Stability Of Doxorubicin Research Articles

Construction of AIEgen functionalized nanomicelles and their stability study through ‘seesaw-like’ fluorescence changes

As nanocarriers, nanomicelles play vital roles in the toolbox of drug delivery. The stability of nanomicelles affects the nanomedicines’ bioactivity. Therefore, it is important to understand the stability of nanomicelles for further improvements. Here, we report a strategy to construct new nanomicelles (NM) by introducing aggregation-induced emission (AIE) functional group tetraphenylethylene (TPE) in the component polymer vitamin E (d-α-tocopheryl polyethylene glycol 1000 succinate) (TPGS). The stability of doxorubicin (DOX) loaded nanomicelles DOX@NM in different conditions was studied by fluorescence analysis. The fluorescence changes of DOX@NM are ‘seesaw-like’ when they transform between assembled and disassembled forms. In the assembled form, TPE gives emission from AIE effect, while in the disassembled form, the fluorescence of DOX is observed due to the disappearance of ACQ effect.

Voltammetric glassy carbon sensor approach for the extended stability studies of doxorubicin in lyophilized dosage form

Doxorubicin (DOX) is an anthracycline antibiotic that is widely used in the clinical treatment of cancer patients. DOX has a high market value. Electroanalytical methods for DOX analysis are an alternative and promising approach compared to chromatographic techniques. In this context, electroanalysis provides a low-cost method for determining drugs such as DOX lyophilized powder for the injection. Differential pulse voltammetry with a glassy carbon electrode was used. DOX stability after reconstitution was performed, and the correct time for safe administration to patients in hospitals was determined. The electroanalytical method showed a limit of detection of 0.54��mol�L?1 and limit of quantification of 1.83 �mol L�1, which is enough for the application in quality control of DOX. The high-performance liquid chromatography analysis was also applied in pharmaceutical samples containing DOX to compare with the proposed method, showing that the obtained results are relatively similar for both methods. Therefore, the electroanalytical approach shows the viability of an attractive alternative technique for applying this sensor for drug quality control.

Doxorubicin Stability and Retention on PEGylated Graphene Oxide Nanocarriers Adjacent to Human Serum Albumin.

Drug stability and retention on nanocarriers is essential for maximizing the drug targeting and therapeutic efficiency. PEGylation of graphene oxide (GO) as a drug nanocarrier is widely known to prolong its circulation time in the body, thereby increasing the probability of drug delivery system interactions with the proteins in the blood stream. Herein, molecular dynamics (MD) simulations were performed to investigate the interactions between doxorubicin (DOX)-loaded GO and PEGylated GO (PEGGO) nanocarriers with human serum albumin (HSA), a prevalent human blood protein and among the first to be adsorbed on the DOX-loaded nanocarriers. The results indicate that drug stability and retention on PEGGO nanocarriers are far more superior to the GO nanocarriers (control) when in contact with HSA. It is also demonstrated in this work that the PEGGO nanocarriers retain the DOX molecules irrespective of the HSA Sudlow site I and II orientations, thereby revealing their robustness in DOX loading.

Competition Between Heparin and Polyethylene Glycol as Biofunctionalization for Improving Stability of Liposomal Doxorubicin

In order to improve liposomal doxorubicin stability, differentiation between Heparin and Polyethylene Glycol (PEG) as biofunctionalization for liposomal doxorubicin has been investigated by measuring the entrapment efficiency, size distribution, zeta potential, evaluating the in vitro potential cytotoxicity against MCF-7 (Breast cancer cell) and stability in serum by measuring the drug release rate. We synthesized Four liposomal formulations: (A) Conventional liposomes; DPPC:DOX, (B) Positively charged PEGylated liposomes; DPPC:CHOL:SA:PEG:DOX (C) Negatively charged PEGylated liposomes: DPPC:CHOl:DCP:PEG:DOX (D) positively charged liposomes to conjugate heparin; DPPC:CHOL:SA:DOX. Entrapment efficiency of doxorubicin dramatically increased after PEGylation and conjugation with heparin. In addition, zeta potential was changed upon the encapsulation of doxorubicin into conventional and PEGylated liposomes which indicates that DOX encapsulated completely into liposomes. For heparin conjugated liposomes, zeta potential was slightly changed. Sulphorhodamine-B (SRB) assay showed a greater cytotoxic effect of the liposomal doxorubicin formulations at different concentrations with respect to free drug against MCF-7 cell lines. The anticancer activity order was observed between the various liposome formulations, especially those observed with conjugated heparin liposomes. Slower drug release rate showed an order of D > C > B > A that means stability showed an order of D > C > B > A. From above results, the most stable liposomal doxorubicin formulation was the liposomal formulation D. The results optimized using heparin than PEG as biofunctionalization. Further studies are suggested for better understanding why heparin improves the stability of liposomal doxorubicin.

Acetate ions enhance load and stability of doxorubicin onto PEGylated nanodiamond for selective tumor intracellular controlled release and therapy.

A successful drug delivery device for cancer chemotherapy should ideally be able to load drugs highly, bring the drug preferentially into tumor cells and reduce its distribution in normal tissue to enhance therapeutic efficacy. To this purpose, a novel protocol for DOX-loaded PEGylated nanodiamond (ND-PEG-DOX/NaAc, NPDA) was fabricated using sodium acetate medium. The NPDA nanoparticles exhibited a maximum loading efficiency (99 wt%) with ultra-low drug leakage (7 wt%). Examination by confocal microscope and flow cytometer showed that the NPDA uptake by cells was time-dependent, with a slow and sustained drug release from the lysosomes at a low pH. Also, when CHO (a normal cell) and MCF-7 (a cancer cell) were treated with NPDA, the results demonstrated that NPDA preferentially accumulated much more in tumor cells than in normal cells, which implied that NPDA has the ability to selectively kill tumor cells. In addition, NPDA can inhibit the migration and proliferation of tumor cells and change the cell cycle compared to the free drug. Outcomes from this work suggest that NPDA would be a promising drug delivery platform and the preparation of such a drug delivery system will also have implications in improving the biomedical applications of smart nanodiamond carriers.

Stability of Doxorubicin and Vincristine in Various Infusion Solutions for VAD Therapy

Doxorubicin and vincristine were added to various infusion solutions used for vincristine,doxorubicin and dexamethazone (VAD) chemotherapy.The infusion solutions were kept at room temperature,and stability was evaluated after 3,16,24,40,48,64,72,88 and 96 hours using high performance liquid chromatography.Doxorubicin and vincristine were stable in all infusion solutions up to 24 hours as residual contents were still over 90% at this time.Afterwards,a drop in vincristine content was observed for the infusion solution of physiological saline and this was considered to be due to adsorption of vincristine onto ethylene vinyl acetate copolymer,the material from which the infusion solution container was made.

Utilization of a sol–gel method for encapsulation of doxorubicin

The sol-gel pre-doping method was used to encapsulate doxorubicin in silica gels and optimum conditions of preparation of drug-loaded gel were established, ensuring both reproducible and effective results of quantitative encapsulation of doxorubicin and its gradual but complete release. Doxorubicin was encapsulated in polysiloxane polymers using the method based on sol-gel encapsulation without a catalyst, with an acid catalyst (HCl) and a base catalyst (NH3). The time of gelation of the gel loaded with doxorubicin, encapsulation efficiency of the drug and the degree of release of the drug from the gel are all affected by the kind of catalyst (acidic or basic) or its absence at the gel preparation stage, and the temperature of the gelation process. The time of sol gelation when using the NH3 or HCl catalyst was 9 days at 21°C, 2 days at 30°C and 1.5 days at 37°C, while for the gel prepared without a catalyst it was 90 days at 21°C, 75 days at 30°C and 70 days at 37°C. The efficiency of doxorubicin encapsulation was 99.5 ± 0.5% (w/w) for acid-catalyzed gel, 98.9 ± 1.01% (w/w) for base-catalyzed gel and 86.4 ± 11.6% (w/w) for non-catalyzed gel. A 100% (w/w) release of doxorubicin by diffusion through pores was found only in the case of base-catalyzed gel after a 140-h incubation time. For acid-catalyzed gel and non-catalyzed gel, the total amounts of released doxorubicin after 140 h of incubation were 3-5% (w/w) and 9-11% (w/w), respectively. The stability of doxorubicin encapsulated in the three kinds of gel matrices was found to be improved compared to the stability of a free form of the drug in solution.

The stability of doxorubicin and ldarubicin in plasma and whole blood

The stability of doxorubicin and idarubicin was studied in spiked human EDTA-, heparin-plasma and whole blood at room temperature (RT) and at +4°C. The analysis was performed by capillary electrophoresis (CE). Under each sel of conditions, doxorubicin and idarubicin concentrations decreased rapidly with time; the decrease was insignificantly more rapid with doxorubicin. Neither doxorubicinol nor idarubicinol were detectable. In order to obtain comparable plasma levels, doxorubicin and idarubicin containing blood samples should be centrifuged and stored at −20°C immediately.

Reduced UV-induced degradation of doxorubicin encapsulated in polyethyleneglycol-coated liposomes.

The aim of this study was to investigate the stability of doxorubicin encapsulated in polyethyleneglycol-coated liposomes (Doxil) under UV-A light. High performance liquid chromatography and a fluorimetric method were used to quantify doxorubicin in bulk solution and doxorubicin in Doxil formulation. The photodegradation of Doxil was significantly lower in comparison to the photodegradation of the free drug and showed no concentration dependency at the measured concentration range of 5-50 microg/ml. During and after UV-A irradiation, there was no leakage of the drug from liposomes to the medium. After induced leakage of doxorubicin from the liposomes by the ionophore nigericin, the degradation kinetics of Doxil were identical to that of free doxorubicin. High intraliposomal doxorubicin concentration and intraliposomal acidic pH are the two critical factors that protect DXR in Doxil from UV-A degradation.

Doxorubicin stability in syringes and glass vials and evaluation of chemical contamination

ABSTRACTThe concentration of reconstituted doxorubicin hydrochloride solution (2 mg/mL) was evaluated during 124 days storage in original manufacturer’s vials and two different brands of syringes (Terumo, Monoject) at 4°C and 23°C.On each of 14 study days the doxorubicin hydrochloride concentration was determined using a validated, stability-indicating liquid chromatographic method. On each day pH, colour, physical inspection and the concentration of 2-mercaptobenzothiazole (MBT), 2-(2-hydroxyethylmercapto) benzothiazole (HMBT) and di-2-ethylhexylphthalate (DEHP) was also measured.During the 124-day study period all solutions stored at 4°C and 23°C retained more than 90 percent of the initial doxorubicin hydrochloride concentration, remained clear and had no change in UV-VIS spectrum absorbance or pH. On day 124, mass balance indicated that approximately 3.5 percent of the doxorubicin had degraded at room temperature and about one percent had degraded at 4°C. The MBT, HMBT and DEHP concentrations were below detectable limits.We conclude that doxorubicin solutions (2 mg/mL) stored at 4°C or 23°C in the original glass vial are stable for 124 days. Since investigations have failed to demonstrate contamination of these solutions stored in Terumo or Monoject syringes, we conclude that doxorubicin solutions (1 mg/ml and 2 mg/ml) are stable when stored at 4°C or 23°C in syringes, and maintain acceptable product purity.RESUMELa concentration de la solution de chlorhydrate de doxorubicine reconstituee (2 mg/ml) a ete evaluee pendant 124 jours d'entreposage dans les flacons originaux des fabricants et dans deux differentes marques de seringues (Terumo et Monoject) a 4°C et 23°C.La concentration de chlorhydrate de doxorubicine a ete determinee chaque jour pendant quatorze jours d’etude en utilisant une methode de chromatographie liquide approuvee pour determiner la stabilite. Pendant chaque jour d'etude on a aussi mesure le pH, la couleur, l'analyse physique ainsi que la concentration de deux produits chimiques: 2-mercaptobenzothiazole (MBT), 2-(2-hydroxyetlzylmercapto) benzothiazole (HMBT) et du di-2-ethylhexylphtlzalate (DEHP).Pendant la periode d'etude de 124 jours, toutes les solutions entreposees a 4°C et 23°C ont retenu plus de 90 pour cent de la concentration initiale de chlorhydrate de doxorubicine; elles sont demeurees claires et sans aucun changement d'absorbance de spectre UV-VIS ou de pH. Au jour 124, la balance de masse indiquait qu'environ 3.5 pour cent de la doxorubicine s'etaient degrades a la temperature de la piece et a peu pres un pour cent s'etaient degrades a 4°C les concentrations de MBT, HMBT et DEHP etaient en dessous des limites qu'on peut detecter (100, 100 et 200 ng/mL respectivement) dans toutes les solutions.Nous concluons donc que les solutions de doxorubicine (2 mg/ml) entreposees a 4°C ou 23°C en flacons de verre originaux sont stables pendant 124 jours. Puisque les experimentations n'ont pas reussi a demontrer que les solutions (1 mg/ml and 2 mg/ml) entreposees dans des seringues Terumo ou Monoject etaient contaminees, nous concluons que les solutions de doxorubicine sont stables lorsqu'entreposees dans des seringues a 4°C ou 23°C et maintiennent une purete acceptable du produit.

Effect of Urine pH on the Stability of Doxorubicin and its Recovery from Bladder Instillations

Doxorubicin (1 mg/ml) was shown to be stable when added to urine samples with a mean natural pH of 5.4 and in urine buffered to a mean pH of 4.6. However, at alkaline pH (mean = 8.1) there was a biphasic degradation of doxorubicin (mean t1/2 = 3.24 and 89 h respectively). The data indicate that buffering intravesical doxorubicin to pH 4.6 (acetate buffer) or pre-dosing of patients with ammonium chloride may minimise loss of active drug during the time for which the drug is retained in the bladder. Recovery of doxorubicin following 1 hour's retention in the bladder was similar (77%) for doses of 38/48 or 78 mg. It is suggested that a dose of 50 mg (1 mg/ml) is sufficient to ensure an adequate delivery of active drug to the bladder wall.

Stability of intravenous admixtures of doxorubicin and vincristine

The stability of doxorubicin and vincristine in admixtures containing both drugs in 0.9% sodium chloride injection, 0.45% sodium chloride and Ringer's acetate injection, and 0.45% sodium chloride and 2.5% dextrose injection was studied. Doxorubicin hydrochloride was added to 30-mL quantities of each base solution to achieve initial doxorubicin concentrations of 1.40 mg/mL and to 0.9% sodium chloride injection to achieve concentrations of 1.88 and 2.37 mg/mL. Vincristine sulfate was added to each doxorubicin admixture to achieve vincristine concentrations of 0.033 and 0.053 mg/mL. All admixtures were protected from light and stored in polysiloxan bags that are used with portable delivery devices. Admixtures were kept at temperatures of 25, 30, and 37 degrees C. Samples withdrawn immediately after preparation and at 1, 2, 4, 7, 10, and 14 days were analyzed by high-performance liquid chromatography for content of each drug. The stability of doxorubicin was dependent on temperature and composition of the base solution. Analysis of data from the samples containing 0.45% sodium chloride and Ringer's acetate injection showed that doxorubicin concentrations were less than 90% of the initial concentration by 12 hours at 37 degrees C, 35 hours at 30 degrees C, and 62 hours at 25 degrees C, and visual changes occurred in all of these admixtures over the course of the study. Vincristine degradation also was most rapid in 0.45% sodium chloride and Ringer's acetate admixtures. Data analysis showed that concentrations of vincristine were less than 90% of initial after eight days at 25 degrees C, five days at 30 degrees C, and three days at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Degradation of doxorubicin and daunorubicin in human and rabbit biological fluids

The stability of doxorubicin (DOX) and daunorubicin (DNR) in rabbit and human plasma, bile and urine and in rabbit faeces was studied in the presence or absence of light, and at body, room and cold room temperatures. Fluorescence was determined by spectrofluorimetry after normal and reversed phase HPLC. Under each set of conditions, DOX and DNR fluorescence decreased with time; the decrease was more rapid with DOX. As the parent drugs were degraded, apolar compounds were formed which behaved like 7-deoxyaglycones and generally did not compensate for the loss in fluorescence of the parent drug. The degradation of anthracyclines occurred even in the absence of light, was not due to bacterial contamination and was faster at higher pH or temperature. The rapid degradation of DOX and DNR in biological fluids at body temperature may have implications on the disposition of anthracyclines in vivo. Prior to analysis, biological fluids and solutions containing anthracyclines should be processed quickly at 4 degrees C, in the absence of light, and at a pH no greater than 6 to avoid degradation.