Composition for creating vascular occlusions
||Composition for creating vascular occlusions
||Krall, et al.
||June 27, 2006
||March 30, 2001
||Kerber; Charles W. (La Mesa, CA)
Knox; Kimberly (La Mesa, CA)
Krall; Robert E. (Alpine, CA)
||Prohold Technologies, Inc. (El Cajon, CA)|
|Attorney Or Agent:
||Gray Cary Ware & Freidenrich, LLP
||424/422; 424/601; 424/605; 424/617; 424/649; 424/78.08; 424/78.31; 424/78.35; 424/78.37; 514/526; 514/527; 514/558; 514/560; 514/690; 514/730; 514/824; 514/834; 514/930; 514/944; 514/970; 604/500
|Field Of Search:
||514/527; 514/526; 514/690; 514/730; 514/558; 514/560; 514/824; 514/834; 514/930; 514/944; 514/970; 424/601; 424/605; 424/617; 424/649; 424/78.08; 424/78.31; 424/78.37; 424/78.35; 424/422; 604/49; 604/53
||A61K 31/275; A61K 31/05; A61K 31/12; A61K 33/24; A61K 33/42
|U.S Patent Documents:
||4740534; 5525334; 5624685; 5695480; 5702361; 5759194; 5795331; 6143352; 6174919; 6476069; 2002/0018752; 2003/0194389
|Foreign Patent Documents:
||Barr, John D., "Temporary and Permanent Occlusion of Cerebral Arteries," Neuroendovascular Surgery, vol. 11, No. 1, Jan. 2000, pp. 27-38.cited by other.
Berthelsen, B. et al., "Embolization of Cerebral Arteriovenous Malformations with Bucrylate," Acta Radiologica, vol. 31, 1990, pp. 13-21. cited by other.
Freeny, Patrick C. et al., "Transcatheter Therapy of Genitourinary Abnormalities Using Isobutyl 2-Cyanoacrylate (Bucrylate)," AJR, vol. 133, Oct. 1979 pp. 647-656. cited by other.
Gobin, Dr. Y. Pierre et al., "Treatment of Brain Arteriovenous Malformations by Embolization and Radiosurgery," J Neurosurg, vol. 85, 1996, pp. 19-28. cited by other.
Halbach, Dr. Van V. et al., "Preoperative Balloon Occlusion of Arteriovenous Malformations," Neurosurgery, vol. 22, No. 2, 1988, pp. 301-308. cited by other.
Kerber, Dr. Charles W. and Wong, Wade, "Liquid Acrylic Adhesive Agents in Interventional Neuroradiology," Neuroendovascular Surgery, vol. 11, No. 1, Jan. 2000, pp. 85-99. cited by other.
Lefkowitz, Dr. Michael A. et al., "Balloon-assisted Guglielmi Detachable Coiling of Wide-necked Aneurysms: Part II--Clinical Results," Neurosurgery, vol. 45, No. 3, Sep. 1999, pp. 531-538. cited by other.
Levy, Dr. David I., "Embolization of Wide-necked Anterior Communication Artery Aneurysm: Technical Note," Neurosurgery, vol. 41, No. 4, Oct. 1997, pp. 979-982. cited by other.
Malek, Dr. Adel M. et al., "Balloon-assist Technique for Endovascular Coil Embolization of Geometrically Difficult Intracranial Aneurysms," Neurosurgery, vol. 46, No. 6, Jun. 2000, pp. 1397-1407. cited by other.
Mericle, Robert A., M.D., "Temporary Balloon Protection as an Adjunct to Endosaccular Coiling of Wide-necked Cerebral Aneurysms", Neurosurgery, vol. 41, No. 4, Oct. 1997, pp. 1992-1998. cited by other.
Moret, J et al., "The "Remodeling Technique" in the Treatment of Wide Neck Intracranial Aneurysms," Interventional Neuroradiology, vol. 3, 1997, pp. 21-35. cited by other.
Pelz, David M. et al., "Preoperative Embolization of Brain AVMs with Isobutyl-2 Cyanoacrylate," AJNR, vol. 9, Aug. 1988, pp. 757-764. cited by other.
Rao, V.R.K. et al., "Dissolution of Isobutyl 2-Cyanoacrylate on Long-Term Follow-Up," AJNR, vol. 10, Jan./Feb. 1989, pp. 135-141. cited by other.
Spiegel, S. M. et al., "Adjusting the Polymerization Time of Isobutyl-2 Cyanoacrylate," American Journal of Neuroradiology, vol. 7, Jan./Feb. 1986, pp. 109-112. cited by other.
Vinuela, F.V. et al., "Dominant-Hemisphere Arteriovenous Malformations: Therapeutic Embolization with Isobutyl-2-Cyanoacrylate," AJNR, vol. 4, Jul./Aug. 1983, pp. 959-966. cited by other.
Vinuela, Fernando et al., "Progressive Thrombosis of Brain Arteriovenous Malformations After Embolization with Isobutyl 2-Cyanoacrylate," AJNR, vol. 4, Nov./Dec. 1983, pp. 1233-1238. cited by other.
Vinuela, Fernando et al., "Angiographic Follow-Up of Large Cerebral AVMs Incompletely Embolized with Isobutyl-2-Cyanoacrylate," AJNR, vol. 7, Sep./Oct. 1986, pp. 919-925. cited by other.
||A composition including 2-hexyl cyanoacrylate and goal is useful in treating arteriovenous malformations (AVMs) and other body lumens to be blocked.
||What is claimed is:
1. A composition for creating therapeutic vascular occlusions in an animal comprising a mixture of: (a) Part 1 comprised of 2-hexyl cyanoacrylate, hydroquinone,p-methoxyphenol and phosphoric acid; and (b) Part 2 comprising gold metal powder, ethyl myristate and a sterilized a large chain fatty acid ester in liquid form and a stabilized polymer of 2-hexylcyanoacrylate in weak aqueous bicarbonate solution .
2. The composition of claim 1 wherein Part 1 comprises about 100 PPM hydroquinone, 100 PPM p-methoxyphenol, 250 PPM phosphoric acid and the remainder 2-hexyl cyanoacrylate.
3. The composition of claim 2 wherein Part 2 comprises about 65 percent by weight gold, about 30 percent by weight ethyl myristate and the remainder said sterilized stabilized polymer of 2-hexylcyanoacrylate in weak aqueous bicarbonate solution .
4. The composition of claim 1 wherein Part 2 includes sulfur dioxide as a stabilizer.
5. A method for creating therapeutic vascular occlusions in an animal needing therapeutic vascular occlusion comprising the steps of: (a) Mixing together Part 1 comprised of 2-hexyl cyanoacrylate, hydroquinone, p-methoxyphenol and phosphoricacid with Part 2 comprising gold metal powder, ethyl myristate and a sterilized a large chain fatty acid ester in liquid form, and a stabilized polymer of 2-hexylcyanoacrylate in weak aqueous bicarbonate solution ; and (b) injecting administrating themixture into a vascular site needing occlusion with the gold metal powder suspended in the mixture .
||BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a composition used to treat arteriovenous malformations ("AVMs") and other vascular abnormalities. The composition includes a cyanoacrylate liquid monomer and gold in a prepolymerized polymer of cyanoacrylate. Thecomposition is placed into the body lumen via standard catheter procedures or directly percutaneously.
2. Description of the Related Art
AVMs and vascular tumors, especially those of the brain, are exceedingly difficult to treat. These growths may occur all over the body, but are especially difficult to treat when in the brain or brain stem. The composition of the invention isespecially useful in treating neurological AVMs, but may also be used to treat tumors anywhere in the body.
Cyanoacrylate adhesives have been used surgically but are limited in their usefulness by cytotoxicity and heat generation. The brain is unusually sensitive to cytotoxicity and heat.
The art described in this section is not intended to constitute an admission that any patent, publication or other information referred to herein is "prior art" with respect to this invention, unless specifically designated as such. In addition,this section should not be construed to mean that a search has been made or that no other pertinent information as defined in 37 C.F.R. .sctn. 1.56(a) exists.
SUMMARY OF THE INVENTION
The invention provides a composition that may be placed in a body lumen including veins and arteries by super selective catheterization or direct puncture using standard tools of the interventional angiographer. The composition of the inventionhas been successfully tested in simulated models of the AVMs and tumors under fluoroscopy and in systems that closely resembles the neurological condition of the human body. Further studies have been done in the pig rete. The rete is a body of finearteries that allows the blood to flow into the pig brain which closely resembles normal human AVMs.
The composition is a cyanoacrylate which involves mixing two separate containers of the material immediately prior to administration of the material into the AVM by catheter. The composition may contain seven ingredients which are divided intotwo parts prior to mixture and use. It furnishes properties that are useful for closing neurological AVMs. The product can also be used to close any growth resembling an AVM in any part of the body. Because of the sensitive nature of the tissues inthe brain, the general sensitivity of the product must be controlled. In less sensitive areas, the product will work equally as well.
Part I consists of a cyanoacrylate liquid monomer containing pure phosphoric acid (250 ppm) hydroquinone (100ppm) and P-methoxyphenol (1200 ppm). This composition is stable and unchanging we believe for over two years. The container in which Part I is stored requires cleaning and preparation before such stability can be achieved. The liquid monomer of choicefor this usage is 2-hexyl cyanoacrylate.
Part II consists of pure powdered gold (5.times.3 microns), a small amount of prepolymerized polymer of the same cyanoacrylate and ethyl myristate. Any of the large chain fatty acid esters will work to replace ethyl myristate so long as they areliquids.
The pre-polymerized polymers of cyanoacrylate are unstable and change their structures and properties even in the solid state. The change is exponential and therefore the polymer must be used within a limited amount of time before deteriorationoccurs.
The polymer is prepared by addition of part 1 to a rapidly stirring weak bicarbonate-water solution. The addition must be added drop-wise to avoid unpolymerized masses from forming. The solid polymer is washed thoroughly with pure water toremove any traces of bicarbonate, then washed thoroughly with pure methanol to remove the water. Methanol dries rapidly and when the polymer is further dried at a high reduced pressure for 16-18 hours, it is considered dry. The polymer must be used inthe next step within 24 hours to obtain consistent results in the final product. This mixture must be sterilized within 72 hours from the time of preparation.
Part II is sterilized with ethylene oxide gas with the stopper held in an open position. Ethylene oxide is an alkylating agent and after sterilization the prepolymerized polymer is stable. Hence, the stability and sterilization of part 2 arecarried out simultaneously. The sterilized samples of Part II are capped in a clean room under sterile handling conditions.
The pre-polymerized polymer can be stabled by treatment with any of the strong alkylating agents, like ethylene oxide, ketone, etc.
This composition of matter has good cohesion as well as adequate adhesion to function well for AVMs and other similar uses within the vascular tree. The cohesion keeps the material together during the time required for it to polymerize. Theadhesion makes it stick to the artery walls.
The polymerized device will cause a modest but desirable inflammatory response in the treated tissues.
A Formulation for Arteriovenous Malformations and Tumors
It is desirable to prepare a formulation for the intravascular occlusion of AVMs and Tumors that will have the following properties: The product has a very slow rate of biodegradation. Both liquid and solid forms should have excellent cohesion. The delivered product should have medium adhesion The delivered product must be radiopaque. The solid polymer should be soft and pliable. The delivered product must have a very low or negligible histotoxicity. The deposited product must have no longterm negative properties such as carcinogenicity, teratogenicity, systemic toxicity or other unpredictable biological and medical effects. The products must be sterile. The delivered product must have good few characteristics for selectivecatheterization. The product must be stable on storage for an extended period of time. The formulation should be made from pure products and be reproducible for simple manufacturing procedures. The product formulation is:
TABLE-US-00001 Part I (M1) 2-Hexyl Cyanoacrylate 999,550 ppm Hydroquinone 100 ppm p-Methoxyphenol 100 ppm Pure Phosphoric Acid 250 ppm Part II (M2) Pure Gold 1.0000 g Pure Ethyl Myristate 0.5000 g FMS* 0.0200 g *FMS is a specially preparedpolymer of 2-hexyl cyanoacrylate and must be used within 24 hours of preparation or will change and be unusable. Further, it must be sterilized within 72 hours.
Each item of this formulation is critical to the proper performance of the product.
This cyanoacrylate homolog was chosen because it biodegrades very slowly in blood or any living tissue. The secondary alcohol will biodegrade several thousand times slower than its primary derivative. This very slow degradation rate also lowersgreatly the histotoxicity.
When the amount of hydroquinone is reduced by half (50 ppm) the product shows low shelf life stability. Large amounts over 100 ppm do not seem to effect the product stability. This inhibitor lowers the effect of the high energy free radicalsthat may appear in the cyanoacrylate.
The slow polymerization of cyanoacrylates even under refrigeration is caused by low energy free radicals. When 100 ppm of p-methoxyphenol is present this slow polymerization is prevented and long term stability is achieved. Less p-methoxyphenol(50 ppm) will not protect the product.
The faintest trace of sulfur dioxide is present in the product. One part per million can be seen and less is present. However, this very faint trace adds to the stability of Neuracryl* ml in the ampule.
Tantalum, platinum and gold are all radiopaque. Gold was best for us because it could be suspended colloidally in the mixture. One gram of gold is used per device.
Subbicates, fatty acid esters and other plasticizers, are useful for fastening the polymers of the cyanoacrylates. they also will stabilize the pre-formed polymers of the cyanoacrylates so that they may be used as thickeners. We have chosenethyl myristate, an esterified, biocompatible fatty acid because of the convenience of purification and analysis and because is works well to give the formulation the desirable properties.
FMS is the polymer of 2-hexyl cyanoacrylate formed in a weak, aqueous sodium bicarbonate solutions. The polymer diners in structure and size depending on how it is formed. This polymer will remain stable until M2 can be formulated. The polymermust be formed and dried completely before use. The final formulation of M2 must occur within 24 hours because the ethyl myristate stabilized FMS until sterilization can be performed. After sterilization the product is stable for several years.
M1 and M2 are mixed immediately before use. The mixture should he used within 4 hours after mixing. If there is a delay, the syringe should be turned over several times a minute to resuspend the gold which will be settled.
* * * * *