Dataset Information

Development of a Lyophilized Formulation of Pegaspargase and Comparability Versus Liquid Pegaspargase.

ABSTRACT:

Introduction

Pegaspargase, a pegylated asparaginase, is a core component in the treatment of acute lymphoblastic leukemia. Pegaspargase in liquid form has a limited shelf life of 8 months due to depegylation, leading to changes in purity and potency over time. Lyophilization is an approach that can improve the stability of biological drug conjugates.

Methods

Here we describe the development of a lyophilized formulation of pegaspargase and present results of a series of tests demonstrating that the lyophilized form has comparable physicochemical properties to the liquid form.

Results

Stability tests of critical quality attributes, including purity, potency, aggregates and total free polyethylene glycol, demonstrate that lyophilized pegaspargase remains stable for at least 3 years, with optimum stability achieved with storage under refrigerated conditions (2-8 °C).

Conclusions

Lyophilization improved the stability of pegaspargase without altering other physicochemical properties, permitting a prolonged shelf life of at least 2 years when stored at 2-8 °C. This may enable greater storage flexibility and allow for better management of pegaspargase.

Funding

Study Sponsor: Baxalta (now part of Takeda). Publication Sponsor: Servier Affaires Médicales.

SUBMITTER: Faschinger AM

PROVIDER: S-EPMC6822849 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Somatropin is recombinant human growth hormone (GH) used for the treatment of growth failure in children and GH deficiency in adults. Two concentrations of a liquid formulation have been developed: 5.83 and 8.0 mg/mL. This trial compared the pharmacokinetics (PK), safety and tolerability of these two liquid concentrations against the freeze-dried (FD) formulation in healthy volunteers.In an open-label, single-centre, three-way crossover study, volunteers (aged 18-45 years) were given subcutaneous injections of the reconstituted FD and two liquid formulations in random sequential order, each at 4 mg/dose, with a 1-week wash-out period between doses. To suppress endogenous GH secretion, intravenous somatostatin was infused continuously 1 hour before to 24 hours after each dose, achieving a cumulative dose of 3 mg. Primary PK endpoints were area under the serum concentration-time curve (AUC0-t) and maximum serum concentration (Cmax). For each of the two liquid formulations, bioequivalence with the FD formulation was concluded if the 95% confidence intervals (CIs) for the estimated test/reference ratios of geometric means of AUC0-t and Cmax were within the standard pre-specified acceptance range (0.80-1.25).Fifteen men and 15 women enrolled (safety population, n = 30; PK population, n = 28). Bioequivalence with the FD formulation could be shown for both liquid formulations. The ratios of geometric means (95% CI) were 1.046 (0.980, 1.117) and 0.991 (0.929, 1.058) for AUC0-t and 0.954 (0.875, 1.040) and 0.955 (0.876, 1.041) for Cmax for the 5.83 and 8.0 mg/mL formulations, respectively. No significant differences between the three treatments in half-lives, time to reach Cmax, clearance or volume of distribution were observed. After injection, the most common side-effects were pain or injection-site reactions (all of mild intensity). There were no clinically significant abnormal vital signs, ECG or laboratory findings. There were 56 treatment-related adverse events (AEs): 49 mild, 6 moderate and 1 severe (vomiting). No serious AEs occurred. The pattern of AEs was as expected and all resolved by study end.Both concentrations of a new liquid multi-dose formulation are bioequivalent to the FD reference formulation and all are well tolerated.NCT01034735.

Project description:The development of reduced-risk products is aimed at providing adult smokers, who are unable to quit, with alternatives to cigarettes that present less risk of harm and smoking-related disease. The use of flavors in the development of these reduced-risk products fulfils an important role in product acceptance. While most flavors are also used by the food industry and are considered safe when ingested, their impact when inhaled is still debated. To overcome this research gap, we developed a three-step approach combining real-time cellular analysis, phenotypic high-content screening assays and gene expression analysis. As a case study, a list of 28 flavors, commonly used in e-liquid formulation, were selected and dissolved individually or as a mixture in a Base Solution composed of propylene glycol, vegetable glycol, and 0.6% nicotine. Various dilutions of these mixtures were assessed in normal human bronchial epithelial cells. Using a real-time impedance-based assay, a Tox-Score corresponding to the ratio of the Base Solution EC50 over flavored solution EC50 was determined for each tested e-liquid. We complemented the e-liquid evaluation by computing a Phenotypic-Score that recapitulates the exposure effects measured using a battery of high-content screening endpoints. Using a systems toxicology approach, we also identified and quantified perturbed molecular pathways impacted specifically by the Base Solution or by the 28-flavor mixture. To conclude, employing a three-pillar based approaches to investigate the effects of flavored solutions in vitro, we were in a position to identify individual flavors that appeared to have the potential to contribute greatly to the overall mixture effect (citronellol and alpha-pinene). Finally, by assessing modified mixtures we showed that, although cytotoxic effect where found when assessed individually, alpha-pinene was not contributing to the overall mixture cytotoxicity. Most of the cytotoxic effect appeared to mainly derive by the presence of citronellol and remaining flavors were still contributing due to synergistic effects.