RESUMEN
Octanorm (marketed as cutaquig® in Canada and US [2018] and registered in several European countries [2019]) is a new immunoglobulin subcutaneous 16.5% liquid for the treatment of patients with primary immune deficiency (PID) and secondary immune deficiency (SID) depending on country's specific indications. Octanorm contains ≥96% human IgG and is characterized by especially low concentrations of polymers and aggregates, IgA and IgM, a physiological osmolality along with a low isoagglutinin titer. The Octanorm manufacturing process is based on the well-established IVIG octagam® 5% and 10% process, but yields a higher immunoglobulin concentration of 16.5% in the final product. Octanorm shows a distribution of immunoglobulin G subclasses closely proportional to native human plasma and comprises a broad spectrum of antibodies against infectious agents. Potential procoagulant activity is not detectable. IgG functionality and physico-chemical integrity have been demonstrated by state-of-the-art-methods. The virus safety of Octanorm is ensured via a combination of three validated independent methods as part of the manufacturing process. Substantial prion depletion during the manufacturing process has also been demonstrated. Compared with other commercially available subcutaneous immunoglobulin (SCIG) 20% products, Octanorm 16.5% shows a lower viscosity, which is a valuable feature that allows for a more comfortable infusion experience.
Asunto(s)
Biomarcadores Farmacológicos , Inmunoglobulina G/química , Adulto , Estabilidad de Medicamentos , Femenino , Humanos , Inmunoglobulina G/uso terapéutico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Infusiones SubcutáneasRESUMEN
The aim of this work was to evaluate the effects of incorporating thrombin in arabinogalactan (AG)/ß-glucan (BG)-based carriers. The products were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray powder diffraction (XRPD) and X-ray photoelectron spectroscopy techniques. Results, especially deconvoluted XRPD patterns indicated creation of new phases and potential complex formation. Results also highlighted that the AG carrier leads to higher residual thrombin-specific activity, while the in vivo haemostatic effect was enhanced when insoluble BG was present in the matrix. Our results confirm that thrombin can be successfully added to the carriers and that these materials are promising alternatives to standard vehicles.
Asunto(s)
Portadores de Fármacos , Galactanos , Trombina/administración & dosificación , beta-Glucanos , Animales , Portadores de Fármacos/química , Femenino , Galactanos/química , Hemostasis/efectos de los fármacos , Humanos , Masculino , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Espectroscopía de Fotoelectrones , Difracción de Polvo , Ratas Wistar , Proteínas Recombinantes/administración & dosificación , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X , beta-Glucanos/químicaRESUMEN
The objective of this work was development and evaluation of gel-forming lyophilized formulation with recombinant human thrombin for topical administration. The influence of pH, ionic strength and buffer type on protein stability was evaluated as part of the pre-formulation screening studies. Results indicated an optimal pH from 6.0 to 7.0 and increased stability with increasing content of sodium chloride. The tested buffer types had no significant effect on thrombin stability. For further development, thermosensitive Pluronic® F-127 was employed as a bulking and gelling agent. Physical and mechanical characterization and viscosity measurement confirmed the gel-forming properties of the formulation at the application temperature of 32 °C. Several techniques (addition of well-soluble polyols, different freezing protocols and reconstitution under vacuum) were tested to decrease the reconstitution time. The obtained results revealed that a vacuum in the vial headspace is crucial for acceptable reconstitution. The freeze drying process has no negative impact on recombinant thrombin stability, and this was confirmed by reverse-phase-HPLC, activity assay and optical density measurements.
Asunto(s)
Composición de Medicamentos/métodos , Hemostáticos/administración & dosificación , Poloxámero/química , Proteínas Recombinantes/administración & dosificación , Trombina/administración & dosificación , Química Farmacéutica/métodos , Cromatografía Líquida de Alta Presión , Liofilización , Geles , Hemostáticos/química , Humanos , Concentración de Iones de Hidrógeno , Concentración Osmolar , Estabilidad Proteica , Proteínas Recombinantes/química , Cloruro de Sodio/química , Temperatura , Trombina/química , Factores de Tiempo , ViscosidadRESUMEN
Lyophilisation is a well-established method for drying of various substances with a wide range of applications in the pharmaceutical area. During the last decade its relevance increases with a number of therapeutically used proteins. A sensitive protein drug may undergo several changes, like unfolding and loss of activity due to various stresses during the lyophilisation process. Understanding of these processes (freezing, primary drying, secondary drying) is fundamental for manufacturing of a drug product with desired properties, namely its safety and efficacy. In order to reduce costs and increase the quality, new technologies are being rapidly developed and established in industrial lyophilisation (e.g. process analytical technologies, control nucleation techniques).
Asunto(s)
Proteínas/química , Liofilización , CongelaciónRESUMEN
Recombinant human thrombin (rhThrombin) is a potential hemostatic alternative to bovine and human plasma-derived thrombin. Hemostatic, liver regeneration effect and plasma concentrations of rhThrombin (SCILL) tested in the form of solution and hydrogels (thermo-sensitive poloxamer gel and carbomer gel; hameln rds) were evaluated. In the bleeding model, rhThrombin was applied locally on the bleeding site. The time to hemostasis was measured. The rhThrombin in liquid form as well as the thermo-sensitive gel forming formulation significantly reduced the bleeding time in comparison to saline. In the regeneration model, a cut in the form "V" was made on the liver and rhThrombin in both formulations was applied at defined concentrations to the wound for 5 min. The rats survived 1, 3 and 5 days after the injury and treatment. Histological examination showed better results in the group treated with rh Thrombin gel in comparison to the liquid form - solution; differences were insignificant. Low [(125)I]-rhThrombin radioactivity was evaluated in plasma after topical application (solution and both hydrogels) at hemostatic effective doses to partial hepatectomy in rats. Locally applied rh Thrombin on the rat damaged liver tissue never reached pharmacologically active systemic levels. The plasmatic levels and the content of this active protein in injured liver tissue were lower after application of its hydrogels versus solution.