Novel delivery systems for coagulation proteins

Area of Science:

• Biochemistry
• Pharmacology
• Materials Science

Background:

• Long-term hemophilia prophylaxis necessitates stable clotting factor formulations for alternative delivery.
• Current delivery methods for clotting factors pose challenges for sustained therapeutic levels.

Purpose of the Study:

• To develop stable liquid formulations of human coagulation factors for long-term hemophilia prophylaxis.
• To evaluate the stability and bioavailability of novel formulations for subcutaneous delivery.

Main Methods:

• Development of aqueous-formulated human coagulation factor IX (hCFIX) and freeze-dried human coagulation factor VIII (hCFVIII).
• Assessment of in vitro half-life at different temperatures.
• Evaluation of subcutaneous (s.c.) and intravenous (i.v.) bioavailability in animal models.
• Utilizing hydrogels of hCFIX with N,O-carboxymethyl chitosan (NOCC) for sustained release.

Main Results:

• Aqueous hCFIX demonstrated an in vitro half-life of 6 weeks at 37°C and 18 months at 4°C.
• Subcutaneous injection of hCFIX showed up to 16% bioavailability compared to i.v. dose.
• S.c. implanted pumps delivering hCFIX achieved >2% of normal human plasma levels.
• hCFIX in NOCC hydrogels provided prolonged plasma levels after s.c. injection.
• Freeze-dried hCFVIII in non-aqueous solvents exhibited an in vitro half-life of up to 80 days at 37°C.

Conclusions:

• Stable liquid formulations of hCFIX and hCFVIII are achievable for hemophilia prophylaxis.
• Alternative delivery modes, such as s.c. injection and hydrogel formulations, offer potential for improved pharmacokinetic profiles.
• These advancements pave the way for more convenient and effective long-term hemophilia management.