Stability Of Paclitaxel Research Articles

Determination of Paclitaxel Solubility and Stability in the Presence of Injectable Excipients

Due to poor aqueous solubility of paclitaxel, cremophor is one of the excipients used to improve solubility in Taxol while it is responsible for a number of adverse effects such as anaphylactic shock. This research was aimed to determine the solubility and stability of paclitaxel in the presence of intravenous injectable excipients. For this purpose, the solubility of paclitaxel was measured in PEG 400, ethanol, miglyol 812, octanoic acid and oleic acid using the shake flask method. Paclitaxel showed the highest solubility in PEG 400 because of possible hydrophobic interaction of the drug with polyethylene chains. The solubility of paclitaxel in ethanol was higher than its aqueous solubility, accentuating the importance of hydrogen bonding. The solubility of paclitaxel was slightly improved in octanoic acid, oleic acid and miglyol 812, presumably for less matching hydrophobic-hydrophilic balance of their molecules with paclitaxel. The stability of paclitaxel was examined in PEG 400, ethanol, and their binary mixture. Paclitaxel exhibited highest stability in the latter case. Probably, this is because of the matching polarity of PEG 400–ethanol mixture with paclitaxel. The effect of anhydrous citric acid on the stability of paclitaxel was also studied. Citric acid significantly improved the stability because it set pH of the prepared compositions in the range of 3 – 5, where paclitaxel exhibited the slowest rate of degradation. The prepared compositions were introduced in aqueous media in various concentrations to study precipitation due to dilution. Precipitation has been observed at all concentrations because paclitaxel is greatly insoluble in water and resists re-dissolving.

Utilization of novel self-nanoemulsifying formulations (SNEFs) loaded paclitaxel for the treatment prosperity of bladder cancer

BackgroundLimited drug penetration into solid tumors has been one of the potential causes of resistance to chemotherapy for the treatment of bladder cancer. The aim of the studies was to develop non-toxic nanoemulsion carriers of paclitaxel and to evaluate their ability to serve as a tool increasing and/or controlling the penetration of paclitaxel through the bladder tissue. MethodsVarious oil-in-water non-toxic self-nanoemulsifying formulations (SNEFs) were developed using Cremercoor MCT, Kollisolv MCT, Miglyol 812, 810, Capmul MCM, Imwitor 988, Imwitor 742 with TO106V, Tween 85, HCO30, Kolliphor EL and Cremophor RH40 at size ranges from approximately 19 to 110 nm that are capable of enhancing the solubility and stability of paclitaxel. Visual assessment was employed and droplet size measurement was taken into initial consideration for optimized SNEFs. Paclitaxel was added with the oil/surfactant mixture before dispersing the mixture in water to form SNEF. The penetration study of the optimal SNEFs formulation was compared with the raw paclitaxel dispersion using transwell apparatus. ResultsInitial characterisation and solubility studies showed that mixed glycerides of Kollisolv MCT/Imwitor 742 with water-soluble surfactant (high HLB) containing formulations generated highly efficient SNEFs as they are stable and produced lower nanodroplets with higher drug loading. The results have demonstrated that the SNEFs have good ability to retain its characteristics under conditions similar to that found in the urinary bladder up to 48 h. However, the results also showed that chemosensitivity of cancer cells exposed to paclitaxel was attenuated in the presence of SNEFs. Larger size SNEFs have shown to induce more inhibitory effects on paclitaxel activity. The reduction effects of SNEFs on doxorubicin (a relatively water-soluble drug) efficacy were almost absent, indication a poor loading of such compounds. ConclusionThe reduction of the efficacy of SNEF loaded treatments does not give a strong indication of their ability to penetrate as examined their ability to penetrate through the cultivated multicell layers (MCL) of bladder cancer. However, these results may open the horizon to reflect the use of SNEFs in the introduction of intravenous paclitaxel because of its potential role in reducing the injection site toxicity.

Dual thermoresponsive and pH-responsive self-assembled micellar nanogel for anticancer drug delivery

In this article, we prepared a dual thermoresponsive and pH-responsive self-assembled micellar nanogel for anticancer drug delivery by using a degradable pH-responsive ketal derivative, mPEG2000-Isopropylideneglycerol (mPEG-IS, PI) polymer. The purpose of this study is to develop an injectable dual-responsive micellar nanogel system which has a sol-gel phase transition by the stimulation of body temperature with improved stability and biocompatibility as a controlled drug delivery carrier for cancer therapy. The pH-responsive PI was designed with pH-responsive ketal group as hydrophobic moieties and PEG group as hydrophilic moieties. The PI micelles encapsulated paclitaxel (PTX) was fabricated. Then, the PI micelles were formed in a thermo-nanogel. The micellar nanogel could improve the solubility and stability of PTX. The physiochemical properties of PI micelles and micellar nanogel were characterized. The results showed that dual-responsive micellar nanogel could carry out sol-gel transition at 37 °C. The PI polymer can spontaneously self-assemble into micellar structure with size of 100–200 nm. The dual-responsive micellar nanogel could be degraded under lower pH condition. The test in vitro PTX release showed that dual-responsive micellar nanogel could release about 70% for 70 h under pH 5.0 while about 10% release at pH 7.4 and pH 9.0. The dual-responsive micellar nanogel was of lower cytotoxicity and suppressed tumor growth most efficiently. The micellar nanogel will be a new potential dual-responsive drug delivery system for cancer therapy.

Effect of Unpurified Cremophor EL on the Solution Stability of Paclitaxel

Taxol for Injection Concentrate contains a solution of paclitaxel in a 50:50 v/v mixture of Cremophor EL (cleaned):ethanol. Cleaned, rather than unpurified, Cremophor EL is used as a cosolvent because paclitaxel was observed to be less stable in the presence of unpurified Cremophor. In order to understand the cause of this paclitaxel instability, various studies were performed. The results of these studies, coupled with the examination of degradation products, suggested that carboxylate anions present in the unpurified Cremophor catalyze the degradation of paclitaxel by general base catalyzed ethanolysis. Stabilization of Taxol for Injection Concentrate prepared with unpurified Cremophor can be achieved by addition of strong acids, resulting in neutralization of the carboxylate anions. Separately, a quality control test for the cleaning procedure of Cremophor is needed to insure stability of Taxol for Injection Concentrate. A colorimetric indicator test was identified which can distinguish between good and poor quality cleaned Cremophor as it pertains to paclitaxel stability.

파클리탁셀을 함유한 지질나노입자의 제조와 인공 소화액에서의 안정성 평가

Peroral administration is the most convenient one for the administration of pharmaceutically active compounds. Most of poorly water-soluble drugs administered via the oral route, however, remain poorly available due to their precipitation in the gastrointestinal (GI) tract and low permeability through intestinal mucosa. In this study, one of drug delivery carriers, lipid nanoparticles (LNPs) were designed in order to reduce side effects and improve solubility and stability in GI tract of the poorly water soluble drugs. However, plain LNPs are generally unstable in the GI tract and susceptible to the action of acids, bile salts and enzymes. Accordingly, the surface of LNPs was modified with polyethylene glycol (PEG) for the purpose of improving solubility and GI stability of paclitaxel (PTX) in vitro. PEG-modified LNPs containing PTX was prepared by spontaneous emulsification and solvent evaporation (SESE) method and characterized for mean particle diameter, entrapping efficiency, zeta potential value and in vitro GI stability. Mean particle diameter and zeta potential value of PEG-modified LNP containing PTX showed approximately 86.9 nm and -22.9 mV, respectively. PTX entrapping efficiency was about 70.5% determined by UV/VIS spectrophotometer. Futhermore, change of particle diameter of PTX-loaded PEG-LNPs in simulated GI fluids and bile fluid was evaluated as a criteria of GI stability. Particle diameter of PTX-loaded PEG-LNPs were preserved under 200 nm for 6 hrs in simulated GI fluids and bile fluid at when DSPE-mPEG2000 was added to formulation of LNPs above 4 mole ratio. As a result, PEG-modified LNPs improved stability of plain LNPs that would aggregate in simulated GI fluids and bile solution. These results indicate that LNPs modified with biocompatible and nontoxic polymer such as PEG might be useful for enhancement of GI stability of poorly water-soluble drugs and they might affect PTX absorption affirmatively in gastrointestinal mucosa.

Aqueous N,N-diethylnicotinamide (DENA) solution as a medium for accelerated release study of paclitaxel

N,N-Diethylnicotinamide (DENA) was identified as an excellent hydrotropic agent for paclitaxel (PTX) in our previous studies. The aqueous solubility of PTX was increased by several orders of magnitude in the presence of DENA. Because of such a high hydrotropic property, DENA was used as a release medium providing a sink condition for the release of PTX from poly(lactic-co-glycolic acid) (PLGA) matrices. The release profiles of PTX from PLGA matrices into DENA, serum and phosphate-buffered saline (PBS) were compared. The stability of PTX in DENA and the degradation of PLGA molecules in DENA were examined. The degradation rate constant of PTX in 2 M DENA was similar to those in other aqueous solutions. The use of 2 M DENA as a release medium allowed differentiation of the release profiles of PTX from PLGA matrices made of different PLGA compositions. The PTX release from PLGA matrices was much faster in DENA solution than in serum or PBS, and the concentration of DENA affected the PTX release rate. The presence of DENA in the release medium increased the hydrolysis rate of PLGA polymers. The faster release of PTX from PLGA matrices in DENA solution may be due to the high PTX solubility and faster degradation of PLGA polymers in the presence of DENA. Our study suggests that the aqueous DENA solution can be used for the accelerated release study of PTX from PLGA matrices.

Influence of cationic lipids on the stability and membrane properties of paclitaxel‐containing liposomes

Paclitaxel (taxol) is a poorly soluble anticancer agent that is in widespread clinical use. Liposomes provide a less toxic vehicle for solubilizing the drug and increasing the therapeutic index of paclitaxel in model tumor systems. The role of liposome membrane composition in the stability of paclitaxel‐containing formulations is understood partially for neutral and anionic liposomes, but poorly for other compositions. We investigated the effect of dialkyl cationic lipids on the stability and physical properties of paclitaxel‐containing liposomes, using circular dichroism (CD), fluorescence spectroscopy, and differential interference contrast microscopy (DIC). DOTAP (1,2‐dioleoyl‐3‐trimethylammonium propane), a cationic lipid used frequently for gene delivery, was combined at various ratios with dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), or distearoylphosphatidylcholine (DSPC). In the absence of DOTAP, the stability of liposomes containing ≥3 mol% paclitaxel was observed to follow the following rank order: DPPC >DSPC > DMPC. Increasing concentrations of DOTAP increased the physical stability of all compositions, and maximal stabilization was achieved at 30–50 mol% DOTAP, depending on the paclitaxel concentration and the acyl chain length of the phosphatidylcholine. The relationship between stability and mole fraction of DOTAP was complex for some compositions. DOTAP exerted a major fluidizing effect on DMPC, DPPC, and DSPC membranes, and the addition of paclitaxel at 3–8 mol% did not increase fluidity further. Studies of membrane phase domain behavior using the probe Laurdan (6‐dodecanoyl‐2‐dimethylaminonaphthalene) indicated that both paclitaxel and DOTAP were miscible with the phosphatidylcholine phase. The physical events leading to destabilization of formulations are hypothesized to arise from concentration‐dependent paclitaxel self‐association rather than immiscibility of the membrane lipids. Given the increased incorporation and stability of paclitaxel in DOTAP‐containing membranes and the potential for enhanced interaction with cells, cationic liposomes may provide a therapeutic advantage over previously described liposome formulations. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1091–1105, 2001

Studies on factors influencing stability and recovery of paclitaxel from suspension media and cultures of Taxus cuspidata cv Densiformis by high-performance liquid chromatography

An HPLC method was developed for quick scanning of taxanes from large numbers of plant cell suspension samples. The method was optimized for analysis of a range of taxanes of differing polarity. Identification of a standard mixture of paclitaxel and 12 related taxanes was achieved in less than 15 min using a gradient mode and a Microsorb-MV C 8 column. The method was used to investigate the influence of several factors on stability and recovery of paclitaxel from suspension media and cultures of Taxus cuspidata cv Densiformis. Incubation time had the most significant influence on stability of paclitaxel, contributing 88% to the total variation. Shaking contributed 6% to the total variation. Light contributed only 0.25% to the total variation. Analysis of test samples of suspension cultures of T. cuspidata cv Densiformis over a 4 week period show paclitaxel, 10-deacetylbaccatin III, and baccatin III levels ranging from 0 to 149 μg/L, from 0 to 1.9 mg/L, and from 0 to 583 μg/L, respectively.

Compatibility and Stability of Paclitaxel Combined with Cisplatin and with Carboplatin in Infusion Solutions

To evaluate the physical compatibility and chemical stability of paclitaxel at concentrations of 0.3 and 1.2 mg/mL with cisplatin 0.2 mg/mL in NaCl 0.9% injection and with carboplatin 2 mg/mL in NaCl 0.9% injection and dextrose 5% injection over 7 days at 4, 23, and 32 degrees C. The test samples were prepared in polyolefin bags of the infusion solutions at the required drug concentrations. Evaluations were performed initially and after 4 hours, and 1, 3, 5, and 7 days of storage at temperatures of 4, 23, and 32 degrees C for physical and chemical stability. Physical stability was assessed by using visual observation in normal light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the three drugs was evaluated by using three stability-indicating HPLC analytical techniques. All samples were physically stable through 1 day. However, microcrystalline precipitation of paclitaxel occurred in 3 days in some samples and within 5 days in all samples. Paclitaxel concentrations remained above 90% in all samples throughout the study. Cisplatin admixtures exhibited paclitaxel concentration-dependent decomposition with cisplatin losses of approximately 5-8% in 4 hours and approximately 20% in 1 day at 23 and 32 degrees C in the paclitaxel 1.2 mg/mL admixtures. With paclitaxel 0.3 mg/mL in the admixtures, cisplatin losses were about 10% in 7 days at these temperatures. Carboplatin in admixtures with both concentrations of paclitaxel was stable for 7 days at 4 degrees C, but sustained losses of about 10% and 12% in 3 days at 23 and 32 degrees C, respectively. Admixtures of paclitaxel 0.3 and 1.2 mg/mL with cisplatin and carboplatin are limited in their utility time by both paclitaxel microcrystalline precipitation and decomposition of cisplatin and carboplatin. The admixture of paclitaxel 1.2 mg/mL with cisplatin 0.2 mg/mL in NaCl 0.9% injection exhibits unacceptable cisplatin loss in 24 hours. All other combinations were physically and chemically stable for at least 24 hours at 4, 23, and 32 degrees C.

Stability of paclitaxel in 5% dextrose injection or 0.9% sodium chloride injection at 4, 22, or 32°C

Stability of paclitaxel in 5% dextrose injection or 0.9% sodium chloride injection at 4, 22, or 32°C

Stability of paclitaxel and fluconazole during simulated Y-site administration

Stability of paclitaxel and fluconazole during simulated Y-site administration

Stability of paclitaxel with ondansetron hydrochloride or ranitidine hydrochloride during simulated Y-site administration

The stability of paclitaxel with either ondansetron hydrochloride or ranitidine hydrochloride during simulated Y-site injection at room temperature was studied. Triplicate test solutions of paclitaxel 0.3 and 1.2 mg/mL were admixed 1:1 with ondansetron 0.03 and 0.3 mg/mL (as the hydrochloride salt) or ranitidine 0.5 and 2.0 mg/mL (as the hydrochloride salt). Also, paclitaxel 1.2 mg/mL was admixed 1:1:1 with ondansetron 0.3 mg/mL and ranitidine 2.0 mg/mL. The solutions were stored in glass containers at room temperature, and samples were removed at zero, one, two, and four hours for immediate assay. At the time of the assay and before any dilution, each sample was visually inspected for clarity, color, and precipitation, and the pH was determined. Drug concentrations were measured by stability-indicating high-performance liquid chromatographic procedures. Throughout the study, more than 90% of the initial concentrations of paclitaxel, ondansetron, and ranitidine remained in the solutions. No precipitates, color changes, or haziness was seen. The changes in pH were minor. Paclitaxel in concentrations of 0.3 and 1.2 mg/mL was stable when mixed with either ondansetron (0.03 or 0.3 mg/mL, as the hydrochloride salt) or ranitidine (0.5 or 2.0 mg/mL, as the hydrochloride salt) and stored in glass containers for four hours. Paclitaxel 1.2 mg/mL was also stable when mixed with both ondansetron 0.3 mg/mL and ranitidine 2.0 mg/mL and stored in glass containers for four hours.

Paclitaxel Stability and Compatibility in Polyolefin Containers

To determine the compatibility and stability of paclitaxel in polyolefin containers. The following paclitaxel concentrations were determined by a stability-indicating HPLC method: 0.3 and 1.2 mg/mL diluted in dextrose 5% for injection, USP (D5W) or sodium chloride 0.9% for injection, USP (NS). The solutions were prepared in polyolefin containers and the stability and compatibility were monitored for 48 hours when stored at ambient temperature (20-23 degrees C) and normal fluorescent lighting. A mixture of the drug carrier consisting of approximately 10% polyoxyethylated castor oil (Cremophor EL) and 10% ethanol in D5W and NS, without paclitaxel, was studied to differentiate the effect of paclitaxel from the effect of the drug carrier on the container. Paclitaxel concentrations, pH changes, and visual clarity were used as stability and compatibility indicators. Paclitaxel concentrations remained at 96-99 percent of the initial concentration for up to 48 hours when placed in the polyolefin containers. No changes in color or visual clarity were noted. Only minor changes in the pH of the admixtures were observed. Paclitaxel diluted in D5W or NS at concentrations of 0.3 and 1.2 mg/mL is stable and compatible in flexible, polyolefin containers for up to 48 hours.