Composition for delivery of hematopoietic growth factor

Patent Number: 6875441

This patent teaches ways of formulating G-CSF so as to have better pharmacological properties. Specifically the patent is trying to address the problem of: "...administration of hematopoietic growth factors such as G-CSF, GM-CSF, SCF and Flt3-L, requires 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. This is due to the creation of large bolus bursts of drug shortly after injection, leading to supraphysiologic levels of drug, followed by rapid drops in plasma drug levels as the drug is cleared from the body by normal clearance processes. Upon the next injection, the pattern is repeated with large spikes in plasma levels followed by sub-therapeutic levels until the next injection. 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. In addition, local skin reactions and mild to moderate splenomegaly have been reported."

The invention teaches to overcome this problem by "administration of a composition that comprises a hematopoietic growth factor, a first biocompatible polymer, a second biocompatible polymer and a liquid vehicle. The first biocompatible polymer and the liquid vehicle interact in such a manner and are present in such proportions that the composition exhibits reverse-thermal viscosity behavior, in that the viscosity of the composition increases with increasing temperature over at least some temperature range. The second biocompatible polymer is a protective colloid. 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."

Unfortunately, the invention seems to be restricted to G-CSF as seen in the two independent claims:

A hematopoietic growth factor delivery composition, the composition comprising: a hematopoietic growth factor capable of stimulating hematopoietic cell activity when administered to a mammalian host; a first biocompatible polymer and a liquid vehicle in which the first biocompatible polymer is at least partially soluble at some temperature, the first biocompatible polymer interacting with the liquid vehicle to impart reverse thermal viscosity behavior to the composition over at least some temperature range, so that the composition is in a lower-viscosity form when the temperature of the composition is at a first temperature within the range and the composition is in a higher-viscosity form when the temperature is at second temperature within the range that is higher than the first temperature; and a second biocompatible polymer being a protective colloid that inhibits the dissolution into aqueous liquids of the first biocompatible polymer at least when the composition is in the higher-viscosity form; wherein the liquid vehicle comprises from 60 weight percent to 96 weight percent of the composition, the first biocompatible polymer comprises from 5 weight percent to 33 weight percent of the composition, and the second biocompatible polymer comprises from 0.1 weight percent to 5 weight percent of the composition: and wherein the hematopietic growth factor comprises G-CSF, the first biocompatible polymer comprises a polyoxyalkylene block copolymer comprising at least one block of a polyoxyethylene and at least one block of a polyoxypropylene, and the second biocompatible polymer comprises a cellulosic polymer.



A hematopoietic growth factor delivery composition, the composition comprising: a hematopoietic growth factor capable of stimulating hematopoietic cell activity when administered to a host; a first biocompatible polymer and a liquid vehicle in which the first biocompatible polymer is at least partially soluble at some temperature, the first biocompatible polymer interacting with the liquid vehicle to impart reverse thermal viscosity behavior to the composition over at least some temperature range, so that the composition is in a lower-viscosity form when the temperature of the composition is at a first temperature within the range and the composition is in a higher-viscosity form when the temperature is at second temperature within the range that is higher than the first temperature; and a second biocompatible polymer being a protective colloid that inhibits the dissolution into aqueous liquids of the first biocompatible polymer at least when the composition is in the higher-viscosity form; wherein the liquid vehicle comprises from 60 weight percent to 96 weight percent of the composition, the hematopoietic growth factor comprises from 0.00000001 weight percent to 0.000005 weight percent of the composition, the first biocomipatible polymer comprises from 5 weight percent to 33 weight percent of the composition and the second biocompatible polymer comprises from 0.1 weight percent to 5 weight percent of the composition; and wherein the hematopoietic growth factor comprises G-CSF, the first biocompatible polymer comprises a polyoxyalkylene block compolymer comprising at least one block of a polyoxyethylene and at least one block of a polylxpropylene, and the second biocompatible polymer comprises a cellulosic polymer.

View this patent on the USPTO website.