Biodel (United States)

This review summarizes the clinical development of a family of ultra-rapid-acting recombinant human insulin formulations. These formulations use ethylenediaminetetraacetic acid (EDTA) to chelate zinc and thereby destabilize insulin hexamers. In addition, insulin monomer surface charges are chemically masked with citrate to prevent reaggregation. The first phase 1 trials were performed using BIOD-090, an acidic 25 unit U/ml insulin formulation, which contained disodium-EDTA (NaEDTA). When compared with regular human insulin (RHI) and/or insulin lispro in multiple phase 1 studies, BIOD-090 consistently showed more rapid absorption and/or onset of action. A standard meal challenge study also demonstrated improved postprandial glucose profiles associated with BIOD-090. However, increased patient exposure in larger phase 3 trials showed that this formulation was associated with an increased incidence of local injection site reactions, most commonly pain. A next generation formulation, BIOD-100, contained the same excipients as a standard insulin concentration of 100 U/ml. BIOD-100 maintained an ultra-rapid action profile and was associated with modest but significantly improved toleration when compared with BIOD-090. In order to further improve toleration, the hypothesis that NaEDTA contributed to discomfort by chelating endogenous calcium was tested by either substituting calcium-EDTA for NaEDTA or by adding calcium chloride to the NaEDTA formulation. These calcium formulations essentially eliminated the excess discomfort associated with BIOD-090 but were associated with less optimal pharmacokinetic profiles in humans. Recent efforts have succeeded in developing ultra-rapid-acting human insulin formulations with acceptable injection site toleration by optimizing concentrations of calcium (BIOD-125) and with the use of magnesium sulfate to mitigate discomfort (BIOD-123). Similar formulation technology has also been shown to accelerate absorption of insulin analogs in animal models.

In order to enhance the absorption of insulin following subcutaneous injection, excipients were selected to hasten the dissociation rate of insulin hexamers and reduce their tendency to reassociate postinjection. A novel formulation of recombinant human insulin containing citrate and disodium ethylenediaminetetraacetic acid (EDTA) has been tested in clinic and has a very rapid onset of action in patients with diabetes. In order to understand the basis for the rapid insulin absorption, in vitro experiments using analytical ultracentrifugation, protein charge assessment, and light scattering have been performed with this novel human insulin formulation and compared with a commercially available insulin formulation [regular human insulin (RHI)]. Analytical ultracentrifugation and dynamic light scattering were used to infer the relative distributions of insulin monomers, dimers, and hexamers in the formulations. Electrical resistance of the insulin solutions characterized the overall net surface charge on the insulin complexes in solution. The results of these experiments demonstrate that the zinc chelating (disodium EDTA) and charge-masking (citrate) excipients used in the formulation changed the properties of RHI in solution, making it dissociate more rapidly into smaller, charge-masked monomer/dimer units, which are twice as rapidly absorbed following subcutaneous injection than RHI (Tmax 60 ± 43 versus 120 ± 70 min). The combination of rapid dissociation of insulin hexamers upon dilution due to the zinc chelating effects of disodium EDTA followed by the inhibition of insulin monomer/dimer reassociation due to the charge-masking effects of citrate provides the basis for the ultra-rapid absorption of this novel insulin formulation.

VIAject® is a formulation of human insulin with a very fast onset of action. Previous studies used VIAject in a concentration of 25 U/ml and a pH of 4 [VIAject 25 (VJ25)]. Objective of this double blind, three-way crossover study was to compare the pharmacodynamic/pharmacokinetic properties of a novel formulation of VIAject with a concentration of 100 U/ml and a neutral pH [VIAject 7 (VJ7)] with VJ25 and insulin lispro (LIS). Forty-three patients with type 1 diabetes [aged 43 (21-65) years, BMI 24.1 (20-28) kg/m(2) and HbA1c 7.5 (5.7-9.5) %] participated in this study. They received subcutaneous injections of 12 U of each insulin formulation under euglycaemic glucose clamp conditions. VJ7 was bioequivalent to VJ25 [90% confidence interval (CI) of the ratios for total insulin AUCs and maximum insulin concentration (C(INS max) ) was within 0.80-1.25]. VJ7 showed a faster absorption compared to LIS [time to C(INS max) 23 vs. 60 min; difference (CI) -30 (-35 to -23)] and faster onset of action [time to early half-maximal glucose infusion rate (GIR) 25 vs. 44 min; -18 (-26 to -10)], and a higher AUC of glucose infusion rate (AUC(GIR) ) in the first 60 min after injection [176 vs. 107 mg/kg; ratio 1.65 (1.27 to 2.14)], contributing to a slightly higher value for AUC(GIR 0-480) [1263 vs. 1095 mg/kg; 1.15 (1.06 to 1.26)]. Maximum GIR was similar between VJ7 and LIS [6.1 vs.6.6 mg/kg/min; ratio 0.93 (0.86 to 1.01)], whereas the duration of action (t(GIR50%-late) ) was longer with VJ7 [274 vs. 228 min; 50 (25 to 73)]. This formulation of VIAject is bioequivalent to the previously used formulation and has a faster absorption/onset of action than LIS.

VIAJECT (VJ) ist eine neuartige Formulierung von Normalinsulin mit generischen Zusatzstoffen, die sich im Vergleich zu üblichen Normalinsulin durch bessere pharmakologische Eigenschaften auszeichnet. Dazu wurde eine klinisch-experimentelle Glucose-Clamp-Studie mit 10 gesunden Probanden durchgeführt (Alter (MW±STD: 40±8 Jahre; BMI: 22,5±2,5kg/m2). An 5 verschiedenen Studientagen erhielten die Probanden mit einer Spritze subkutane abdominale Injektionen von 12 IU Normalinsulin, 12 U Insulin Lispro oder 3, 6 und 12 IU VJ. Die Serum-Insulinkonzentrationen nach Injektion von Normalinsulin und VJ wurden mit einem Chemolumineszenz-Test bestimmt (MLT). Die Insulin Lispro-Konzentrationen wurden mit einem spezifischen ELISA (Linco) gemessen. Im Vergleich zu Insulin Lispro und Normalinsulin steigen die Serum-Insulinkonzentrationen nach Injektion von VJ schneller auf halb-maximale und maximale Konzentrationen an (TCmax-50/TCmax: 3 IU: 12±13/54±44min, 6 IU: 7±3/51±48min, 12 IU: 18±18/60±43min vs. Lispro 26±10/66±34min, p<0.05/N.S. vs. 12 IU VJ und Normalinsulin 37±22/120±70min, p<0.05/p<0.001 vs. 12 IU VJ). Die Serum-Insulinkonzentrationen nach Injektion von VJ sanken rascher ab als Normalinsulin. Bedingt durch diese pharmakokinetischen Eigenschaften war die relative Bioverfügbarkeit (Verhältnis der AUCs korrigiert für die applizierten Dosen bezogen auf Insulin Lispro) von VJ gut (AUC0–360min: 3U: 166%. 6 U: 163%, 12 U: 146%). Die beschriebenen pharmakokinetischen Eigenschaften führten zu entsprechenden pharmakodynamischen Wirkungen. Diese Studie zeigt, dass diese Formulierung von Normalinsulin durch eine schnelle Insulinabsorption charakterisiert ist, die mindestens so rasch ist wie die von kurzwirkenden Insulinanaloga und deutlich schneller als die von handelsüblichem Normalinsulin. Das rasche Abfluten von Viaject und die gute relative Bioverfügbarkeit machen diese Insulinformulierung zu einem attraktiven Kandidaten für die prandiale Insulintherapie.