Thrombolytic agents and methods of treatment for thrombosis

Details Thrombolytic agents and methods of treatment for thrombosis Thrombolytic agents and methods of treatment for thrombosis

1999-11-08

2001-03-06

Harrison, Robert H. (Department: 1619)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S009520, C424S491000, C424S493000

Reexamination Certificate

active

06197345

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a new and improved pharmaceutical composition and method for treating thrombosis in animals. The methods and composition of the invention can be used as an anticoagulant therapy to induce thrombolysis and to relieve trauma associated with obstruction of smaller vessels.
BACKGROUND OF THE INVENTION
Thrombosis, the formation and development of a blood clot or thrombus within the vascular system, while a life saving process when it occurs during a hemorrhage, can be life threatening when it occurs at any other time. The thrombus can block a vessel and stop blood supply to an organ or other body part. If detached, the thrombus can become an embolus and occlude a vessel distant from the original site.
In the healthy person there is a balance between clot formation (thrombosis) which is needed to minimize blood loss and to repair blood vessels, and clot lysis (fibronolysis) which maintains the patency of blood vessels. When thrombosis occurs without concomitant fibronolysis effects can lead to strokes.
Traditional thrombolytic agents used are not clot specific and while they do break up the thrombus and facilitate fibronolysis they also put the patient at significant risk as all clotting is inhibited and a patient could bleed to death from a small abrasion elsewhere. Current thrombolytic agents include streptokinase which is derived from Beta-hemolytic streptococci. When combined with plasminogen, streptokinase catalyzes the conversion of plasminogen to plasmin, the enzyme responsible for clot dissolution in the body. Three major problems encountered with the use of streptokinase therapy include its systemic lytic effects coupled with a long half life. Because the anticoagulant activity of streptokinase is indiscriminent (non clot specific) and prolonged (half life 10-18 minutes), bleeding is a common complication which must be carefully monitored during 12 hours following immediately after administration. Further because streptokinase is a bacterial protein, it is strongly antigenic and can produce a variety of allergic reactions including anaphylaxis, particularly when administered to a patient who has previously received streptokinase therapy or who has had a recent streptococcal infection.
Another popular agent for use in treatment of thrombosis is urokinase, an enzyme protein secreted by the parenchyma cells of the human kidney. It acts to direct activation of plasminogen to form plasmin. This is different from streptokinase which first forms a complex with plasminogen to activate plasmin to dissolve the clot. Urokinase is also non clot specific (activates circulating non clot bound plasminogen as well as clot bound plasminogen) but has a shorter half life than streptokinase. Its administration is associated with fewer bleeding complications despite the fact that a systemic lytic state is also produced. Urokinase is produced by the kidney and as such it is not antigenic and well suited for use if subsequent thrombolytic therapy is needed. The major problem with urokinase is that it is difficult and expensive to produce precluding its extensive clinical use.
The most recently developed drug in treating of thrombolysis is recombinant tissue plasminogen activator. Approved by the FDA in November of 1987, tissue plasminogen activator (t-PA) is a naturally occurring enzyme (thus non antigenic) that is clot specific and has a very short half life (3-5 minutes). It converts plasminogen to plasmin after binding to the fibrin-containing clot. This clot specificity results in an increased concentration and activity of plasmin at the site of the clot, where it is needed. This characteristic of t-PA prevents the induction of the systemic lytic state that occurs with streptokinase and urokinase activity. However the results of studies comparing the streptokinase and t-PA show similar incidences of bleeding following administration. Successful gene cloning has made sufficient quantities of t-PA available for clinical use, however, the recombinant technology necessary for its production have also resulted in a prohibitive cost. As can be seen a need in the art exists for a thrombolysis therapy which is clot specific, which does not induce a systemic lytic state and which is inexpensive and non antigenic to patients.
SUMMARY OF THE INVENTION
According to the invention a thrombolytic therapy is provided which is site-specific and non-antigenic. The therapy involves the use of a pharmaceutical composition which comprises microbubbles of a diameter of about 0.1 to 10 microns, the interior of which has been enhanced with an insoluble gas such as fluorocarbon gas, helium or sulfur hexafluoride and which gas is encapsulated in a protein-coated shell. The invention uses agents and methods traditionally used in ultrasound imaging and as such provides a means for visualization of the clot as it is being lysed. Quite unexpectedly it was found that the insoluble gas microspheres of the invention act themselves as a thrombolytic agent in the presence of an ultrasound field and work as well as traditional thrombolytic agents such as urokinase.
DETAILED DESCRIPTION OF THE INVENTION
Ultrasonic imaging has long been used as a diagnostic tool to aid in therapeutic procedures. It is based on the principle that waves of sound energy can be focused upon an area of interest and reflected to produce an image. Generally an ultrasonic transducer is placed on a body surface overlying the area to be imaged and ultrasonic energy, produced by generating and receiving sound waves, is transmitted. The ultrasonic energy is reflected back to the transducer where it is translated into an ultrasonic image. The amount of characteristics of the reflected energy depend upon the acoustic properties of the tissues, and contrast agents which are echogenic are preferably used to create ultrasonic energy in the area of interest and improve the imaging received. For a discussion of contrast echographic instrumentation, see, DeJong and, “Acoustic Properties of Ultrasound Contrast Agents”, CIP-GEGEVENS KONINKLIJKE BIBLIOTHEEK, DENHAG (1993), pp. 120 et seq.
Contrast echocardiography has been used to delineate intracardiac structures, assess valvular competence, and demonstrate intracardiac shunts. Myocardial contrast echocardiography (MCE) has been used to measure coronary blood flow reserve in humans. MCE has been found to be a safe and useful technique for evaluating relative changes in myocardial perfusion and delineating areas at risk.
Ultrasonic vibration has also been used in the medical field to increase the absorption of various medicaments. For example in Japanese Patent Kokai number 115591/1977 discloses that percutaneous absorption of a medicament is enhanced by applying an ultrasound vibration. U.S. Pat. Nos. 4,953,565 and 5,007,438 also disclose a technique of percutaneous absorption of medicaments by the aid of ultrasonic vibration. U.S. Pat. No. 5,315,998 discloses a booster for drug therapy comprising microbubbles in combination ultrasonic energy to allow the medicament to diffuse and penetrate at the site of interest.
Quite surprisingly applicant has demonstrated that a microbubble composition in combination with ultrasound therapy can act as a thrombolytic medicament causing clot lysis at the site of a thrombus. In the presence of ultrasound the microbubbles themselves act as a medicament and are as effective as traditional thrombolytic agents such as urokinase or t-PA. The pharmaceutical composition of the invention comprises a liquid containing microbubbles of an insoluble gas having a diameter of 0.1 to 10 microns. The microbubbles are formed by entrapping microspheres of a gas into a liquid. The microbubbles are made of various gases preferably inert gases as xenon, krypton, argon, neon, helium, or fluorocarbon gases. The liquid includes any liquid which can form microbubbles. Generally any inert gas can be used. It must be gaseous at body temperature and be nontoxic. The gas must also form stable microbubbles of average size of between about 0.1 and 10 microns in di

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