Long-term physicochemical stability of acyclovir 5 mg/mL solution stored in polypropylene bags as a simulated hospital stock preparation.

PURPOSE: To investigate the long-term chemical and physical stability of 5-mg/mL acyclovir solution in polypropylene bags stored at 5°C ± 3°C for 2 months in order to determine the feasibility of batch production by a centralized intravenous additive service. METHODS: Eight empty 100-mL polypropylene bags (bags A) and 8 empty 250-mL bags (bags B) were respectively filled with 60 mL and 200 mL of 5-mg/mL acyclovir and 0.9% sodium chloride injection (NaCl) under aseptic conditions through a semiautomated manufacturing process and vacuum packed before storage at 5°C ± 3°C. Four bags A and 4 bags B were tested for chemical stability via a stability-indicating high-performance liquid chromatography (HPLC) method immediately after preparation (time 0) and after 7, 14, 21, 28, 35, 42, and 63 days. Samples for microbiological assay were collected on days 0 and 63 from 4 bags A and 4 bags B immediately after breaking the vacuum. Osmolality, pH, and physical stability were assessed by visual examination, Subvisible particle counting was performed on 6 additional bags (3 each of bags A and B). RESULTS: Mean percentage loss of acyclovir relative to the mean experimental concentration at time 0 was below 5% over the 63-day study period.. No significant differences of pH, no change in color and no precipitate were observed during the study. Subvisible particle counts were compliant with European Pharmacopoeia requirements. Acyclovir solutions remained sterile over the 63 days of the study. CONCLUSION: Extemporaneously prepared acyclovir 5 mg/mL solutions in 0.9% NaCl stored in polypropylene bags were chemically and physically stable over 63 days when stored at 5°C ± 3°C.

Nucleotide lipid-based hydrogel as a new biomaterial ink for biofabrication.

One of the greatest challenges in the field of biofabrication remains the discovery of suitable bioinks that satisfy physicochemical and biological requirements. Despite recent advances in tissue engineering and biofabrication, progress has been limited to the development of technologies using polymer-based materials. Here, we show that a nucleotide lipid-based hydrogel resulting from the self-assembly of nucleotide lipids can be used as a bioink for soft tissue reconstruction using injection or extrusion-based systems. To the best of our knowledge, the use of a low molecular weight hydrogel as an alternative to polymeric bioinks is a novel concept in biofabrication and 3D bioprinting. Rheological studies revealed that nucleotide lipid-based hydrogels exhibit suitable mechanical properties for biofabrication and 3D bioprinting, including i) fast gelation kinetics in a cell culture medium and ii) shear moduli and thixotropy compatible with extruded oral cell survival (human gingival fibroblasts and stem cells from the apical papilla). This polymer-free soft material is a promising candidate for a new bioink design.

Simulation program of a cytotoxic compounding robot for monoclonal antibodies and anti-infectious sterile drug preparation.

The aim of this study was to develop a specific simulation program for the validation of a cytotoxic compounding robot, KIRO® Oncology, for the preparation of sterile monoclonal antibodies and anti-infectious drugs. The impact of excipient formulations was clearly measured using simulation accuracy tests with worst case excipient (i.e. viscous, foaming) and allowed to correct the robotic settings prior to real production. Corrections brought accuracies within the acceptable range of ±5%. KIRO® Oncology robot has also the capacity of self-cleaning and a simulation combining media fill test, and environmental monitoring was able to validate the aseptic process including simulation of worst case conditions and highlighting the areas not accessible to self-cleaning to be corrected by additional manual cleaning measures. The risk of chemical contamination was simulated by using fluorescent dye of the process with high-risk excipient formulation and overpressure vials. Quality control reliability was simulated by using a model drug, and final concentration was determined by high-performance liquid chromatography-ultraviolet detection. Finally, productivity was simulated using different models of production showing the impact of the type of drug, the number of vials and the poor standardization of the process.

Micro- and nano-formulations for bioprinting and additive manufacturing.

Recent developments in bioprinting have enabled an optimized formulation of bioinks by incorporating pharmaceuticals into cell-containing gel matrices. The proof-of-printability of a variety of forms has been provided, such as particles and fibers in the nanometric or micrometric range like dendrimers or micelles, although this is still lacking for some (liposomes for example). Resulting composite bioinks have the advantage of (i) improving cell growth and differentiation, (ii) delivering active molecules or (iii) improving mechanical properties of bioinks, printed scaffolds or the printing process. Improvement of these properties brings bioprinting one step forward toward clinical applications. Applications are reviewed for each field of improvements.

Formulation and characterization of a 0.1% rapamycin cream for the treatment of Tuberous Sclerosis Complex-related angiofibromas.

Medicines for the treatment of rare diseases frequently do not attract the interest of the pharmaceutical industry, and hospital pharmacists are thus often requested by physicians to prepare personalized medicines. Tuberous Sclerosis Complex (TSC) is a rare disease that causes disfiguring lesions named facial angiofibromas. Various topical formulations of rapamycin (=sirolimus) have been proved effective in treating these changes in small case series. The present study provides for the first time characterization of a 0.1% rapamycin cream formulation presenting good rapamycin solubilisation. The first step of the formulation is solubilisation of rapamycin in Transcutol(®), and the second step is the incorporation of the mixture in an oil-in-water cream. A HPLC stability-indicating method was developed. Rapamycin concentration in the cream was tested by HPLC and confirmed that it remained above 95% of the initial concentration for at least 85days, without characteristic degradation peaks. The preparation met European Pharmacopoeia microbial specifications throughout storage in aluminum tubes, including when patient use was simulated. Odour, appearance and colour of the preparation were assessed and no change was evidenced during storage. The rheological properties of the cream also remained stable throughout storage. To conclude, we report preparation of a novel cream formulation presenting satisfactory rapamycin solubilisation for the treatment of TSC cutaneous manifestations, with stability data. The cream is currently being used by our patients. Efficacy and tolerance will be reported later.