Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Blood
Reexamination Certificate
1992-12-29
2001-09-04
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Blood
C424S530000, C424S531000, C424S532000, C424S534000, C514S002600, C514S021800, C530S380000, C530S381000, C530S383000
Reexamination Certificate
active
06284285
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides a simple, rapid, and inexpensive method and apparatus for small-scale preparation of tissue repair promoting substances needed in medical and veterinary practice. The substances are isolated from biological material obtained from human or animal individuals. The compositions comprising the biologically active substances prepared according to the invention offer significant benefits to the subject treated therewith in that they, in addition to efficiently promoting tissue repair, have few or no harmful side effects.
BACKGROUND OF THE INVENTION
In recent years several naturally occurring biological substances, especially from mammals, have been isolated and their biological properties have been established. Parallel to this development, fields of application of these substances have been discovered, and the need of suitable methods for their isolation have therefore increased. Examples of such substances are substances recovered from human blood, and methods for large-scale production using blood pooled from several donors have been developed.
However, the drawbacks of these large-scale production methods are numerous. First, the obtainment of blood from donors (voluntary or paid) causes well-known problems, such as the problem of limited access to a sufficient amount of biological material due to limitations with respect to the number of donors and the amount of blood which can be collected from the individual donor. Secondly, the collection procedures, storage and distribution of the material obtained require time and considerable financial ressources. Thirdly, the large-scale production of the substances under sterile conditions necessitates advanced and expensive equipment, and the waste of material during these numerous and laborious isolation steps is substantial.
Furthermore, the quality of the substances in the product obtained is substantially decreased compared to the quality of the substances present in the original native biological material. Thus, the yield of biologically active well-functioning substances may be very low. Storage of biological material over prolonged periods is known to result in spontaneous degradation of the various substances. Procedures (i.e. heating) employed in order to prevent/reduce the risk of transmission of infectious microorganisms substantially increase the extent of the denaturation of the substances and thus the loss of biological activity. A method which completely inactivates any kind and any amount of microorganisms and at the same time preserves the biological activity of the substances in question has not yet been developed.
A product prepared from numerous donors is inhomogeneous, and every component in the product represents a potential immunogen, i.e. administering the product to a human or animal individual in need thereof may result in harmful immunological reactions in said individual. The severity of such allergic/immunological reactions ranges from minor inconveniences to fatal anaphylactic reactions or disabling immunological diseases.
A field in which the administration of biological substances has become important is the field of promoting tissue repair, e.g. wound healing. It is now known that several substances contribute to the obtainment of tissue repair. During the repair of a tissue injury, chain reactions which release several substances occur, and these substances contribute to the body's mechanisms of tissue repair including hemostasis. Essential to this complex defence mechanism of the body are substances naturally present in whole blood. Some of these substances are present in plasma under normal conditions and undergo modifications during the tissue repair process. Other substances are under normal conditions present in the blood cells and are released from these cells during the tissue repair process.
Coagulation factors are substances in the blood that are essential to the clotting process and hence, to the maintenance of the hemostasis needed in tissue repair. Blood coagulation is the sequential process by which the multiple coagulation factors of the blood interact, ultimately resulting in an insoluble fibrin network. Coagulation factor I is also called fibrinogen. Fibrinogen can be converted into fibrin which forms the essential part of the blood clot. Fibrin is converted to an insoluble supporting network of fibrous material. The conversion takes place by the action of an enzyme such as thrombin. Coagulation factor VIII, also known as the antihemophilic factor, participates in blood coagulation. Coagulation factor XIII is the fibrin stabilizing factor. It polymerizes fibrin monomers so that they become stable and insoluble, thus enabling the formation of a stable clot.
Also participating in the coagulation processes are the platelet derived factors, the so-called platelet factors 1-4, e.g. platelet factor 2, which accelerates the thrombin-fibrinogen reaction. The platelet-derived growth factor (PDGF) is known as a potent mitogen, which e.g. promotes the proliferation of fibroblast cells needed in tissue repair. Furthermore, epidermal growth factor (EGF) which promotes epithelial growth is present in the platelets.
Another important component present in plasma is the protein fibronectin, which plays a role in cell proliferation and in fibrin interaction.
Knowledge of the molecular basis for the sequence of the biochemical phenomena involved in tissue repair has promoted the need for development of suitable isolation procedures for the various biochemical substances involved in the repair. Compositions comprising the isolated tissue repair promoting substances have many applications in medical and veterinary practice, e.g. in wound repair and in oozing surfaces, as control of local bleeding, e.g. in liver and spleen repair, in prevention of peritoneal adhesion-formation by local fibrin sealing, as closure of postoperative fistulae, and as fixation of skin grafts. The application of a composition containing tissue repair promoting substances in a concentrated form to a mammal in need of the treatment, e.g. treatment of a surgical wound, may shorten the wound healing period considerably.
An important aspect of the use and manufacture of compositions comprising tissue repair promoting substances is the employment of the composition for achieving substantial intermediary initial adhesion between injured tissue surfaces. E.g. wound healing an be efficiently promoted by topically applying a composition comprising fibrinogen in a concentrated form to a mammal in need of the treatment, and at the same time providing means for the enzymatic conversion of the fibrinogen to a firm supporting fibrous network. The use of such a tissue-adhesive system will probably increase, especially in surgical practice where it provides excellent means for obtaining hemostasis, closing leakages from fluid containing compartments etc.
The isolation and use of fibrinogen compounds for tissue repair is well-known, cf. AT No. 359,653, DE No. 3,002,934, DE No. 3,203,775, DE No. 3,105,624, EP No. 0,068,047, WO 86/01814 and EP No. 0,068,149.
These known methods are typically large-scale preparations of substances from a blood pool obtained from more than one donor, often from a blood pooled from several hundreds or thousands of individual donors. Furthermore, the procedures usually involve several laborious purification steps such as repeated washing procedures. Usually lyophilization, which is a laborious time- and material-consuming procedure, is employed. Sterilization procedures such as sterile filtration are often needed. The overall recoveries of biologically active substances recovered by such procedures are low.
SUMMARY OF THE INVENTION
The object of the present invention is the provision of a simple and inexpensive method for small-scale production of substances useful in tissue repair, in particular substances isolated from blood plasma, e.g., coagulation factors, and substances derived from blood cells, such as the platelet-derived growth factor (PDGF).
The present
Brinks Hofer Gilson & Lione
Dockrey Jasper W.
E. R. Squibb & Sons Inc.
Witz Jean C.
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