Composition for delivery of hematopoietic growth factor

Abstract

A hematopoietic growth factor delivery composition includes a hematopoietic growth factor, a liquid vehicle, a first biocompatible polymer and a second biocompatible polymer. The composition exhibits reverse-thermal viscosity behavior, due to interaction between the first biocompatible polymer and the liquid vehicle. The second biocompatible polymer helps to protect the first biocompatible polymer from being dissolved in vivo following administration to a host.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims a priority benefit under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 60 / 214,298 entitled “COMPOSITION AND METHOD FOR DELIVERY OF HEMATOPOIETIC GROWTH FACTOR” filed Jun. 26, 2000 and to U.S. Provisional Patent Application No. 60 / 274,891 entitled “COMPOSITION AND METHOD FOR DELIVERY OF HEMATOPOIETIC GROWTH FACTOR” filed Mar. 9, 2001, the entire contents of each of which are incorporated herein by reference as if each were set forth herein in full.FIELD OF THE INVENTION [0002] The present invention relates to compositions for delivery of hematopoietic growth factors. BACKGROUND OF THE INVENTION [0003] Functionally, hematopoietic growth factors can be considered to belong to one of three groups. The first or multilineage group includes interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) which act on early colony forming units (CFU's) including colony forming unit-granul...

AI Technical Summary

Benefits of technology

[0014] The hematopoietic growth factor delivery composition of the present invention provides for sustained delivery of hematopoietic growth factors, thereby advantageously increasing the plasma half-life of hematopoietic growth factors, and thereby also reducing the number of administrations, and therefore the number of injections, required for treatment. Moreover, the saw-tooth profiles of drug plasma levels experienced conventionally should be reduced with less frequent administrations, as should side effects caused by the frequent injections with conventional treatments. Furthermore, it has been found in at least some cases, that the activity of the hematopoietic growth factor is significantly improved when administered in the composition of the present invention, relative to conventional formulation and administration. Therefore, not only should fewer administrations be required for a treatment program, but less hematopoietic growth factor should also be required in many instances, which would be expected to generally reduce the severity of side effects.

[0016] The reverse-thermal viscosity behavior of the delivery composition permits the delivery composition to be administered to a host as a lower-viscosity flowable medium, which then converts to a higher-viscosity form in vivo. The hematopoietic growth factor is then advantageously released in a sustained manner from the protective environment of the higher-viscosity form of the delivery composition. To accomplish this result, the delivery composition should exhibit reverse-thermal viscosity behavior over at least some temperature range below the physiologic temperature of the host. The presence of the second biocompatible polymer helps to protect the composition from premature degradation in vivo due to invasion by aqueous biological fluids, such as are encountered by the delivery composition inside the host after administration. The inclusion of the second biocompatible polymer, therefore, is important to help protect the delivery composition so that the delivery composition can successfully make the transition from the lower-viscosity flowable medium to the higher-viscosity form following administration. Also, the second biocompatible polymer helps to inhibit premature dissolution in vivo of the higher-viscosity form, thereby promoting a prolonged release of the hematopoietic growth factor. Surprisingly, the inclusion of the second biocompatible polymer has also resulted in an observed significant increase in the activity of the hematopoietic growth factor under at least some circumstances. Although the mechanism of this enhancement is not well understood, the enhancement in activity of the observed hematopoietic growth factor with the composition is significant and surprising.

[0017] In one embodiment, the composition exhibits a reverse-thermal gelation property, which is a special case of reverse-thermal viscosity behavior in which the higher-viscosity form of the delivery composition is a gel (i.e., gelatinous substance). In this preferred embodiment of the delivery composition, the composition should have a reverse-thermal liquid-gel transition temperature that is no higher than the physiologic temperature of the host. The composition is then administerable to the host as a flowable medium at a chilled temperature, and as the delivery composition warms in the host following administration the delivery composition converts to the gel form. Because the gel form is typically substantially immobile, the hematopoietic growth factor is released within the host at the desired location from the protective environment of the gel to facilitate sustained delivery of the hematopoietic growth factor.

[0019] Also, for enhanced performance, the hematopoietic growth factor should be uniformly dispersed throughout the gel, which can typically be accomplished by mixing the composition at a temperature at which the first biocompatible polymer / liquid vehicle combination is in the form of a flowable liquid solution of the first biocompatible polymer in the liquid vehicle. In this way the hematopoietic growth factor can be dissolved in or uniformly dispersed throughout the solution, and then the temperature of the composition can be raised to convert the composition to the gel form for storage prior to use.

Problems solved by technology

One of the problems associated with the hematopoietic growth factors such as G-CSF, GM-CSF, SCF and Flt3-L, is the need for multiple daily injections.

This, in turn leads to another common disadvantage of current injectable therapies such as these, that being the creation of a saw-toothlike effect of plasma drug levels.

An additional problem with current hematopoietic growth factor therapy includes fever and mild-to-moderate bone pain in patients receiving high doses over a long period.

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