formulation, in which a needle for internal administration, a channel, and a container for containing the liquid formulation are connected in that order, wherein the needle is the flow channel. connected to a first end of a channel, said container being connected to a second end of said channel, said channel having an internal diameter of 2.3 mm or less over a continuous section of at least 20 cm including said first end; and wherein the liquid formulation is configured to be internally administered through the needle at a flow rate of 1.5 mL/min or less.

According to the device of the present invention, a liquid formulation containing cells and/or microparticles can be administered by adjusting the administration rate of the cells and microparticles.

The composition of the liquid formulation basically conforms to the composition described above for medically and/or pharmaceutically acceptable agents. Therefore, only the differences will be described here.

Liquid formulations used in this embodiment contain cells and/or microparticles.
The cells contained in the liquid preparation conform to the content described above regarding cells in "[2] Cell preparation".

Microparticles used in liquid preparations are not particularly limited as long as they are medically and/or pharmaceutically acceptable microparticles. For example, lipid particles such as lipidoids, liposomes, and lipoplexes, polymer compounds, nanotubes, and the like may be used. The material of fine particles is not particularly limited. For example, resin materials such as polystyrene and glycidyl methacrylate; metal materials such as iron, gold and silver; metal oxides such as zirconia, titania and iron oxide; magnetic materials such as ferrite; . The fine particle surface may be surface-modified with any functional group as necessary, and may be bound with a functional molecule such as an antibody or a dispersion stabilizer such as polyethylene glycol, polyvinylpyrrolidone, or polypeptide. In the case of lipid particles, ionic lipids such as cationic lipids, anionic lipids, neutral lipids, pegylated lipids, aminoalcohol lipids, phospholipids, steroidal lipids such as cholesterol, or combinations thereof can also be included.

The size of fine particles is not particularly limited. The size of microparticles can be determined, for example, by sedimentation velocity. The sedimentation velocity of fine particles in the present invention may be, for example, 0.50 μm/s to 50 μm/s when physiological saline is used as a solvent. The lower limit is, for example, 0.50 μm/s, 0.60 μm/s, 0.90 μm/s, 1 μm/s, 2 μm/s, 3 μm/s, 4 μm/s, 5 μm/s, 6 μm/s, 7 μm/s , 8 μm/s, 9 μm/s, 10 μm/s, 11 μm/s, 12 μm/s, 13 μm/s, 14 μm/s, 15 μm/s, and the upper limits are, for example, 50 μm/s, 49 μm/s, 45 μm/s, 40 μm/s, 35 μm/s, 30 μm/s, 25 μm/s, 22 μm/s, 20 μm/s, 19 μm/s, 18 μm/s, 16 μm/s, 15 μm/s.

In addition, if the diameter of the fine particles is, for example, 30 μm or less, 25 μm or less, 20 μm or less, 19 μm or less, 18 μm or less, 17 μm or less, 16 μm or less, 15 μm or less, 14 μm or less, 13 μm or less, 12 μm or less, 11 μm or less, or 10 μm or less For example, it may be 5 μm or more, 6 μm or more, 7 μm or more, 8 μm or more, 9 μm or more, or 10 μm or more.

The concentration of fine particles is not particularly limited. It can be appropriately determined according to the dosage form, the type of microparticles, the purpose of use, and the age, weight, symptoms, etc. of the subject of administration. Specifically, for example, 1×10 ⁴ /mL or more, 2×10 ⁴ /mL or more, 3×10 ⁴ /mL or more, 4×10 ⁴ /mL or more, 5×10 ⁴ /mL or more, 6×10 ⁴ /mL or more, 7×10 ⁴ /mL or more, 8×10 ⁴ /mL or more, 9×10 ⁴ /mL or more, 1×10 ⁵ /mL or more, 2×10 ⁵ /mL or more, 3×10 ⁵ /mL or more mL or more, 4×10 ⁵ /mL or more, 5×10 ⁵ /mL or more, 6×10 ⁵ /mL or more, 7×10 ⁵ /mL or more, 8×10 ⁵ /mL or more, 9×10 ⁵ /mL or more , 1×10 ⁶ /mL or more, 1.5×10 ⁶ /mL or more, 2×10 ⁶ /mL or more, and 1×10 ⁹ /mL or less, 9×10 ⁸ /mL or less, 8×10 ⁸ /mL or less, 7×10 ⁸ /mL or less, 6×10 ⁸ /mL or less, 5×10 ⁸ /mL or less, 4×10 ⁸ /mL or less, 3×10 ⁸ /mL or less, 2× 10 ⁸ /mL or less, 1 x 10 ⁸ /mL or less, 9 x 10 ⁷ /mL or less, 8 x 10 ⁷ /mL or less, 7 x 10 ⁷ /mL or less, 6 x 10 ⁷ /mL or less, 5 x 10 ⁷ /mL or less, 4 x ¹⁰⁷ /mL or less, 3 x ¹⁰⁷ /mL or less, 2 x 107 ^/ mL or less, 1 x ¹⁰⁷ /mL or less, 9 x ¹⁰⁶ /mL or less, 8 x ¹⁰⁶ /mL Below, 7×10 ⁶ /mL or less, 6×10 ⁶ /mL or less, 5×10 ^{6 /mL or less, 4×10 6 /} mL or less, 3×10 ⁶ /mL or less, 2.5×10 ⁶ /mL Below, it can be 2×10 ⁶ /mL or less. If the liquid formulation contains microparticles and cells, they may be combined and within the above ranges.

The needle for internal administration used in the device of this embodiment conforms to the content described above in "[3] Administration method of cell preparation".

The container for containing the liquid preparation used in the device of this embodiment conforms to the content described above regarding the container for containing the cell preparation in "[3] Administration method of cell preparation".

A channel refers to a space in which a liquid can flow in a specific direction. In this specification, the channel may or may not have openings other than the liquid inlet and outlet. Moreover, the flow path may be provided with backflow prevention means.

The material of the channel is not particularly limited. The material of the part that contacts the liquid preparation is not particularly limited as long as the liquid preparation that has passed through the channel is not harmful to the administration subject. For example, it may be composed of an organic material such as a resin or a biomolecule, an inorganic material such as a metal, or a combination thereof. Also, for example, it may be made of a soft material, a hard material, or a combination thereof. For example, in addition to the materials mentioned above for the tube, polyester, polyolefin, styrenic resin, polycarbonate, acrylic resin, fluororesin, aromatic polyetherketone resin, polyamide, polysulfone, polyarylate, polyetherimide, glass, or a combination thereof, etc. can be used.

The shape of the channel is not particularly limited. For example, it may be tubular, or it may be shaped like a chip having a groove-like channel inside. Moreover, the internal shape of the channel is not particularly limited. For example, it may be circular, elliptical, substantially circular, fan-shaped, substantially fan-shaped, polygonal, or a combination thereof. If the internal shape is other than circular, the internal diameter of the channel refers to the diameter of the largest inscribed circle. The outer and inner shape of the channel may change along the way.

The inner diameter of the channel having the first end connected to the needle conforms to the description regarding the first tube in "[3] Administration method of cell preparation".

The internal diameter of the channel at the second end that connects with the container may be the same or different than the internal diameter of the channel at the first end. For example, the inner diameter of the channel at the second end is greater than the inner diameter of the channel at the first end.

The inner diameter and length of the channel at the second end conform to the description regarding the first tube in "[3] Administration method of cell preparation".

The channel of the device of this aspect may consist of two or more channels connected in series with each other. In this case, the shape, material, inner diameter, etc. of the channels may be different for each channel, or may be common to all or some of the channels.

When the flow path is composed of two or more flow paths, there are no particular restrictions on the manner of connection between the flow paths. If multiple flow paths are used, for example, all or some of the connections may be made by flow connections and the inner diameter may vary discontinuously, or flow connections may not be used and the inner diameter may vary throughout the tube. may change continuously.

The arrangement of the channel connecting portion and the channel is not particularly limited. The arrangement of the flow path connecting portion, the flow path having the first end, and the flow path having the second end relates to the tube connecting portion, the first tube, and the second tube in "[3] Administration method of cell preparation" According to the description.

The channel may have one or more selected from the group consisting of a turn-up portion, a flow rate control portion, a stop portion, a flow rate display portion, and a degassing portion. The content of each part conforms to the description in “[3] Administration method of cell preparation”.

The number of each part mentioned above is not particularly limited. One or more of each may be included. Also, the position of each part is not particularly limited. For example, a channel with a first end may have it, a channel with a second end may have it, or any other channel may have it. Also, one device may function as a plurality of units.

The administration rate of the liquid preparation conforms to the description regarding the flow rate in "[3] Administration method of cell preparation".

[5] Kit for Cell Preparation Administration The present invention further relates to a kit for use in the method for administering the cell preparation.

Specifically, for example, a kit for administering a cell preparation comprising a tube, wherein the tube is used in combination with a needle for internal administration and a container for containing the cell preparation, and the needle is the first tube of the tube. one end, the container being connected to a second end of the tube, the tube having an inner diameter of 2.3 mm or less over a continuous section of at least 20 cm including the first end, and The kit relates to a kit, wherein the formulation is administered internally at a flow rate of 1.5 mL/min or less. The kit has only a tube as an essential component, and is used in combination with other elements (eg, cell preparation, container, needle, etc.) for the administration method described in "[3] Administration method of cell preparation".

The tube of the kit conforms to the tube in "[3] Administration method of cell preparation". The tubing included in the kit may have a first end and/or a second end, or neither. Preferably, the kit of this aspect includes a tube having a first end. The kit may contain two or more tubes, and may additionally contain needles, containers, cell preparations, connection means with containers, and the like. The tube of the kit can have one or more selected from the group consisting of a turn-up portion, a flow rate control portion, a stop portion, a tube connection portion, a flow rate display portion and a degassing portion. The content of each part conforms to the description in “[3] Administration method of cell preparation”.

For example, a tube having an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm is combined with a connecting part (such as a bottle needle) connected to a container for containing a cell preparation, an infusion tube, and a flow rate adjusting part. , a set for cell administration is also an embodiment of the kit of the present invention.

Also, for example, a kit for administering a cell preparation comprising a container for containing the cell preparation, wherein the container is used in combination with a needle and a tube for internal administration, and the needle is attached to the first end of the tube. wherein the container is connected to a second end of the tube, the tube having an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including the first end, and the cell preparation is flowed at a flow rate of 1 It relates to a kit administered internally at 5 mL/min or less. The kit has only a container as an essential component, and is used in combination with other elements (eg, cell preparation, tube, needle, etc.) for the administration method described in "[3] Administration method of cell preparation".

The container of the kit conforms to the container in “[3] Administration method of cell preparation”. The kit may contain two or more containers depending on the purpose, the type of cell preparation, etc., and may additionally contain a needle, a tube, a cell preparation, means for connecting to the tube, and the like.

[6] Tube for administration of cell preparation The present invention further relates to a tube for use in the administration method of the cell preparation.

The tube of this embodiment is a tube for connecting a container for containing a cell preparation and a needle for internal administration, the needle is connected to the first end of the tube, and the container is the first end of the tube. 2, the tube has an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including the first end, and is provided with means for connecting to the container, and the cell preparation has a flow rate of It relates to a tube for internal administration at 1.5 mL/min or less.

The tube of this aspect has a first end and a second end and has means for connection with the container. The configuration of the tube of this embodiment conforms to the description in "[3] Administration method of cell preparation".

The means for connecting with the container includes, for example, a bottle needle, but is not particularly limited as long as the cell preparation in the container is appropriately transferred into the tube. Moreover, the tube of this aspect can have one or more selected from the group consisting of a folding portion, a flow rate adjusting portion, a stopping portion, a tube connecting portion, a flow rate indicating portion, and a degassing portion. The content of each part conforms to the description in “[3] Administration method of cell preparation”.

The present invention will be specifically described in the following examples, but the present invention is not limited by the examples.

(Example 1)
<Tube installation conditions>
Transfusion set TB-PU300L for terfusion pump (tube inner diameter 3.0 mm, tube length 220 cm, manufactured by Terumo Corporation) (corresponding to the second tube) was placed 115 cm from the tip of the bottle needle used for connection with the container. It was cut, and a three-way stopcock L-type 360° lock (manufactured by Top Co., Ltd.) was attached to the cut surface as a tube connecting portion. At this time, the clamp was left in the tube. Cell suspension (Mesenchymal stem cells suspended in physiological saline at a cell concentration of 2×10 ⁶ cells/mL. Other ingredients include a cryoprotectant. Rotational viscometer TV-20 (manufactured by Toki Sangyo Co., Ltd.) ) was measured at a rotation speed of 10 rpm and a temperature of 22 ° C.) The bottle needle of the tube was inserted into the rubber stopper of the sampling port of the container (flow bag F-050) filled with the tube and the cells. A vessel filled with suspension was connected. A top extension tube X1-L 120 (tube inner diameter 1.1 mm, tube length 120 cm, manufactured by Top Co., Ltd.) (corresponding to the first tube) is connected to the three-way stopcock attached to the tube, and its downstream end (the 1 end) was attached with an indwelling needle (Surflow Flash SR-FS2419W (manufactured by Terumo Corporation)). The container filled with the cell suspension was suspended on an infusion stand, and the portion of the second tube 35 cm to 57 cm downstream from the container was placed on a terfusion infusion pump TE-171E (manufactured by Terumo Corporation) attached to the infusion stand. Installed in tube guide. The second tube was installed so that the upstream end (second end) was higher than the downstream end (tube connecting portion) so that the entire tube was at 90° to the horizontal plane. The first tube is installed so that the section from the three-way stopcock to about 5 cm has the same angle as the second tube, and is bent at a portion about 5 cm from the three-way stopcock to form a curved portion (in FIG. 2-1 The downstream portion after the “curved portion” (corresponding to the “turned portion” in FIG. 14) was set at 0° with respect to the horizontal plane. A schematic diagram of the tube installation method is shown in Figure 2-1.

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate of the infusion pump was set to 1 mL/min, and the cell suspension in the container was dripped using the pump. About 1 mL of the cell suspension flowing out from the indwelling needle was collected. The cell concentration of each cell suspension collected was determined as described below. The measurement results are shown in FIG.

(Example 2)
<Tube installation conditions>
Transfusion set TB-PU300L for terfusion pump (tube inner diameter 3.0 mm, tube length 220 cm, manufactured by Terumo) (corresponding to the second tube) was placed 150 cm from the tip of the bottle needle used for connection with the container. It was cut, and a three-way stopcock L-type 360° lock (manufactured by Top Co., Ltd.) was attached to the cut surface as a tube connecting portion. At this time, the clamp was left in the tube. The bottle needle of the tube was inserted into the rubber stopper of the sampling port of the container (flow bag F-050) filled with the same cell suspension as in Example 1, and the tube and the container filled with the cell suspension were connected. A top extension tube X1-L 120 (tube inner diameter 1.1 mm, tube length 120 cm, manufactured by Top Co., Ltd.) (corresponding to the first tube) is connected to the three-way stopcock attached to the tube, and its downstream end (the 1 end) was attached with an indwelling needle (Surflow Flash SR-FS2419W (manufactured by Terumo Corporation)). The container filled with the cell suspension was suspended on an infusion stand, and the portion of the second tube 45 cm to 67 cm downstream from the container was placed on a terfusion infusion pump TE-171E (manufactured by Terumo Corporation) attached to the infusion stand. Installed in tube guide. The second tube was installed so that the upstream end (second end) was higher than the downstream end (tube connecting portion) so that the entire tube was at 90° to the horizontal plane. The first tube is installed so that the section from the three-way stopcock to about 5 cm has the same angle as the second tube, and is bent at a portion about 5 cm from the three-way stopcock to form a curved portion (in FIG. 2-1 The downstream portion after the “curved portion”, which corresponds to the “turned portion” in FIG. A schematic diagram of the tube installation method is shown in Example 2 of FIG. 2-1.

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate of the infusion pump was set to 1 mL/min, and the cell suspension in the container was dripped using the pump. About 1 mL of the cell suspension flowing out from the indwelling needle was collected. The cell concentration of each cell suspension collected was determined as described below. The measurement results are shown in FIG.

(Example 3)
<Tube installation conditions>
Transfusion set TB-PU300L for terfusion pump (tube inner diameter 3.0 mm, tube length 220 cm, manufactured by Terumo) (corresponding to the second tube) was placed 150 cm from the tip of the bottle needle used for connection with the container. It was cut, and a three-way stopcock L-type 360° lock (manufactured by Top Co., Ltd.) was attached to the cut surface as a tube connecting portion. At this time, the clamp was left in the tube. The bottle needle of the tube was inserted into the rubber stopper of the sampling port of the container (flow bag F-050) filled with the same cell suspension as in Example 1, and the tube and the container filled with the cell suspension were connected. A top extension tube X1-L 120 (tube inner diameter 1.1 mm, tube length 120 cm, manufactured by Top Co., Ltd.) (corresponding to the first tube) is connected to the three-way stopcock attached to the tube, and its downstream end (the 1 end) was attached with an indwelling needle (Surflow Flash SR-FS2419W (manufactured by Terumo Corporation)). The container filled with the cell suspension was suspended on an infusion stand, and the portion of the second tube 45 cm to 67 cm downstream from the container was placed on a terfusion infusion pump TE-171E (manufactured by Terumo Corporation) attached to the infusion stand. Installed in tube guide. The second tube was installed so that the upstream end (second end) was higher than the downstream end (tube connecting portion) so that the entire tube was at 90° to the horizontal plane. The first tube is installed so that the section from the three-way stopcock to about 5 cm has the same angle as the second tube, and is bent at a portion about 5 cm from the three-way stopcock to form a curved portion (in FIG. 2-1 The downstream portion after the “curved portion”, which corresponds to the “turned portion” in FIG. A schematic diagram of the tube installation method is shown in Example 3 of FIG. 2-1.

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate of the infusion pump was set to 1 mL/min, and the cell suspension in the container was dripped using the pump. About 1 mL of the cell suspension flowing out from the indwelling needle was collected. The cell concentration of each cell suspension collected was determined as described below. The measurement results are shown in FIG.

(Example 4)
<Tube installation conditions>
Transfusion set TB-PU300L for terfusion pump (tube inner diameter 3.0 mm, tube length 220 cm, manufactured by Terumo) (corresponding to the second tube) was placed 150 cm from the tip of the bottle needle used for connection with the container. It was cut, and a three-way stopcock L-type 360° lock (manufactured by Top Co., Ltd.) was attached to the cut surface as a tube connecting portion. At this time, the clamp was left in the tube. The bottle needle of the tube was inserted into the rubber stopper of the sampling port of the container (flow bag F-050) filled with the same cell suspension as in Example 1, and the tube and the container filled with the cell suspension were connected. A top extension tube X1-L 120 (tube inner diameter 1.1 mm, tube length 120 cm, manufactured by Top Co., Ltd.) (corresponding to the first tube) is connected to the three-way stopcock attached to the tube, and its downstream end (the 1 end) was attached with an indwelling needle (Surflow Flash SR-FS2419W (manufactured by Terumo Corporation)). The container filled with the cell suspension was suspended on an infusion stand, and the portion of the second tube 45 cm to 67 cm downstream from the container was placed on a terfusion infusion pump TE-171E (manufactured by Terumo Corporation) attached to the infusion stand. Installed in tube guide. The second tube was installed so that the upstream end (second end) was higher than the downstream end (tube connecting portion) so that the entire tube was at 90° to the horizontal plane. The first tube is installed so that the section from the three-way stopcock to about 5 cm has the same angle as the second tube, and is bent at a portion about 5 cm from the three-way stopcock to form a curved portion (in FIG. 2-2 "Corrugated part", corresponding to "turned part" in FIG. Schematic diagrams of tube installation methods are shown in Examples 4 and 6 of FIG. 2-2.

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate of the infusion pump was set to 1 mL/min, and the cell suspension in the container was dripped using the pump. About 1 mL of the cell suspension flowing out from the indwelling needle was collected. The cell concentration of each cell suspension collected was determined as described below. The measurement results are shown in FIG.

(Example 5)
<Tube installation conditions>
Terfusion blood transfusion set TB-U300L (tube inner diameter 2.5 mm, tube length 140 cm, manufactured by Terumo Corporation) was attached to the rubber stopper of the sampling port of the container (flow bag F-050) filled with the same cell suspension as in Example 1. (corresponding to the second tube) was inserted to connect the tube and the container filled with the cell suspension. A top extension tube X1-L 120 (tube inner diameter 1.1 mm, tube length 120 cm, manufactured by Top Co., Ltd.) (corresponding to the first tube) is connected to the connector (tube connecting portion) at the downstream end of the tube, An indwelling needle (Surflow Flash SR-FS2419W (manufactured by Terumo Corporation)) was attached to its downstream end (first end). A container filled with cell suspension was hung on an infusion stand. The second tube was installed so that the upstream end (second end) was higher than the downstream end (tube connecting portion) so that the entire tube was at 90° to the horizontal plane. The first tube is installed so that a section up to about 5 cm from the connection with the second tube has the same angle as the second tube, and a section about 5 cm from the connection with the second tube. The downstream part after the curved part (corresponding to the “curved part” in FIG. 2-2 and the “turned part” in FIG. 14) was installed so as to have an upward slope of 90° with respect to the horizontal plane. Schematic diagrams of tube installation methods are shown in Examples 5, 7, and 8 of FIG. 2-2.

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate was adjusted to 1 mL/min by adjusting the clamp attached to the second tube, and the cell suspension in the container was added dropwise. About 1 mL of the cell suspension flowing out from the indwelling needle was collected. The cell concentration of each cell suspension collected was determined as described below. The measurement results are shown in FIG.

(Example 6)
<Tube installation conditions>
Transfusion set TB-PU300L for terfusion pump (tube inner diameter 3.0 mm, tube length 220 cm, manufactured by Terumo) (corresponding to the second tube) was placed 150 cm from the tip of the bottle needle used for connection with the container. It was cut, and a three-way stopcock L-type 360° lock (manufactured by Top Co., Ltd.) was attached to the cut surface as a tube connecting portion. At this time, the clamp was left in the tube. The bottle needle of the tube was inserted into the rubber stopper of the sampling port of the container (flow bag F-050) filled with the same cell suspension as in Example 1, and the tube and the container filled with the cell suspension were connected. A JMS extension tube JV-ND1150FL (tube inner diameter 1.0 mm, tube length 150 cm, manufactured by JMS) (corresponding to the first tube) is connected to the three-way stopcock attached to the tube, and its downstream end (first end) was attached with an indwelling needle (Surflow Flash SR-FS2419W (manufactured by Terumo Corporation)). The container filled with the cell suspension was suspended on an infusion stand, and the portion of the second tube 45 cm to 67 cm downstream from the container was placed on a terfusion infusion pump TE-171E (manufactured by Terumo Corporation) attached to the infusion stand. Installed in tube guide. The second tube was installed so that the upstream end (second end) was higher than the downstream end (tube connecting portion) so that the entire tube was at 90° to the horizontal plane. The first tube is installed so that the section from the three-way stopcock to about 5 cm has the same angle as the second tube, and is bent at a portion about 5 cm from the three-way stopcock to bend the curved portion (" (corresponding to the "curved part" and the "turned part" in FIG. 14), and the downstream part was installed so as to have an upward slope of 90° with respect to the horizontal plane. Schematic diagrams of tube installation methods are shown in Examples 4 and 6 of FIG. 2-2.

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate of the infusion pump was set to 1 mL/min, and the cell suspension in the container was dripped using the pump. About 1 mL of the cell suspension flowing in from the indwelling needle was collected. The cell concentration of each cell suspension collected was determined as described below. The measurement results are shown in FIG.

(Example 7)
<Tube installation conditions>
Nipro transfusion set TFP-301E D200 CL Z (tube inner diameter 3.15 mm, tube length 150 cm, manufactured by Nipro) was attached to the rubber stopper of the sampling port of the container (flow bag F-050) filled with the same cell suspension as in Example 1. (product) (corresponding to the second tube) was inserted to connect the tube and the container filled with the cell suspension. A top extension tube X2-WL100 (tube inner diameter 2.2 mm, tube length 100 cm, manufactured by Top Co., Ltd.) (corresponding to the first tube) is connected to the connector (tube connecting portion) at the downstream end of the tube, and the An indwelling needle (Surflow Flash SR-FS2419W (manufactured by Terumo Corporation)) was attached to the downstream end (first end). The container filled with the cell suspension is suspended on an infusion stand, and the part of the second tube 45 cm to 67 cm downstream from the container is attached to the infusion stand Taftec Infusion Pump 2 FP-N17 (manufactured by Nipro). Installed in tube guide. The second tube was installed so that the upstream end (second end) was higher than the downstream end (tube connecting portion) so that the entire tube was at 90° to the horizontal plane. The first tube is installed so that a section up to about 5 cm from the connection with the second tube has the same angle as the second tube, and a section about 5 cm from the connection with the second tube. The downstream part after the curved part (corresponding to the “curved part” in FIG. 2-2 and the “turned part” in FIG. 14) was installed so as to have an upward slope of 90° with respect to the horizontal plane. Schematic diagrams of tube installation methods are shown in Examples 5, 7, and 8 of FIG. 2-2.

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate of the infusion pump was set to 1 mL/min, and the cell suspension in the container was dripped using the pump. About 1 mL of the cell suspension flowing out from the indwelling needle was collected. The cell concentration of each cell suspension collected was determined as described below. The measurement results are shown in FIG.

(Example 8)
<Tube installation conditions>
Terfusion blood transfusion set TB-U300L (tube inner diameter 2.5 mm, tube length 140 cm, manufactured by Terumo Corporation) was attached to the rubber stopper of the sampling port of the container (flow bag F-050) filled with the same cell suspension as in Example 1. ) (corresponding to the second tube) was inserted to connect the tube and the container filled with the cell suspension. A top extension tube X2-WL100 (tube inner diameter 2.2 mm, tube length 100 cm, manufactured by Top Co., Ltd.) (corresponding to the first tube) is connected to the connector (tube connecting portion) at the downstream end of the tube, and the An indwelling needle (Surflow Flash SR-FS2419W (manufactured by Terumo Corporation)) was attached to the downstream end (first end). The second tube was installed so that the upstream end (second end) was higher than the downstream end (tube connecting portion) so that the entire tube was at 90° to the horizontal plane. The first tube is installed so that a section up to about 5 cm from the connection with the second tube has the same angle as the second tube, and a section about 5 cm from the connection with the second tube. The downstream part after the curved part (corresponding to the “curved part” in FIG. 2-2 and the “turned part” in FIG. 14) was installed so as to have an upward slope of 90° with respect to the horizontal plane. Schematic diagrams of tube installation methods are shown in Examples 5, 7, and 8 of FIG. 2-2.

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate was adjusted to 1 mL/min by adjusting the clamp attached to the second tube, and the cell suspension in the container was added dropwise. About 1 mL of the cell suspension flowing out from the indwelling needle was collected. The cell concentration of each cell suspension collected was determined as described below. The measurement results are shown in FIG.

(Comparative example 1)
<Tube installation conditions>
Terfusion blood transfusion set TB-U300L (tube inner diameter 2.5 mm, tube length 140 cm, manufactured by Terumo Corporation) was attached to the rubber stopper of the sampling port of the container (flow bag F-050) filled with the same cell suspension as in Example 1. ) was inserted to connect the tube and the container filled with the cell suspension. A winged needle (winged intravenous needle SV-25DLK (Surflow Flash SR-FS2419W, manufactured by Terumo)) was attached to the connector at the downstream end of the tube. A portion of the second tube 45 cm to 67 cm downstream from the container was set in the tube guide of a Terfusion infusion pump TE-171E (manufactured by Terumo Corporation) attached to an infusion stand, and the tube portion from the container to the pump. The tube was installed at 90° to the horizontal plane.The downstream end of the tube was located lower than the outlet of the pump, and was installed in a curved shape with some slack.The inclination angle of the tube was set upstream. The side of the tube is about 45° to the horizontal plane, the angle of inclination decreases toward the downstream side, and the downstream end is about 20° to the horizontal plane.The schematic diagram of the tube installation method is shown in FIG. shown in

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate of the pump was set to 1 mL/min, and the cell suspension in the container was dripped using the pump. About 1 mL of the cell suspension flowing out from the butterfly needle was collected, and the cell concentration of the collected cell suspension was measured as described later. The measurement results are shown in FIG.

(Comparative example 2)
<Tube installation conditions>
Terfusion blood transfusion set TB-U300L (tube inner diameter 2.5 mm, tube length 140 cm, manufactured by Terumo Corporation) was attached to the rubber stopper of the sampling port of the container (flow bag F-050) filled with the same cell suspension as in Example 1. ) was inserted to connect the tube and the container filled with the cell suspension. An indwelling needle (Surflow Flash SR-FS2419W (manufactured by Terumo Corporation)) was attached to the connector at the downstream end of the tube. The container filled with the cell suspension was suspended on an infusion stand, and the tube was bent at 90° at 70 cm from the connection with the container. The downstream portion after the curved portion was installed so as to be 0° with respect to the horizontal plane. A schematic diagram of the tube installation method is shown in Comparative Example 2 of FIG.

<Collection of dropped cell suspension and measurement of cell concentration>
The flow rate was adjusted to 1 mL/min by adjusting the clamp attached to the tube, and the cell suspension in the container was added dropwise. About 1 mL of the cell suspension flowing out from the indwelling needle was collected. The cell concentration of each cell suspension collected was determined as described below. The measurement results are shown in FIG.

(Evaluation example 1)
<Evaluation of Concentration and Divergence Rate of Dropped Cell Suspension>
In Examples 1 to 8 and Comparative Examples 1 and 2, the cell concentration of each cell suspension collected about 1 mL each was measured. The measurement results are shown in FIGS. 4-13. Next, in Examples 1 to 8 and Comparative Examples 1 and 2, the cell concentration of each cell suspension collected about 1 mL each, and the cell concentration of the cell suspension in the bag (container) (2 × 10 ⁶ cells / mL), and in each example and comparative example, the average deviation rate was determined by averaging the deviation rates in the collected whole cell suspension (Table 1 (Table 1 -1 shows the same content)). The deviation rate was calculated using the following formula.

As shown in FIGS. 4 to 13, in Examples 1 to 8, the concentration of the collected cell suspension after dropping was constant, and the concentration of the cell suspension contained in the container (2×10 ⁶ cells/ mL). On the other hand, the concentration of the recovered cell suspension after dropping in Comparative Examples 1 and 2 was lower than the concentration of the cell suspension contained in the container (2×10 ⁶ cells/mL) and was maintained constant. It fluctuated up and down without a hitch. In addition, as shown in Table 1, the average deviation rate is -10% or less (absolute value is 10% or less) in Examples 1 to 8, and the cell suspension of the same concentration as the cell suspension in the container A turbid liquid was dropped, but in Comparative Examples 1 and 2, the value was more than -25% (the absolute value was more than 25%), and the concentration of the dropped cell suspension was the cell concentration in the container. was greatly deviated from

From these results, in Examples 1 to 8 using the first tube, the cell concentration, in other words, the number of cells per liquid volume, can be administered while maintaining the set value (concentration of the cell preparation to be administered). It has been shown. As a result of visual observation, in Examples 1 to 8, no retention or sedimentation of cells was observed in the tubes. On the other hand, in Comparative Examples 1 and 2, which do not use the first tube, administration at a constant cell concentration was not possible, and the cell concentration in the solution flowing out of the needle deviated greatly from the set value (the concentration of the cell preparation to be administered). rice field. In addition, in Comparative Examples 1 and 2, a phenomenon of cell sedimentation within the tube was observed during administration.

1. container 2 . Second tube 3 . 4. first tube; needle 5 . drip stand

Claims (18)

A cell preparation for internal administration at a flow rate of 1.5 mL/min or less,
Used in combination with a container for containing the cell preparation and a tube connecting the needle for internal administration,
The tube has an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including the connection with the needle.
Said cell preparation. 2. The cell preparation according to claim 1, wherein the subject for internal administration is under 15 years old. 2. The cell preparation according to claim 1, wherein the body weight of the subject for said internal administration is 50 kg or less. 2. The cell preparation according to claim 1, which is attached with a label, a package insert, or an instruction manual describing the method of said internal administration. A device for administering a liquid formulation in which a needle for administration into the body, a channel, and a container for containing the liquid formulation are connected in that order,
said needle is connected to a first end of said channel and said container is connected to a second end of said channel;
the channel has an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including the first end;
The device, wherein the liquid formulation is configured to be administered internally through the needle at a flow rate of 1.5 mL/min or less. 6. The device according to claim 5, wherein the liquid formulation comprises cells and/or microparticles having a sedimentation velocity of 0.50 μm/s to 50 μm/s. 6. The device of claim 5, wherein said liquid formulation is a cell formulation. 7. The device of claim 6, wherein the microparticles have a diameter of 5 μm to 30 μm. 6. The device of claim 5, wherein the inner diameter of the channel at the second end is greater than the inner diameter of the channel at the first end. 6. Apparatus according to claim 5, wherein the channel is composed of two or more channels connected to each other. 11. The device of claim 10, wherein the two or more channels are connected by a channel connector. 12. The device of claim 11, wherein the fluid connection is positioned lower than the first end. 6. The device of claim 5, wherein the channel with the second end is arranged at 90[deg.]±20[deg.] to the horizontal plane. 6. The device of claim 5, wherein the channel having the first end has a fold. 6. Apparatus according to claim 5, wherein the channel has a flow rate control. 16. The device of Claim 15, wherein the flow rate regulator comprises an infusion pump or a syringe pump. A cell preparation administration kit comprising a tube,
The tube is used in combination with a needle for internal administration and a container for containing the cell preparation,
said needle is connected to a first end of said tube and said container is connected to a second end of said tube;
the tube has an inner diameter of 2.3 mm or less in a continuous section of at least 20 cm including the first end;
The cell preparation is administered in vivo at a flow rate of 1.5 mL/min or less,
Said kit. 18. The kit of claim 17, wherein said tube is a tube having both a first end and a second end.

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