Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-11-06
2003-06-03
Low, Christopher S. F. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S013800, C514S014800, C514S015800, C424S457000, C424S426000, C424S468000, C424S480000, C424S489000, C424S490000, C424S499000, C530S303000
Reexamination Certificate
active
06573238
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to pharmaceutical compositions. In particular, the invention relates to methods for preparing biodegradable microparticles, as well as compositions comprising biodegradable microparticles including entrapped polypeptides, such as IGF-1, for sustained-release.
BACKGROUND OF THE INVENTION
Insulin-like growth factor-I (IGF-1) belongs to a family of polypeptides known as somatomedins. IGF-1 is structurally and functionally similar to, but antigenically distinct from, insulin. In this regard, IGF-1 is a single-chain polypeptide with three intrachain disulfide bridges and four domains known as the A, B, C and D domains, respectively. The A and B domains are connected by the C domain, and are homologous to the corresponding domains of proinsulin. The D domain, a carboxy terminal extension, is present in IGF-1 but is absent from proinsulin. IGF-1 has 70 amino acid residues and a molecular mass of approximately 7.5 kDa. Rinderknecht,
J. Biol. Chem
. (1978) 253:2769; and Rinderknecht,
FEBS Lett
. (1978) 89:283. For a review of IGF, see Humbel,
Eur. J. Biochem
. (1990) 190:445-462.
IGF-1 has been reported to stimulate growth and division of a variety of cell types, particularly during development. See, e.g., EP 560,723 A and 436,469 B. IGF-1 has also been shown to be useful for the treatment of osteoporosis. See, for example, U.S. Pat. No. 5,374,620. Thus, processes such as skeletal growth and cell replication are affected by IGF-1 levels. Furthermore, IGF-1 has been reported to be useful in the treatment of pancreatic disorders (WO 93/25226), renal diseases (U.S. Pat. No. 5,106,832) and cardiac disorders (U.S. Pat. No. 5,434,134).
Due to the widely varied clinical applications for IGF-1, compositions with desirable characteristics are in great demand and several IGF-1 formulations have been made. See, e.g., U.S. Pat. Nos. 5,126,324, 5,374,620 and 5,681,814. These compositions are typically formulated as liquid injectables for parenteral delivery. However, such compositions often require frequent injections which are inconvenient, uncomfortable and subject to poor patient compliance. Furthermore, several disorders for which treatment with IGF-1 is indicated require high doses of IGF-1 not achievable by conventional modes of delivery. Thus, there is a need for IGF-1 compositions which allow for controlled, sustained-delivery of adequate doses of IGF-1.
Particulate carriers have been used in order to achieve controlled, parenteral delivery of therapeutic compounds. Such carriers are designed to maintain the active agent in the delivery system for an extended period of time. Examples of particulate carriers include those derived from polymethyl methacrylate polymers, as well as microparticles derived from poly(lactides) (see, e.g., U.S. Pat. No. 3,773,919) and poly(lactide-co-glycolides), known as PLG (see, e.g., U.S. Pat. No. 4,767,628). Polymethyl methacrylate polymers are nondegradable while PLG particles biodegrade by random nonenzymatic hydrolysis of ester bonds to lactic and glycolic acids which are excreted along normal metabolic pathways.
Slow-release formulations containing various polypeptide growth factors have been described. For example, International Publication No. WO 94/12158 describes growth hormone controlled-release systems formed by spraying a polymer and dry protein into a freezing solution of liquid nitrogen to form polymeric microspheres. U.S. Pat. No. 5,134,122 describes methods of forming microparticles that include salts of peptides such as LHRH. International Publication No. WO 96/37216 describes IGF-1 formulations comprising IGF-1 and hydrophobic polymers. Lam et al.,
Am. Assn. Pharm. Sci
. Western Regional Meeting (Apr. 24-25, 1997) Abstract F-21 and Tada et al.,
Proc. Intl. Symp. Control. Rel. Bioact. Mater
. (1997) 24:889-890, describe IGF-1 PLG microspheres formed by a spray freeze-drying technique and European Publication No. EP 442,671 A2 describes microcapsules containing various polypeptides.
However, the controlled release of adequate amounts of IGF-1 and other proteins over a defined period remains difficult to achieve. Thus, there is a continued need for IGF-1 sustained-release formulations, as well as methods of preparing microparticle compositions that provide for the continuous release of polypeptides.
DISCLOSURE OF THE INVENTION
The present invention is based on the surprising discovery that the use of biodegradable microparticles, such as those derived from a poly(&agr;-hydroxy acid), and including IGF-1 entrapped in the form of a highly concentrated viscous “syrup”, provide for continuous delivery of IGF-1 for extended periods of time. This syrup has an IGF-I concentration of at least about 250 mg/ml, a density of about 1.0 g/ml to about 1.2 g/ml, and a viscosity of about 13,000 centipoise (cps) to about 19,000 cps, as measured at ambient temperature (23° C.)
Additionally, the present invention provides a particularly efficient method for incorporating a desired polypeptide into a biodegradable microparticle by first preparing the polypeptide of interest in a highly concentrated, viscous form and carrying out microparticle formation at lowered, yet not freezing, temperatures. The method allows increased amounts of the protein of interest, e.g., 90% of more of the protein provided, to be incorporated into the microparticle.
Accordingly, in one embodiment, the invention is directed to a method of making a biodegradable microparticle comprising:
(a) preparing a polypeptide in a highly concentrated viscous form;
(b) combining the polypeptide with a polymer selected from the group consisting of a poly(&agr;-hydroxy acid), a polyhydroxybutyric acid, a polycaprolactone, a polyorthoester and a polyanhydride, wherein the polymer is present at a concentration of about a 1%-30% in an organic solvent and further wherein the polypeptide is present at 0.1% to about 40% (w/w);
(c) emulsifying the polymer/polypeptide solution to form an emulsion;
(d) adding an emulsion stabilizer to the emulsion under conditions that allow microparticles to form;
(e) removing organic solvent from the stabilized emulsion; and
(f) recovering the microparticles.
In another embodiment, the invention is directed to a method of making a biodegradable microparticle comprising:
(a) preparing an IGF-1 or IGF-1 analog composition at a pH of about pH 5.5 to about pH 6.0, in a highly concentrated viscous syrup;
(b) cooling the IGF-1 or IGF-1 analog composition to a temperature of about 2° C. to about 8° C.;
(c) combining the cooled IGF-1 or IGF-1 analog composition with a poly(&agr;-hydroxy acid) polymer selected from the group consisting of poly(L-lactide), poly(D,L-lactide) and poly(D,L-lactide-co-glycolide), wherein the polymer is present at a concentration of about 5%-20% in methylchloride and further wherein the IGF-1 is present at about 3% to about 20% (w/w);
(d) emulsifying the polymer/IGF-1 solution at a temperature of about 2° C. to about 8° C.;
(e) adding polyvinyl alcohol as an emulsion stabilizer to the polymer/IGF-1 emulsion under conditions that allow microparticles to form;
(f) removing organic solvent from the stabilized polymer/IGF-1 emulsion; and
(g) recovering the microparticles.
In yet other embodiments, the invention is directed to microparticles made using the above methods and sustained-release formulations comprising the microparticles.
In still a further embodiment, the invention is directed to a method of delivering IGF-1 or an IGF-1 analog to a vertebrate subject comprising administering to the vertebrate subject a pharmaceutically effective amount of the sustained-release formulations above.
These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.
REFERENCES:
patent: 3773919 (1973-11-01), Boswell, Jr. et al.
patent: 4542025 (1985-09-01), Tice et al.
patent: 4767628 (1988-08-01), Hutchinson
patent: 5126324 (1992-06-01), Clark et al.
patent: 5134122 (1992-07-01), Orsolini
patent: 5374620 (1994-12-01), Clark et al.
pa
Hora Maninder
O'Hagan Derek
Shirley Bret
Singh Manmohan
Blackburn Robert P.
Chiron Corporation
Guth Joseph H.
Kam Chih-Min
Low Christopher S. F.
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