Classifications

• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
  • A01N1/02—Preservation of living parts
  • A01N1/0205—Chemical aspects
  • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
  • A01N1/02—Preservation of living parts

Definitions

• This invention relates to the technical field of cooling organs in transplantation medicine, in particular to a cooling gel.
• cooling the tissue or organ to be transplanted is a common measure to reduce the speed of metabolic processes and achieve a preservation of the organs. Temperatures as low as ⁇ 5° C. are achieved by means of finely crushed ice preparations. Since it is necessary to work in a sterile environment, this finely crushed ice usually is produced by freezing sterile isotonic saline or 5% glucose solution, which are commercially available as infusion solutions filled in bags.
• Freezing is effected in the packaging material at temperatures ⁇ 15° C. in a deep freezer. Subsequently, the ice block obtained is converted into a finely crushed ice slush by applying mechanical energy onto the bag, such as a hammer blow. Subsequently, the comminuted ice is removed in a sterile environment and the organ or tissue is treated with the same.
• the crushed ice is subject to further requirements. First of all, it should be comminuted so fine that it can be formed around the organ region and can also be placed around smaller areas. Furthermore, the aqueous solution obtained when melting the ice slush should rather have a pH in the range between 5 and 7 and should be approximately isotonic, i.e. should rather have physiological conditions, so as not to damage the tissue. All substances obtained must be medically compatible, so that the rest of the thawed solution possibly left in the operating area does not present a risk. The latter is achieved by freezing isotonic, pH-neutral 0.9% saline or e.g. also a 5% glucose solution, which are employed as infusion solutions. After melting such solutions, the same are physiologically well-tolerated and do not damage the organs.
• the ice mixtures described above have the disadvantage that they are not optimal in mechanical terms for enclosing e.g. small organ areas, i.e. they have no flexibility.
• EP 1 649 842 describes the use of a cooling gel for cooling organs as a cooling material in an envelope suitable for this purpose.
• the direct contact of the cooling gel with the organ is not described.
• a composition which is particularly suitable for such purpose is not disclosed.
• EP 970 707 describes a gelatin-based cooling gel.
• the cooling gel described there neither is used for cooling organs nor is the composition adapted for such application.
• a cooling gel of the invention is soft and formable at temperatures between ⁇ 5° C. and +4° C. and while being physiologically acceptable, also has the necessary cold capacity for cooling organ and tissue regions.
• cooling gel is liquefied at temperatures >5° C. and easily runs off from the organs after thawing and thus is easily removable.
• the preparation exclusively contains non-toxic constituents, so that, in case residual amounts are left in the organism after performing the cooling, the same is completely harmless.
• Such cooling gel has a gelatin content of 3-20 wt-%, preferably between 6 and 10 wt-%.
• Such composition advantageously contains electrolytes which are physiologically acceptable, such as sodium, potassium, magnesium, calcium and lactate, at least are isotonized, but possibly can also be enriched up to an osmolarity of 600 mosmol/kg.
• the gelling range of such gels ideally lies between +5° C. and ⁇ 5° C.
• Succinyl gelatin is a gelatin cross-linked by succinic acid.
• cooling gels in which succinyl gelatin is used as gelatin therefore have an ideal mix of mechanical stability and good formability within the highly relevant temperature range of ⁇ 5° C. to +4° C. and in addition have a good cooling capacity.
• a cooling preparation of the invention can be produced from an aqueous solution, be filled in plastic containers and sterilized, similar to the case of known gelatin preparations which are used as plasma volume substitute.
• the cooling preparation only consists of gelatin or gelatin derivatives, lactate and electrolytes. Electrolytes preferably are contained in the following concentrations: 150-300 mmol/l sodium, 5-10 mmol/l potassium, 1.5-3 mmol/l magnesium, 1.5-3 mmol/l calcium, 100-200 mmol/l chloride. Lactate preferably is contained in the concentration of 30-60 mmol/l.
• compositions of the invention differ from the latter preparations by the much higher content of gelatin derivative and possibly also by the higher content of electrolytes.
• the aqueous solution thus obtained is filled in a container, such as a polyethylene or PVC bag, and is converted into the transparent gel form at temperatures of ⁇ 8° C. to 3° C. (e.g. by putting it into a freezer adjusted to the corresponding temperature).
• gelling is performed at temperatures of ⁇ 5° C. to 1° C.
• the preparation can be deep-frozen at ⁇ 10° C. to ⁇ 30° C., preferably ⁇ 15° C. to ⁇ 20° C., particularly preferably at approximately ⁇ 18° C., and the deep-frozen hard preparation can then be heated to a temperature of ⁇ 5° C. or more and thus be transferred into a gel-like consistency.
• a mechanically easily formable structure thus is assumed within about 60 minutes, which is transparent.
• This mass can be stored in a refrigerator at temperatures of ⁇ 5° C. to 4° C. for up to 24 hours, and in this period it can be used as a cooling preparation.
• a deep-frozen preparation can also be put into a refrigerator of 2-8° C. Within about 12 hours, the same assumes a formable, transparent gel-ice structure which can likewise be used as a cooling preparation within the following 24 hours.
• Gelatin is a collagenic protein.
• collagen occurring in the animal body is not water-soluble. It consists of triple helices of the collagenic proteins, which congregate to collagen fibrils and thus form bones, cartilages, vessels etc.
• Gelatin usually is obtained from animal collagen, frequently from pork rinds, but every gelatin from natural collagen is suitable for the invention.
• collagen first is digested and the triple helices are broken up. The collagenic protein thus is transferred into a water-soluble form. With correspondingly high gelatin concentrations in the solution, the collagenic proteins are cross-linked at lower temperatures and form a gel-like consistency.
• the properties of the natural gelatin can be changed by adding an agent to the gelatin which changes the cross-linking properties of the gelatin.
• cross-linking agents such as urea or succinic acid (succinyl acid) or its salt, gelatin derivatives are obtained.
• gelatin or gelatin derivatives in medical solutions is known from commonly used plasma or blood volume expanders. These solutions can contain gelatin derivatives such as succinyl gelatin, oxypolygelatin or urea cross-linked gelatin solutions, but differ from the preparations of the invention by the much smaller concentration range of the gelatin derivative.
• the invention is practicable for the skilled person by varying said parameters for each physiologically acceptable cross-linked gelatin.
• succinyl gelatin compared to natural gelatin, urea cross-linked gelatin or oxypolygelatin, is particularly useful to form mechanically sufficient gels at deep temperatures.
• succinyl gelatin describes a gelatin derivative cross-linked with succinic acid or its salt or succinic anhydride, and the term gelatin succinate also is used as a synonym.
• the preparations of the invention ideally should be sufficiently liquid at room temperature, so that they can easily be removed again from the cooled organ area.
• the liquid phase offers the advantage at room temperature that such solutions can be filled or produced more easily.
• gelatin concentrations below 3% like those of commercially available gelatin infusion solutions used as plasma volume expanders, do not lead to gels with the desired mechanical stability and, depending on their chemical structure, in part form gels only with difficulty. Such preparations pass over too fast, i.e. within an only small temperature range, from a highly formable but mechanically not sufficiently stable condition into a mechanically highly stable non-formable condition.
• the osmolality can be adjusted up to 650 mosmol/kg, since such a range still is acceptable for infusions which are injected into a peripheral vein.
• An osmolality in the range from 280-600 is preferred, and a range from 400-550 mosmol/kg is particularly preferred.
• the crystallization temperature of the ice can be adjusted correspondingly.
• Gelatin preparations with gelatin succinate with a concentration >3% are quite particularly preferred. This gelatin derivative forms mechanically sufficiently stable gels already at relatively low concentrations as compared to oxypolygelatin derivatives and urea cross-linked gelatin preparations.
• the strength of the gelatin preparations can be increased up to a content of 3 mmol/l by a physiological addition of magnesium or calcium.
• the preferred solutions can be prepared from photogelatin, although all natural gelatins and their derivatives can be used. Gelatins or gelatin derivatives with a mean molecular weight of 25-45 kD are preferred. The same are dissolved in water for injections and possibly decomposed thermally, thereafter cross-linked or derivatized with succinic anhydride.
• the solutions can be depyrogenized by means of hydrogen peroxide.
• the solution After addition of the electrolytes for obtaining isotonic conditions or of calcium or magnesium, the solution ideally is sterile-filtered, filled in plastic containers and/or heat-sterilized.
• T 0 ⁇ 5° C. ⁇ 5° C.
• T 1 h ⁇ 2.5° C. ⁇ 3.5° C.
• T 2 h ⁇ 2° C. ⁇ 3.5° C.
• T 3 h ⁇ 1° C. ⁇ 3.5° C.
• T 4 h 0° C. 0° C.
• Both gels are mechanically stable with hardly a tendency towards flowing.

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• 2007
  • 2007-10-01 DE DE102007047040A patent/DE102007047040A1/de not_active Ceased
• 2008
  • 2008-09-17 US US12/733,970 patent/US20100297599A1/en not_active Abandoned
  • 2008-09-17 CN CN200880109576A patent/CN101808510A/zh active Pending
  • 2008-09-17 WO PCT/EP2008/007789 patent/WO2009046820A2/de active Application Filing
  • 2008-09-17 JP JP2010526197A patent/JP2010540478A/ja active Pending
  • 2008-09-17 EP EP08802312.2A patent/EP2205066B1/de not_active Not-in-force
  • 2008-09-17 EP EP16161850.9A patent/EP3123861A1/de not_active Withdrawn
• 2013
  • 2013-12-06 US US14/098,903 patent/US8865397B2/en not_active Expired - Fee Related

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