U.S. patent application number 10/275104 was filed with the patent office on 2003-08-28 for carbohydrate medical solution and sulphite stabilisator in a multiple compartment container and use thereof.
Invention is credited to Linden, Torbjorn, Olsson, Lars-Fride, Wieslander, Anders.
Application Number | 20030159953 10/275104 |
Document ID | / |
Family ID | 20279819 |
Filed Date | 2003-08-28 |
United States Patent
Application |
20030159953 |
Kind Code |
A1 |
Linden, Torbjorn ; et
al. |
August 28, 2003 |
Carbohydrate medical solution and sulphite stabilisator in a
multiple compartment container and use thereof
Abstract
The invention relates to a multiple compartment container for
sterile medical solutions, particularly solutions for peritoneal
dialysis containing a carbohydrate stabilisation compound, a
carbohydrate medical solution containing said carbohydrate
stabilisation compound and a method for the preparation
thereof.
Inventors: |
Linden, Torbjorn; (Linderod,
SE) ; Wieslander, Anders; (Lund, SE) ; Olsson,
Lars-Fride; (Lund, SE) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Family ID: |
20279819 |
Appl. No.: |
10/275104 |
Filed: |
March 3, 2003 |
PCT Filed: |
May 18, 2001 |
PCT NO: |
PCT/SE01/01125 |
Current U.S.
Class: |
206/219 |
Current CPC
Class: |
A61J 1/10 20130101; A61M
1/287 20130101; A61K 33/00 20130101; A61P 7/08 20180101; A61K 31/70
20130101; A61P 13/12 20180101; A61J 1/2093 20130101; A61P 7/00
20180101; A61K 31/10 20130101; A61J 1/2027 20150501; A61K 31/10
20130101; A61K 2300/00 20130101; A61K 31/70 20130101; A61K 2300/00
20130101; A61K 33/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
206/219 |
International
Class: |
B65D 025/08 |
Claims
1. Multiple compartment container for sterile medical solutions,
wherein said solutions are present in two or more compartments, and
at least one of said solutions comprises a carbohydrate compound,
characterised in that at least one sulphite compound is present in
one or more of said compartments.
2. Multiple compartment container according to claim 1, wherein
said sulphite compound is selected from the group consisting of
HSO.sub.3.sup.-, S.sub.2O.sub.5.sup.2-or SO.sub.3.sup.2-, having a
positive counter ion or mixtures thereof, preferably NaHSO.sub.3,
Na.sub.2S.sub.2O.sub.5 or Na.sub.2SO.sub.3 or a mixture
thereof.
3. Multiple compartment container according claim 1 or 2, wherein
said sulphite compound is a monosulphite compound, the total amount
of monosulphite compound in said container being equal to 0.01-10
mmol, per liter of the total amount of solution in said container,
preferably 0.05-1 mmol, per liter of the total amount of solution
in said container, most preferably 0.05-0.5 mmol, per liter of the
total amount of solution in said container.
4. Multiple compartment container according to claim 1 or 2,
wherein said sulphite compound is a disulphite compound, the total
amount of disulphite compound in said container being equal to
0.005-5 mmol per liter of the total amount of solution in said
container, preferably 0.025-0.5 mmol, per liter of the total amount
of solution in said container, most preferably 0.025-0.25 mmol, per
liter of the total amount of solution in said container.
5. Multiple compartment container according to claim 3 or 4,
wherein the pH of the mixed solution in said container is between
5.0-8.0, more preferably between 6.0-8.0, most preferably between
7.0-7.5.
6. Multiple compartment container according to any of claims 1-5,
wherein said carbohydrate is glucose and the total amount of
glucose in said container is about 4% by weight of the total amount
of solution in said container.
7. Multiple compartment container according claims 1 to 6, wherein
said carbohydrate compound is not present in all compartments,
preferably in only one of two compartments in a two compartment bag
or in only two of three compartments in a three compartment
bag.
8. Multiple compartment container according claim 7, wherein the pH
of said compartments containing said carbohydrate compound is
between 2.0 and 7,5, preferably between 2.0 and 5,5, more
preferably between 3 and 4 and most preferably about 3,2.
9. Multiple compartment container according to claim 7 or 8,
wherein said sulphite is a monosulphite compound and wherein said
concentration monosulphite after mixing of said different solutions
give rise to a final solution with a concentration of monosulphite
compound of 0.01-10 mM, preferably 0.05-1 mM, most preferably
0.025-0.25 mM.
10. Multiple compartment container according to claim 7 or 8,
wherein said sulphite is a disulphite compound and wherein said
concentration disulphite after mixing of said different solutions
give rise to a final solution with a concentration of disulphite
compound of 0.005-5 mM, preferably 0.025-0.5 mM, most preferably
0.025-0.25 mM.
11. Multiple compartment container according to any of claims 7 to
10, wherein said carbohydrate compound is glucose and said
container is a three compartment bag and wherein the concentration
of glucose after mixing of said different solutions give rise to a
final solution in the range of 1.5 to 4%, preferably about 1.5, 2.5
or 4% by weight of glucose based of the total amount of final
solution.
12. Multiple compartment container according to any of claims 1-11,
wherein said container is sterilised using heat treatment.
13. Multiple compartment container according to any of claims 1-12,
wherein said multiple compartment container contains medical
solutions for preparing a final solution for peritoneal dialyses by
mixing two or more of said medical solutions.
14. A sterile medical solution comprising a carbohydrate compound,
at least one sulphite compound selected from the group consisting
of HSO.sub.3.sup.-, S.sub.2O.sub.5.sup.2- or SO.sub.3.sup.2-,
having a positive counter ion or mixtures thereof, preferably
NaHSO.sub.3, Na.sub.2S.sub.2O.sub.5 or Na.sub.2SO.sub.3 or a
mixture thereof, wherein said sulphite compound is a monosulphite
compound, present in a concentration of between 0.01-10 mM or a
disulphite compound, present in a concentration of between 0.005-5
mM.
15. A sterile medical solution according to claim 14, wherein said
sulphite compound is a monosulphite compound, present in a
concentration of preferably 0.05-1 mM, most preferably 0.05-0.5
mM.
16. A sterile medical solution according to claim 14 or 15, wherein
said solution is heat sterilised.
17. A sterile medical solution according to any of claims 14-16,
wherein said solution is a solution for peritoneal dialysis.
18. A sterile medical solution according to any of claims 14-17,
wherein said solution is used in a three compartment container.
19. A method of stabilising a carbohydrate containing sterile
medical solution wherein in that at least one sulphite compound is
added to said solution in a concentration of preferably 0.05-1 mM,
most preferably 0.05-0.5 mM if said sulphite component is a
monosulphite compound, and in a concentration of 0.005-5 mM,
preferably 0.025-0.5 mM, most preferably 0.025-0.25 mM if said
sulphite component is a disulphite compound.
20. A method according to claim 19, wherein said sulphite compound
is selected from the group consisting of HSO.sub.3.sup.-,
S.sub.2O.sub.5.sup.2- or SO.sub.3.sup.2-, having a positive counter
ion or mixtures thereof, preferably NaHSO.sub.3,
Na.sub.2S.sub.2O.sub.5 or Na.sub.2SO.sub.3 or a mixture
thereof.
21. A method according to claim 19 or 20, wherein said solution is
heat sterilised.
22. Use of a carbohydrate containing sterile medical solution
according to any of claims 14-18 for the preparation of a multiple
compartment container according to any of claims 1-13.
Description
TECHNICAL FIELD
[0001] 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.
BACKGROUND
[0002] Sterilisation of medical solutions such as, for example,
peritoneal dialyses (PD) solutions, is commonly performed through
the addition of energy, either in the form of radiation or heat.
WO-A-9705852 discloses a multiple compartment container including
sterile peritoneal dialyses solutions, which is heat-sterilised in
an autoclave.
[0003] In recent years scientists have become aware of the toxicity
of decomposition compounds of carbohydrates in PD solutions.
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 PD
solutions were tested after dilution with cell growth media on
cultured fibroblasts. 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).
[0004] A patient on peritoneal dialysis (PD) uses between 8 and 20
litres of dialysis 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 during 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.
Winchester, N.Y.: Field, Rich, 261-264) and that these degradation
products mediate basal cytotoxicity (Barile F A, 1994, Introduction
to in vitro cytotoxicity. Florida: CRC Press, 27-35). This means
that they act upon fundamental life processes, which involve
structures and functions common to all living cells such as
membrane integrity, mitochondrial activity, or synthesis of
proteins and DNA. These basal cell functions support organ specific
cell functions. Thus, glucose degradation products capable of
affecting basal cell activities are likely to interfere with
specialised cell functions such as IL-1.beta. release from
mononuclear cells.
[0005] Glucose, an osmotic agent commonly used in PD solutions is
known to degrade into carbonyls such as formaldehyde, acetaldehyde,
metylglyoxal, 3-deoxyglucosone and glyoxal.
[0006] 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.
Further, 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.
SUMMARY OF THE INVENTION
[0007] On the above background it is an object of the present
invention to provide a multiple compartment container for sterile
medical solutions of the kind referred to above in which
decomposition of carbohydrates and/or the negative effects of the
decomposition products are reduced. 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.
[0008] 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.
[0009] Additionally 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.
[0010] Furthermore the invention relates to the use of a
carbohydrate containing solution for the preparation of a multiple
compartment container.
[0011] Finally, 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.
BRIEF DESCRIPTION OF THE DRAWING
[0012] In the following detailed portion of the present
description, the invention will be explained in more detail with
reference to an exemplary embodiment shown in the drawings, in
which FIG. 1 is a frontal view on a multiple compartment container
according to an embodiment of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0013] 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.
[0014] Definitions
[0015] The term "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. One example is a multiple compartment
container used for peritoneal dialysis containing medical
solutions, which are sold under the brand Physioneal.RTM. and
Gambrosol.RTM. trio.
[0016] 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.
[0017] The term "final solution" is intended to mean a solution
obtained by mixing one or more of the medical solutions in the
container.
[0018] The term "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 defmed 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.
[0019] The term "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.
[0020] The term "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.
[0021] Furthermore, the sulphite compound could be used as an
antioxidant or to scavenge toxic or allergenic compounds in vivo,
such as in the body fluids. Examples of such 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
HSO.sub.3.sup.-, S.sub.2O.sub.5.sup.2- and SO.sub.3.sup.2-.
Examples of sulphite compounds to be used are NaHSO.sub.3,
Na.sub.2S.sub.2O.sub.5 and Na.sub.2SO.sub.3 or any other of
sulphite compound or derivative thereof, natural or synthetic, or
mixtures thereof.
[0022] The term "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
[0023] The term "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. Specifically
contemplated are 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.
[0024] The term "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.
[0025] Multiple Compartment Containers Employing a Medical
Solution.
[0026] 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. Furthermore one or more of the
compartments may include an electrolyte, a buffer and any other
pharmaceutically acceptable additive or other component.
[0027] Additionally, the container comprises at least two
compartments, preferably three or more compartments, most
preferably three. In at least one of the compartments there is
provided 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.
[0028] Furthermore 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).
[0029] 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.
[0030] As shown in FIG. 1 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.
[0031] 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).
[0032] Furthermore, border 3 is provided with a filling tube 12, a
medicament tube 15 including a removable cap 16. When cap 16 is
removed, tube 15 forms an entrance site for introducing any type of
beneficial agent or medicament into compartment 9 as desired, such
as antibiotics.
[0033] 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. Thus there
is formed a first upper compartment 44 and a second upper
compartment 45, each being accessed via introduction tubes 46,47.
The large lower compartment 9 comprises the electrolytes necessary
for the solution to be formed (final solution), such as NaCl,
MgCl.sub.2, lactate etc., dissolved in water in a manner known per
se.
[0034] 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%.
[0035] When breaking the breakable portion of connection tube 48,
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.
[0036] If the bag should be used as a nutritional solution, the
large compartment 9 may comprise only NaCl or any other suitable
composition as used today but excluding glucose.
[0037] It is mentioned that the glucose can be exchanged with a
glucose like component, such as glucose polymers, as an osmotic
agent.
[0038] Furthermore, the sterile medical solutions comprising a
carbohydrate, may include an electrolyte, a buffer such as lactate
and any other pharmaceutically acceptable additive.
[0039] According to one embodiment of the invention 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.
[0040] If a monosulphite compound such a bisulphate is used, 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.
If 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.
[0041] If 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.
[0042] 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.
[0043] Additionally, in a preferred embodiment, 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". Preferably the
sterilisation is performed by heat treatment most preferable at
about 121.degree. C. for 20 minutes (Ph. Eur. (current)).
[0044] Solution
[0045] 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. Furthermore the "sulphite compound" could be used as an
antioxidant or to scavenge toxic or allergenic compounds in vivo,
such as in the body fluids.
[0046] 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.
[0047] If a monosulphite compound such a bisulphite is used, 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. If 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.
[0048] If 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.
[0049] 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.
[0050] Preferably the medical solution is a sterile medical
solution.
[0051] Additionally, the sulphite compound may be provided to the
carbohydrate solution prior or after sterilisation.
[0052] Furthermore, the sterilisation is performed using any
conventional sterilisation method as defined above under the term
"sterilisation". Preferably the sterilisation is performed by heat
treatment within the range of 100-150.degree. C., for 1-130
minutes, more preferably at 121.degree. C. for 20 minutes (Ph. Eur.
(current)).
[0053] The solution may be any medical solution which comprises a
carbohydrate with or without other components. Preferably 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).
[0054] Additionally 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.
[0055] Method
[0056] 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.
[0057] Preferably the method is used for preparation of medical
solution(s) used for peritoneal dialysis.
[0058] Even more preferably the medical solution (s) is/are used in
a multiple compartment container for peritoneal dialysis, such as a
three compartment container.
[0059] Preferably, 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.
[0060] If 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.
[0061] If 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.
[0062] When a disulphite compound is used it is also preferably
added in an amount to give a concentration in the final solution
which is half of the concentration used for a corresponding
monosulphite compound.
[0063] 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.
[0064] More preferably the method is used for the preparation of a
sterile multiple compartment.
[0065] Additionally, the sulphite compound is provided to the
carbohydrate solution prior or after sterilisation.
[0066] Furthermore, the sterilisation is performed using any
conventional sterilisation method as defined above under the term
"sterilisation". Preferably the sterilisation is performed by heat
treatment within the range of 100-150.degree. C., for 1-130
minutes, more preferably at 121.degree. C. for 20 minutes (Ph. Eur.
(current)).
[0067] 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 defmed under the term "sterilisation", and
preferably the method will be used for the preparation of medical
solutions used for peritoneal dialysis or the like. By way of
adding 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. Preferably, 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.
[0068] Furthermore the sulphite compound could be used as an
antioxidant or to scavenge toxic or allergenic compounds in vivo,
such as in the body fluids.
[0069] Additionally 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.
[0070] 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.
MATERIALS AND METHODS
[0071] Determination of Glucose Degradation Products:
[0072] Chemicals: 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 Univeritt 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).
[0073] Equipment: Two HPLC systems were used for the determination
of glucose degradation products (GDP). One HPLC consisted of an
Hewlett Packard liquid chromatograph serie 1050 equipped with an
UV-detector and an autosampler. The second HPLC system consisted of
an Hewlett Packard liquid chromatograph serie 1100 equipped with an
autosampler and Waters Refractive Index detector model 410. Hewlett
Packard Chem Station software rev. A.06.03, NT 4.0 was used for the
data handling.
[0074] Determination of 3-deoxyglucosone (3-DG): 3-DG was
determined using 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 .mu.M.
Standards and samples were prepared by adding 100.mu.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.mu.m, 25 cm .times.4, 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 .mu.l. The limit of quantification was 1 .mu.M.
[0075] Determination of 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 .mu.M acetaldehyde, and
1.7-16.7 .mu.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 .mu.m, 15 cm.times.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 .mu.l. The limit of quantification was for
acetaldehyde. 1.1 .mu.M. And for formaldehyde 1.7 .mu.M.
[0076] Determination of glyoxal and methylglyoxal: Glyoxal and
methylglyoxal were determined as quinoxalines using
1,2-phenylenediamine. The standards were prepared in the range
3.5-51.7 .mu.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
.mu.m, 25 cm.times.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) acetonitrile and 75% (weight/volume)
0.05 M sodiumphosphate. At the gradient at 6 minutes the mobile
phase was 30% acetonitrile 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 .mu.l. The limit of
quantification for glyoxal was 3.5 .mu.M and for methylglyoxal 2.8
.mu.M.
[0077] In Vitro Assay for Cytotoxicity
[0078] Medical solutions used for peritoneal dialysis were mixed
with one part cell growth medium and 10% (volume/volume) fetal calf
serum was added (Wieslander et al., 1991, Kidney Int. 40:77-79).
Basal cytotoxicity of medical solution used for peritoneal dialysis
were determined on mouse fibroblasts cells L-929 (CCL-1; ATTC,
Rockville, Md., USA) as described earlier (Wieslander et al. 1993,
Advances in Peritoneal Dialys, 9:31-35) and expressed as inhibition
of cellgrowth (ICG).
EXAMPLE 1
[0079] Three Compartment Container with Sulphite in the Glucose
Compartment
[0080] A multiple compartment container as shown in FIG. 1,
containing following medical solutions in the three compartments
44, 45 and 9.
[0081] Compartment 44 containing 100 ml of the composition:
1 glucose 30% calcium 20 mM magnesium 5 mM sodium 132 mM bisulphite
1 mM pH 3.2
[0082] Compartment 45 contains 100 ml of the composition:
2 glucose 50% calcium 33 mM magnesium 8 mM sodium 132 mM bisulphite
1 mM pH 3.2
[0083] Compartment 9 contains 1900 ml with the composition:
3 bicarbonate 40 mM sodium 132 mM pH 6.7
[0084] By mixing the contents of compartment 44 and compartment 9,
a final solution suited for peritoneal dialysis is obtained with
the following concentrations:
4 glucose 1.5% calcium 1.0 mM bicarbonate 38 mM sodium 132 mM
magnesium 0.25 mM bisulphite 0.05 mM
[0085] By mixing the contents of compartment 45 and compartment 9,
a final solution suited for peritoneal dialysis is obtained with
the following concentrations:
5 glucose 2.5% calcium 1.65 mM bicarbonate 38 mM sodium 132 mM
magnesium 0.4 mM bisulphite 0.05 mM
[0086] By mixing the contents of both compartments 44 and 45 with
the contents of compartment 9, a final solution suited for
peritoneal dialysis is obtained with the following
concentrations:
6 glucose 4.0% calcium 2.5 mM bicarbonate 36 mM sodium 132 mM
magnesium 0.6 mM bisulphite 0.1 mM
EXAMPLE 2
[0087] Three Compartment Container with Sulphite in Electrolyte
Compartment
[0088] A multiple compartment container as shown in FIG. 1,
containing following medical solutions in the three compartments
44,45 and 9.
[0089] Compartment 44 contains 100 ml of the composition:
7 glucose 30% calcium 20 mM magnesium 5 mM sodium 132 mM pH 3.2
[0090] Compartment 45 contains 100 ml of the composition:
8 glucose 50% calcium 33 mM magnesium 8 mM sodium 132 mM pH 3.2
[0091] Compartment 9 contains 1900 ml with the composition:
9 bicarbonate 40 mM sodium 132 mM bisulphite 0.1 mM pH 6.7
[0092] By mixing the contents of compartment 44 and compartment 9,
a final solution suited for peritoneal dialysis is obtained with
the following concentration:
10 glucose 1.5% calcium 1.0 mM bicarbonate 38 mM sodium 132 mM
magnesium 0.25 mM bisulphite 0.095 mM
[0093] By mixing the contents of compartment 45 and compartment 9,
a final solution suite for peritoneal dialysis is obtained with the
following concentration:
11 glucose 2.5% calcium 1.65 mM bicarbonate 38 mM sodium 132 mM
magnesium 0.4 mM bisulphite 0.095 mM
[0094] By mixing the contents of both compartments 44 and 45 with
the contents of compartment 9, a final solution suited for
peritoneal dialysis is obtained with the following
concentration:
12 glucose 4.0% calcium 2.5 mM bicarbonate 36 mM sodium 132 mM
magnesium 0.6 mM bisulphite 0.090 mM
EXAMPLE 3
[0095] Two Compartment Container with Sulphite in Glucose
Compartment or Three Compartment Container with both Glucose
Compartments Mixed.
[0096] The solutions used in example 3 and 4 were as described in
example 1 and 2 except for that 50% glucose was used in all glucose
compartments giving slightly different volumes for the
compartments.
[0097] Two different sets of solutions were prepared, one
electrolyte compartment with the volume 1.875 L and one glucose
containing compartment with different amounts of bisulphite added,
this volume was 125 ml. The solutions were sterilised at
121.degree. C. for 1 hour and mixed post sterilisation. The
concentrations post mixing of electrolytes were 132 mM Na.sup.+,
1.35 mM Ca.sup.+, 0.25 mM Mg.sup.2+, 95.2 mM Cl.sup.- and 40 mM
lactate.
[0098] 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.
[0099] 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.
EXAMPLE 4
[0100] Two Compartment Container with Sulphite in Electrolyte
Compartment or Three Compartment Container with both Glucose
Compartments Mixed
[0101] As described in example 3 except for that sulphite was added
to the electrolyte compartment. The concentrations of electrolytes,
glucose and sulphite in the final solution were as in example 3.
The sterilised solutions were analysed as in example 3. 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.
EXAMPLE 5
[0102] Analysis of a Solution with or without Sulphite for the
Presence of Formaldehyde Acetaldehyde and ICG.
[0103] Three solutions containing 132 mM Na.sup.+, 1.35 mM
Ca.sup.2+, 0.25 mM Mg.sup.2+, 95.2 mM Cl.sup.-, 40 mM lactate and
1.5% glucose was heat sterilised at 121.degree. C. for 1 hour. 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.sup.+, 1.35 mM Ca.sup.2+, 0.25 mM
Mg.sup.+, 95.2 mM Cl.sup.-, 40 mM lactate and 1.5% glucose were
mixed with sodium bisulfite to different concentration of sodium
bisulphite (0, 0.5, 1 mM) and was heat sterilised at 121.degree. C.
for 1 hour.
[0104] 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.
* * * * *