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Publication numberUSRE40640 E1
Publication typeGrant
Application numberUS 10/941,013
Publication dateFeb 17, 2009
Filing dateSep 15, 2004
Priority dateJun 23, 1993
Also published asDE69418286D1, DE69418286T2, EP0656203A1, EP0656203B1, EP0656203B3, US5676962, USRE38919, WO1995000120A1
Publication number10941013, 941013, US RE40640 E1, US RE40640E1, US-E1-RE40640, USRE40640 E1, USRE40640E1
InventorsJuan Cabrera Garrido, Juan Cabrera Garcia-Olmedo
Original AssigneeBtg International Ltd.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Injectable microfoam containing a sclerosing agent
US RE40640 E1
Abstract
Injectable microfoam for scleroteraphy. The sclerotherapy of varices is based on the injection of liquid substances capable of suppressing them. The present invention relates to the preparation of sclerosing substances in the form of a microfoam. The microfoam is prepared with sclerosing agents, and is then injected in the vein to be treated, so that the microfoam displaces the blood contained in the vein and provides for the contact of the sclerosing agent with the vascular endothelium, with a predetermined known concentration and during a controllable time.
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Claims(40)
1. Prepared or extemporaneously prepared injectable microfoam for therapeutic uses characterized in that the microfoam is prepared with any sclerosing substance.
2. Injectable microfoam for therapeutic uses, according to claim 1, characterized in that the sclerosing substance is polydocanol.
3. Injectable microfoam for therapeutic uses, according to claim 1, characterized in that the sclerosing substance is sodium tetradecyl sulfate.
4. Injectable microfoam for therapeutic uses, according to claim 1, characterized in that the sclerosing substance is a hypertonic glucostated or glucosaline solution.
5. Injectable microfoam for therapeutic uses, according to claim 1, characterized in that the sclerosing substance used is chromated glycerol.
6. Injectable microfoam for therapeutic uses, according to claim 1, characterized in that the sclerosing substance used is ethanolamine oleate.
7. Injectable microfoam for therapeutic uses, according to claim 1, characterized in that the sclerosing substance used is sodium morrhuate.
8. Injectable microfoam for therapeutic uses, according to claim 1, characterized in that the sclerosing substance used is any iodated solution.
9. A method for phlebologic treatment comprising injecting the microfoam of claim 1 into vessels to be treated.
10. A method for phlebologic treatment comprising injecting the microfoam of claim 2 into vessels to be treated.
11. A method for phlebologic treatment comprising injecting the microfoam of claim 3 into vessels to be treated.
12. A method for treatment of esophageal varices comprising injecting the microfoam of claim 1 into vessels to be treated.
13. A method for treatment of esophageal varices comprising injecting the microfoam of claim 2 into vessels to be treated.
14. A method for treatment of esophageal varices comprising injecting the microfoam of claim 3 into vessels to be treated.
15. A method for proctologic treatment comprising injecting the microfoam of claim 1 into vessels to be treated.
16. A method for proctologic treatment comprising injecting the microfoam of claim 2 into vessels to be treated.
17. A method for proctologic treatment comprising injecting the microfoam of claim 3 into vessels to be treated.
18. A method for angiologic treatment comprising injecting the microfoam of claim 1 into vessels to be treated.
19. A method for angiologic treatment comprising injecting the microfoam of claim 2 into vessels to be treated.
20. A method for angiologic treatment comprising injecting the microfoam of claim 3 into vessels to be treated.
21. An injectable microfoam for therapeutic use that is prepared or extemporaneously prepared comprising
at least one sclerosing substance chosen from polidocanol, sodium tetradecyl sulfate, hypertonic glucosated solutions, hypertonic glucosaline solutions, chromated glycerol, ethanolamine oleate, sodium morrhuate, and iodated solutions, and
a gas component, wherein the gas component consists essentially of oxygen or a mixture of oxygen and carbon dioxide.
22. The injectable microfoam of claim 21, wherein the at least one sclerosing substance is polidocanol.
23. The injectable microfoam of claim 21, wherein the microfoam further comprises at least one substance with a foaming capacity.
24. The injectable microfoam of claim 21, wherein the at least one sclerosing substance is sodium tetradecyl sulfate.
25. The injectable microfoam of claim 23, wherein the at least one substance with a foaming capacity is chosen from polysorbate 20, polysorbate 80, and polygeline.
26. A method of phlebologic treatment comprising
injecting an effective amount of a prepared or extemporaneously prepared injectable microfoam into a vessel in need of phlebologic treatment,
wherein said injectable microfoam comprises at least one sclerosing substance chosen from polidocanol, sodium tetradecyl sulfate, hypertonic glucosated solutions, hypertonic glucosaline solutions, chromated glycerol, ethanolamine oleate, sodium morrhuate, and iodated solutions, and
a gas component, wherein the gas component consists essentially of oxygen or a mixture of oxygen and carbon dioxide.
27. The method of claim 26, wherein the at least one sclerosing substance is ploidocanol.
28. The method of claim 26, wherein the microfoam further comprises at least one substance with a foaming capacity.
29. The method of calim 26, wherein the at least one sclerosing substance is sodium tetradecyl sulfate.
30. The method of claim 26, wherein the at least one substance with a foaming capacity is chosen from polysorbate 20, polysorbate 80, and polygeline.
31. A method of angiologic treatment comprising
injecting an effective amount of a prepated or extemporaneously prepared injectable microfoam into a vessel in need of angiologic treatment,
wherein said injectable microfoam comprises at least one sclerosing substance chosen from polidocanol, sodium tetradecyl sulfate, hypertonic glucosated solutions, hypertonic glucosaline solutions, chromated glycerol, ethanolamine oleate, sodium morrhyatem and iodated solutions, and
a gas component, wherein the gas component consists essentially of oxygen or a mixture of oxygen and carbon dioxide.
32. The method of claim 31, wherein the at least one sclerosing substance is polidocanol.
33. The method of claim 31, wherein the microfoam further comprises at least one substance with a foaming capacity.
34. The method of claim 31, wherein the at least one sclerosing substance is sodium tetradecyl sulfate.
35. The method of claim 33, wherein the at least one substance with a foaming capacity is chosen from polysorbate 20, polysorbate 80, and polygeline.
36. A method of treating esophageal varices comprising
injecting an effective amount of a prepared or extemporaneously prepared injectable microfoam into a vessel in need of such treatment,
wherein said injectable microfoam comprises at least one sclerosing substance chosen from polidocanol, sodium tetradecyl sulfate, hypertonic glucosated solutions hypertonic glucosaline solutions, chromated glycerol, ethanolamine oleate, sodium morrhuate, and iodated solutions, and
a gas component, wherein the gas component consists essentially of oxygen or an mixture of oxygen and carbon dioxide.
37. The method of claim 36, wherein the at least one sclerosing substance is polidocanol.
38. The method of claim 36, wherein the microfoam futher comprises at least one substance with a foaming capacity.
39. The method of claim 36, wherein the at least one sclerosing substance is sodium tetradecyl sulfate.
40. The method of claim 38, wherein the at least one substance with a foaming capacity is chosen from polysorbate 20, polysorbate 80, and polygeline.
Description

This is a continuation of international application Serial No. PCT/ES94/00064, filed Jun. 21, 1994.

Notice: More than one reissue application has been filed for the reissue of U.S. Pat. No. 5,676,962, which is a continuation of international application Serial No. PCT/ES94/00064, filed Jun. 21, 1994. The reissue applications are application No. 10/941,013 (the present application), filed Sep. 15, 2004, which is a continuation application of 10/458,806, filed Jun. 11, 2003, now Reissue Pat. No. 38,919.

PRIOR ART

SchlerosisSclerosis of varices is based on injecting liquid substances in them, which causing a localized inflammatory reaction propitiates the elimination of these abnormal veins.

Upon injecting a sclerosing agent, a mixture thereof with the blood contained in the vein is produced and diluted in an unknown proportion. The results are uncertain (due to overdose or underdose) and limited to short varicose segments. As the size of the varices to be injected decreases, the lesser this dilution is and the results that are obtained are more foreseeable. Nowadays, sclerosis is a technique chosen in cases of small and medium-sized varices. Surgery is used for those varices with a diameter equal or larger than 7 mm.

Sclerosis and surgery complement each other at this time, but sclerotherapy continues without being able to be applied to large varicose trunci.

In these large sized varices, upon injecting a sclerosing substance, the concentration thereof in the vein, its homogenous distribution in the blood and the time that it is going to be in contact with the inside walls of the tretedtreated vein are unknown.

In 1946 Orbach injected in small caliber varices some few cubic centimeters of air and verified displacement of the blood inside the vessel, which is occupied by the injected air. The sclerosing agent introduced afterwards is more effective than if it has been injected into the blood.

In thick varices, upon injecting air, the described phenomenon of displacement of the blood by the injected air does not take place, but rather this forms a bubble inside the vein that makes the process ineffective in these vessels.

This same author conceived, a few years latelater, injection of foam obtained by agitating in a container containing sodium tetradecyl sulfate, an anionic sclerosing detergent with a high foaming capacity.

The process turns out to be rather useless due to the large-sized bubbles formed and dangerous due to the collateral effects of the atmospheric nitrogen, not very soluble in blood.

Both methods had very little practical repercussion as they were used only in small varices.

DESCRIPTION OF THE INVENTION

This invention refers to the preparation of a sclerosing microfoam.

In accordance with the present invention it has been discovered that injecting in a horizontal position a microfoam of pharmacologically inert sterile physiological serum, it is verified that the microfoam causes displacement of the blood contained in the vessel, even in more developed varices, due to the fact that the pressure of the blood contained in them horizontally is low.

The lifting of the injected member decreases even more the venous pressure, facilitating the exclusive filling of the vein with microfoam; this remaining in the vessel while the patient is not lifted from the examination table.

Upon replacing the prepared microfoam with the physiological serum by microfoam prepared with a sclerosing agent and injecting it in the vein, this displaces the blood that the vein contains and guarantees the contact of the sclerosis agent with the endothelium of the vein, at a known concentration and for a controllable amount of time, achieving sclerosis of the entire occupied segment.

The advantages of this process allow:

1. To know the concentration of the sclerosing agent in the vessel, as the microfoam displaces the blood and is not diluted in it like a liquid in it.

2. To guarantee the homogenous distribution of the product of sclerosis in the inside thereof.

3. To control the time in which it is kept in contact with the inside walls of the vein.

All of these factors are not known exactly nor are they controllable with the use of liquid sclerosing agents.

The elaboration of the present invention is carried out with the preparation of a microfoam with any sclerosing agent, such as: polydocanolpolidocanol, sodium tetradeclytetradecyl sulfate, hypertonic glucosated or glucosaline solutions, chromated glycerol, ethanolamine oleate, sodium morrhuate, iodated solutions.

Once the sclerosing microfoam has been prepared by any one of the existing processes, two of which will be described hereinafter, it is introduced in any sterile vessel that can be used later to be injected in the vessels to be treated, and that permits the stability of the same, so that it can be removed by a syringe, or by any other instrument that allows injection thereof into the vessels to be treated.

EXAMPLE 1

The preparation of the sclerosing microfoam is done by mixing in a sterile, hermetic container and connected if desired to a bottle under oxygen pressure, mixture of oxygen and carbon dioxide or other physiological gassesgases; mechanical beating is carried out by means of a micromotor that makes an écouvillon submerged in the sclerosing solution to be foamed turn.

Beating between 8,000 and 15,000 rpm, for a time between 60 and 120 seconds, the microfoam is achieved.

This is introduced into any container that can be used for subsequent storage and later injection into the veins to be sclerosed.

In the event that the sclerosing agent does not have a foaming capacity Polysorbate 20, Polysorbate 80, Polygeline or any other substance with a foaming capacity accepted as inert for intravenous use is added to it.

EXAMPLE 2

The sclerosing agent is introduced into a hermetic, pressurized and sterile container and by stirring the solution the microfoam is achieved, with a outlet from the container for its subsequent use.

The invention can also embrace prepared or extemporaneously prepared injectable microfoam for therapeutic uses characterized in that the microfoam is prepared with any sclerosing substance. In one embodiment, the sclerosing substance in the injectable microfoam is polidocanol. In another embodiment, it is sodium tetradecyl sulfate. In a further embodiment, it is a hypertonic glucostated or glucosaline solution. In still another embodiment, the sclerosing substance can be chromated glycerol. The sclerosing substance in another embodiment is ethanolamine oleate. Another embodiment could envisage sodium morrhuate as the sclerosing substance. Still another, envisages any iodated solution.

The present invention also uses the inventive microfoam in phlebology. The sclerosing substance in the microfoam can be polidocanol or sodium tetradecyl sulfate.

The present invention also uses the inventive microfoam in the treatment of esophageal varices. The sclerosing substance in the microfoam can be polidocanol or sodium tetradecyl sulfate.

The present invention also uses the inventive microfoam in a proctology. The sclerosing substance in the microfoam can be polidocanol or sodium tetradecyl sulfate.

The present invention also uses the inventive microfoam in angiology. The sclerosing substance in the microfoam can be polidocanol or sodium tetradecyl sulfate.

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61K1-Von P. Flöckiger, "Nicht-operative retrograde Varicenverödung mit Varsylschaum", Schweizerische Medizinische Wochenschrift, No. 48, pp. 1368-1370, (1956) with English translation.
62K21-J. Orbach, "Sclerotherapy of Varicose Veins", American Journal of Surgery, vol. LXVI, No. 3, pp. 362-366, Dec. 1944.
63K22-J.R. Cabrera Garrido et al., "Extending the Limits of Sclerotherapy: New Sclerosing Products", Phlépp;pgoe, vol. 50, No. 2, pp. 181-188;997.
64K23-J. Cabrera; "Application Techniques for Sclerosant in Micro-Foam Form"; pp. 39-44.
65K24-Video (VHS) tape of Compression Sclerotherapy, H.R., Bernbach, M.D. and English Translation of the Documentation Accompanying the Video K24; pp. 1-16.
66K25-Dr. J.C. Wollmann et al.; Evaluation of the Test; Kreussler Pharma; pp. 17-28, Jan. 29, 2003.
67K2-H. Mayer et al., "On the aetiology and treatment of varices of the lower extremities", Angiology, Chirurgische Praxis, pp. 521-528, (1957) with English translation.
68K3-Meyer's Encyclopedia, 5th Edition, vol. 15, pp. 386 (1895) with English translation.
69K5-Dr. Med. Jo{umlaut over (z)}e Baridevic; "Varicosclerozation in Phlebological Practice", The Journal for Doctors, in Clinic and Practice; XXI Volume No. 3, pp. 126-136; Jan. 11, 1989, and translation into English.
70K6-W. Gillesberger; "The Equipment of the Dermatologist Working in the Field of Phlebology", the Journal for Skin Diseases; vol. 44 (18), pp. 669-674; 1969 and translation into English.
71K7-Dr. E. Lunkenhelmer; letter to Chem. Fabrik Kreussler & Co.; Mar. 20, 1967 and translation into English.
72K8-Gianni Belcaro; "Mirco-sclerotherapy"; Sclerotherapy in Venous Disease; pp. 89-95; 2002.
73K9-M. Schadeck; "Ultrasound-controlled Sclerotherapy of the Great Saphenous Veins"; Phlébologie; vol. 46, No. 4, pp. 673-682, 1993 and translation into English.
74L. Ferguson, "Ligation of Varicose Veins, Ambulatory Treatment Preliminary To Sclerosing Injections", Annals of Surgery, vol. CII, pp. 304-314, 1935.
75L. Moszkowiez, "Treatment of Varicose Veins with Sugar Injections, combined with vein ligation", Zentralblatt fur Chirurgie, No. 28, pp. 1731-1736, 1927 and translation into English.
76L. Reiner, "The Activity of Anionic Surface Active Compounds in Producing Vascular Obliteration", Surface Active Sclerosing Agents, Proceedings of the Society for Experimental Biology and Medicine, vol. 62, pp. 49-54, May-Jun. 1946.
77M. Battezzati et al., "Treatment of Lower Limb Varices with Multiple Endermic Ligations and Sclerosant Injections Combined or not with Stripping of the long Saphenous Vein's higher region", Minerva Chirurgica, pp. 936-939, 1952 and translation into English.
78M.H. Steinberg, "Evaluation of Sotradecol in Sclerotherapy of Varicose Veins", Angiology The Journal of Vascular Diseases, vol. 6, No. 6, pp. 519-532, Dec. 1955.
79M.J. Oppenheimer et al., "In vivo Visualization of Intracardiac Structures with Gaseous Carbon Dioxide-Cardiovascular-Respiratory Effects and Associated Changes in Blood Chemistry", American Journal of Physiology, vol. 186, pp. 325-334, Jul.-Sep. 1956.
80Maarz, "Nil nocerel: Life-Threatening anaphylactic Incidents in Connection with Sclerosing of Varicose Veins", Munchener Medizinische Wochenschrift, vol. 27, No. 35, 1954.
81Meyer's Encyclopedia, 5th Edition, 1895, vol. 15, pp. 386.
82P. Jaeger, "The Current Treatment Standard for Crural Ulcer and Varices", Deutsche Medizinische Wochenschrift, vol. 77, No. 14, pp. 421-425, Apr. 4, 1952 and translation into English.
83P. Piulachs et al., "Pathogenic Study of Varicose Veins", Angiology, The Journal of Vascular Diseases, vol. 4, No. 1, pp. 59-100, Feb. 1953.
84P. Piutaches et al., "Pathogenic Considerations on Varicose Veins Developed in Pregnancy", Lyon Chirurigical, Bulletin offical de la Socirte de Chriurgie de Lyon, vol. 47, No. 3, pp. 263-278, Apr. 1952 and translation into English.
85R. Bayeux, "Comparative Resistance of Dog and Rabbit to Intravenous Injection of Oxygen", Compt. Rend. vol. 156, pp. 1329-1331, 1913, with Abstract in English.
86R. Foote, "Treatment", Varicose Veins, Chapter 5, p. 65 and 86, 1949.
87R. Jung, "Injection Treatment of Varicose Veins", Praxis, pp. 195-198, 1950 and translation into English.
88R. May, "Impairments and Risks of the Treatment of Varicose Veins", Münchener Medizinische Wochenschrift, No. 1, pp. 13-16, Jan. 1956 and translation into English.
89R. Rowden-Foote; "Varicose Veins Hemorrhoids and Other Conditions-Their Treatment by Injection"; London, H.K. Lewis & Co. Ltd.; pp. 13-45, 106-119; 1944.
90R. Zingg, "Experimental tests with the new sclerosing agent Geigy", pp. 1-9, 1948.
91R.E. Weston et al., "The Influence of Denitrogenation on the Response of Anesthetized Dogs to Intravenously Injected Oxygen", vol. 26, pp. 837-848, 1946.
92R.M. Moore et al., "Injections of Air and Carbon Dioxide into a Pulmonary Vein", Annals of Surgery, vol. 112, pp. 212-218, 1940.
93R.S. Handley, "The Treatment of Varicose Veins", The Practitioner-Diseases of the Veins, No. 993, vol. 166, pp. 228-235, Mar. 1951.
94R.W. Décoppet, "The Sclerotherapy of Varices with Thrombophilic Patients", Swiss Medical Weekly Journal, 86th year, No. 20, pp. 509-513, May 19, 1956 and translation into English.
95Sigg, "Regarding treatment of varicose veins and their complications", Dermatologica, vol. 100, p. 317, 1950 and translation into English.
96Vons Hans Brücke et al., "The combined foam sclerosis of varices", Wiener Medizinische Wochenschrift, vol. 104, No. 1, pp. 111-113, Jan. 1954 and translation into English.
97W. Heyerdale et al., "Management of Varicose Veins of the Lower Extremities", Annals of Surgery, vol. 114, pp. 1042-1049, 1941.
98W. Leun et al., "The Limits and Risks of the Sclerotherapy of Varicose Veins", German Medical Weekly Journal, No. 7, pp. 257-260, Feb. 18, 1955 and translation into English.
99Written commentary tracking the DVDs submitted with Supplemental Information Disclosure Statement of Mar. 24, 2004.
Classifications
U.S. Classification424/423, 424/484, 514/945, 424/489, 514/708, 424/422, 514/706, 514/709
International ClassificationA61F2/01, A61K9/12, A61F2/00
Cooperative ClassificationY10S424/07, Y10S514/945, A61K9/122
European ClassificationA61K9/12B
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