Captopril oral solution for pediatric use: formulation, stability study and palatability assessment in vivo

Abstract he aim of this work was to develop an oral solution of captopril at 5 mg/mL preservative-free. Two formulations were prepared, one containing sweetener (formulation 1) and the other without this excipient (formulation 2). The results found of validation parameters from analytical method performed by HPLC for captopril were, linearity 0.9998, the limit of detection 15.71 µg/mL, the limit of quantification 47.60 µg/mL, repeatability 1.05%, intermediate precision 2.42%, accuracy intraday 101,53%, accuracy inter-day 99.85%. Moreover, the results found for captopril disulfide were, linearity 0.9999, limit of detection 0.65 µg/mL, limit of quantification 1.96 µg/mL, repeatability 2.28%, intermediate precision 1.51%, accuracy intraday 101.36%, accuracy inter-day 100.29%. The appearance of formulations was clear and colorless, pH measures were 3.12 and 3.04, dosage of captopril and captopril disulfide were 99.45% and 99.82%, 0.24% and 0.12% for formulation 1 and formulation 2, respectively. The stability study demonstrated that the concentration of captopril and captopril disulfide in the formulations was > 90% and below 3%, respectively. The in vivo palatability study in animals and humans showed that Formulation 1 containing the sweetener had better acceptance. Thus, the sweetener was able to improve the unpleasant taste of the formulation

Rapid assessment and prediction of the efficiency of two preservatives against S. aureus in cosmetic products using High Content Screening-Confocal Laser Scanning Microscopy.

Most cosmetic products are susceptible to microbiological spoilage due to contaminations that could happen during fabrication or by consumer's repetitive manipulation. The composition of cosmetic products must guarantee efficient bacterial inactivation all along with the product shelf life, which is usually assessed by challenge-tests. A challenge-test consists in inoculating specific bacteria, i.e. Staphylococcus aureus, in the formula and then investigating the bacterial log reduction over time. The main limitation of this method is relative to the time-consuming protocol, where 30 days are needed to obtain results. In this study, we have proposed a rapid alternative method coupling High Content Screening-Confocal Laser Scanning Microscopy (HCS-CLSM), image analysis and modeling. It consists in acquiring real-time S. aureus inactivation kinetics on short-time periods (typically 4h) and in predicting the efficiency of preservatives on longer scale periods (up to 7 days). The action of two preservatives, chlorphenesin and benzyl alcohol, was evaluated against S. aureus at several concentrations in a cosmetic matrix. From these datasets, we compared two secondary models to determine the logarithm reduction time (Dc) for each preservative concentration. Afterwards, we used two primary inactivation models to predict log reductions for up to 7 days and we compared them to observed log reductions. The IQ model better fits datasets and the Q value gives information about the matrix level of interference.

Monitoring and controlling bacteria in pharmaceutical industries water system.

AIM: This research aimed to monitor pharmaceutical water system by sampling water from all treatment stages, identify bacterial isolates from each phase and determine the most suitable methods to control them. METHODS AND RESULTS: Water samples were collected and examined from pharmaceutical water system in a pharmaceutical factory in Giza, Egypt during 12 months, once per month (from December 2017 to November 2018) from 15 points covering all stages of the treatment process starting from wells, pre-treatment points; treatment points ending with purified points which are the main source of water used in all pharmaceutical process. In all, 216 water samples were collected and examined, 156 isolates were selected according to morphological characteristics. VITEK system 2 (BioMérieux) was used for identification of all isolates resulting in 24 different identified bacteria. Antibiotic assay test using disc diffusion methods were carried out using seven antibiotics from different groups. Several disinfectants were also examined for efficacy against the isolates to control micro-organisms in water treatment stage and manufacturing area. The effect of different preservatives (parabens, acids and alcohols) in various pharmaceutical formulas was also tested on bacterial isolates, 63% of formulas were effective against all bacterial isolates. CONCLUSION: Ciprofloxacin was the most effective antibiotic, mixture of 0·45% peracetic acid plus 2·2% of hydrogen peroxide (Minncare 1%) was maximally effective disinfectant, and Cronobacter sakazakii was the most resistant micro-organism against 22·7% of tested preservatives. SIGNIFICANCE AND IMPACT OF THE STUDY: Controlling pharmaceutical manufacturing operation from pathogenic bacteria that affect the quality of drugs.

Medical devices biocompatibility assessment on HCE: Evidences of delayed cytotoxicity of preserved compared to preservative free eye drops.

A multiple endpoint analysis (MEA) approach on human reconstructed corneal epithelium (HCE) model has been applied to assess the biocompatibility (cytotoxicity and irritation potential) of medical devices (MD): ophthalmology literature clearly shows the need to better assess these products to exclude any potential chronic damage to the ocular surface. Preserved eye drops (Artelac Multidose, Optive multidose and Artelac Rebalance Multidose) and the same without preservative (Artelac Edo, Optive Unidose, Artelac Rebalance Unidose) and Thealoz Duo were tested after acute (24 h + 16 h post incubation) and repeated (2 applications/day for 72 h) exposure using BAK 0.01% as positive control on HCE. Cellular viability, trans-epithelial electrical resistance measurements, LDH release and occludin gene expression were evaluated for each product to discriminate the potential toxicity of preservatives. The BAK 0.01% toxicity on HCE was confirmed following both exposures. The analysis of the same parameters reveals that the 72 h exposure was suitable to identify toxicity and damages to the ocular surface even for 'soft' preserved MD. The results confirm the reliability, sensitivity and predictivity of the MEA on HCE in detecting subclinical signs of cellular toxicity: 'soft' preservatives resulted toxics suggesting that delayed toxicity should be integral part of the biocompatibility assessment of ophthalmic formulations intended for long-term use.

Risk Assessment of the Skin Sensitization Induction Potential of Kathon CG in Rinse-off and Leave-on Personal Care and Cosmetic Products.

BACKGROUND: Kathon CG is a commonly used cosmetic-grade preservative that contains active ingredients methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI). OBJECTIVE: The aim of the study was to perform a skin sensitization induction risk assessment of daily exposure to Kathon CG after use of various personal care and cosmetic products. METHODS: We calculated an estimated daily consumer exposure level for rinse-off and leave-on products using the amount of product applied per application, number of applications per day, a retention factor, the MCI/MI concentration, and body surface area values. We assumed that the products contained the maximum recommended safe concentration of MCI/MI: 15 ppm in rinse-off products and 7.5 ppm in leave-on products. We compared estimated consumer exposure levels with the no expected sensitization induction level for MCI/MI and applied sensitization assessment factors to calculate product-specific margins of safety (MOSs). CONCLUSIONS: The MOSs for rinse-off products ranged from 5 to 63, whereas the MOSs for leave-on products ranged from 0.03 to 1.49. Overall, our results provide evidence that some leave-on products containing the maximum recommended safe concentration of Kathon CG may increase the risk of sensitization induction due to exposure to MCI/MI. In contrast, rinse-off products were not associated with a potential increased risk of skin sensitization induction.

Efficacy of benzalkonium chloride against bioluminescent P. aeruginosa ATCC9027 constructs.

Whole cell biosensors have been seldom used in the pharmaceutical and cosmetics industries for preservative efficacy testing (PET). According to several pharmacopoeias, preservatives should be tested for microbial activity using traditional viable count techniques; the use of whole cell microbial biosensors potentially provides an alternative, fast, and efficient method. The aim of the study was to assess the applicability of Pseudomonas aeruginosa ATCC9027 and its validated bioluminescent strains for preservative efficacy tests using benzalkonium chloride (BKC). Applicability of five constitutively-expressed bioluminescent strains was evaluated for preservative efficacy tests (PET) using bacterial replication, bioluminescence and fluorescence in a three-way study. PET using BKC showed no significant difference between bioluminescence and enumeration. Good correlations between bioluminescence, colony-forming units (CFU) count and fluorescence were obtained for BKC concentrations (R>0.9) between 0.0003-0.0025% against strains containing the constructs lys-pMElux, lpp-pMElux and tat-pMElux. Furthermore, two-way ANOVA analysis showed that the bioluminescent method and traditional plate counting method were equivalent for concentrations of BKC (0.0003-0.01%) during preservative efficacy tests. PET testing with BKC showed that tat-pMElux (R>0.9) had consistently high correlation coefficients between CFU and relative bioluminescence; P. aeruginosa ATCC9027 tatH5-pMElux is the best construct for testing various antimicrobial agents.

Post-marketing assessment of content and efficacy of preservatives in artemisinin-derived antimalarial dry suspensions for paediatric use.

BACKGROUND: Artemisinin-derivative formulations are now widely used to treat falciparum malaria. However, the dry powder suspensions developed for children are few and/or are of poor quality. In addition to the active compound, the presence of a suitable preservative in these medicines is essential. In this study, an evaluation of the preservative content and efficacy in some dry suspensions available on the Kenyan market was performed. METHOD: UV spectrophotometry was used to identify the preservatives in each sample while HPLC-UV was used for quantification. After reconstitution of the powders in water, the dissolution of the preservatives was followed for 7 days. Antimicrobial efficacy of the preservatives was assessed by conducting a preservative efficacy test (PET) following the European pharmacopoeia standards. RESULTS: Four different preservatives were identified namely methylparahydroxybenzoate (MP), propylparahydroxybenzoate (PP), benzoic acid and sorbic acid. MP and PP were identified in Artesiane (artemether 300 mg/100 ml), Alaxin (dihydroartemisinin 160 mg/80 ml) andGvither (artemether 300 mg/100 ml) respectively. Sorbic acid was presentin Artenam (artemether 180 mg/60 ml) while benzoic acid was identified in Santecxin (dihydroartemisinin 160 mg/80 ml) and Artexin (dihydroartemisinin 160 mg/80 ml) respectively. Cotecxin (dihydroartemisinin 160 mg/80 ml) did not contain any of the above preservatives. After reconstitution in water, preservativesin 50%(3/6) of the products did not completely dissolve and the PET results revealed that only Artenam and Gvither met the requirements for antimicrobial efficacy. The other products did not conform. CONCLUSION: These results show that paediatric antimalarial dry powder formulations on the market may contain ineffective or incorrect amounts of preservatives. This is a potential risk to the patient. Studies conducted on the dry powder suspensions should include the analysis of both the active ingredient and the preservative, including the efficacy of the latter.

Stabilisation of vaccines using trehalose (Q-T4) technology.

Efforts directed towards overcoming the problems of vaccine stability must take cost into consideration. One effective approach is the use of a simple stabilization technology applicable, in principle, to every type of vaccine candidate. Following the lead of Nature, the results in this paper show how such techniques based on trehalose have the potential to transform contemporary vaccine manufacture. The possibilities of novel delivery formats and vaccine combinations, currently not feasible, may now also be realised.