Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-11-07
2003-05-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S422000, C424S423000, C424S424000, C424S426000
Reexamination Certificate
active
06562362
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the invention
The present invention relates to liquefied embolic materials capable of sol-gel phase transition in response to in vivo conditions, including temperature, ionic strength, and pH, and their uses. More particularly, the present invention relates to liquefied embolic materials made of copolymers which are based on temperature-sensitive isopropylacrylamide and ionic strength- and/or pH-sensitive monomers. Also, the present invention is concerned with pharmaceutically acceptable, embolic compositions comprising the embolic materials in liquid forms.
2. Description of the Prior Art
Embolotheraphy is a medical technique of closing dysfunctional blood vessels to normalize distorted blood flow or of obstructing the blood flow around lesions, especially cancers, to reduce sizes of the lesions (cancers), induce the withering of the disease entities to death, and simplify the operation for the removal of lesions with a minimal hemorrhage.
In order to embolize blood vessels, there have been developed a variety of embolic materials and devices, from among which the selection of appropriate ones is determined depending on the types, sizes and locations of target blood vessels. Generally, consisting of particulate synthetic polymers, human tissue fragments, or curable liquid materials, embolic materials are classified as “degradable” and non-degradable” depending on their biodegradability.
On the whole, a vascular embolic material must satisfy the following requirements: 1) that it completely embolize target blood vessels, 2) that it exhibit minimal toxicity with substantial absence of side effects to tissues around the locus where it is introduced, 3) that it cause minimal pain and be safe, 4) that it perform embolization with a high rate of success and prevent recurrence of blood flow, 5) that it allow convenience for the operation, 6) it be low in cost, and 7) it be applicable for blood vessels of various loci. Thus far, no vascular embolic materials have been reported which meet all the above requirements. For example, vascular embolic materials heretofore proposed are virtually impossible to apply for all types of embolization for various reasons, such as locations of blood vessels of interest, relevant organs, disease seriousness and so on.
For embolization, there have been developed a variety of types of means, including particulate materials and balloon devices. In recent times, liquid forms of embolic materials have been of special concern to those in the art for their ability to embolize fine blood vessels. Following are the materials suitable for use for this purpose.
Bucrylate (isobutyl-2 cyanoacrylate)
Representative of the embolic materials which can be used in a liquid form at present, bucrylate, widely known as an instantaneous adhesive, is polymerized to a polymer by anion polymerization mechanism in the presence of water. In the medial field, this material is also used as an adhesive for tissues. Because of its rapid polymerization rate, bucrylate may be used in combination with glacial acetic acid to control its reaction rate when being used for embolization. However, this material suffers from the disadvantages of demanding a highly skilled expert in its application for embolization, owing to its polymerization being very difficult to control, and the requirement for use of an injection catheter which is specially designed not to be clogged by the material. What is worse, bucrylate may cause cancers in the body. Thus, it is recommended to use this putative carcinogenic material only for patients who are in critical condition. In addition, the biomedical effects of its biodegradation procedure and products of decomposition are highly controversial.
Silicon
Silicon is injected, along with oligomers, crosslinking agents and catalysts, into blood vessels with the crosslinking rate being controlled by the mixture ratio of the components, as disclosed in U.S. Pat. No. No. 4,551,132. Advantages of the silicon material described in, this reference patent are its superb compatibility with blood without causing cancers. In addition, the silicon material is advantageous in that it is less toxic in vivo than other embolic materials and the length of time taken for coagulation in the blood vessel of a living body can be controlled within a wide range. However, the silicon material suffers from the drawback of being inconvenient for injection because of its high viscosity. Another drawback with the silicon material is that blood vessels, if small in diameter, cannot be selectively embolized by use of the silicon material.
Absolute Ethanol
Absolute ethanol damages endothelial cells of blood vessels and denaturates proteins of the tissues, giving rise to blood coagulation. With these advantages, this material is useful to embolize fine blood vessels. The use of absolute ethanol in embolization is usually accompanied by employing balloon catheters to prevent the backflow of enthanol. For this reason, absolute ethanol is difficult to apply for the embolization of cerebral vascular systems.
Thermosensitive Embolic Material
In recent times, there have been introduced thermosensitive polymers which are liquid at low temperatures but transform into solid forms at the body temperature. U.S. Pat. No. 5,525,334 discloses a method for vascular embolization of blood vessels, which takes advantage of this phase transition of such a thermosensitive polymer. In this method, an aqueous solution of a thermosensitive polymer is introduced into a blood vessel followed by in situ heating of the solution to cause coagulation. Because its phase transition is absolutely dependent on temperature, the material described in the reference patent, based fundamentally on isopropyl acrylamide, has the problem of clogging the catheter in use therewith as a result of the phase transition occurring within the catheter. Also, the thermosensitive embolic material cannot be transformed into a gel mass strong enough to withstand normal blood pressure, so that a complete vascular embolizing effect is not obtained.
Many other materials available for use in embolization have been developed. For example, U.S. Pat. No. 4,172,066 describes spheroidal microgels of a water-swollen or water-swellable, cross-linked polymer such as cross-linked polyacrylamide. In U.S. Pat. No. 4,358,355, there is described a polymeric material comprising acrylamide or derivatives thereof, acrylonitrile or derivatives thereof, acrylic acid and esters, or derivatives thereof, sulphonyl or phosphonyl derivatives, which can be used as components of gels. Another material is found in U.S. Pat. No. 4,732,930 which relates to an ionic gel formed by polymerization of isopropylacrylamide in the presence of an ion-containing monomer. This gel is capable of drastic volume change in response to external conditions. All of the gels described above, however, are problematic in that they cannot completely close blood vessels and may be leaked out of the blood vessels.
SUMMARY OF THE INVENTION
Therefore, it is an object of the present invention to overcome the above problems and disadvantages encountered in the prior art, such as inability to control the polymerization of monomers and to selectively embolize blood vessels of interest and clogging of injection catheters, and to provide a novel liquefied embolic material capable of sol-gel phase transition, which completely embolizes blood vessels of interest and prevents the recurrence of blood streaming in addition to being minimized in toxicity and side effects.
It is another object of the present invention to provide a pharmaceutical composition for embolizing blood vessels, which is based on the embolic material.
Because of its being converted to gel under a specific set of conditions defined by a temperature parameter, an ionic strength parameter and a pH parameter, the liquefied embolic material according to the present invention is free from clogging catheters by being gelled within catheters, unlike conventional materials sensitive only to temperature. Und
Bae You Han
Han Moon Hee
Kang Seong Il
Na Kun
Yi Jin Woo
Bennett Rachel M.
Kwangju Institute of Science and Technology
Page Thurman K.
Rosenberg , Klein & Lee
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