Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/14—Details; Accessories therefor
  • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
  • A61J1/2093—Containers having several compartments for products to be mixed
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
  • A61K31/10—Sulfides; Sulfoxides; Sulfones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • 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
• • 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
  • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
  • A61J1/10—Bag-type containers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/14—Details; Accessories therefor
  • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
  • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
  • A61J1/202—Separating means
  • A61J1/2027—Separating means having frangible parts

Definitions

• the present invention relates to multiple compartment containers including sterile medical solutions, in which at least one solution contains carbohydrate compounds.
• the invention further relates to stabilising carbohydrates in a sterile medical solution. 0 BACKGROUND
• peritoneal dialyses PD
• Sterilisation of medical solutions is commonly performed through the addition of energy, either in the form of radiation or heat.
• PD peritoneal dialyses
• WO-A-9705852 discloses a multiple compartment container including sterile peritoneal dialyses solutions, which is heat-5 sterilised in an autoclave.
• Wieslander et al. reported that all major brands of commercial PD solutions were toxic in contrast to PD solutions sterilised by filtration (Wieslander et al., 1991, Kidney Int, 40:77-79). The PD0 solutions were tested after dilution with cell growth media on cultured f ⁇ broblasts. Furthermore, Wieslander et al. have reported that the glucose degradation products also affect the functional responses involved in host defence (Wieslander et al., 1995, Peritoneal Dialysis Int, 15 (suppl).
• a patient on peritoneal dialysis uses between 8 and 20 litres of dialysis5 solution every day, depending on the treatment. This results in the consumption of 3-7 tons of solution with 1.5-4% glucose (50-175 kg pure glucose) every year. (Wieslander, 1996, Nephrol Dial Transplant 11:958-959), which if the glucose undergoes decomposition also means a non-negligible amount of decomposition compounds. Furthermore, it is well known that some patients experience pain during0 inflow of the dialysis fluid. It has been speculated that the pain could be the result of glucose degradation (Henderson et al., 1985 Frontiers in peritoneal dialysis, ed.
• Glucose an osmotic agent commonly used in PD solutions is known to degrade into carbonyls such as formaldehyde, acetaldehyde, metylglyoxal, 3- deoxyglucosone and glyoxal.
• Sulphite compounds have commonly been used as antioxidant in parenteral emergency drugs to prevent oxidation.
• the mechanism of decomposition of carbohydrates in PD solutions has appears however to have less to do with oxidation and sulphite is not intended to be used as an antioxidant in vitro in the present invention.
• the anti-microbial or antioxidant compounds in parenteral emergency drugs are typically used in concentration which deliver 0.5 to 2 mg of sulphite per ml of undiluted drug injection (Smolinske S, 1992, Clinical toxicology 30:597-606). Such concentrations for preventing oxidation could not be used in PD solutions since they would administer too much sulphite to the patient resulting in adverse toxic effects.
• the multiple compartment container comprises at least one sulphite compound in one or more of the compartments to stabilise decomposition of carbohydrates or to scavenge decomposition products formed during sterilisation and/or storage.
• the invention further relates to a medical solution wherein the solution contains at least one carbohydrate compound and at least one sulphite compound to stabilise decomposition of the carbohydrates or to scavenge decomposition products formed from the carbohydrates during sterilisation or storage of the medical solutions.
• the invention relates to a method of stabilising a carbohydrate containing solution wherein the solution contains at least one sulphite compound to stabilise decomposition of carbohydrates or to scavenge decomposition products formed during sterilisation and/or storage. Furthermore the invention relates to the use of a carbohydrate containing solution for the preparation of a multiple compartment container.
• the invention relates to use of a carbohydrate containing solution for the preparation of a multiple compartment container for the treatment of a patient in need thereof.
• Figure 1 is a frontal view on a multiple compartment container according to an embodiment of the invention.
• the invention is intended for use in treatments of diseases such as uremic disorder or kidney malfunctions, including for example treatments of diseases using peritoneal dialysis.
• multiple compartment container for a medical solution is intended to mean any container comprising more than one compartment, particularly two or three but not limited to three, compartments.
• a multiple compartment container used for peritoneal dialysis containing medical solutions which are sold under the brand Physioneal ® and Gambroso ⁇ ® trio.
• the term "medical solution” is intended to mean any solution useful for medicinal purposes in which, a carbohydrate may be present and in which the carbohydrate undergoes decomposition during either the sterilisation procedure or storage resulting in disadvantageous decomposition products unfavourable for living cells.
• Decomposition products contemplated are for example products such as mono and dicarbonyl compounds, formaldehyde, acetaldehyde, methylglyoxal, 3- deoxyglucosone and glyoxal or the like.
• the storage conditions could be any conventional storage condition, such as room temperature for 2 years.
• One example of a medical solution is a solution, present in one or more of the compartments, used for peritoneal dialysis .
• final solution is intended to mean a solution obtained by mixing one or more of the medical solutions in the container.
• peritoneal dialysis solution is intended to mean a solution comprising an electrolyte, a buffer and an osmotically active compound, wherein the electrolyte comprises ions, such as sodium, potassium, calcium and magnesium; the buffer comprises components, such as acetate, lactate and bicarbonate; and the osmotic compound is a carbohydrate as defined hereinafter.
• Examples of medical solutions for use as peritoneal dialysis solutions may be found in Wieslander et al., 1991, Kidney Int 40:77-79.
• the peritoneal dialysis solution could, prior to dialysis, be present in one or more compartments. In the case of multiple compartments the solutions are mixed prior to peritoneal dialysis.
• carbohydrate compound is intended to mean sugars or sugars acids such as glucose, fructose, mannose, aldonic, alduronic, aldaric acids and their esters with saccharides or a polymer of glucose, fructose, mannose, aldonic, alduronic, aldaric acids and their esters with saccharides or a synthetic form of glucose, fructose, mannose, aldonic, alduronic, aldaric acids and their esters with saccharides or derivatives and mixtures thereof.
• sugars or sugars acids such as glucose, fructose, mannose, aldonic, alduronic, aldaric acids and their esters with saccharides or a polymer of glucose, fructose, mannose, aldonic, alduronic, aldaric acids and their esters with saccharides or a synthetic form of glucose, fructose, mannose, aldonic, alduronic, aldaric acids and their esters with saccharides or derivatives and mixtures thereof.
• sulphite compound is intended to mean a sulphite containing compound with the properties to reduce the content of decomposition products, by for example stabilising the solution, including preventing the generation of decomposition products, or scavenging already formed decomposition products, produced during sterilisation and/or storage of medical solutions containing carbohydrate compounds, as defined above.
• the sulphite compound could be used as an antioxidant or to scavenge toxic or allergenic compounds in vivo, such as in the body fluids.
• toxic or allergenic compounds are metylglyoxal, 3- deoxyglucosone and glyoxal.
• the effect of the sulphite compound can be measured according to the method "Analysis of glucose degradation products” mentioned under “Material and Methods” hereinafter.
• examples of such sulphite compounds are any sulphite, having a positive counter ion, such as sodium, potassium, calcium, magnesium and ammonium, for example HS0 3 " , S 2 0 5 " and S0 3 " .
• sulphite compounds to be used are NaHS0 3 , Na 2 S 2 0 5 and Na 2 S0 3 or any other of sulphite compound or derivative thereof, natural or synthetic, or mixtures thereof.
• stabilising is intended to mean preventing the generation of decomposition products, or scavenging already formed decomposition products, produced during sterilisation and or storage of medical solutions containing carbohydrate compounds
• carbohydrate decomposition products is intended to mean products produced in a carbohydrate solution during any kind of sterilisation and/or during storage, which are products obtained from decomposition of carbohydrates, such as glucose and toxic to eucaryotic and procaryotic cells.
• carbohydrates such as glucose and toxic to eucaryotic and procaryotic cells.
• mono and dicarbonyl compounds such as formaldehyde, acetaldehyde, methylglyoxal, 3-deoxyglucosone and glyoxal or the like.
• the toxicity can be measured according to the method "in vitro assay for cytotoxity" mentioned in "Materials and Methods hereinafter.
• sterilisation is intended to mean any kind of sterilisation, such as radiation, pressure, heat, UV-radiation, radioactive radiation, sterile filtration, radiation using micro waves or other sterilisation methods. Furthermore the sterilisation can be performed using different approaches such as short sterilisation time at a high temperature, sterilisation at low pH, sterilisation with high glucose concentration after removal of catalytic substances.
• the invention relates to multiple compartment containers for sterile medical solutions, particularly solutions for peritoneal dialysis (PD), wherein the medical solutions are present in one or more compartments.
• One or more of the compartments comprises a carbohydrate and at least one sulphite compound in order to reduce the amount of the carbohydrate decomposition products produced during sterilisation and/or storage.
• one or more of the compartments may include an electrolyte, a buffer and any other pharmaceutically acceptable additive or other component.
• the container comprises at least two compartments, preferably three or more compartments, most preferably three.
• a carbohydrate compound in solution and in at least one of the compartments there is provided a sulphite compound to reduce the formation or scavenge already produced decomposition products formed from carbohydrate.
• the "sulphite compound” could be used as an antioxidant or to scavenge toxic or allergenic compounds in vivo, such as in the body fluids.
• Commonly used medical solutions either in single or multiple compartment container(s) for peritoneal dialysis preferably contain glucose in the final solution in a concentration in the range of 1.5 to 4,0 % preferably substantially 1.5, 2.5 or 4 % by weight (based on the final solution).
• Fig. 1 shows a preferred embodiment of the container, in this case a three- compartment bag .
• the bag 1 is made from a continuous tube of a plastics material, which is sealed at both ends by sealing borders 2,3.
• each sealing border comprises several embossments 4 and apertures 5,6,7.
• the embossments 4 enhance the stability of the border 2.
• the aperture 5 in the upper border 2 is intended for hanging the bag during use and the apertures 6,7 in the lower border 3 are for fixation of the bag during the manufacturing operation.
• the lower border 3 is also provided with an outlet tube 14, which connects compartment 9 with the consumer, for example a catheter ending in the abdominal cavity of a patient for peritoneal dialysis. Often tube 14 terminates in a luer connector (not shown in FIG. 1).
• border 3 is provided with a filling tube 12, a medicament tube 15 including a removable cap 16.
• tube 15 forms an entrance site for introducing any type of beneficial agent or medicament into compartment 9 as desired, such as antibiotics.
• the bag 1 is divided into three compartments 9,44,45 by welding seal lines 41 ,42,43.
• the upper compartments 44,45 divided by welding seal line 11 are of equal size and separated form the lower compartment 8 by two sloping welding lines 42,43.
• the large lower compartment 9 comprises the electrolytes necessary for the solution to be formed (final solution), such as NaCl, MgCl 2 , lactate etc., dissolved in water in a manner known per se.
• the first compartment 44 comprises glucose solution having a concentration of about 30% and the second compartment 45 comprises a glucose solution having a concentration of about 50%.
• the contents of the first compartment 44 is mixed with the contents of the lower compartment 9 to form a peritoneal dialysis solution having a concentration of 1.5% of glucose. If the breakable portion of connection tube 49 is broken, the contents of compartment 45 is mixed with the contents of both compartment 9 thereby forming a dialysis solution having a concentration of about 2.5% of glucose. If both breakable portions of connection tubes 48,49 are broken, the contents of both compartments 44 and 45 are mixed with the contents of compartment 9 thereby to form a dialysis solution having a concentration of about 4% of glucose.
• the above dialysis solutions formed by mixing at least one of the glucose containing compartments.
• the large compartment 9 may comprise only NaCl or any other suitable composition as used today but excluding glucose. It is mentioned that the glucose can be exchanged with a glucose like component, such as glucose polymers, as an osmotic agent.
• the sterile medical solutions comprising a carbohydrate may include an electrolyte, a buffer such as lactate and any other pharmaceutically acceptable additive.
• the carbohydrate compound is separately provided in one or more compartments, the rest of the peritoneal dialysis solution compounds being provided in one or more the other compartments.
• the sulphite compound(s) may be present in one or more of said compartments or separately presented in one or more compartments.
• the sulphite compound(s) may be introduced in any of the carbohydrate or electrolyte solution compartments before or after sterilisation. However, some or all components of the medical solution(s) and the sulphite compound are mixed prior to peritoneal dialysis to obtain a final solution.
• a monosulphite compound such as a bisulphate
• it is preferably added to the carbohydrate and/or the electrolyte compartment in an amount to give a final solution within the range of 0.01 - 10 mM, preferably 0.05 - 1 mM, most preferably 0.05 - 0.5 mM.
• a disulphite compound is used it is preferably added to the carbohydrate compartment in an amount to give a final solution within the range of 0.005 - 5 mM, preferably 0.025 - 0.5 mM, most preferably about 0.025 - 0.25 mM.
• a disulphite compound it is preferably added in an amount to give a final solution which is half of the concentration used for the corresponding monosulphite compound.
• the pH of the solution in the carbohydrate compartment is preferably between pH 2.0-7.5, more preferably pH 2-5.5, even more preferably pH 3-4 and most preferably about pH 3.2.
• the pH of the final solution is preferably between 5.0 - 8.0, more preferably between 6.5 - 8.0, most preferably between 7.0 - 7.5 or absolutely most preferably 7.4.
• the multiple compartment container containing the medical solution is sterilised. Any conventional methods and apparatus for sterilisation may be used, such as those mentioned under the definition of the term "sterilisation”.
• the sterilisation is performed by heat treatment most preferable at about 121° C for 20 minutes (Ph. Eur. (current)).
• the invention further relates to a medical solution comprising at least one sulphite compound to be included for the ability to reduce the concentration of decomposition products formed from a carbohydrate by stabilisation or scavenging already formed decomposition products, obtained during sterilisation and/or storage of solutions containing carbohydrate compounds, as defined above.
• a medical solution comprising at least one sulphite compound to be included for the ability to reduce the concentration of decomposition products formed from a carbohydrate by stabilisation or scavenging already formed decomposition products, obtained during sterilisation and/or storage of solutions containing carbohydrate compounds, as defined above.
• the "sulphite compound” could be used as an antioxidant or to scavenge toxic or allergenic compounds in vivo, such as in the body fluids.
• the invention further relates to a medical solution such as a solution used for peritoneal dialysis either in a single or a multiple compartment container, comprising at least one sulphite compound to be included for the ability to reduce decomposition of a carbohydrate present in the solution exposed to sterilisation.
• a medical solution such as a solution used for peritoneal dialysis either in a single or a multiple compartment container, comprising at least one sulphite compound to be included for the ability to reduce decomposition of a carbohydrate present in the solution exposed to sterilisation.
• a monosulphite compound such as a bisulphite
• it is preferably added to the carbohydrate and/or the electrolyte compartment in an amount to give a final solution with a concentration within the range of 0.01 - 10 mM, preferably 0.05 - 1 mM, most preferably about 0.05 - 0.5 mM.
• a disulphite compound is used it is preferably added to the carbohydrate compartment in an amount to give a final solution with a concentration within the range of 0.005 - 5 mM, preferably 0.025 - 0.5 mM, most preferably 0.025 - 0.25 mM.
• a disulphite compound is used it is preferably added in an amount to give a final solution which is half of the concentration used for the corresponding monosulphite compound.
• the pH of the carbohydrate solution is not critical and could be in any range, suitable the pH is between pH 2.0-7.5, more preferably pH 2-5.5, even more preferably pH 3-4 and even more preferably about pH 3.2.
• the pH of the final solution is preferably between 5.0 - 8.0 and more preferably 6.5 - 8.0 and most preferably 7.0 - 7.5.
• the medical solution is a sterile medical solution.
• the sulphite compound may be provided to the carbohydrate solution prior or after sterilisation.
• the sterilisation is performed using any conventional sterilisation method as defined above under the term "sterilisation”.
• the sterilisation is performed by heat treatment within the range of 100-150° C, for 1- 130 minutes, more preferably at 121° C for 20 minutes (Ph. Eur. (current)).
• the solution may be any medical solution which comprises a carbohydrate with or without other components.
• the solution is a medical solution such as a solution used for peritoneal dialysis, preferably medical solution(s) for single or multiple compartment container(s) for peritoneal dialysis, more preferably two or three compartment containers, even more preferably a three compartment container.
• Medical solutions used for peritoneal dialysis preferably contain glucose in an amount to give a glucose concentration in the range of 1.5 to 4%, preferably about 1.5, 2.5 or 4 % by weight in the final solution (based on the total final solution).
• the medical solution is a solution used to scavenge toxic or allergenic compounds in vivo, preferably a medical solution used to scavenge toxic or allergenic compounds in body fluids.
• the invention further relates to a method for stabilising or scavenging the decomposition of carbohydrate components produced in a medical solution during sterilisation and/or storage, comprising providing a sulphite compound to the solution prior or after the sterilisation process in order to reduce decomposition of the carbohydrate components in the medical solution.
• the method is used for preparation of medical solution(s) used for peritoneal dialysis.
• the medical solution (s) is/are used in a multiple compartment container for peritoneal dialysis, such as a three compartment container.
• the method is used for preparation of a multiple compartment container used for peritoneal dialysis, wherein the sulphite compound may be added either to the carbohydrate compartment or to the electrolyte compartment of a multiple compartment.
• a monosulphite compound is used it is preferably added to the carbohydrate solution in an amount to give a concentration in the final solution within the range of 0.01 - 10 mM, preferably 0.05 - 1 mM, most preferably 0.05 - 0.5 mM.
• a disulphite compound is used it is preferably added to the carbohydrate solution in an amount to give a concentration in the final solution within the range of 0.005 - 5 mM, preferably 0.025 - 0.5 mM, most preferably 0.025 - 0.25 mM.
• the pH of the carbohydrate compartment is preferably between pH 2.0-7.5, more preferably pH 2-5.5, even more preferably pH 3-4 and most preferably about pH 3.2.
• the method is used for the preparation of a sterile multiple compartment.
• the sulphite compound is provided to the carbohydrate solution prior or after sterilisation.
• the sterilisation is performed using any conventional sterilisation method as defined above under the term "sterilisation”.
• the sterilisation is performed by heat treatment within the range of 100-150° C, for 1- 130 minutes, more preferably at 121° C for 20 minutes (Ph. Eur. (current)).
• the method according to the invention is intended to be used for medical solutions, in which the medical solution needs to be sterile, by a method as defined under the term "sterilisation", and preferably the method will be used for the preparation of medical solutions used for peritoneal dialysis or the like.
• a sulphite compound in small amounts to the solution either prior or after sterilisation, decomposition of the carbohydrate components into toxic compounds in the solution is prevented or the toxic compounds are scavenged.
• medical solutions to be used for peritoneal dialysis preferably contain glucose in an amount to give a glucose concentration range between 1.5 to 4%, preferably about 1.5, 2.5 or 4 % by weight in the final solution.
• the sulphite compound could be used as an antioxidant or to scavenge toxic or allergenic compounds in vivo, such as in the body fluids.
• the invention provides the use of a carbohydrate containing solution for the preparation of a multiple compartment container, preferably a three compartment container, suitable for peritoneal dialysis. Specifically the invention provides the use of a carbohydrate containing solution for the preparation of a multiple compartment container for the treatment of an animal in need thereof.
• Acetonitrile (Lab Scan, Ireland) and methanol (Lab Scan, Ireland) were of HPLC grade. 2,3- diaminonaphtalene was supplied by ICN, USA. 3-deoxyglucosone 56 % (weight/weight) was synthesised by T. Henle Technische Univeritat Dresden. Sodiumphosphate p.a. and Glyoxal 30 % (weight/volume) supplied by Merck (Germany), methylglyoxal 40 % (weight/volume), 2,4-di- nitrophenylhydrazine (2,4-DNPH) and 1,2-phenylenediamine were supplied by Sigma Chemical (USA). Acetaldehyde p.a. was supplied by Fluka (Germany).
• 2,3-diaminonaphtalene as derivative reagent.
• the samples were diluted 50 times to a total volume of 1 ml prior to analysis.
• the standards were prepared in the range 1-6 ⁇ M.
• Standards and samples were prepared by adding lOO ⁇ l 0.1% (2,3- diaminonaphtalene to 1 ml sample and incubated for 16 hours in room temperature in dark.
• the analytical column was a Water Symmetry C18 column (5 ⁇ m, 25 cm x4, 6 mm). The elution of the substance was performed at constant flow rate of 1.0 ml/min by using a gradient of acetonitrile/water.
• the percentage of acetonitrile/water (volume/volume) was initially 25/75, and 12 minutes later 25/75, at 15 minutes 60/40 and at the gradient stop 30 minutes 60/40.
• the wavelength was set at 268 nm and the injected volume was 20 ⁇ l.
• the limit of quantification was l ⁇ M.
• acetaldehyde and formaldehyde The samples for the determination of acetaldehyde were diluted 20 times to a final volume of 4 ml, prior to analysis. Acetaldehyde was prepared as hydrazone derivatives using 2,4-DNPH as derivative reagent. The standards were prepared in range 1.1 - 11.4 ⁇ M acetaldehyde, and 1.7-16.7 ⁇ M formaldehyde. Standards and samples were prepared by adding 2 ml 0.08 % (weight/volume) 2,4-DNPH to 4 ml of each sample.
• the sample were concentrated on a solid phase extraction C18 column (Bond Elut LRC 200 mg/3 ml) and after rinsing with water, eluted with 1.6 ml acetonitrile.
• the analytical column was a Supelco C18 column (5 ⁇ m, 15 cm x 4,6 mm).
• the elution of the substances was performed at constant flow of 1.7 ml/min by using a linear gradient of acetonitrile/water.
• the percentage acetonitrile/water (volume/volume) was initially 35/65 and at the gradient stop 12 minutes later 80/20.
• the wavelenght was set at 240 nm and the injected volume was 20 ⁇ l.
• the limit of quantification was for acetaldehyde.
• Glyoxal and methylglyoxal were determined as quinoxalines using 1,2-phenylenediamine.
• the standards were prepared in the range 3.5-51.7 ⁇ M methylglyoxal.
• Standards and samples were prepared by adding 0.6 ml 0.4 % (volume/volume) 1,2-phenylenediamine to 1 ml of each sample.
• the analytical column was Supelco C18 column (5 ⁇ m, 25 cm x 4,6 mm).
• the elution of the substances was performed at constant flow of 1.0 ml / min using a mobile phase of initial 25 % (volume/volume) acetonitrate and 75 % (weight/volume) 0.05 M sodiumphosphate. At the gradient at 6 minutes the mobile phase was 30 % acetonitrate and 70 % millipore water and at gradient stop 9 minutes the percentages were 25/75.
• the wavelength was set at 312 nm and the injected volume was 20 ⁇ l.
• the limit of quantification for glyoxal was 3.5 ⁇ M and for methylglyoxal 2.8 ⁇ M.
• Three compartment container with sulphite in the glucose compartment A multiple compartment container as shown in FIG. 1, containing following medical solutions in the three compartments 44, 45 and 9.
• Compartment 45 contains 100 ml of the composition: glucose 50% calcium 33 mM magnesium 8 mM sodium 132 mM bisulphite 1 mM pH 3.2
• Compartment 9 contains 1900 ml with the composition: bicarbonate 40 mM sodium 132 mM pH 6.7
• Compartment 44 contains 100 ml of the composition: glucose 30% calcium 20 mM magnesium 5 mM sodium 132 mM pH 3.2
• Compartment 45 contains 100 ml of the composition: glucose 50% calcium 33 mM magnesium 8 mM sodium 132 mM pH 3.2
• Compartment 9 contains 1900 ml with the composition: bicarbonate 40 mM sodium 132 mM bisulphite 0.1 mM pH 6.7
• a final solution suited for peritoneal dialysis is obtained with the following concentration: glucose 1.5% calcium 1.0 mM bicarbonate 38 mM sodium 132 mM magnesium 0.25 mM bisulphite 0.095 mM
• a final solution suite for peritoneal dialysis is obtained with the following concentration: glucose 2.5% calcium 1.65 mM bicarbonate 38 mM sodium 132 mM magnesium 0.4 mM bisulphite 0.095 mM
• the concentration of glucose were 4 % (w/v) and the concentration of sulphite were 0. 0.01, 0.05, 0.1, 0.2 and 0.5 mM in the final solution.
• the sterilised solutions were analysed in the In vitro assay of cytotoxicity mentioned under Materials & Methods. The results from the assay showed that an increase of the sodium bisulphite resulted in a decrease of the ICG value, which means that there is a decrease in the content of the toxic decomposition products after addition of a sodium bisulphite.
• the sterilised solutions were mixed with sodium bisulphite to three different concentrations of sodium bisulphite (0, 0.5, 1 mM). Three solutions containing 132 mM Na + , 1.35 mM Ca 2+ , 0.25 mM Mg 2+ , 95.2 mM
• the sterilised six solutions were analysed in the In vitro assay of cytotoxicity and determination of acetaldehyde and formaldehyde mentioned under Materials & Methods.
• the results from the In vitro assay of cytotoxicity showed that an increase of the sodium bisulphite resulted in a decrease of the ICG value, which means that there is a decrease in the content of the toxic decomposition products.
• the results from the assay " determination of acetaldehyde and formaldehyde” showed decreased levels of both acetaldehyde and formaldehyde in the solutions containing sodium bisulphite, even down to levels under detection limit.

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• 2000
  • 2000-05-25 SE SE0001939A patent/SE0001939D0/xx unknown
• 2001
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  • 2001-05-18 AU AU2001260918A patent/AU2001260918B8/en not_active Ceased
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