The present invention concerns a method and an apparatus for reducing the degradation of heat sensitive components in medical substances during heat sterilisation, wherein the medical substances are contained in a multiple chamber recipient that comprises a first chamber with a first medical substance and at least one second chamber with an amount of a second medical substance that is smaller than that of the first medical substance, and the multiple chamber recipient is heated to a predetermined temperature for sterilising the medical substances, is held at this temperature for a predetermined time period and is subsequently cooled.
The method can, for example, be utilised with multiple chamber recipients with medical substances for parenteral feeding/nutrition, however the method is in particular to be used with multiple chamber recipients that contain medical substances for generating a dialysis fluid for peritoneal dialysis.
Currently, haemodialysis is mainly used for acute kidney failure while for chronic kidney failure, besides transplantation, haemodialysis and peritoneal dialysis are utilised. In the case of peritoneal dialysis, the abdominal cavity is repeatedly filled at intervals with a dialysis fluid that is then removed after a hold time. The dialysis fluid is generally a buffered ionic solution with an osmotic means, wherein currently glucose is mainly used as an osmotic means and lactate is mainly used as a buffer. In this way, urea and other substances normally removed from the kidneys and excess water can be removed from the body. These dialysis fluids are produced in factories, transferred to plastic bags of two to five liter capacity and sterilised, in a similar manner to solutions for parenteral nutrition.
A disadvantage of these dialysis fluids is the presence of degradation products. At present, it is assumed that during heat sterilisation these degradation products and the accompanying brownish colour of the fluid are produced by the glucose. It is further presumed that some of these degradation products are responsible for bioincompatability reactions generated by the dialysis fluid. Studies confirm that the degradation products react strongly with biological tissue and have a substantial effect on the immune system and the cells of the peritoneum, either alone or in combination with lactate and/or a low pH value.
Theoretically, the dialysis fluids could be rendered sterile by filtration in place of the heat sterilisation. In practice, however, this is not possible because essentially all countries stipulate that medical solutions must be sterilised by heat.
However, it is known that the degradation of glucose can be markedly reduced when the sterilisation temperature is increased and simultaneously the sterilisation time shortened. It is likewise known that the glucose degradation depends strongly on the pH value, and for example is at its lowest with a pH value between 3.0 and 3.5. However, a peritoneal dialysis fluid with such a low pH value is not permitted for the treatment of patients, for this a pH value of a little over 7 would be optimal, for example 7.1 to 7.4. As a compromise, therefore, a pH value of about 5.3 is set for conventional dialysis fluids. However, from a medical point of view, this is still too low and is probably the cause of infusion pain in some patients. Furthermore substantial amounts of degradation products are still generated during heat sterilisation, which is undesirable for the reasons already mentioned.
An improvement is proposed in WO 93/09820. In the dialysis fluid disclosed here, the glucose is isolated in a small separate second chamber from the rest of the dialysis fluid located in a first chamber. The glucose is separated in this second chamber with a high concentration and a low pH value, so that the formation of degradation products of glucose during heat sterilisation is substantially reduced. The pH value of the glucose in the separate second chamber is about 3.2, while the remainder of the solution in the larger chamber has a pH value of around 7. After mixing the glucose with the rest of the solution the mixture has a pH value of around 6.4, which offers an additional advantage in terms of tolerance by patients.
In WO 97/05852 a further development of this dialysis fluid is known in which the glucose is separated into two separate chambers, namely a second and third chamber, each with different concentrations. The concentrations are selected such that upon mixing the glucose from the second chamber with the rest of the solution in the first chamber, a dialysis fluid with a glucose concentration of 1.5% is obtained, upon mixing the clucose from the third chamber with the rest of the solution in the first chamber a glucose concentration of 2.5% is obtained, and upon mixing the glucose in the second and third chambers with the rest of the solution in the first chamber a glucose concentration of 4% is obtained. In this way, the three most useful glucose concentrations can be made available with one dialysis fluid recipient, which offers a great advantage in terms of logistics and storage. In addition, this dialysis fluid contains low amounts of degradation products as a result of the low pH values in the second and third chambers.
Although this already represents a clear reduction in the amount of degradation products in the dialysis fluid, there is still a significant amount of degradation products present owing to the high glucose concentration. As a result of the small quantities in the second and third chambers compared to that of the remaining solution in the first chamber, the glucose concentrations in these second and third chambers will be heated much faster during the heat sterilisation than the rest of the solution in the first chamber, which contains the remaining components. This leads to the glucose in the second and third chambers being held for an unnecessary long period at the sterilisation temperature, which results in the unnecessary increase in degradation products. Consequently, while a considerable reduction in degradation products is achieved compared to conventional dialysis fluids, the quantity of degradation products present is nevertheless still unnecessarily high.
Finally, it is also possible to reduce the formation of degradation products during heat sterilisation of multiple chamber recipients by means of a two step heating procedure. In this, the heating of the multiple chamber recipient in the autoclave is interrupted at a predetermined temperature, so that the temperatures in the first and second, and possibly the third, chamber can become essentially equal. Subsequently, the heating of the multiple chamber recipient proceeds to the predetermined sterilisation temperature. However, it is difficult with this procedure to find the exact intermediate temperature at which no, or only few, degradation products will be formed during the hold period.
In view of this background it is thus an object of the present invention to provide a method, whereby the degradation of heat sensitive components in medical substances during heat sterilisation is reduced, wherein the medical substances are contained in a multiple chamber recipient having a first chamber with a first medical substance and at least a second chamber with an amount of a second medical substance that is smaller relative to the first medical substance, and the multiple chamber recipient is heated to a predetermined temperature to sterilise the medical substances, is held at this temperature for a predetermined time and is subsequently cooled.
This object is achieved in that the second chamber with the second medical substance is thermally insulated during the heating of the multiple chamber recipient.
In this way, a method is provided that reduces the degradation of heat sensitive components in the second chamber during the heat sterilisation of multiple chamber recipients with different substances. The end product after mixing the contents of the chamber thus likewise contains substantially lower amounts of degradation products.
The second chamber can contain a quantity of a medical substance that is low relative to that in the first chamber. If this substance contains components that form degradation products when held for a long period at the sterilisation temperature, it will be prevented that they are heated faster and consequently remain at the sterilisation temperature longer than the substance in the first chamber. However, it is also possible that the second chamber contains the same amount of a medical substance as the first chamber, but with some of the components of this substance being very heat sensitive, so that they may be subjected to the sterilisation temperature only for a shorter period of time relative to the substance in the first chamber. By means of the thermal insulation of the second chamber, the heating of the second chamber can also be deliberately delayed, as a result of which the desired hold time at the sterilisation temperature can be set.
The hold time of the second chamber at the sterilisation temperature can advantageously be more precisely adjusted, in accordance with a preferred embodiment, when the thermal insulation is removed at a predetermined time after commencing the heating of the multiple chamber recipient. In this way the point in time at which the second chamber of the multiple chamber recipient is also exposed to the heating environment can be accurately set. Furthermore, since the point in time of the cooling of the multiple chamber recipient is also predetermined, a precisely controlled heat sterilisation with a defined hold time at the sterilisation temperature is also separately possible for the second chamber.
In accordance with a further preferred embodiment, the time for removing the thermal insulation is advantageously determined such that the first and second medical substances in the first and second chambers have essentially the same F value at the end of the hold time. F is utilised here as a gauge of the capacity of a sterilisation process to kill microbes, or the sterilisation capacity of a sterilisation process, and is predominantly utilised in the food industry and in medicine. It is a reference gauge and signifies a specific rate of microbes killed during a sterilisation process, F representing the time required to achieve this specific death rate at 121xc2x0 C.
If the first and second medical substances have essentially the same F value, then this indicates that both substances have undergone essentially the same degree of sterilisation and, in particular, that the second chamber or the second substance has not been subjected to an unnecessary over-sterilisation as a result of overheating. Overheating the second chamber would lead to a substantial increase in the degradation products. It is to be noted at this point that a correlation exists between the F value and the degradation in the sense that with an increasing F value, the degradation products also increase, and vice versa.
In order to achieve an adequate sterilisation of the multiple chamber recipient, the latter is advantageously heated to a temperature of between 100xc2x0 C. and 135xc2x0 C., preferably to a temperature of 121xc2x0 C. The sterilisation process is advantageously controlled such that the multiple chamber recipient is held for between 1 minute to several hours at this predetermined temperature, and preferably 15 minutes.
The method for reducing the degradation of heat sensitive components in medical substances described here is not limited only to multiple chamber recipients with two chambers, but may also be applied to multiple chamber recipients with more than two chambers. Therefore, according to another preferred embodiment, the method is utilised for a multiple chamber recipient that additionally includes a third chamber with an amount of a third medical substance that is smaller relative to that of the first medical substance, the third chamber being thermally insulated together with the second chamber during heating of the multiple chamber recipient. Here also the second chamber with the second medical substance and the third chamber with the third medical substance are advantageously arranged in a thermally insulating jacket, that is opened a predetermined time after commencing heating of the multiple chamber recipient. The second chamber and the third chamber can contain different amounts of the same substance or also the same amount of different substances.
The time at which the thermal insulation is removed is likewise advantageously defmed such that the first and second and third medical substances in the first and second and third chambers have essentially the same F value at the end of the hold time. If the second and third chambers contain different amounts of a medical substance, the F value of the largest amount is determinate for the removal of the thermal insulation. This should be essentially the same as the F value in the first chamber. The F value of the smaller amount in the other chamber will then be somewhat higher; this deviation from the desired F value has to be accepted in view of the required sterilisation of the larger amount. However, in order to achieve a nearly equivalent F value in this case also, the insulation can be formed differently in areas. For example, it could be formed thinner in the area of the second or third chamber, when these contain a larger amount, so that the sterilising heat reaches the large amount before the removal of the insulation and is able to heat this a little. Or, the second and third chambers will be respectively insulated such that the insulation of each can be successively removed independently of one another.
The thermally insulating jacket may take any desired form. For example, it can consist of an insulating material which, upon reaching a predetermined temperature will collapse or shrink, thus allowing the elevated surrounding temperature to reach the multiple chamber recipient. In this way the heating of the second and possibly also the third chamber will be delayed, and as a result, the time during which the second and possibly the third chamber are held at the sterilisation temperature can be controlled.
Another possibility for a thermally insulating jacket is a container with thermally insulating walls. The second and possibly the third chamber would be laid in this container with the first chamber remaining outside, and the container would be closed. In this manner, the second and possibly the third chamber will be thermally insulated, so that initially only the first chamber is heated. When the predetermined point in time is reached, the container is opened and the second chamber and possibly third chamber will be exposed to the sterilising heat and heated to the same temperature as the first chamber. In this way, the hold time of the second and possibly third chambers can be precisely determined independently of that of the first chamber. When the predetermined hold time of the first chamber is terminated, the multiple chamber recipient is cooled down. During this, care should be taken that the cooling occurs rapidly, so that degradation products are not formed unnecessarily as a result of slow cooling.
The method can be applied to multiple chamber recipients of any desired form, however it is advantageously utilised with a multiple chamber recipient formed as a flexible bag. The method can likewise be applied to multiple chamber recipients that hold any desired medical substance. For example, the multiple chamber recipient may hold substances for parenteral feeding. Also, the substances can take any desired form. For example, the medical substances can be solutions in liquid form, they can also be concentrates in powder form. However, the method is preferably applied to multiple chamber bags containing medical substances for the production of a dialysis fluid for peritoneal dialysis. According to a preferred embodiment, the second medical substance and third medical substance in the second and third chambers, respectively, comprise different concentrations of glucose, that is required for the dialysis fluid, or, according to another preferred embodiment, the same concentration of glucose in different quantities.
USPTO Backgrounds
USPTO Backgrounds