WO2018225673A1 - Procédé de réduction de l'agrégation cellulaire et composition thérapeutique à agrégation cellulaire réduite - Google Patents

Procédé de réduction de l'agrégation cellulaire et composition thérapeutique à agrégation cellulaire réduite Download PDF

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WO2018225673A1
WO2018225673A1 PCT/JP2018/021333 JP2018021333W WO2018225673A1 WO 2018225673 A1 WO2018225673 A1 WO 2018225673A1 JP 2018021333 W JP2018021333 W JP 2018021333W WO 2018225673 A1 WO2018225673 A1 WO 2018225673A1
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cell
cells
solution
cell preparation
ringer
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孝洋 木原
明美 黒宮
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Ｄｓファーマアニマルヘルス株式会社
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Definitions

  • the present disclosure relates to a method for reducing cell aggregation in the field of regenerative medicine / cell medicine, a therapeutic composition with reduced cell aggregation, and the like.
  • Regenerative and cell therapy that treats diseases by administering cells to the living body has been actively developed.
  • the cell preparation when cells to be administered adhere to each other to form an aggregate, it may cause embolization or prevent quantitative administration when administered into blood vessels. Therefore, in the field of regenerative medicine / cell medicine, development of a method for reducing cell aggregation is strongly desired.
  • An object of the present invention is to provide a method for reducing cell aggregation upon administration of a cell preparation, a therapeutic composition with reduced cell aggregation, a method for producing the same, and the like.
  • the present invention provides, in one embodiment, a method for producing a therapeutic composition comprising mammalian cells, comprising dispersing the mammalian cells with about 3% to about 10% aqueous glucose solution or Ringer's acetate solution. To do.
  • the present invention provides a therapeutic composition comprising mammalian cells in about 3% to about 10% aqueous glucose solution or Ringer's acetate solution, or in a mixture of the aqueous glucose solution or Ringer's acetate solution and a cell preservation solution. provide.
  • the present invention provides a cell preparation comprising mammalian cells, wherein the cells are dispersed in about 3% to about 10% aqueous glucose solution or Ringer's acetate solution and administered to a mammal.
  • Cell preparations are used.
  • the invention in a further aspect, is a method of treating a disease in a mammal, comprising Dispersing mammalian cells with about 3% to about 10% aqueous glucose solution or Ringer's acetate solution to provide a therapeutic composition, and administering the resulting therapeutic composition to a mammal .
  • Glucose and Ringer's acetate solution have low toxicity to the living body and can be used at low cost. According to the present invention, it has become possible to produce a therapeutic composition in which cell aggregation at the time of administration of a cell preparation is reduced safely and inexpensively, and in which cell aggregation is reduced.
  • FIG. 1 shows the survival rate of beagle adipose tissue-derived stem cells dispersed in a 5% aqueous glucose solution.
  • FIG. 2 shows the survival rate of stem cells derived from beagle adipose tissue dispersed with 5% aqueous glucose solution or Ringer's acetate solution.
  • % relating to concentration means “w / v%” unless otherwise specified.
  • the cell preparation of the present invention includes mammalian cells.
  • mammals include mice, rats, hamsters, guinea pigs, rabbits, dogs, cats, pigs, cows, goats, horses, sheep, monkeys, humans, and the like.
  • the mammal is a non-human mammal.
  • the mammal is a dog, cat, pig or horse, more preferably a dog or cat.
  • the mammal is a dog, particularly a beagle or a golden retriever.
  • the cells in this specification include stem cells, fibroblasts, epithelial cells, white blood cells and the like.
  • stem cells include embryonic stem cells (ES cells), embryonic germ stem cells (EG cells), iPS cells, and somatic stem cells.
  • somatic stem cells include mesenchymal stem cells, neural stem cells, and hematopoietic stem cells.
  • the stem cell may be a cell produced by any method.
  • the stem cell is a mesenchymal stem cell.
  • Mesenchymal stem cells can be obtained by known methods from adipose tissue, bone marrow, umbilical cord blood and the like.
  • the mesenchymal stem cells are derived from adipose tissue, such as subcutaneous adipose tissue.
  • Cell preparations include, but are not limited to, typically 10 4 to 10 8 cells per preparation. In certain embodiments, the cell preparation comprises 10 5 to 10 7 or 2.5 ⁇ 10 6 to 5 ⁇ 10 6 cells.
  • the cell preparation may be frozen or non-frozen.
  • the cell preparation usually contains a cell preservation solution in addition to mammalian cells. Examples of the components of the cell preservation solution include phosphoric acid, DMSO, sodium salt (for example, sodium chloride), potassium salt (for example, potassium chloride), serum, glycerol and the like.
  • the cell preservation solution is phosphate buffered saline (PBS) containing about 5% DMSO (eg, Dulbecco's PBS (D-PBS)), and the cell preparation is a mammal in said solution.
  • PBS phosphate buffered saline
  • D-PBS usually contains 0.02% potassium chloride, 0.02% sodium dihydrogen phosphate, 0.8% sodium chloride, and 0.115% disodium hydrogen phosphate.
  • a mammalian cell in a cell preparation When a mammalian cell in a cell preparation is dispersed with an aqueous glucose solution or Ringer's acetate solution, a therapeutic composition for administration to a mammal is obtained.
  • the cells may be dispersed by a normal method in the technical field. For example, an appropriate amount of an aqueous glucose solution or Ringer's acetate solution may be added to the cells and mixed by pipetting or the like, and the obtained cell suspension may be further diluted with an aqueous glucose solution or Ringer's acetate solution to a desired cell concentration.
  • the cells and the aqueous glucose solution or Ringer's acetate solution may be mixed, or the cell preparation containing the cell and the cell preservation solution and the aqueous glucose solution or Ringer's acetate solution may be directly mixed.
  • the cells are dispersed by mixing the cell preparation with an aqueous glucose solution or Ringer's acetate solution.
  • 0.5 ⁇ 10 6 to 1 ⁇ 10 6 cells are administered per kg body weight of the mammal.
  • the number of cells administered per individual is 0.5 ⁇ 10 6 to 4 ⁇ 10 7 , and when 2 kg to 20 kg, 1 ⁇ 10 6 to 2 ⁇ 10 7 pieces.
  • the total amount of the therapeutic composition is not limited, but is, for example, 30 ml to 50 ml, and can be appropriately changed according to the number of cells administered.
  • a therapeutic composition is obtained by mixing a cell preparation with an aqueous glucose solution or Ringer's acetate solution
  • the amount of the aqueous glucose solution or Ringer's acetate solution is appropriately changed according to the number of cells administered and the cell concentration of the cell preparation. For example, 1 to 8 ml of cell preparation and 29 to 22 ml of glucose aqueous solution or Ringer's acetate solution are mixed to make a total volume of 30 ml, or 9 to 16 ml of cell preparation and 41 to 34 ml of glucose aqueous solution or Ringer's acetate solution are mixed to make the total volume. The case where it makes 50 ml is mentioned.
  • the amount of aqueous glucose solution or Ringer's acetate solution is such that the cell preparation is diluted about 2.5 to 100 times, about 5 to 100 times, or about 2.5 to 75 times.
  • the cell concentration of the therapeutic composition is not limited, but is usually 10 3 cells / ml to 10 8 cells / ml, preferably 10 3 cells / ml to 10 6 cells / ml, more preferably 10 4 cells / ml. ⁇ 10 6 pieces / ml.
  • aqueous glucose solution an aqueous glucose solution of about 3% to about 10%, preferably about 5% to about 10%, more preferably about 5% is used.
  • the aqueous glucose solution may be commercially available as an injection solution, for example, Otsuka Sugar Solution 5% (Otsuka Pharmaceutical Factory), 5% Sugar Solution Kit H (Nipro Corporation), Photo Sugar Solution 5% (Light Pharmaceutical Co., Ltd.).
  • the acetate Ringer solution is an infusion solution in which acetate ions are added to Ringer solution obtained by adding K + and Ca 2+ to physiological saline.
  • Ringer's acetate solution usually contains sodium chloride, potassium chloride, sodium acetate hydrate, and sodium acetate hydrate.
  • the Ringer's acetate solution preferably contains 0.6% sodium chloride, 0.03% potassium chloride, 0.02% calcium chloride hydrate, and 0.38% sodium acetate hydrate.
  • What is marketed as an injection solution can be used as a Ringer's acetate solution, for example, Solaceto F (Nipro Corporation), Solugen F injection (Hikari Pharmaceutical Co., Ltd.), etc. are illustrated.
  • the therapeutic composition comprises mammalian cells in about 3% to about 10% aqueous glucose solution or Ringer's acetate solution. In another embodiment, the therapeutic composition comprises mammalian cells in a mixture of about 3% to about 10% glucose or Ringer's acetate and cell preservation solution.
  • the therapeutic composition may contain mammalian cells in a mixture of about 3% to about 10% glucose or acetate Ringer's solution and phosphate buffered saline containing about 5% DMSO, eg, 99% to 60% mixture of about 3% to about 10% aqueous glucose solution or Ringer's acetate solution and 1% to 40% phosphate buffered saline (eg, D-PBS) containing about 5% DMSO Or phosphate buffered saline containing 99% to 80%, about 3% to about 10% aqueous glucose or Ringer's acetate solution and 1% to 20% about 5% DMSO (eg, D- PBS).
  • the therapeutic composition includes, in addition to the cells and components of glucose or acetate Ringer's solution, phosphate, DMSO, potassium salt, and sodium salt, and no other components.
  • the therapeutic composition can be administered to a living body by a known method.
  • it can be administered intravascularly (intravenous or intraarterial) or intrathecally, or directly transplanted into a target tissue.
  • the therapeutic composition is administered intravenously.
  • Intravenous administration can be by injection or infusion.
  • the therapeutic composition can be filled into, for example, an infusion bag or infusion bottle, preferably a plastic infusion bottle, such as PLABOTTLE® (Otsuka Pharmaceutical Factory, Inc.). ).
  • Cell preparations and therapeutic compositions of the present invention include, for example, intervertebral disc herniation, autoimmune diseases (eg systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, aplastic anemia, systemic sclerosis, multiple sclerosis, type 1 Diabetes, autoimmune hepatitis, Crohn's disease (including fistula), ulcerative colitis, etc., cirrhosis, liver failure, chronic hepatitis, hypercholesterolemia, dilated cardiomyopathy, ischemic heart disease, chronic renal failure, acute Nephropathy, bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, emphysema, pulmonary artery hypertension, acute respiratory distress syndrome, chronic obstructive pulmonary disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, central nerve injury, Multiple system atrophy, cerebral infarction, fracture fusion failure, bilateral limb dispar
  • a method for producing a therapeutic composition comprising mammalian cells, comprising dispersing the mammalian cells with about 3% to about 10% aqueous glucose solution or Ringer's acetate solution.
  • the cell is a stem cell.
  • the stem cell is a mesenchymal stem cell. 4).
  • the mesenchymal stem cells are adipose tissue-derived mesenchymal stem cells. 5).
  • the method according to any one of 1 to 4 above, wherein the mammalian cell is a dog or cat cell. 6). 6. The method according to 5 above, wherein the mammalian cell is a canine cell. 7). 7.
  • the dog is a beagle or a golden retriever. 8).
  • the mammalian cell is derived from adipose tissue.
  • the adipose tissue is subcutaneous adipose tissue.
  • the aqueous glucose solution is about 5% aqueous glucose solution.
  • the total amount of the therapeutic composition is 30 to 50 ml. 12 12.
  • the cell preparation comprises cells at about 2.5 ⁇ 10 6 cells / ml. 17. 17.
  • the cell preparation comprises mammalian cells in phosphate buffered saline containing about 5% DMSO. 18.
  • the cell preparation is diluted 2.5 to 100 times with an aqueous glucose solution or Ringer's acetate solution.
  • the therapeutic composition comprises cells at 10 4 cells / ml to 10 6 cells / ml. 20.
  • the therapeutic composition comprises 99% to 60%, about 3% to about 10% glucose aqueous solution or Ringer's acetate solution, and 1% to 40% phosphate buffered saline containing about 5% DMSO. 20. The method according to any one of 1 to 19 above, wherein the mixed solution contains mammalian cells. 21. 21. The method according to any one of 1 to 20 above, wherein the therapeutic composition is for treating a disease in a mammal.
  • a therapeutic composition comprising mammalian cells in about 3% to about 10% aqueous glucose solution or Ringer's acetate solution, or a mixture of said aqueous glucose solution or Ringer's acetate solution and cell preservation solution.
  • 2 ' The therapeutic composition according to 1 'above, wherein the cell is a stem cell.
  • 3 ' The therapeutic composition according to 2 'above, wherein the stem cells are mesenchymal stem cells.
  • the therapeutic composition comprises 99% to 60%, about 3% to about 10% glucose aqueous solution or Ringer's acetate solution, and 1% to 40% phosphate buffered saline containing about 5% DMSO.
  • a cell preparation comprising mammalian cells, the cell preparation being used to obtain a therapeutic composition for dispersing the cells with about 3% to about 10% glucose aqueous solution or Ringer's acetate solution to administer to mammals.
  • 2 '' The cell preparation according to 1 '' above, wherein the cell is a stem cell.
  • 3 '' The cell preparation according to 2 '' above, wherein the stem cells are mesenchymal stem cells.
  • 4 ''. The cell preparation according to 3 '' above, wherein the mesenchymal stem cells are adipose tissue-derived mesenchymal stem cells. 5 ''. 5.
  • the cell preparation according to any one of the above 1 ′′ to 17 ′′, wherein the therapeutic composition comprises cells at 10 4 cells / ml to 10 6 cells / ml. 19 ''.
  • the therapeutic composition comprises 99% to 60%, about 3% to about 10% glucose aqueous solution or Ringer's acetate solution, and 1% to 40% phosphate buffered saline containing about 5% DMSO.
  • a method of treating a disease in a mammal comprising: Dispersing mammalian cells with about 3% to about 10% aqueous glucose solution or Ringer's acetate solution to obtain a therapeutic composition, and administering the resulting therapeutic composition to a mammal.
  • 2 ''' The method according to 1 '''above, wherein the cell is a stem cell. 3 '''. The method according to 2 ′ ′′ above, wherein the stem cell is a mesenchymal stem cell. 4 '''. The method according to 3 ''above, wherein the mesenchymal stem cells are adipose tissue-derived mesenchymal stem cells. 5 '''.
  • Method. 14 '''. The method of 13 ′ ′′ above, wherein the cell preparation comprises cells at 2.5 ⁇ 10 6 to 5 ⁇ 10 6 cells / ml. 15 '''.
  • the cell preparation comprises cells in phosphate buffered saline containing about 5% DMSO.
  • the therapeutic composition comprises 99% to 60%, about 3% to about 10% glucose aqueous solution or Ringer's acetate solution, and 1% to 40% phosphate buffered saline containing about 5% DMSO.
  • the method according to any one of 1 ′ ′′ to 18 ′ ′′, wherein mammalian cells are contained in the mixed solution.
  • the same frozen cells (5 ⁇ 10 6 cells / ml) as described above were thawed, and 1 ml of this cell solution was prepared using 20% aqueous glucose solution, 20% aqueous glucose solution and distilled water for injection. 5%, 5%, 7%, 10% aqueous glucose solution or 4 ml of physiological saline solution, and 5 ml of the resulting cell suspension (1 ⁇ 10 6 cells / ml) is filled into an infusion bag and mixed occasionally. While standing for 30 to 40 minutes, cell aggregation was visually confirmed. In addition, cell aggregation was also confirmed when 5 ⁇ 10 6 cells were dispersed in 5 ml of 5% aqueous glucose solution after removing the cell preservation solution.
  • the survival rate of the cells dispersed with 5% glucose aqueous solution (product name: Otsuka sugar solution 5%) or acetate Ringer's solution (product name: Solaceto F infusion solution) was evaluated.
  • the same frozen cells as described above were thawed, the cell preservation solution was removed, and 5 ⁇ 10 6 cells were suspended in the solutions 1 to 9 (5 ml each) in Table 6, and the cell viability after 3 hours was evaluated. As a result, good cell viability was obtained in solutions 1 to 5, 7, and 9 (FIG. 2).

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Abstract

L'invention concerne : un procédé de fabrication d'une composition thérapeutique contenant des cellules de mammifère, ledit procédé comprenant la dispersion des cellules de mammifère dans une solution aqueuse de glucose ayant une concentration d'environ 3 à 10 % ou une solution d'acétate de Ringer ; une préparation cellulaire pouvant être utilisée pour sa fabrication ; une méthode thérapeutique utilisant la composition thérapeutique, etc.
PCT/JP2018/021333 2017-06-06 2018-06-04 Procédé de réduction de l'agrégation cellulaire et composition thérapeutique à agrégation cellulaire réduite WO2018225673A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009031606A1 (fr) * 2007-09-07 2009-03-12 Jcr Pharmaceuticals Co., Ltd. Agents thérapeutiques et prophylactiques pour l'arthrite
JP2009242265A (ja) * 2008-03-28 2009-10-22 Jcr Pharmaceuticals Co Ltd アトピー性皮膚炎治療剤
JP2012115253A (ja) * 2010-11-09 2012-06-21 Otsuka Pharmaceut Factory Inc 幹細胞懸濁液
JP2016008198A (ja) * 2014-06-24 2016-01-18 国立大学法人名古屋大学 間質性膀胱炎の治療

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3015545B1 (fr) 2013-06-28 2018-12-26 Otsuka Pharmaceutical Factory, Inc. Solution contenant un tréhalose et un dextrane pour la transplantation de cellules de mammifères
WO2016076428A1 (fr) 2014-11-14 2016-05-19 日本赤十字社 Procédé et solution pour la cryoconservation de sang de cordon ombilical et de sang périphérique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009031606A1 (fr) * 2007-09-07 2009-03-12 Jcr Pharmaceuticals Co., Ltd. Agents thérapeutiques et prophylactiques pour l'arthrite
JP2009242265A (ja) * 2008-03-28 2009-10-22 Jcr Pharmaceuticals Co Ltd アトピー性皮膚炎治療剤
JP2012115253A (ja) * 2010-11-09 2012-06-21 Otsuka Pharmaceut Factory Inc 幹細胞懸濁液
JP2016008198A (ja) * 2014-06-24 2016-01-18 国立大学法人名古屋大学 間質性膀胱炎の治療

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