Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-05-21
2004-11-23
Kim, Vickie (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S200100, C435S128000, C514S561000, C514S563000, C514S689000
Reexamination Certificate
active
06822002
ABSTRACT:
The invention described herein relates to the use of L-carnitine and its alkanoyl derivatives, optionally in the form of a pharmaceutically acceptable salt as osmotic agents in solutions for medical use, particularly in peritoneal dialysis.
BACKGROUND OF THE INVENTION
Patients suffering from end-stage renal disease (or ESRD) must either undergo dialysis therapy or be submitted to a kidney transplant. Both therapeutic interventions are extremely demanding, both from the point of view of the quality of life of the patient and in terms of social costs. For a review of dialytic therapy see, for example, Pastan S. and Bailey J. in the New England Journal of Medicine, 14 May 1998, pp. 1428-1436, incorporated herein for reference in its entirety.
Dialytic therapy comprises two types of treatment, namely peritoneal dialysis and haemodialysis. There are major differences between the two types of dialysis, such as, in the case of haemodialysis, the cost of the therapy, the need for dedicated departments with expensive equipment and qualified staff, and the quality of life of the patient. Peritoneal dialysis, on the other hand, enjoys greater favour on account of its simplicity of execution, which can be handled by the patient himself in the form of self-medication. In Italy, for example, 15% of dialysis patients use peritoneal dialysis, which is practically the same as in the USA (16%), while the percentages of patients on peritoneal dialysis are higher in Canada (38%) and the United Kingdom (52%), and get up to as much as 90% in Mexico. The reason for these different rates is also to be attributed to the lower cost of peritoneal dialysis as compared to the cost of haemodialysis which not all national health systems are prepared to bear. We should, however, not overlook the fact that peritoneal dialysis allows the patient to maintain a less constrained life-style, since the dialysis session can be planned with a certain measure of autonomy in the course of the person's normal activities. In addition, automatic devices also allow dialysis during the hours of the night.
Despite this, the choice between the two types of dialysis is not a free one; for instance, peritoneal dialysis is indicated for patients with cardiac insufficiency or unstable angina who cannot support the alterations of blood flow and/or arterial blood pressure that accompany the haemodialysis session (see reference cited above).
One can postulate a therapeutic progression for the ESRD patient which starts with peritoneal dialysis, proceeds via haemodialysis and finally reaches a stage where a kidney transplant is needed.
Peritoneal dialysis is not without disadvantages and unwanted adverse effects. These drawbacks can be placed in two distinct, even if related, categories, namely adverse clinical effects and technological problems. The purpose of the invention described herein is to remedy these disadvantages and adverse effects.
In the typical execution of a peritoneal dialysis session, a plastic catheter is implanted in the peritoneal cavity and anchored to the subcutaneous tissues. A dialysis solution contains physiological amounts of sodium, calcium, magnesium, compatible physiological buffer and a non-toxic osmotic agent, of such a nature as to make the solution hyperosmolar as compared to the plasma. The solution is infused via the catheter into the peritoneal cavity where it then remains for several hours. During this time, the peritoneal membrane exchanges solutes by diffusion in such a way as to obtain replacement with fresh fluid. Given that renal function decreases in the first few years of dialysis, the dose of dialysis fluid to be exchanged increases in the course of time.
Peritonitis is the serious complication that occurs most frequently. Other types of complications are losses of amino acids and albumin, incompatibility of the dialysis solution, volume effects in the peritoneal cavity, metabolic consequences, symptoms affecting the digestive tract, reduced appetite and others (for a review see C. M. Mion, R. and Gokal and N. P. Mallick, Lancet, 1999; 353; 823-28).
One of the most pressing problems in the peritoneal dialysis sector is the choice of a suitable osmotic agent.
The requisites of an ideal solution for peritoneal dialysis include:
supplying the nutritional requirement and avoiding adverse metabolic effects;
ensuring minimal absorption of the osmotic agent, which, in any case, must be non-toxic;
being capable of correcting acidosis and having a physiological pH;
in addition to considerations with technological implications, such as apyrogenicity, absence of metals and residues of synthetic materials, the solution must also inhibit bacterial and fungal growth, must not damage the immune defences and must be inert in relation to the peritoneal membrane. A typical solution for peritoneal dialysis contains glucose in various concentrations as an osmotic agent, and various amounts of lactate (which has replaced acetate owing to problems of intolerance on the part of the patient), sodium, potassium and calcium. Buffer systems have also been studied in an attempt to solve the problem of sterilization and stabilization of the solution.
As regards the sterilization aspect, this is a critical technological problem; in fact, heat sterilization, commonly used in the sector of solutions for medical use, causes degradation of glucose, with consequent production of toxic secondary derivatives, such as aldehydes and 5-hydroxy-methylfurfural. Traditionally heat sterilization of the solution containing glucose (also indicated as dextrose) is done at a pH between 5.0 and 5.5, precisely in order to avoid caramelization of the glucose. The acid pH leads to further problems for the patient using the solution, such as, for example, abdominal pain and sclerosis of the peritoneal membrane, which entails a reduction of the elimination of solutes (Schmidt et al., Arch. Int. Med., 141; 1265-1266, 1981).
The purpose of the invention described herein is also to provide a solution to the complex problems related to the use of glucose as an osmotic agent in solutions for peritoneal dialysis.
Glucose is extensively used owing to its great availability on the market and its low cost. It is a relatively safe substance, but its use at high concentrations and its prompt absorption lead to short ultrafiltration times, and metabolic complications, such as hyperinsulinaemia, hyperlipidaemia, and weight gain. In addition, hyperosmolarity and low pH can damage the mesothelium and macrophages. Moreover, the potential glycosylation of stromal proteins leads to further damage to the peritoneum. Also reported is the inhibition of phagocytosis, bactericidal activity and the synthesis of LTB
4
in peripheral blood neutrophils. In continuous ambulatorial peritoneal dialysis (CAPD), where the application time can be as much as 6 hours or more, the glucose concentrations are very high to be able to maintain the ultrafiltration capacity. For a review of the biocompatibility of solutions for peritoneal dialysis see C. J. Holmes in Peritoneal Dialysis International, Vol. 13, pp. 88-94, 1993.
To overcome the problems created by the use of glucose as an osmotic agent in peritoneal dialysis, the state of the art directs experts in the field towards two distinct types of solution:
1) the use of low-molecular-weight osmotic agents, capable of sustaining ultrafiltration with minimal metabolic effects, without, however, altering the ultrafiltration profile;
2) the use of high-molecular-weight osmotic agents in an attempt to act on both factors.
Of the various low-molecular-weight agents proposed, to date only glycerol and mixtures of amino acids would appear to be of a certain clinical interest. In Italy, for example, a 1.1% multi-amino-acid solution is being marketed by Baxter under the trade mark Nutrineal® PD2 and PD4.
These proposed alternatives to glucose are not problem-free; other saccharides have metabolic effects: for example, fructose gives rise to hypertriglyceridaemia and hyperosmolarity, sorbitol hyperosmolarity and accumulation, xylito
Kim Vickie
Nixon & Vanderhye P.C.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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