Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
2000-04-25
2001-04-10
Bhat, Nina (Department: 1761)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S094100, C424S094620, C424S530000, C210S782000
Reexamination Certificate
active
06214338
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns compositions, methods and apparatuses for making concentrated plasma and tissue sealant, for sealing tissue, for rapid separation of higher molecular weight components in mixtures, for rapid separation of blood plasma and for rapid separation of particulate components in mixtures. The present invention is particularly applicable to preparation and use of autologous tissue sealant.
2. Discussion of the Background
Fibrin Glues and Sealants
Various substances have been tried to meet the need for a suitable tissue adhesive for use in surgical procedures. Completely synthetic materials such as cyanoacrylate have been tried and been found wanting. Natural fibrin glues and sealants made from blood components were recognized early in the development of this technology. Surgical “fibrin sealants” (sometimes called “fibrin glues”) made up of human fibrinogen activated by bovine thrombin are used extensively in Europe. Such fibrin sealants have been shown to be superior to synthetic adhesives or traditional surgery in many situations. In addition they reduce the need for blood transfusions. Academic and surgical opinion on fibrin sealants is very favorable. A recent review says:
Fibrin sealants are the most successful tissue adhesives to date. They have many advantages over adhesive technologies such as cyanoacrylates and marine adhesives in terms of biocompatibility, biodegradation and hemostasis. There are several commercial products in Europe but none in the United States due to the current regulatory stance against pooled plasma blood products (Sierra, 1993; vide infra).
In current practice, fibrin sealant is made by isolating a concentrate of human fibrinogen, fibronectin and factor XIII, usually by cryoprecipitation, and combining it immediately before use with bovine (or sometimes human) thrombin. The thrombin converts the fibrinogen to fibrin which rapidly gels to form a transient hemostatic plug, which is then stabilized by factor XIII. Fibronectin provides adhesion for cells repopulating the clot and tissue. The most common method of application of fibrin sealant is mixing of concentrated fibrinogen from pooled human blood with bovine thrombin and calcium immediately before use.
Fibrin sealant is not available in the U.S. commercially, but is in Europe (TISSEEL®, TISSUCOL®/Immuno; BERIPLAST®/Behring). Many papers have been published on its use.
Use of fibrin sealant in the United States is limited to preparation within the clinic outside FDA control. The reasons for FDA reluctance to approve these products in the United States are:
virus transmission (e.g., HIV, hepatitis) from pooled human blood
1
and
immunological reactions to bovine thrombin
2
, for example thrombin and factor V inhibitors or foreign body reactions
3
.
These FDA concerns are so serious that the FDA has not approved any fibrin sealant product, despite strong interest from surgeons and very favorable comparative studies in the literature.
These circumstances have led to much attention being given to methods to isolate an autologous counterpart of the fibrinogen containing component in the TISSUCOL system in a practical manner. These efforts are discussed in the reviews cited below. The following from a review by Thompson
4
shows that the value of stat autologous fibrinogen is much anticipated: Fibrin glue is composed of two separate solutions of fibrinogen and thrombin. When mixed together, these agents mimic the last stages of the clotting cascade to form a fibrin clot. Fibrin glue is available in Europe but is not commercially available in the U.S.; therefore, investigators have extemporaneously compounded their own fibrin glue. Fibrinogen can be obtained from pooled, single-donor, and autologous blood donors and is usually isolated by the process of cryoprecipitation . . . The safest preparations use the patient's own blood to prepare fibrin glue . . . Use of . . . autologous blood results in minimal risk of disease transmission, but it requires anticipated use as in an elective procedure. The use of autologous blood usually is not possible in trauma or an emergency surgical procedure.
Siedentop
5
describes a number of approaches to the precipitation of fibrinogen from plasma in the context of the proposed use of this material as the fibrinogen furnishing component of a fibrin glue. Four methods were suggested: precipitation with ethanol, use of unfractionated plasma, cryoprecipitation, and precipitation with ammonium sulfate. Epstein
6
suggests the use of a fibrinogen preparation from autologous plasma obtained using polyethylene glycol precipitation. A system for preparing autologous tissue adhesive using a relatively complex system based on ethanol precipitation has been described by Weis-Fogh
7
. Because none of these methods has yet produced a clearly superior autologous sealant, research in the past five years has continued on several approaches including plasma sealant
8
, ethanol precipitation
9
and rapid cryoprecipitation
10
. Prior patents are discussed in later sections, Autologous Precipitate Sealants and Autologous Plasma Sealants.
None of these methods is readily adaptable for convenient use of an autologous plasma fraction as an adhesive which can be prepared quickly during the surgical procedure. All of the approaches suggested for preparation of the fibrinogen containing fraction for this purpose are too time-consuming and complex to be finished in a short enough time to be accomplished during the surgery. Also, in some procedures, such as cryoprecipitation, special equipment, such as refrigerated centrifuges, is required. While the prior art approach is to prepare the composition in advance, this immediately imposes the necessity for additional procedures for identification and retrieval of the samples matched with the patient, and the concomitant opportunity for error, besides the inconvenience to the patient, who must then arrange time for an additional medical appointment. And, of course, this practice is not possible when the surgery is conducted on an emergency basis.
Several useful reviews on surgical glues generally and on fibrin glues particularly have been published (Sierra, D. H. “Fibrin sealant adhesive systems: a review of their chemistry, material properties and clinical applications.”
J Biomater Appl
7 (4 1993): 309-52; Wiseman, David M., David T. Rovee, and Oscar M. Alverez. “Wound Dressings: Design and Use.” In
Wound Healing: Biochemical & Clinical Aspects
, ed. I. Kelman Cohen, Robert F. Diegelmann, and William J. Lindblad. 562-580. 1st ed., Vol. Philadelphia: W. B. Saunders Company, 1992). A review of devices used by surgeons discusses fibrin glue in context of both hemostatic agents and adhesive agents (Edlich, Richard F., George T. Rodeheaver, and John G. Thacker. “Surgical Devices in Wound Healing Management.” In
Wound Healing: Biochemical & Clinical Aspects
, ed. I. Kelman Cohen, Robert F. Diegelmann, and William J. Lindblad. 581-600. 1st ed., Vol. Philadelphia: W. B. Saunders Company, 1992). A review of the role of fibrin and fibrinogen in blood coagulation has also been published (Jackson, C. M. and Y. Nemerson. “Blood coagulation.”
Annu Rev Biochem
49 (811 1980): 765-811). Other reviews, in reverse chronological order, include:
(1) Lerner, R. and N. S. Binur. “Current status of surgical adhesives.”
J Surg Res
48 (2 1990): 165-81.
(2) Gibble, J. W. and P. M. Ness. “Fibrin glue: the perfect operative sealant?”
Transfusion
30 (8 1990): 741-7.
(3) Thompson, D. F., N. A. Letassy, and G. D. Thompson. “Fibrin glue: a review of its preparation, efficacy, and adverse effects as a topical hemostat.”
Drug Intell Clin Pharm
22 (12 1988): 946-52.
Biological Precipitate Sealants
The vast majority of prior methods for preparing blood derived glues or sealants use fibrinogen precipitated (usually cryoprecipitated) from pooled plasma, a method first published in 1972
11
. Most biological sealant patents are improvements on cryoprecipitation. Most go through a lyophiliza
Antanavich Richard D.
Dorian Randel
Bhat Nina
Flehr Hohbach Test Albritton & Herbert LLP
PlasmaSeal LLC
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