The present invention relates to pharmaceutical compositions of blood factors for subcutaneous administration.

Typically, blood factors have been prepared as pharmaceutical compositions for intravenous administration. The compositions have been based on the active protein, often conjugated to a polymer such as polyethylene glycol (PEG) to improve the half-life in circulation. Intravenous administration of PEGylated blood factors as therapeutic agents is therefore well understood and widely accepted. Liposomal formulations of naked (i.e. unconjugated and without modification) blood factors such as Factor VIII and Factor IX substances are known also, see for example WO 95/04524.

Pharmaceutical compositions comprising Factor VIII and liposomes modified by the presence of polyethylene glycol are described in WO 99/55306 in which the blood factor is not encapsulated in the liposome. However, the formulations are prepared for intravenous administration. Additional formulations of other proteins are described in WO 2004/091723 where the proteins include blood clotting factors. The proteins are said to bind to the liposomes in a non-covalent manner through interaction with the polyethylene glycol present on the surface of the liposomes. However, the formulations of blood clotting factors prepared according to the examples of this document are also for intravenous administration.

Other examples of formulations of blood factors, Factor VIII and Factor VIIa, present as a conjugate with PEG are shown in WO 2011/135307 and WO 2011/135308 respectively where the actual formulations prepared were for intravenous administration. WO 2013/156488 also describes a dosage form of modified therapeutic agents, including blood factors such as Factor VIII (FVIII) and Factor VIIa (FVIIa), for subcutaneous administration.

Factor VIII has also been found to be capable of association with PEGylated liposomes, i.e. the blood factor is not encapsulated inside the liposome (Baru et al Thromb. Haemost., 93, pages 1061-1068, (2005)). However, the compositions of FVIII were only prepared as formulations for intravenous administration.

Further studies by Peng et al inThe AAPS Journal,14(1), pages 25-42 (2011) disclose an alternative approach based on FVIII encapsulated in liposomes which are subsequently PEGylated by passively adding PEG to the liposomes after preparation. In one experiment in Peng et al the liposomal formulation is administered subcutaneously (SC) to investigate immunogenicity but there is no suggestion of a therapeutic purpose to this administration. In Peng et al there is also a specific reference to the paper of Baru et al (2005) and a statement that the approach of Baru et al “exposed FVIII to plasma components such as proteases and IgGs”. Liposomes prepared according to the method of Baru et al (2005) containing recombinant Factor VIII have been administered intravenously to subjects (Spira et alBlood,108 (12), pages 3668-3673 (2012)).

Current methodologies for formulating blood factors for administration rely on intravenous modes of administration. This is problematic since the patient inevitably receives a large bolus injection of the active agent at several time points leading an uneven therapeutic level of agent in the blood of the patient.

There is therefore a need for pharmaceutical composition of a blood factor which can provide a safe and effective dosage.

According to the present invention there is provided a pharmaceutical composition for subcutaneous administration comprising a blood factor and a colloidal particle comprising approximately 0.5 to 20 mole percent of an amphipathic lipid derivatized with a biocompatible hydrophilic polymer, wherein the blood factor is not encapsulated in said colloidal particle.

The colloidal particles may be substantially neutral and the polymer may carry substantially no net charge. The colloidal particles may have a mean particle diameter of between about 0.03 to about 0.4 microns (μm), for example having a mean particle diameter of approximately 0.1 microns (μm). A mean particle diameter in this range may increase the circulation time of the particles in vivo and prevent their adsorption by the reticuloendothelial system (RES).

The blood factor may be selected from the group consisting of Factor VIII, Factor VIIa, Factor VII, Factor IX, Factor X, Factor Xa, Factor XI, Factor V, Factor XII, Factor XIII, von Willebrand's Factor (vWF), prothrombin, or Protein C and/or a fragment thereof. The blood factor may be used in a lyophilised form when preparing the pharmaceutical composition.

