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AAPS PharmSciTech 2008
Comparative Study
Topics: Alcohols; Chemistry, Pharmaceutical; Drug Stability; Pediatrics; Pharmaceutical Solutions; Phenobarbital; Solubility
PubMed: 18686037
DOI: 10.1208/s12249-008-9112-2 -
American Journal of Health-system... Dec 2015The results of a study to determine the stability of solutions of furosemide and chlorothiazide over 96 hours are reported.
PURPOSE
The results of a study to determine the stability of solutions of furosemide and chlorothiazide over 96 hours are reported.
METHODS
Chlorothiazide and furosemide were diluted in 5% dextrose USP to final concentrations of 10 and 1 mg/mL, respectively, and combined. In addition, sample solutions of chlorothiazide in dextrose, furosemide in dextrose, and dextrose alone were prepared for control purposes. The resulting solutions were analyzed immediately after preparation and 24, 48, 72, and 96 hours later using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) system with an electrospray ionization source. Mixtures and samples were diluted 10,000-fold prior to LC-MS/MS analysis so that concentrations of both drugs would be within the assay's linear range of detection.
RESULTS
LC-MS/MS analysis showed that chlorothiazide typically eluted at 2.6 minutes and furosemide at 4.8 minutes. Each compound was degraded by exposure to strong ultraviolet light in a time-dependent manner. Both unmixed and mixed solutions retained over 90% of the original concentrations of chlorothiazide and furosemide for up to 96 hours. Furosemide and chlorothiazide are commonly used concomitantly to maximize diuresis in pediatric patients; the study findings suggest that solutions of furosemide and chlorothiazide can be combined in the same syringe without loss of stability for up to 96 hours.
CONCLUSION
Solutions of chlorothiazide (10 mg/mL) and furosemide (1 mg/mL) stored either separately or together in polypropylene syringes remained stable for up to 96 hours at room temperature and protected from light.
Topics: Chlorothiazide; Chromatography, Liquid; Diuretics; Drug Stability; Drug Storage; Furosemide; Humans; Pharmaceutical Solutions; Syringes; Tandem Mass Spectrometry
PubMed: 26637518
DOI: 10.2146/ajhp150023 -
Radiation Oncology (London, England) Aug 2020This study was an open-label, 2-arms, monocentric, randomized clinical trial comparing Xonrid®, a topical medical device, versus standard of care (SOC) in preventing... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
A monocentric, open-label randomized standard-of-care controlled study of XONRID®, a medical device for the prevention and treatment of radiation-induced dermatitis in breast and head and neck cancer patients.
BACKGROUND
This study was an open-label, 2-arms, monocentric, randomized clinical trial comparing Xonrid®, a topical medical device, versus standard of care (SOC) in preventing and treating acute radiation dermatitis (ARD) in Head and Neck Cancer (HNC) and Breast Cancer (BC) patients undergoing radiotherapy (RT).
METHODS
Eligible HNC and BC patients were randomized 1:1 to receive Xonrid® + SOC or SOC during RT. Patients were instructed to apply Xonrid® on the irradiated area three times daily, starting on the first day of RT and until 2 weeks after RT completion or until the development of grade ≥ 3 skin toxicity. The primary endpoint was to evaluate the proportion of patients who developed an ARD grade < 2 at the 5th week in both groups. Secondary endpoints were median time to grade 2 (G2) skin toxicity onset; changes in skin erythema and pigmentation and trans-epidermal water loss (TEWL); patient-reported skin symptoms. All patients were evaluated at baseline, weekly during RT and 2 weeks after treatment completion. The evaluation included: clinical toxicity assessment; reflectance spectrometry (RS) and TEWL examination; measurement of patients' quality of life (QoL) through Skindex-16 questionnaire.
RESULTS
Eighty patients (40 for each cancer site) were enrolled between June 2017 and July 2018. Groups were well balanced for population characteristics. All BC patients underwent 3-Dimensional Conformal RT (3D-CRT) whereas HNC patients underwent Volumetric-Modulated Arc Therapy (VMAT). At week 5 the proportion of BC patients who did not exhibit G2 ARD was higher in Xonrid® + SOC group (p = 0.091). In the same group the onset time of G2 ARD was significantly longer than in SOC-alone group (p < 0.0491). For HNC groups there was a similar trend, but it did not reach statistical significance. For both cancer sites, patients' QoL, measured by the Skindex-16 score, was always lower in the Xonrid® + SOC group.
CONCLUSION
Despite the failure to achieve the primary endpoint, this study suggests that Xonrid® may represent a valid medical device in the prevention and treatment of ARD at least in BC patients, delaying time to develop skin toxicity and reducing the proportion of patients who experienced G2 ARD during RT treatment and 2 weeks later.
TRIAL REGISTRATION
The study was approved by the Ethical Committee of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT 52/14 - NCT02261181 ). Registered on ClinicalTrial.gov on 21st August 2017.
Topics: Administration, Cutaneous; Adult; Breast Neoplasms; Female; Gels; Head and Neck Neoplasms; Humans; Middle Aged; Pharmaceutical Solutions; Prognosis; Radiodermatitis; Radiotherapy; Standard of Care; Survival Rate
PubMed: 32791985
DOI: 10.1186/s13014-020-01633-0 -
Peritoneal Dialysis International :... Jul 2021Previous studies suggested that automated peritoneal dialysis (APD) could be improved in terms of shorter treatment times and lower glucose absorption using bimodal...
BACKGROUND
Previous studies suggested that automated peritoneal dialysis (APD) could be improved in terms of shorter treatment times and lower glucose absorption using bimodal treatment regimens, having 'ultrafiltration (UF) cycles' using a high glucose concentration and 'clearance cycles' using low or no glucose. The purpose of this study is to explore such regimes further using mathematical optimization techniques based on the three-pore model.
METHODS
A linear model with constraints is applied to find the shortest possible treatment time given a set of clinical treatment goals. For bimodal regimes, an exact analytical solution often exists which is herein used to construct optimal regimes giving the same / urea and/or weekly creatinine clearance and UF as a 6 × 2 L 1.36% glucose regime and an 'adapted' (2 × 1.5 L 1.36% + 3 × 3 L 1.36%) regime.
RESULTS
Compared to the non-optimized (standard and adapted regimes), the optimized regimens demonstrated marked reductions (>40%) in glucose absorption while having an identical weekly creatinine clearance (35 L) and UF (0.5 L). Larger fill volumes of 1200 mL/m (UF cycles) and 1400 mL/m (clearance cycles) can be used to shorten the total treatment time.
CONCLUSION
These theoretical results imply substantial improvements in glucose absorption using optimized APD regimens while achieving similar water and solute removal as non-optimized APD regimens. While the current results are based on a well-established theoretical model for peritoneal dialysis, experimental and clinical studies need to be performed to validate the current findings.
Topics: Creatinine; Dialysis Solutions; Humans; Peritoneal Dialysis; Peritoneum; Prescriptions; Ultrafiltration; Urea
PubMed: 33910417
DOI: 10.1177/08968608211010055 -
Chemical & Pharmaceutical Bulletin 2023Benzalkonium chloride (BAC) is a useful preservative for ophthalmic solutions but has some disadvantageous effects on corneal epithelium, especially keratinocytes....
Benzalkonium chloride (BAC) is a useful preservative for ophthalmic solutions but has some disadvantageous effects on corneal epithelium, especially keratinocytes. Therefore, patients requiring the chronic administration of ophthalmic solutions may suffer from damage due to BAC, and ophthalmic solutions with a new preservative instead of BAC are desired. To resolve the above situation, we focused on 1,3-didecyl-2-methyl imidazolium chloride (DiMI). As a preservative for ophthalmic solutions, we evaluated the physical and chemical properties (absorption to a sterile filter, solubility, heat stress stability, and light/UV stress stability), and also the anti-microbial activity. The results indicated that DiMI was soluble enough to prepare ophthalmic solutions, and was stable under severe heat and light/UV conditions. In addition, the anti-microbial effect of DiMI as a preservative was considered to be stronger than BAC. Moreover, our in vitro toxicity tests suggested that DiMI is safer to humans than BAC. Considering the test results, DiMI may be an excellent candidate for a new preservative to replace BAC. If we can overcome manufacturing process issues (soluble time and flushing volume) and the insufficiency of toxicological information, DiMI may be widely adopted as a safe preservative, and immediately contribute to the increased well-being of all patients.
Topics: Humans; Benzalkonium Compounds; Ophthalmic Solutions; Preservatives, Pharmaceutical; Epithelium, Corneal
PubMed: 37394604
DOI: 10.1248/cpb.c23-00115 -
Chemical & Pharmaceutical Bulletin Feb 2003The anti-tack action of polyvinylpyrrolidone (PVP) on hydroxypropylmethylcellulose (HPMC) solution was elucidated using a probe test method. The influence of PVP of...
The anti-tack action of polyvinylpyrrolidone (PVP) on hydroxypropylmethylcellulose (HPMC) solution was elucidated using a probe test method. The influence of PVP of varying molecular weights at various PVP concentrations and solution temperatures on the tackiness of HPMC solution was studied. The viscosity, surface tension, cloud point and solution spectroscopy of HPMC solutions and glass transition temperature of HPMC films, with and without PVP, were investigated. The tackiness of HPMC solutions in response to the addition of PVP, at different concentrations of HPMC and using HPMC with varying contents of hydroxypropyl/methoxyl substitution, was also evaluated. PVP is a commonly used binder and adhesive. However, it reduced the tack of the HPMC solution when used at low concentrations, without affecting the state of hydration of HPMC. Lower molecular weight PVP was more effective as an anti-tack agent owing to suitable hydrodynamic size to intersperse among the HPMC chains. The degree of reduction in tack values was more pronounced for HPMC that showed a greater extent of interaction between polymer chains such as when high concentration of HPMC or low solution temperature was employed. This indicated that the tack reduction property of PVP relied on its ability to interact with the HPMC chains. The profile of reduction in tack values was affected by the contents of HPMC substitution and was a result of net reduction in the extent of hydrogen bonding between HPMC chains. It was significantly correlated to the changes of viscosity and surface tension of the HPMC solutions but not to the glass transition temperatures of the polymers prepared as solid films. The results suggested that the anti-tack action of PVP was attributed to its ability to interact with HPMC chains in the aqueous medium and consequently to reduce the extent of HPMC-HPMC bonding.
Topics: Hypromellose Derivatives; Methylcellulose; Pharmaceutical Solutions; Povidone; Surface Tension; Viscosity
PubMed: 12576641
DOI: 10.1248/cpb.51.107 -
Biological & Pharmaceutical Bulletin 2016Intraocular irrigating solution containing 1 µg/mL adrenaline is widely used during cataract surgery to maintain pupil dilation. Prepared intraocular irrigating...
Intraocular irrigating solution containing 1 µg/mL adrenaline is widely used during cataract surgery to maintain pupil dilation. Prepared intraocular irrigating solutions are recommended for use within 6 h. After the irrigating solution is admistered for dilution, the adrenaline may become oxidized, and this may result in a decrease in its biological activity. However, the stability of adrenaline in intraocular irrigating solution is not fully understood. The aim of this study was to evaluate the stability of adrenaline in clinically used irrigating solutions of varying pH. Six hours after mixing, the adrenaline percentages remaining were 90.6%±3.7 (pH 7.2), 91.1%±2.2 (pH 7.5), and 65.2%±2.8 (pH 8.0) of the initial concentration. One hour after mixing, the percentages remaining were 97.6%±2.0 (pH 7.2), 97.4%±2.7 (pH 7.5), and 95.6%±3.3 (pH 8.0). The degradation was especially remarkable and time dependent in the solution at pH 8.0. These results indicate that the concentration of adrenaline is decreased after preparation. Moreover, we investigated the influence of sodium bisulfite on adrenaline stability in irrigating solution. The percentage adrenaline remaining at 6 h after mixing in irrigating solution (pH 8.0) containing sodium bisulfite at 0.5 µg/mL (concentration in irrigating solution) or at 500 µg/mL (concentration in the undiluted adrenaline preparation) were 57.5 and 97.3%, respectively. Therefore, the low concentration of sodium bisulfite in the irrigating solution may be a cause of the adrenaline loss. In conclusion, intraocular irrigation solution with adrenaline should be prepared just prior to its use in surgery.
Topics: Drug Stability; Epinephrine; Hydrogen-Ion Concentration; Ophthalmic Solutions; Ophthalmologic Surgical Procedures; Sulfites; Time Factors
PubMed: 27150155
DOI: 10.1248/bpb.b15-00916 -
Journal of Pharmacy & Pharmaceutical... 2013Although the world's population is ageing and as a result of this an increasing number of patients are experiencing difficulty in swallowing, there remains a lack of... (Review)
Review
Although the world's population is ageing and as a result of this an increasing number of patients are experiencing difficulty in swallowing, there remains a lack of commercially available oral liquids for both these older and paediatric patients. This presents a problem to health care professionals, especially the pharmacist in practice, who is often required to provide a solution for these patients by preparing oral liquids extemporaneously from commercially available products. Preparation of these oral liquids is challenging, both due to the lack of pharmacopoeial and stability-indicating formulae and the fact that their stability is not only determined by the active pharmaceutical ingredient, but also the ability of excipients from the commercial product to interact with each other and the active pharmaceutical ingredient. This increases the complexity of the stability considerations to be taken into account within these oral liquids, highlighting the number of parameters to be considered in the extemporaneous preparation of oral liquids. This paper presents new evidence on the stability of 42 oral liquids prepared from commercially available products, reported on in the literature since the previous review published in 2006. However, unlike the previous review where the stability concerns in 7.2% of the extemporaneously prepared oral liquids were mainly due to interaction between the active pharmaceutical ingredients and the excipients in the commercial product, most of these stability considerations have been recognised and this has resulted in the authors proposing solutions to these problems prior to the extemporaneous preparation of the oral liquid. As such this paper also focuses on the increased level of research that has been undertaken to solve previous issues related to stability, especially in terms of the use of commercial products, which is common practice in the extemporaneous preparation of oral liquids.
Topics: Administration, Oral; Drug Stability; Excipients; Humans; Pharmaceutical Solutions; Pharmacists
PubMed: 24021292
DOI: 10.18433/j38887 -
Chemical & Pharmaceutical Bulletin 2016The use of naked unmodified small interfering RNA (N-siRNA) without vector has previously been investigated as a pulmonary therapy. However, little is known regarding...
The use of naked unmodified small interfering RNA (N-siRNA) without vector has previously been investigated as a pulmonary therapy. However, little is known regarding stabilities and aerodynamic particle sizes of N-siRNA-containing droplets; nebulizers have not yet been optimized for N-siRNA solutions. Thus, in this study, we investigated the feasibility of inhaled N-siRNA solutions for pulmonary therapy using nebulization. Various nebulizers and N-siRNA concentrations were assessed in terms of siRNA integrity after nebulization, and inhalation properties including aerodynamic particle size were examined. In comparison with ultrasonic-, air-jet-, and vibrating-mesh nebulizers, N-siRNA integrity was not affected by nebulization. Thus, in further experiments, performances of N-siRNA aerosols with different nebulizers and N-siRNA concentrations were evaluated and screened using an aerodynamic particle sizer (APS) which employed the time-of-flight principle or a cascade impactor. Mean mass aerodynamic diameters of N-siRNA-containing droplets from vibrating-mesh nebulizers tended to decrease with increasing N-siRNA concentrations, reflecting the influence of N-siRNA solutions on surface tension, as indicated by contact angles. These data indicate the utility of APS instruments for investigating the nebulized characteristics of expensive drugs including siRNAs and may facilitate the development of N-siRNA inhalation formulations.
Topics: Administration, Inhalation; Aerosols; Electrophoresis, Agar Gel; Humans; Lung Diseases; Nebulizers and Vaporizers; Particle Size; Pharmaceutical Solutions; Polymers; RNA, Small Interfering; Surface Tension
PubMed: 26726746
DOI: 10.1248/cpb.c15-00615 -
MAbs 2021Subcutaneous injection of a low volume (<2 mL) high concentration (>100 mg/mL) formulation is an attractive administration strategy for monoclonal antibodies (mAbs) and...
Subcutaneous injection of a low volume (<2 mL) high concentration (>100 mg/mL) formulation is an attractive administration strategy for monoclonal antibodies (mAbs) and other biopharmaceutical proteins. Using concentrated solutions may also be beneficial at various stages of bioprocessing. However, concentrating proteins by conventional techniques, such as ultrafiltration, can be time consuming and challenging. Isolation of the dense fraction produced by macroscopic liquid-liquid phase separation (LLPS) has been suggested as a means to produce high-concentration solutions, but practicality of this method, and the stability of the resulting protein solution have not previously been demonstrated. In this proof-of-concept study, we demonstrate that LLPS can be used to concentrate a mAb solution to >170 mg/mL. We show that the structure of the mAb is not altered by LLPS, and unperturbed mAb is recoverable following dilution of the dense fraction, as judged by H nuclear magnetic resonance spectroscopy. Finally, we show that the physical properties and stability of a model high concentration protein formulation obtained from the dense fraction can be improved, for example through the addition of the excipient arginine·glutamate. This results in a stable high-concentration protein formulation with reduced viscosity and no further macroscopic LLPS. Concentrating mAb solutions by LLPS represents a simple and effective technique to progress toward producing high-concentration protein formulations for bioprocessing or administration.Arginine·glutamate (Arg·Glu), Carr-Purcell-Meiboom-Gill (CPMG), critical temperature (T), high-performance size-exclusion chromatography (HPSEC), liquid-liquid phase separation (LLPS), monoclonal antibody (mAb), nuclear magnetic resonance (NMR), transverse relaxation rate (R).
Topics: Antibodies, Monoclonal; Chemistry, Pharmaceutical; Humans; Liquid-Liquid Extraction; Pharmaceutical Solutions; Proof of Concept Study; Protein Stability
PubMed: 34225583
DOI: 10.1080/19420862.2021.1940666