Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-02-27
2003-05-06
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S021000
Reexamination Certificate
active
06559132
ABSTRACT:
This application is a 371 of PCT/NO99/00278, filed Sep. 9, 1999.
The present invention relates to a composition comprising heparin to be used as a non-thrombogenic surface coating agent when in contact with arterial blood flow. It also relates to a device treated on the surface thereof with such a composition.
BACKGROUND OF THE INVENTION
Thrombosis is a major health problem in the industrialized world. Thrombosis related diseases cause the death of several millions of people every year and the health care costs have been estimated to be over 90 billion US dollars just for the USA.
There are two different kinds of thrombosis, arterial and venous. As the names suggest the arterial thrombosis occurs in the arteries and the venous thrombosis occurs in the veins. The arterial thrombus is formed at high flow rates and platelets are the main component. Platelets are small cells, diameter around 2 &mgr;m, circulating in the blood. Their main function is to participate in the haemostasis. When platelets are exposed to collagen in damaged or altered vessel walls or in wounds or when exposed to foreign surfaces they adhere to the surfaces, become activated and start to form aggregates. When this occurs in an artery a thrombus with aggregated platelets is formed. The arterial thrombus has also been called the white thrombus because of its appearance which is due to the fact that it mainly contains platelets and very few erythrocytes (red blood cells).
The venous thrombus is formed at low flow rates and the blood coagulation system is the major participant. In plasma a number of proenzymes and effector proteins are present that together constitute the coagulation system. The system can be triggered in several ways and in a cascade-like process one enzyme activates a proenzyme and the formed enzyme activates the next proenzyme. The final enzyme formed is thrombin and that cleaves off two peptides from the plasma protein fibrinogen, which then results in a rapid aggregation of the modified fibrinogen to form a gel, and a fibrin clot or thrombus is formed. The venous thrombus is called the red thrombus because it contains erythrocytes embedded in fibrin.
Diseases related to arterial thrombosis are: myocardial infarction, thrombotic stroke, and peripheral arterial disease. In myocardial infarction a thrombus is formed in one of the coronary arteries and the blood supply to the corresponding part of the heart muscle is stopped or strongly diminished resulting in death of that part of the heart muscle. In thrombotic stroke the blood flow in a cerebral artery is blocked by a thrombus, which usually has been formed somewhere else in the circulation and followed the blood flow to the brain. As the brain is very sensitive to oxygen deprivation, the part of the brain supplied by blood from this artery will be damaged.
Myocardial infarction and thrombotic stroke are very serious conditions with high mortality and therefore, many treatment efforts today intend to prevent them from occurring. The mostly used drug is aspirin (acetylsalicylic acid), which inhibits the activation and aggregation of platelets and thereby prevents the arterial thrombus formation. Large clinical studies have shown that one aspirin a day significantly reduces the risk for having myocardial infarction. For prevention of thrombotic stroke there is also another drug which is commonly used. That is Ticlopedin, which also inhibits platelet aggregation but through somewhat different mechanisms than aspirin.
Diseases related to venous thrombosis are deep venous thrombosis (DVT) and pulmonary embolism. In deep venous thrombosis a thrombus is formed in one of the veins in the extremities usually the legs. That thrombus diminishes the return flow of blood and results in diminished blood supply to that part of the leg or arm. The leg or arm becomes swollen and painful. The condition as such is not life-threatening but if not treated the thrombus can grow and extend and pieces can leave by the return flow and get stuck in the lungs. That condition which is life-threatening is called pulmonary embolism. The clinical practice in dealing with venous thrombosis can be divided into prevention and treatment. However, the drugs used are the same—the difference is in the dosing and time of treatment.
The drugs used are heparin, low molecular weight heparin and dicoumarol derivatives. All of them act as to diminish coagulation and fibrin formation, which is the key process in venous thrombosis. Heparin is a sulfate-containing polysaccharide, which on large scale is isolated from intestinal mucus of swine. It has for many decades been used clinically as an agent for the treatment and prevention of venous thrombosis. Heparin is heterogeneous with a molecular weight from 5,000 to 30,000 daltons and with an average molecular weight of about 12,000-15,000 daltons. Heparin and low molecular weight heparin exert anticoagulant activity by drastically increasing the rate whereby the physiological coagulation inhibitor, antithrombin III (AT), inactivates activated coagulation factors. Only about one third of heparin molecules do bind AT and have a strong anticoagulant activity. This is related to the fact that they contain a specific pentasaccharide sequence with a strong affinity for AT. This fraction of heparin is called the high affinity or HA-fraction. The residual part, the low affinity (LA) fraction, is essentially devoid of anticoagulant activity. Regarding the more important thing, the in vivo antithrombotic activity, the situation is more complex, as not only activation of AT is important but also other mechanisms, such as release of Tissue Factor Pathway Inhibitor (TFPI) contribute to the antithrombotic effect. LA-heparin releases TFPI and thus contributes to the antithrombotic effect of whole heparin despite having no anticoagulant activity.
Heparin also affects platelets but it acts as a weak stimulator of platelet aggregation and it also potentiates the platelet aggregatory action of adenosine diphosphate. There is no difference between the HA- and LA-heparin regarding their ability to affect platelets in this respect as shown by Holmer et al., Thromb Res 1980; 18: 861-69.
Dicoumarol derivatives have antithrombotic action through diminishing synthesis of some coagulation factors in their biologically active forms. That process takes some time and that is why the dicoumarol derivatives cannot be used for immediate antithrombotic treatment.
During the last two decades there has been a large progress in the development of devices for various types of implantation or use in machines, where there is contact with blood. However, that has also created a new type of thrombosis problem. When blood comes into contact with other materials than the fresh natural wall of the blood vessel, activation of the coagulation system starts to occur and thrombotisation can follow. The thromboses formed are of the arterial type with platelets as a dominating element when the foreign surface is subjected to arterial blood flow (Hanson et al. Biomaterials 1982; 519-30). In venous blood flow the situation is mixed with both platelets and coagulation involved.
To prevent thrombosis in devices it is possible to use antiplatelet and antithrombotic drugs. This is not an ideal solution however, as that imposes a bleeding risk and further drug treatment often has to go on for long times which is a disadvantage. That is why far going efforts have been made to find materials of reduced tendency to form thrombosis. Various polymers and plastic materials have been tried. The hydrophilicity/hydrofobicity of the surface has been varied but no break-through composition has been found. As platelets are negatively charged at physiological pH, studies have been performed with surfaces containing negative charges, where it could be expected that the adhesion would be diminished due to the electrostatic repulsion. So far the most successful example of making a surface less thrombogenic through coating of the surface with a negatively charged polymer is to use heparin for the coating to
Carmeda AB
Nixon & Vanderhye P.C.
O'Sullivan Peter
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