EP1626705A1 - Low sodium solution - Google Patents
Low sodium solutionInfo
- Publication number
- EP1626705A1 EP1626705A1 EP04733508A EP04733508A EP1626705A1 EP 1626705 A1 EP1626705 A1 EP 1626705A1 EP 04733508 A EP04733508 A EP 04733508A EP 04733508 A EP04733508 A EP 04733508A EP 1626705 A1 EP1626705 A1 EP 1626705A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- glucose
- sodium
- compartment
- solution
- concentration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims description 132
- 239000011734 sodium Substances 0.000 title claims description 132
- 229910052708 sodium Inorganic materials 0.000 title claims description 130
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 129
- 239000008103 glucose Substances 0.000 claims abstract description 128
- 239000000243 solution Substances 0.000 claims abstract description 103
- 239000008155 medical solution Substances 0.000 claims abstract description 40
- 238000000502 dialysis Methods 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 35
- 229910001415 sodium ion Inorganic materials 0.000 claims abstract description 19
- 239000007857 degradation product Substances 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 52
- 239000011575 calcium Substances 0.000 claims description 52
- 229910052791 calcium Inorganic materials 0.000 claims description 52
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 51
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 43
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 41
- 239000011777 magnesium Substances 0.000 claims description 41
- 229910052749 magnesium Inorganic materials 0.000 claims description 41
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 34
- 238000004659 sterilization and disinfection Methods 0.000 claims description 33
- 239000012530 fluid Substances 0.000 claims description 28
- 239000003792 electrolyte Substances 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229960001031 glucose Drugs 0.000 claims 19
- 235000001727 glucose Nutrition 0.000 claims 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 59
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 54
- 229940001447 lactate Drugs 0.000 description 45
- 235000002639 sodium chloride Nutrition 0.000 description 28
- 239000011780 sodium chloride Substances 0.000 description 27
- 241000700159 Rattus Species 0.000 description 14
- 239000000385 dialysis solution Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- 239000006172 buffering agent Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 210000004379 membrane Anatomy 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 239000003330 peritoneal dialysis fluid Substances 0.000 description 8
- 238000000108 ultra-filtration Methods 0.000 description 7
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 6
- 239000001110 calcium chloride Substances 0.000 description 6
- 229910001628 calcium chloride Inorganic materials 0.000 description 6
- 238000005094 computer simulation Methods 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 238000004088 simulation Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- NOEGNKMFWQHSLB-UHFFFAOYSA-N 5-hydroxymethylfurfural Chemical compound OCC1=CC=C(C=O)O1 NOEGNKMFWQHSLB-UHFFFAOYSA-N 0.000 description 5
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 4
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- ZGCHLOWZNKRZSN-NTSWFWBYSA-N 3-deoxyglucosone Chemical compound OC[C@@H](O)[C@@H](O)CC(=O)C=O ZGCHLOWZNKRZSN-NTSWFWBYSA-N 0.000 description 3
- UHPMJDGOAZMIID-UHFFFAOYSA-N 3-deoxyglucosone Natural products OCC1OC(O)C(=O)CC1O UHPMJDGOAZMIID-UHFFFAOYSA-N 0.000 description 3
- 206010016803 Fluid overload Diseases 0.000 description 3
- 206010069568 Ultrafiltration failure Diseases 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- -1 organic acid salts Chemical class 0.000 description 3
- 210000003200 peritoneal cavity Anatomy 0.000 description 3
- 230000008092 positive effect Effects 0.000 description 3
- WNKYVCKDIDTELO-NJXYFUOMSA-N (2r)-6-hydroxy-2-(hydroxymethyl)-2h-pyran-5-one Chemical compound OC[C@@H]1OC(O)C(=O)C=C1 WNKYVCKDIDTELO-NJXYFUOMSA-N 0.000 description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 2
- 229940015043 glyoxal Drugs 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 2
- 239000002357 osmotic agent Substances 0.000 description 2
- 210000004303 peritoneum Anatomy 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000001540 sodium lactate Substances 0.000 description 2
- 229940005581 sodium lactate Drugs 0.000 description 2
- 235000011088 sodium lactate Nutrition 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 241001065350 Lundia Species 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 210000003815 abdominal wall Anatomy 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000009141 biological interaction Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000002844 continuous effect Effects 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 239000000819 hypertonic solution Substances 0.000 description 1
- 229940021223 hypertonic solution Drugs 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 235000003715 nutritional status Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
- A61M1/1654—Dialysates therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
- A61M1/287—Dialysates therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the present invention relates to a medical solution, a method for preparing the medical solution, a container for preparation of the solution, use of said solution for manufacture of a medicament for treatment of dialysis, and a method of treatment of dialysis with said solution.
- Peritoneal dialysis is a method for exchanging solutes and water in capillary vessels of a patient's peri- toneum with hypertonic solution, which is infused into the peritoneal cavity.
- the principle of this method is diffusion of solutes transported according to the concentration gradient and water migration due to osmotic differences. This method has many advantages, e.g. no special apparatus is commonly required. It gives less influence on the hemodynamics because extracorporeal circulation of the patient's blood is not necessary, and further the peritoneal dialysis is a continuous treatment and therefor more similar to the function of the kidneys.
- Peritoneal dialysis is usually classified as continuous ambulatory peritoneal dialysis (CAPD) , intermittent peritoneal dialysis (IPD) , continuous cyclic peritoneal dialysis (CCPD) or automated peritoneal dialysis (APD) .
- peritoneal dialysis a catheter is permanently implanted in the abdominal wall of the patient and about 1.5 to 2.5 1 of the dialysis fluid is normally introduced via the catheter into the peritoneal cavity. The peritoneal cavity is flooded with this fluid, left for an appropriate lapse of time and then drained. Removal of solutes and water takes place across the peritoneum, which acts as a semipermeable membrane.
- the dialysis fluid normally used for peritoneal dialysis is an aqueous solution comprising an osmotic agent such as glucose and the like, electrolytes such as sodium, potassium, calcium, magnesium, and organic acid salts such as sodium lactate, sodium bicarbonate, or sodium pyruvate.
- the components of these peritoneal dialysis fluids are selected to control the levels of electrolytes or the acid-base equilibrium, to remove waste materials and to efficiently carry out ultrafiltration.
- Peritoneal dialysis patients tend to have disturb- ances in their sodium and water balance. To correct this, it has previously been necessary to increase the glucose concentration in the dialysate in order to remove enough water from the patient. Since glucose load in peritoneal dialysis patients is a burden on their nutritional sta- tus, it is important to reduce the glucose load as much as possible.
- EP-A1-1 008 341 discloses a glucose-containing pre- paration for peritoneal perfusion also containing sodium and having an almost neutral pH.
- GDP Glucose Degradation Products
- aldehydes Nailsson-Thorel CB, Muscalu N, Andren AH, Kjellstrand PT, and Wieslander AP : Heat sterilisation of fluids for peritoneal dialysis gives rise to aldehydes. Perit. Dial. Int. 13 (3) : 208-213, 1993; and EP-Bl 0 668 785) .
- These aldehydes are not only known to be cytotoxic but also to severely accelerate AGE (advanced glycation end product) formation.
- the chemical nature of the GDP in peritoneal dialysis fluids is not yet fully understood.
- One of the best known GDP is 5-HMF (5-Hydroxymethylfuraldehyde) and various pharmacopoeias restrict the concentration of 5-HMF in medical fluids .
- the limits that are set are, however, often much higher than those found in peritoneal dialysis fluids .
- Other identified and quantified GDPs in peritoneal dialysis fluids are formaldehyde, acetaldehyde, methylgloxal, glyoxal, 2-furaldehyde, 3-deoxyglucosone (3-DG) and 3,4- dideoxyglucosone (3,4-DGE).
- Table 1 demonstrates that the preservation of the membrane was after three months ani- fested as higher ultrafiltration capacity in rats exposed to a low GDP fluid (GambrosolTMtrio) compared to rats exposed to a conventional PD fluid, with acidic pH and high concentration of GDP (Carlsson 0 et al, Preserved ultra- filtration with a PD solution containing less glucose degradation products after 3 months of intraperitoneal injections in rats. Perit. Dial. Int. 21(Suppl. 2): S145, 2001) .
- the first panel shows simulated UF volume in an average patient during .a 4-hour dwell, wherein (Conventional) indicate dialysis using a conventional PD fluid containing 1.5% glucose and 132 mM sodium, (Low sodium) a solution containing 1.5% glucose and 102 mM, and (Compensated low sodium) a solution containing 2.5% glucose and 102 mM sodium.
- the first panel shows that the UF volume is dependent on both the sodium and the glucose concentration.
- the second panel shows sodium removal from the same set of simulations as above. When a low sodium concentration is used, it is important to have a high UF volume as in compensated low sodium where the reduced osmolality due to decreased sodium chloride concentration has been compensated for by an increased glucose concentration, which attenuates the sodium removal.
- the object of the present invention is to solve the above-mentioned problem.
- this object is achieved by a medical solution comprising sodium ions in a concentration of 90-125 mM, glucose in a concentration of 1-5% by weight, and a low level of glucose degradation products, wherein said solution is sterile and has a pH of 6.5-8.0.
- the invention relates to a method for preparing said solution.
- the present invention also relates to a container for preparation of the solution.
- the invention relates to the solution according to the invention for use as a medicament .
- the invention relates to use of said solution for manufacture of a medicament for dialysis .
- the present invention relates to a method for treatment of dialysis, said method comprising administering of the solution according to the invention to a patient having a need therefor.
- Fig. 1 is a graph showing computer simulated fluid (upper diagram) and sodium removal (after three months of peritoneal exposure) with time for a conventional low sodium solution and for a lactate based biocompatible (low GDP and near a neutral pH) low sodium solution according to a preferred embodiment of the invention. Simulations have been performed based on data from the above-mentioned study by Musi et al. The computer model is based on the three-pore model of peritoneal transport. Fig.
- FIG. 2 is a graph (upper diagram) showing computer simulations of the dialysate volume with time for a conventional low sodium solution and for a biocompatible low sodium solution containing bicarbonate according to the invention, as well as a graph (lower diagram) showing the sodium removal with time for a conventional low sodium solution and for a biocompatible low sodium solution containing bicarbonate according to a preferred embodiment of the invention.
- Fig. 3 describes computer simulations using human data.
- the upper panel shows UF volume after 240 min dwell time using either a 1.5% glucose solution with 132 mM sodium (conventional) , a low sodium solution containing 1.5% glucose and 102 mM sodium, or a low sodium solution with the osmolality corrected to the same level as the conventional solution i.e. 2.5% glucose and 102 mM sodium.
- Fig. 4 describes the results from a computer simulation for rats where input data from a study by Musi et al . have been used (Musi B. et al Biocompatibility of peritoneal dialysis fluids: Long-term exposure of nonuremic rats. Perit. Dial. Int. 24(l):37-47, 2004) where rats were treated for 12 weeks with either a conventional solution containing GDPs or with a low GDP solution (Gambrosol trio) . Data from those two groups were used in the simulation (A 0 / ⁇ x and L P S) to test the effect of long- term treatment with different GDP content.
- the first and second bar represent simulations using a 3.9% glucose solution with 132 mM sodium, while the third and fourth bar represent simulations with a solution containing 3.9% glucose and 102 mM sodium.
- the upper panel shows UF volume and the lower panel shows sodium removal.
- the container used according to one embodiment of the present invention is based on the multicompartment bag disclosed in WO 99/27885 (Gambro AB) , in which diffe- rent solutes may be kept in separate compartments of the bag with a view to, inter alia, regulating the concentration of active ingredients in the finally prepared peritoneal dialysis solution.
- the container in WO 99/27885 thus comprises a large compartment containing sodium bicarbonate, sodium lactate and sodium chloride, as well as a plurality of small compartments containing e.g. calcium ions, sodium ions, chloride ions, and glucose.
- the container is sterilised in an autoclave with the solutions in situ in said co - partments .
- One or more of the small compartments are connected to the large compartment by frangible pins or peelable seals, whereby the contents of the compartments may be mixed and the peritoneal dialysis solution is obtained.
- Fig. 1 shows computer simulations of intraperitoneal volume and sodium removal from rats treated with conventional and biocompatible peritoneal dialysis solutions respectively during three months.
- the simulation is performed for a 600 g rat treated with a PD solution containing 3.9% glucose and 102 mM sodium. Since the UF volume is preserved in animals treated with a biocompatible solution, the effect from a low sodium solution is more pronounced in this case compared to animals treated with conventional solutions. More precisely, from the graphs in Figs 1 and 2, it can be seen that the sodium removal with time for a biocompatible, with or without bicarbonate, low sodium solution according to a preferred embodiment of the invention is more pronounced than the sodium removal with time for a conventional low sodium solution. Thus, the sodium overload decreases more efficiently with a bio- compatible low sodium solution according to the invention than with a conventional low sodium solution. The concentration of sodium, for both solutions, is in this embodiment 102 mM.
- dialysate volume is larger for a biocompatible, with or without bicarbonate, low sodium solution according to one embodiment of the invention than for a conventional low sodium solution.
- concentration of sodium for these solutions is also 102 mM.
- ⁇ UL Na in connection with Figs 1 and 2 means ultra low sodium content.
- Bicarbonate alone, or in combination with reduction of GDP, can also in the short-term increase ultrafilt- ration, presumably the result of the neutral pH inducing less vasodilatation of the capillaries.
- a biocompatible low sodium solution according to the present invention comprising sodium ions in a concentration of 90-125 mM, glucose in a concentration of 1-5% by weight, and a low level of glucose degradation products, wherein said solution is sterile and has a pH of 6.5-8.0, is prepared in a multicompartment container, e.g. according to WO 99/27885.
- a solution comprising sodium ions is thus provided in a first compartment of the container and a solution comprising glucose is provided in at least one further compartment that is delimited from the first compartment during sterilisation of the container and its contents.
- the whole container may thus be heat sterilised with the solutions in situ in said compartments.
- the sterilisation is, for instance, heat sterilisation effected in an autoclave at a temperature of at least 100°C, e.g. above 120°C.
- the sterilisation time may vary depending on the sterilisation temperature, the type of container and the contents therein to be sterilised.
- the sterilisation can, however, also be effected for separated interconnectable containers comprising the solutions to be sterilised and provided with connection means with sterile connecting valves for sterile connection.
- the contents of the first compartment may be mixed with the contents of at least one of said further compartments to form a biocompatible solution with the characteristics as stated above.
- the prepared medical solution according to the invention comprises in one embodiment a concentration of sodium ions of 100-115 mM. Further, a prepared medical solution according to the invention comprises in one embodiment a glucose concentration of 1.5-4% by weight. Even further, in another embodiment a prepared medical solution according to the invention has a pH of 7.0-7.8. In another embodiment the medical solution, after mixing, comprises a concentration of sodium ions of 102 M, a glucose concentration of either 1.5%, 2.5% or 3.9% by weight and a pH of 7.4. In still another embodiment the medical solution contains, after mixing, a sodium concentration of 102-115 mM and a glucose concentration of 2.0%, 2.5%, or 4.3% by weight and a pH of 7.4.
- the medical solution after mixing, also comprises bicarbonate at a concentration of 5 mM to 45 mM, e.g. 25 mM to 40 mM, or lactate at a concentration of 5 mM to 45 mM, e.g. 25 mM to 40 mM, or a combination of both where the total concentration of bicarbonate and lactate does not exceed 45 mM, e.g. a concentration of lactate of 10 mM and a concentration of bicarbonate of 30 mM.
- the medical solution also comprises other electrolytes, e.g. one or more of potassium, calcium and magnesium.
- the container used for the method of preparing the medical solution according to the invention comprises two compartments, i.e. a first compartment comprising sodium ions and a second compartment comprising glucose.
- the container used for the preparing of the medical solution comprises three compartments, i.e. a first compartment comprising sodium ions and two compartments comprising glucose.
- the glucose concentration in at least one further compartment is provided to be above 10%, e.g. above 20%, such as above 40%, by weight.
- the pH in the at least one further compartment including glucose is 2-5.
- sodium ions may also be provided in the at least one further compartment containing glucose.
- the first compartment of the container further also contains bicarbonate ions and/or lactate.
- the container used according to the present inven- tion may also contain one or more further compartments in addition to the three compartments mentioned above, if desired.
- each compartment is in practice not critical. Each compartment volume depends on the volume of constituent to be present therein.
- the compartment which accommodates the buffer solution is larger than the compartment/compartments accommodating the glucose solution and is also the compartment in which the solution/solutions from the other compartments is/are mixed with the sodium solution.
- the solution according to the invention is a solution for use as a medicament.
- the medical solution according to the invention is a dialysis solution, e.g. a peritoneal dialysis solution.
- the present invention also relates to a method of treatment of dialysis, wherein the solution according to the invention is administered to a patient having a need therefor.
- the method for treatment according to a preferred embodiment is peritoneal dialysis.
- low levels of glucose degradation products means that the amount of degradation products from the glucose is so low in the medical solu- tion according to the present invention that it is not more toxic to cultured cells than dialysis solutions according to prior art.
- the total sum of the glucose degradation products (5-HMF, 3,4-DGE, glyoxal, methyglyoxal, 3-DG, formalde- hyde, and acetaldehyde) in the biocompatible low sodium solution is below 150 ⁇ M for fluids with 1.5% glucose, e.g. below 75 ⁇ M, below 225 ⁇ M for fluids with 2.5% glucose, e.g.
- biocompatible solution means that any biological interaction that is not intended as a part of the treatment does not exist between the solution, and the substances therein, and the living organism, thus not causing toxic or injurious effects on bio- logical function.
- sterile used herein means a condition of a medical device or solution that is free from viable micro-organisms .
- the medical solution according to the present inven- tion may also be accomplished by having one or more of the substances in one or more compartments in powder form, which powder is to be mixed with at least one solution to form the final medical solution.
- the peritoneal dialysis solution according to the present invention may also comprise other physiologically compatible constituents, e.g. further osmotic agents, such as proteins and peptides, e.g. albumin, as well as antioxidants, such as bisulphite.
- physiologically compatible constituents e.g. further osmotic agents, such as proteins and peptides, e.g. albumin, as well as antioxidants, such as bisulphite.
- the peritoneal dialysis solution of the present invention described above is applicable not only to con- tinuous ambulatory peritoneal dialysis (CAPD) but also to intermittent peritoneal dialysis (IPD) , continuous cyclic peritoneal dialysis (CCPD) , and automated peritoneal dialysis (APD) .
- CAPD con- tinuous ambulatory peritoneal dialysis
- IPD intermittent peritoneal dialysis
- CCPD continuous cyclic peritoneal dialysis
- API automated peritoneal dialysis
- the medical solution according to the present inven- tion has been tested in clinical trials, proving to be hypotensive.
- the low level of sodium ions in the solution increases the sodium removal from the patient's body, affecting the fluid overload in the body, thus reducing the blood pressure.
- the pH of the finally mixed sterilised solution is 6.5-7.5 for a lactate containing solution and 7.0-7.8 for a bicarbonate and bicar- bonate/lactate containing solution.
- Two compartment container with a first compartment 1 comprising sodium ions and a second compartment 2 comprising glucose as well as calcium chloride.
- the container After providing the solution comprising sodium ions in the first compartment and the solution comprising glucose in the second compartment, the container, with the two compartments and the solutions therein, is sterilised at a temperature of 121 °C.
- the compartments are delimited from each other during the sterilisation.
- the sterile contents of compartment 1 and 2 are mixed to constitute the sterile final medical solution .
- Compartment 1 Volume 1960 ml Sodium 100.38 mM Calcium 0.70 mM Magnesium 0.27 mM Chloride 60.23 mM Lactate 31.58 mM Bicarbonate 10.50 mM
- the method is accomplished according to Example 1, except that after the sterilisation the contents of compartment 1 are mixed with either the contents of compartment 2 or the contents of compartment 3 or the contents of both compartments 2 and 3.
- the method is accomplished according to Example 1, except that after the sterilisation the contents of compartment 1 are mixed with either the contents of compartment 2 or the contents of compartment 3 or the contents of both compartments 2 and 3.
- first compartment 1 comprising other electrolytes and buffering substances and two further compartments 2 and 3 comprising glucose as well as sodium chloride.
- Example 5 Three compartment container where all compartments contain sodium chloride and in addition, first compartment 1 comprising other electrolytes and buffering substances and two further compartments 2 and 3 comprising glucose as well as sodium chloride.
- first compartment 1 comprising other electrolytes and buffering sub ⁇ stances and two further compartments 2 and 3 comprising glucose as well as sodium chloride and calcium chloride,
- first compartment 1 comprising other electrolytes and buffering substances and two further compartments 2 and 3 comprising glucose as well as sodium chloride.
- Lactate can be exchanged either completely or partially with another buffering substance, e.g. bicarbonate.
- the method is accomplished according to Example 1, except that after the sterilisation the contents of com- partment 1 are mixed with either the contents of compartment 2 or the contents of compartment 3 or the contents of both compartments 2 and 3.
- first compartment 1 comprising other electrolytes and buffering substances and two further compartments 2 and 3 comprising glucose as well as sodium chloride.
- first compartment 1 comprising other electrolytes and buffering substances and two further compartments 2 and 3 comprising glucose as well as sodium chloride and calcium chloride
- Compartment 1 Volume 1900 ml
- first compartment 1 comprising other electrolytes and buffering sub- stances and two further compartments 2 and 3 comprising glucose as well as sodium chloride.
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15180762.5A EP2962683A1 (en) | 2003-05-28 | 2004-05-17 | Low sodium solution |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0301577A SE0301577L (en) | 2003-05-28 | 2003-05-28 | Low sodium solution |
US52372203P | 2003-11-19 | 2003-11-19 | |
PCT/SE2004/000754 WO2004105730A1 (en) | 2003-05-28 | 2004-05-17 | Low sodium solution |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP15180762.5A Division EP2962683A1 (en) | 2003-05-28 | 2004-05-17 | Low sodium solution |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1626705A1 true EP1626705A1 (en) | 2006-02-22 |
Family
ID=20291448
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04733508A Ceased EP1626705A1 (en) | 2003-05-28 | 2004-05-17 | Low sodium solution |
EP15180762.5A Withdrawn EP2962683A1 (en) | 2003-05-28 | 2004-05-17 | Low sodium solution |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP15180762.5A Withdrawn EP2962683A1 (en) | 2003-05-28 | 2004-05-17 | Low sodium solution |
Country Status (4)
Country | Link |
---|---|
EP (2) | EP1626705A1 (en) |
CA (2) | CA2524094C (en) |
SE (1) | SE0301577L (en) |
WO (1) | WO2004105730A1 (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8202248B2 (en) | 2004-08-18 | 2012-06-19 | Sequana Medical Ag | Dialysis implant and methods of use |
AU2012217696B2 (en) | 2011-02-16 | 2015-11-12 | Sequana Medical Nv | Apparatus and methods for treating intracorporeal fluid accumulation |
US8585635B2 (en) | 2012-02-15 | 2013-11-19 | Sequana Medical Ag | Systems and methods for treating chronic liver failure based on peritoneal dialysis |
WO2017191301A1 (en) | 2016-05-06 | 2017-11-09 | Gambro Lundia Ab | System for proportioning fluids |
US10716922B2 (en) | 2016-08-26 | 2020-07-21 | Sequana Medical Nv | Implantable fluid management system having clog resistant catheters, and methods of using same |
US10769244B2 (en) | 2016-08-26 | 2020-09-08 | Sequana Medical Nv | Systems and methods for managing and analyzing data generated by an implantable device |
US11559618B2 (en) | 2017-05-24 | 2023-01-24 | Sequana Medical Nv | Formulations and methods for direct sodium removal in patients having severe renal dysfunction |
US10898631B2 (en) * | 2017-05-24 | 2021-01-26 | Sequana Medical Nv | Direct sodium removal method, solution and apparatus to reduce fluid overload in heart failure patients |
WO2024008684A1 (en) | 2022-07-08 | 2024-01-11 | Zytoprotec Gmbh | Peritoneal dialysis fluid |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5589197A (en) * | 1993-10-04 | 1996-12-31 | Baxter International, Inc. | Low sodium peritoneal dialysis solution |
WO2001017534A1 (en) * | 1999-09-10 | 2001-03-15 | Baxter International Inc. | Bicarbonate-based solution in two parts for peritoneal dialysis or substitution in continuous renal replacement therapy |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9103395D0 (en) | 1991-11-18 | 1991-11-18 | Gambro Ab | SYSTEM USING ENSTERIL MEDICAL SOLUTION CONTAINING GLUCOSE OR GLUCOSE-LIKE SUBSTANCES AND A SOLUTION INTENDED FOR THIS SYSTEM |
SE510030C2 (en) * | 1995-08-08 | 1999-04-12 | Gambro Ab | Method of mixing sterile medical solution and container for carrying out the procedure |
ATE270096T1 (en) | 1997-08-22 | 2004-07-15 | Shimizu Pharma | PREPARATION CONTAINING GLUCOSE |
DE19748290B8 (en) * | 1997-10-31 | 2009-09-03 | Fresenius Medical Care Deutschland Gmbh | Solution for peritoneal dialysis |
SE512349C2 (en) | 1997-11-28 | 2000-03-06 | Gambro Lundia Ab | Multi-chamber container for medical solution, procedure for preparation of medical solution for peritoneal dialysis and use of such container for preparation of medical solution |
DE69929550T8 (en) | 1998-05-21 | 2006-12-28 | Nipro Corp. | Albumin-containing solution for peritoneal dialysis |
DE19912850B4 (en) * | 1999-03-22 | 2005-04-07 | Fresenius Medical Care Deutschland Gmbh | Solution, in particular for hemodialysis or peritoneal dialysis, and process for its preparation |
-
2003
- 2003-05-28 SE SE0301577A patent/SE0301577L/en not_active Application Discontinuation
-
2004
- 2004-05-17 CA CA2524094A patent/CA2524094C/en not_active Expired - Lifetime
- 2004-05-17 EP EP04733508A patent/EP1626705A1/en not_active Ceased
- 2004-05-17 EP EP15180762.5A patent/EP2962683A1/en not_active Withdrawn
- 2004-05-17 WO PCT/SE2004/000754 patent/WO2004105730A1/en active Application Filing
- 2004-05-17 CA CA2820174A patent/CA2820174C/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5589197A (en) * | 1993-10-04 | 1996-12-31 | Baxter International, Inc. | Low sodium peritoneal dialysis solution |
WO2001017534A1 (en) * | 1999-09-10 | 2001-03-15 | Baxter International Inc. | Bicarbonate-based solution in two parts for peritoneal dialysis or substitution in continuous renal replacement therapy |
Non-Patent Citations (3)
Title |
---|
IMHOLZ ALEXANDER L T ET AL: "Fluid and solute transport in CAPD patients using ultralow sodium dialysate", KIDNEY INTERNATIONAL, vol. 46, no. 2, 1994, pages 333 - 340, ISSN: 0085-2538 * |
LEYPOLDT JOHN K ET AL: "Ultrafiltration and solute kinetics using low sodium peritoneal dialysate", KIDNEY INTERNATIONAL, vol. 48, no. 6, 1995, pages 1959 - 1966, ISSN: 0085-2538 * |
See also references of WO2004105730A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2524094A1 (en) | 2004-12-09 |
SE0301577L (en) | 2004-11-29 |
CA2524094C (en) | 2014-03-25 |
SE0301577D0 (en) | 2003-05-28 |
CA2820174A1 (en) | 2004-12-09 |
CA2820174C (en) | 2018-12-11 |
WO2004105730A1 (en) | 2004-12-09 |
EP2962683A1 (en) | 2016-01-06 |
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