Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-01-28
2001-02-13
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C514S772300, C514S772600, C514S777000
Reexamination Certificate
active
06187330
ABSTRACT:
BACKGROUND
This invention relates to the field of controlled delivery of peptides or proteins and to compositions useful for the controlled delivery of peptides or proteins.
Polymeric matrices, typically in the form of microspheres, rods, sheets or pellets, have been employed for the sustained or controlled release of drug products. A variety of techniques are known by which active agents can be incorporated into polymer matrices. Examples are solvent evaporation, spray drying, emulsification, or by simple physical mixing of particles of discrete size or shape. None of these approaches can easily be adapted to the incorporation of peptide or protein drugs into polymers due to the delicate nature of peptides and proteins. Peptides and proteins are susceptible to denaturation by solvents, by emulsification or by heat. In order to avoid the instability problem, U.S. Pat. No. 5,019,400 describes a very low temperature casting process for incorporating proteins into controlled release polymer matrices. This technique has several drawbacks, inasmuch as low temperature processing can be very cumbersome, special equipment is needed and moisture condensation during the process represents a potential problem.
It would be desirable to be able to mix the peptide or protein drug into a molten polymer, which could be cast into a defined shape and size. Unfortunately, most proteins denature at a temperature far below the melting point of polymers.
It is also desirable that the peptide or protein drug be stable under the conditions in which it is released from the polymeric matrix within the body. Most bioerodable polymers are depolymerized within the body by the hydrolysis of ester bonds. This hydrolysis can result in local regions of high acidity. Since many peptide or protein drugs are unstable in acidic conditions, this can result in deactivation of the drug before it is released. One such protein drug, which is unstable under acidic conditions, is basic fibroblast growth factor (bFGF). This protein, which has been isolated in forms varying in length, e.g. 146, 154 and 157 amino acid forms, is a potent angiogenic agent as well as a stimulator of cell proliferation and migration during wound healing. The DNA sequence encoding human bFGF and its deduced amino acid sequence are disclosed in U.S. Pat. No. 5,514,566. Because of its angiogenic properties, it is useful in promoting the local growth of new capillary vascular beds in order to bypass blockages in arteries of individuals having atherosclerotic conditions such as coronary artery disease and peripheral vascular disease. This protein is also chemotactic for fibroblasts, which are the chief cells involved in releasing a matrix required for wound healing, including collagen which determines the tensile strength of the healed wounds. In order to deliver bFGF effectively to a desired site and avoid any potential side effects associated with systemic delivery of bFGF in treating such conditions, it would be desirable to provide a controlled release device for implantation at or near the site at which the angiogenic or wound healing activity is required.
SUMMARY OF THE INVENTION
The present invention provides methods and compositions for the controlled release of peptide or protein drugs and methods for the production of compositions and devices useful for the controlled release of peptide or protein drugs.
In one embodiment of the invention, there is provided a composition for the controlled release of a peptide or protein comprising a biocompatible, bioerodable polymer having dispersed therein a glassy matrix phase comprising the peptide or protein and a thermoprotectant, said glassy matrix phase having a glass transition temperature above the melting point of the polymer. Since the peptide or protein drug is stable within the composition, it can conveniently be formed, in its melt stage, into suitably shaped devices to be used as drug delivery implants, e.g. in the form of rods, films, beads or other desired shapes.
In another embodiment of the invention, there is provided a method of controlled release administration of a bioactive peptide or protein to an animal in need of such administration which comprises implanting a device formed from the composition of this invention into such animal.
In yet another embodiment of the invention, there is provided a method for producing a composition for the controlled release delivery of a bioactive peptide or protein which comprises:
(a) dispersing a glassy matrix comprising the bioactive peptide or protein and a thermoprotectant in a biocompatible, bioerodable polymer at a temperature above the melting point of the polymer and below the glass transition temperature of the glassy matrix; and
(b) cooling the dispersion to a temperature at which the polymer is a solid. If desired, the dispersion can be formed or cast into a delivery device having a desired shape prior to cooling.
In preferred embodiments of the invention, the thermoprotectant is selected from the groups consisting of trehalose, melezitose, cellobiose, melibiose, raffinose and lactose. A preferred polymer for use in the compositions and devices of the invention is poly(&egr;-caprolactone) having a melting point below about 65° C.
The compositions and devices of the invention provide excellent controlled release of bFGF, or vascular endothelial growth factor (VEGF), without significant degradation of the protein, either during the manufacture or delivery of the protein in vivo.
REFERENCES:
patent: 5019400 (1991-05-01), Gombotz et al.
patent: 5514566 (1996-05-01), Fiddes et al.
patent: WO 90 13780 (1990-11-01), None
patent: WO 91 16881 (1991-11-01), None
patent: WO 93 10758 (1993-06-01), None
patent: WO 94 05257 (1994-03-01), None
patent: WO 98 43611 (1998-10-01), None
Jennings, Jr. Robert N.
Protter Andrew A.
Wang Yu-Chang John
Yang Bing
Azpuru Carlos A.
Knobbe Martens Olson & Bear LLP
Scios Inc.
LandOfFree
Controlled release delivery of peptide or protein does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Controlled release delivery of peptide or protein, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Controlled release delivery of peptide or protein will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2576894