In the context of essential drug shortages, this article reports a proof of concept for the hospital preparation of a 2% propofol injectable nanoemulsion. Two processes for propofol were assessed: ...mixing propofol with the commercial Intralipid
20% emulsion and a "de novo" process performed using separate raw materials (i.e., oil, water, and surfactant) and optimized for droplet size reduction with a high-pressure homogenizer. A propofol HPLC-UV stability-indicating method was developed for process validation and short-term stability. In addition, free propofol in the aqueous phase was quantified by dialysis. To envision routine production, sterility and endotoxin tests were validated. Only the "de novo" process using high-pressure homogenization gave satisfactory physical results similar to commercialized Diprivan
2%. Both terminal heat sterilization processes (121 °C, 15 min and 0.22 µm filtration) were validated, but an additional pH adjustment was required prior to heat sterilization. The propofol nanoemulsion was monodisperse with a 160 nm mean droplet size, and no droplets were larger than 5µm. We confirmed that free propofol in the aqueous phase of the emulsion was similar to Diprivan 2%, and the chemical stability of propofol was validated. In conclusion, the proof of concept for the in-house 2% propofol nanoemulsion preparation was successfully demonstrated, opening the field for the possible production of the nanoemulsion in hospital pharmacies.
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.
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).
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
A simple, specific and automatable HPLC assay was developed for a simultaneous determination of systemic azoles (fluconazole, posaconazole, voriconazole, itraconazole and its metabolite ...hydroxyl-itraconazole, and ketoconazole) in plasma. The major advantage of this assay was sample preparation by a fully automatable solid phase extraction with Varian Plexa cartridges. C6-phenyl column was used for chromatographic separation, and UV detection was set at a wavelength of 260
nm. Linezolid was used as an internal standard. The assay was specific and linear over the concentration range of 0.05 to 40
μg/ml excepted for fluconazole which was between 0.05 and 100
μg/ml, and itraconazole between 0.1 and 40
μg/ml. Validation data for accuracy and precision for intra- and inter-day were good and satisfied FDA's guidance: CV between 0.24% and 11.66% and accuracy between 93.8% and 108.7% for all molecules. This assay was applied to therapeutic drug monitoring on patients hospitalized in intensive care and onco-hematologic units.
An overview of the biomimetic catalysts used in the oxidative activation of drugs is given, with an emphasis on the use of synthetic metalloporphyrins as models of cytochrome P450 to mimic the in ...vivo metabolism of pharmaceuticals. In addition, a special focus is directed towards the recent results from the authors' group on the oxidative activation of isoniazid, an antitubercular drug.
Abstract
Objectives
Fungal keratitis is a rare but severe cause of infectious keratitis and can lead to blindness. To cure fungal keratitis, antifungal like voriconazole eye drops must be immediately ...administered. As no brand is available on the market, voriconazole ophthalmic solution is compounded in hospital pharmacies using voriconazole powder for intravenous infusion. The aims of our study were to both assess the physico-chemical and microbiological stability of eye drop solutions stored at +2 to 8 °C. Two different High-Density-Polyethylene (HDPE) eye drop dispensing containers were assessed, one with a sterility preserving cap Novelia
®
(Nemera) and the other without sterility preserving cap both provided by CAT laboratory. In addition microbiological quality was assessed during 15 days simulated patient use.
Methods
Multiple batches of voriconazole 10 mg/mL eye drops were prepared and stored at +2 to 8 °C to study their stability over 90 days. All analyses were performed in triplicate. Physical stability was determined, pH determination, osmolarity measurement, and a particle count test was also performed. A high performance liquid chromatography (HPLC-UV) stability indicating method was used to determine chemical stability of the ophthalmic solution over 90 days of storage. For microbiological stability, a sterility test was performed using closed membrane filtration method (Steritest
®
, Merck Millipore) at D0, D90 and D90+15 days after simulated administration of eye drops (D90+15).
Results
For both containers, no variation of visual aspect, pH, osmolality, particle count and final concentration were observed. No microbiological growth was observed after 90 days of storage. At the end of the simulated administration period (D+15), unconstant microbiological growth was only observed in HDPE vials without sterility preserving cap, whereas HDPE vials with a sterility preserving cap Novelia
®
(Nemera) remained sterile.
Conclusions
Voriconazole 10 mg/mL ophtalmic solution was stable during 90 days at +2 to 8 °C in lightproof HDPE vials without sterility preserving cap and HDPE vials with a sterility preserving cap Novelia
®
(Nemera). However, vials with classical cap which are not airtight systems, may microbiologically contaminated during patient’s use than vials with Novelia
®
cap thanks to their innovative valve system.
Isoniazid-NAD truncated adducts embedding a lipophilic fragment were designed, synthesized and evaluated as inhibitors of the enoyl-acyl carrier protein (ACP) reductase (InhA) of
Mycobacterium ...tuberculosis and as antimycobacterial agents. These compounds, planned as bi-substrate inhibitors and inspired from the active metabolite of isoniazid, combine both the nicotinamide moiety of the cofactor NAD and a lipophilic hydrocarbon chain mimic of the InhA substrate. The lipophilic fragment was introduced using either Suzuki–Miyaura cross-coupling or a classical nucleophilic substitution reaction. Several compounds developed in this work were indeed able to inhibit the InhA activity and showed promising antimycobacterial activities. However a direct correlation between the expressed activity and the bi-substrate mode of action could not yet be unambiguously demonstrated.
Mimicking the active metabolite of isoniazid: a way to antimycobacterial agents.
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The synthesis and biological evaluation of azaisoindolinone compounds embedding a lipophilic chain on the framework were performed. These compounds were designed as InhA inhibitors and as ...anti-Mycobacterium tuberculosis agents. Structure–activity relationships concerning the length and the location of the lipophilic chain around the azaisoindolinone framework, the suppression of the phenyl group, the bioisosteric substitution of ether link and alkylating of the tertiary hydroxyl and the hemiamidal nitrogen were also investigated, revealing insightful information and thereby enabling further diversification of the azaisoindolinone scaffold for new antitubercular agents.
Photochemotherapy is used both for solid tumors and in extracorporeal treatment of various hematologic disorders. Nevertheless, its development in oncology remains limited, because of the low ...selectivity of photosensitizers (PS) towards human tumor cells. To enhance PS efficiency, we recently covalently linked a porphyrin (TrMPyP) to a plant lectin (Morniga G), known to recognize with high affinity tumor-associated T and Tn antigens. The conjugation allowed a quick uptake of PS by Tn-positive Jurkat leukemia cells and efficient PS-induced phototoxicity. The present study was performed: (i) to evaluate the targeting potential of the conjugate towards tumor and normal cells and its phototoxicity on various leukemia cells, (ii) to investigate the mechanism of conjugate-mediated cell death. The conjugate: (i) strongly increased (×1000) the PS phototoxicity towards leukemic Jurkat T cells through an O-glycan-dependent process; (ii) specifically purged tumor cells from a 1∶1 mixture of Jurkat leukemia (Tn-positive) and healthy (Tn-negative) lymphocytes, preserving the activation potential of healthy lymphocytes; (iii) was effective against various leukemic cell lines with distinct phenotypes, as well as fresh human primary acute and chronic lymphoid leukemia cells; (iv) induced mostly a caspase-independent cell death, which might be an advantage as tumor cells often resist caspase-dependent cell death. Altogether, the present observations suggest that conjugation with plant lectins can allow targeting of photosensitizers towards aberrant glycosylation of tumor cells, e.g. to purge leukemia cells from blood and to preserve the normal leukocytes in extracorporeal photochemotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The first syntheses of the 1-hydroxy-1-(pyridin-4-yl)-1,2-dihydro-3H-pyrrolo3,4-cpyridin-3-one heterocycle and the 3-aminocarbonyl-4-isonicotinoyl-1,4-dihydropyridine framework present in the ...isoniazid−NAD(P) adducts are described.
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