Prolonged release of GM-CSF

Details Prolonged release of GM-CSF Prolonged release of GM-CSF

1999-11-17

2001-08-14

Azpuru, Carlos A (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S423000, C424S451000, C424S464000, C424S498000, C428S402240

Reexamination Certificate

active

06274175

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is generally in the area of controlled, prolonged release microsphere formulations for recombinant human granulocyte macrophage colony stimulating factor (GM-CSF).
GM-CSF, granulocyte macrophage colony stimulating factor, is a hematopoietic growth factor which promotes the proliferation and differentiation of hematopoietic progenitor cells. The cloned gene for GM-CSF has been expressed in bacteria, yeast and mammalian cells. The endogenous human protein is a monomeric glycoprotein with a molecular weight of about 22,000 daltons. GM-CSF produced in a yeast expression system is commercially available as Leukine® from Immunex Corporation, Seattle, Washington. It is a glycoprotein of 127 amino acids characterized by three primary molecular species having molecular masses of 19,500, 16,800, and 15,500 daltons.
Generally, GM-CSF is administered over a period of at least 6 to 7 days in order to obtain the optimal effect on the white blood cells. Under some circumstances, it is desirable to have a formulation which provides continuous, zero order or first order kinetic release of GM-CSF over a period of approximately one week. Moreover, sustained release formulation of GM-CSF may have advantageous therapeutic utilities not shared by standard liquid formulations. Sustained-release formulations of GM-CSF, however, are not currently available.
Controlled release formulations are well known for drug delivery. Both biodegradable and non-biodegradable polymers have been used to form microcapsules, microspheres or microparticles of various diameters, porosities, and drug loadings with the goal of obtaining release of the encapsulated drug over a period of time, Many formulations that have been developed have been designed for administration by injection, although the majority of controlled release formulations have enteric coatings or are formulations resistant to passage through the gastrointestinal tract that have been developed for oral administration.
It is difficult to achieve linear, controlled release using the standard formulations. Most formulations are designed either to provide very rapid release by diffusion and/or degradation of the polymer forming the microparticle or provide for a burst release followed by some kind of linear release which generally plateaus after a period of tine. U.S. Pat. No. 5,192,741 to Orsolini, et al., is representative of the literature regarding the difficulties in obtaining controlled release from microspheres formed of poly(lactide-co-glycolides) (PL3As). Similarly, lu and Park
J. Pharm. Sci. Technical
49, 13-19 (1995) describes the use of microcapsules, noting that one cannot obtain good release characteristics with microspheres and that protein stability in the microspheres is a problem. Since GM-CSF is an extremely potent compound where the effect may vary widely depending upon the given dosage, it may be advantageous in some circumstances to obtain a more linear release rather than a burst followed by a plateau of drug being released.
Representative of the many patents relating to controlled release are U.S. Pat. No. 4,767,628 to Hutchinson, disclosing multiphasic release of a peptide from a PLGA carrier. Blends of polymers are used is a large matrix delivery system to avoid multiphasic release. U.S. Pat. No. 4,897,268 to Tice, et al., discloses the use of different PLGAs in the same composition, but blends microspheres made of the different PLGAs to achieve linear release. U.S. Pat. No. 4,849,228 to Yamamoto, et al., claims PLGA microspheres having a very low monobasic acid content which allegedly have excellent release characteristics.
It is therefore an object of the present invention to provide a formulation encapsulating GM-CSF which provides for controlled, prolonged release with either zero order kinetics, first order release kinetics or multiphasic release kinetics over a period of greater than one day following administration to a patient by injection.
It is a further object of the present invention to provide a formulation for delivery of GM-CSF for administration orally, transmucosally, topically or by injection.
SUMMARY OF THE INVENTION
Formulations for controlled, prolonged release of GM-CSF have been developed. These are based on solid microparticles formed of the combination of biodegradable, synthetic polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and copolymers thereof with excipients and drug loadings that yield a sustained release over a period of one day to at least one week, when administered orally, transmucosally, topically or by injection. In the preferred embodiment, the microparticles have different as diameters depending on their route of administration. Microparticles administered by injection have diameters sufficiently small to pass through a needle, in a size range of between 10 and 100 microns. Orally administered microparticles are less than 10 microns in diameter to facilitate uptake by the Peyer's patches in the small intestine.
Other embodiments have been developed to alter the release kinetics or the manner in which the drug is distributed in vivo. For example, in some cases a polymer is selected which elicits a mild inflammatory reaction, for example, PLGA and polyanhydrides, which can act as chemoattractant, either due to the polymer itself or minor contaminants in the polymer. In another embodiment, the GM-CSF is administered in a hydrogel which can be injected subcutaneous or at a specific site for controlled release.
The microparticles or hydrogel are administered to the patient in an amount effective to stimulate proliferation of hematopoietic cells, especially white cells. These are most preferably microspheres administered by injection.
Examples demonstrate the preparation of microparticles releasing GM-CSF over a prolonged period with zero order, first order, or multiphasic release kinetics. The type of release kinetics are determined for the particular clinical application. The data demonstrates that it is possible not only to achieve the desired release characteristics but also to retain extremely high levels of bioactivity of the encapsulated GM-CSF. Examples also demonstrate release from hydrogels.


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