RESUMEN
A promising approach to treat diabetes is the development of fully automated artificial/bionic pancreas systems that use both insulin and glucagon to maintain euglycemia. A physically and chemically stable liquid formulation of glucagon does not currently exist. Our goal is to develop a glucagon formulation that is stable as a clear and gel-free solution, free of fibrils and that has the requisite long-term shelf life for storage in the supply chain, short-term stability for at least 7 days at 37°C, and pump compatibility for use in a bihormonal pump. We report the development of two distinct families of stable liquid glucagon formulations which utilize surfactant or surfactant-like excipients (LMPC and DDM) to "immobilize" the glucagon in solution potentially through the formation of micelles and prevention of interaction between glucagon molecules. Data are presented that demonstrate long-term physical and chemical stability (~2 years) at 5°C, short-term stability (up to 1 month) under accelerated 37°C testing conditions, pump compatibility for up to 9 days, and adequate glucose responses in dogs and diabetic swine. These stable glucagon formulations show utility and promise for further development in artificial pancreas systems.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Glucagón/administración & dosificación , Glucagón/química , Páncreas Artificial , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/patología , Perros , Sistemas de Liberación de Medicamentos/instrumentación , Estabilidad de Medicamentos , Femenino , Humanos , Masculino , Soluciones Farmacéuticas/administración & dosificación , Soluciones Farmacéuticas/química , PorcinosRESUMEN
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.
Asunto(s)
Química Farmacéutica/métodos , Diabetes Mellitus/tratamiento farmacológico , Insulina de Acción Corta/administración & dosificación , Insulina de Acción Corta/síntesis química , Animales , Ensayos Clínicos como Asunto/estadística & datos numéricos , Diseño de Fármacos , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Insulina/análogos & derivados , Insulina/síntesis química , Insulina/farmacocinética , Insulina de Acción Corta/farmacocinéticaRESUMEN
BACKGROUND: 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)]. METHOD: 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. RESULTS: 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). CONCLUSIONS: 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.
Asunto(s)
Quelantes/farmacología , Insulina de Acción Corta/farmacocinética , Zinc/metabolismo , Absorción/efectos de los fármacos , Química Farmacéutica/métodos , Ácido Edético/farmacología , Excipientes/química , Excipientes/metabolismo , Excipientes/farmacocinética , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Inyecciones Subcutáneas , Insulina de Acción Corta/administración & dosificación , Insulina de Acción Corta/química , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Electricidad Estática , Propiedades de Superficie/efectos de los fármacos , Factores de Tiempo , Ultracentrifugación , Zinc/química , Zinc/farmacocinéticaRESUMEN
BACKGROUND: A promising approach to treat diabetes is the development of an automated bihormonal pump administering glucagon and insulin. A physically and chemically stable glucagon formulation does not currently exist. Our goal is to develop a glucagon formulation that is stable as a clear ungelled solution, free of fibrils at a pH of 7 for at least 7 days at 37 °C. METHODS: Experimental glucagon formulations were studied for stability at 25 and 37 °C. Chemical degradation was quantified by reverse phase ultra-performance liquid chromatography. Physical changes were studied using light obscuration and visual observations. RESULTS: Glucagon content of Biodel glucagon and Lilly glucagon at pH 2 and pH 4, as measured by high-performance liquid chromatography at 25 °C, was 100% at 7 days compared to 87% and <7%, respectively. Light obscuration measurements indicated Lilly glucagon at pH 4 formed an opaque gel, while Biodel glucagon formulation remained a clear solution beyond 50 days at 37 °C. Visual observations confirmed these results. CONCLUSIONS: Biodel glucagon is a stabilized formulation at physiological pH and remains chemically and physically stable beyond 7 days at 37 °C, suggesting its utility for use in a bihormonal pump.
Asunto(s)
Glucagón/administración & dosificación , Glucagón/química , Sistemas de Infusión de Insulina , Alcoholes/química , Tampones (Química) , Carbohidratos/química , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Concentración de Iones de Hidrógeno , Lisofosfatidilcolinas/química , Soluciones Farmacéuticas , Sustancias Reductoras/química , Temperatura , Factores de TiempoRESUMEN
BACKGROUND: The variability of the metabolic action of insulin after subcutaneous (sc) injection hampers optimal insulin therapy. Insulin formulations with a reduced tendency to form hexamers might exhibit a reduced variability of absorption from the sc insulin depot into the blood stream. METHODS: We investigated the within-subject variability of pharmacodynamic and pharmacokinetic properties of an ultra-fast insulin (UFI) formulation and regular human insulin (RHI) in patients with type 1 diabetes. Fourteen patients participated in six 10-hour euglycemic glucose clamp experiments. In this double-blind, crossover study, subjects were randomly assigned to a sequence of two experimental blocks: each block consisted of three doses of 0.1 IU/kg UFI or RHI, respectively, administered on separate days by abdominal sc injection. RESULTS: Ultra-fast insulin has an earlier onset of action and shorter time to maximal plasma insulin concentration when compared to RHI (tGIR(max) 99 +/- 36 min vs. 154 +/- 74 min, p = 0.002; tC(max) 33 +/- 16 min vs. 97 +/- 39 min, p = 0.00001). The within-subject variability of plasma insulin tC(max) (p = 0.027) and of tGIR(max) (p = 0.022) was less for UFI than for RHI. CONCLUSIONS: In patients with type 1 diabetes, this UFI showed reduced within-subject variability when compared with RHI.