Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-06-04
2001-07-24
Page, Thurman K. (Department: 1645)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S491000, C424S494000, C514S002600, C514S012200, C514S834000, C530S382000
Reexamination Certificate
active
06264988
ABSTRACT:
BACKGROUND OF THE INVENTION
Platelets play a critical role in hemostasis. A deficiency of platelets (thrombocytopenia) or dysfunction of platelets present at normal levels results in longer-than-normal bleeding time and other disorders. Thrombocytopenia is currently treated with platelet concentrates obtained from healthy donors (Rintels el al., 1994
, Transfusion Med
. 8:1131). Such treatment has severe drawbacks, however, including (i) the potential transmission of infectious agents, including bacterial and viral agents, (ii) the short shelf-life of donor platelets and the requirement for specialized equipment and methods for handling and storage of platelets, and (iii) a high incidence of alloimmunization. There is, therefore, an urgent need for a platelet substitute that is both efficacious and safe and can be given to patients of different blood types without major transfusion incompatibility.
Physicians and scientists have long sought a source of artificial platelets. As one example, investigators have attached fibrinogen to erythrocytes (Agam et al., 1992
, Euro J Clin Invest
22:105; Beer et al., 1992
, Blood
79:117; Collar et al., 1992
, J Clin. Invest.
89:546). However, the erythrocyte-based system suffers from i) the difficulty of attaching fibrinogen to large numbers of erythrocytes, ii) the requirement for cross-matching with patients, iii) the inherent short storage life and instability of the treated erythrocytes, iv) the potential of transmission of infectious agents.
Other approaches to replace the need of platelet infusions involve the use of lyophilized human platelets, fibrinogen attached to platelet membrane microvesicles, and other attempts at making artificial platelets. However, these products typically have a short in vivo half life or are not efficacious in vivo.
There is, therefore, a need for a platelet substitute that is convenient and effective.
BRIEF DESCRIPTION OF THE INVENTION
In one aspect the invention relates to a suspension of particles of cross-linked albumin, which are monodisperse in the suspension, and have a size range of primarily from about 50 to about 5000 nanometers diameter. The particles have fibrinogen on the surface of the particle, at least some of which is covalently attached. The suspension is substantially free of large particles and aggregates of particles.
In preferred embodiments the particles comprise human serum albumin cross-linked with a polyaldehyde, such as glutaraldehyde, and human fibrinogen covalently attached by a polyaldehyde, such as glutaraldehyde. In a preferred embodiment the particles have at least about 4×10
12
molecules of fibrinogen per 10
9
particles.
In a preferred embodiment the particles have a sponge-like internal structure with fenestrations on the surface leading to internal matrices. Fibrinogen may be disposed within the internal matrices or cavities.
Particles of the invention may be suspended in a liquid, e.g., an aqueous suspension. Alternatively the suspension may be dried (e.g., lyophilized) to form a powder. Thus the invention also provides a composition comprising a plurality of particles that, upon addition of a liquid such as water or normal saline, forms a suspension of cross-linked albumin particles with a size range of primarily from about 50 to about 5000 nanometers diameter and fibrinogen on the surface, which suspension is substantially free of large particles and aggregates of particles.
In preferred embodiments the composition of the invention, whether as a liquid suspension of particles or a dry powder of particles, includes an excipient.
In another aspect, the invention provides a method of making a composition useful for reducing bleeding time in an animal by the steps of: adding a desolvating agent to an aqueous mixture of a protein and a surfactant, whereupon a turbid mixture comprising substantially monodisperse protein microspheres results; adding a first crosslinking agent to the turbid mixture; removing large particles and aggregates from the mixture; adding a second cross-linking agent, which may be the same as the first cross-linking agent; and adding fibrinogen. In a preferred embodiment the removal of large particles and aggregates is by filtration. In another preferred embodiment the removal of large particles and aggregates is by centrifugation.
In an alternative aspect, the invention provides a method of making a composition by the steps of: adding a desolvating agent to an aqueous mixture of a protein and a surfactant, whereupon a turbid mixture comprising substantially monodisperse protein microspheres; adding a crosslinking agent to the turbid mixture; adding fibrinogen to the mixture whereupon the particles are coated with the fibrinogen; and removing large particles and aggregates from the mixture.
In yet another aspect, the invention provides a method of reducing bleeding time in an animal comprising administering a therapeutically effective amount of the compositions of the invention, for example in the treatment of thrombocytopenia.
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Channavajjala Lakshmi
Hemosphere Inc.
Page Thurman K.
Townsend & Townsend & Crew
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