Biomedical subjects

B Nuijen

Publications and source records attributed to B Nuijen.

17 recordsLinked to original sources

PubMed2006

EO-9 bladder instillations: formulation selection based on stability characteristics and in vitro simulation studies.

A bladder instillation of EO-9 (EOquin) is currently used in phase II clinical trials for the treatment of superficial bladder cancer. Three alternative formulations were developed to improve its pharmaceutical properties and clinical acceptability. Freeze-dried products composed of EO-9, 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD), tri(hydroxymethyl) aminomethane (Tris), and sodium bicarbonate (NaHCO(3)) were tested. Selection of one formulation for further development was based on stability studies. These studies comprised stability of the freeze-dried products, stability after reconstitution and dilution and stability during bladder instillation in an experimental set-up. The stability study of the freeze-dried products showed that the formulation composed of EO-9/HPbetaCD/Tris (4/600/1mg/vial) was most stable. After reconstitution and dilution all products were stable for at least 8h. The product composed of EO9/HPbetaCD/NaHCO(3) (4/600/20mg/vial) was the least stable product both as freeze-dried formulation and after reconstitution and dilution. The bladder instillation simulation experiment showed that all products were stable when mixed with urine of pH 8 and unstable in urine of pH 4 and 6. The degradation products formed in urine were EO-5a and EO-9-Cl. Based on these results, the product composed of EO-9/HPbetaCD/Tris (4/600/1mg/vial) was selected for further pharmaceutical development.

Aziridines↗

PubMed2006

A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer.

To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160 mg+CsA 700 mg on day 1, followed by oral paclitaxel (Taxol) 160 mg+CsA 700 mg on day 8 (group I) or vice versa (group II). Patients received paclitaxel (Taxol) 160 mg as 3-h infusion on day 15. The median (range) area under the plasma concentration-time curve of paclitaxel was 2.06 (1.15-3.47) microg h ml(-1) and 1.97 (0.58-3.22) microg h ml(-1) after oral administration of SMEOF#3 and Taxol, respectively, and 4.69 (3.90-6.09) microg h ml(-1) after intravenous Taxol. Oral SMEOF#3 resulted in a lower median T(max) of 2.0 (0.5-2.0) h than orally applied Taxol (T(max)=4.0 (0.8-6.1) h, P=0.02). The median apparent bioavailability of paclitaxel was 40 (19-83)% and 55 (9-70)% for the oral SMEOF#3 and oral Taxol formulation, respectively. Oral paclitaxel administered as SMEOF#3 or Taxol was safe and well tolerated by the patients. Remarkably, the SMEOF#3 formulation resulted in a significantly lower T(max) than orally applied Taxol, probably due to the excipients in the SMEOF#3 formulation resulting in a higher absorption rate of paclitaxel.

Administration, Oral↗

PubMed2006

Compatibility and stability of the novel anticancer agent ES-285 x HCl formulated with 2-hydroxypropyl-beta-cyclodextrin in infusion devices.

ES-285 x HCl is a novel marine-derived anticancer agent isolated from the clam Spisula polynyma. The compound is pharmaceutically formulated as a lyophilised product containing 25 or 50 mg ES-285 x HCl and 500 or 1000 mg 2-hydroxypropyl-beta-cyclodextrin per dosage unit and requires reconstitution with sterile water for injection before intravenous administration. The aim of this study was to determine the stability and compatibility of ES-285 x HCl in infusion devices. ES-285 x HCl was shown to be stable at concentrations of 10-1400 microg/ml after dilution in 5% dextrose in water and compatible with PE infusion containers and PE and silicone tubing. No sorption on- or into the administration set was observed at concentrations equal to or above 20 microg/ml. In conclusion, ES-285 x HCl infusion solutions can be administered without stability or sorption problems using a PE infusion container and PE or silicone tubing in concentrations equal or above 20 microg/ml in 3-hour or 24-hour infusion administration schedules.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2006

Pharmaceutical development, quality control, stability and compatibility of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum antineoplastic agent AP5346.

AP5346 is a low molecular weight polymer-conjugated platinum antineoplastic agent. The lyophilized drug product has completed a phase I clinical trial. In order to guarantee a constant quality of AP5346 pharmaceutical products, quality control and analysis of the drug substance and final product were performed. The identity of AP5346 was confirmed using 1H NMR, 195Pt NMR and IR spectroscopy. Furthermore, the free platinum content, platinum release characteristics, molecular size and size distribution were established. With the selected analytical techniques, AP5346 could be distinguished very well from its polymeric analogues, such as AP5280 and AP5279. Stability experiments revealed that AP5346 final product is stable for 12 months at 5 degrees C, in the dark. For administration to patients, AP5346 final product is reconstituted with 5% w/v dextrose and diluted in infusion containers. To investigate the influence of container materials, the stability of AP5346 after reconstitution and dilution in infusion containers was determined. The infusion containers investigated were composed of glass, polyvinyl chloride (PVC, intraflex) and low density polyethylene (LD-PE, Ecoflac). AP5346 was shown to be stable after reconstitution and dilution with 5% w/v dextrose in these infusion containers for at least 96 h at 2-8 degrees C in the dark and at room temperature with ambient light conditions.

Antineoplastic Agents↗

PubMed2004

Development and manufacture of diacetylmorphine/caffeine sachets for inhalation via 'chasing the dragon' by heroin addicts.

In 1998, two clinical trials were started in The Netherlands to evaluate the effect of coprescription of heroin and methadone on the mental and physical health and social functioning of chronic, treatment-resistant, heroin-dependent patients. Since 75-85% of the heroin addicts in The Netherlands use their heroin by "chasing the dragon," one of the two study arms concerned the coprescription of inhalable heroin. A pharmaceutical dosage form for inhalable heroin was developed for this trial, consisting of a 3:1 powder mixture of diacetylmorphine base and caffeine anhydrate. We describe the manufacturing process that was developed for filling sachets with this mixture in four dosages using a micro dose auger filler. In order to control product quality, in-process controls were developed to monitor the filling process and quality control tests were performed on the finished product. In-process control results have shown the filling process to be accurate and precise. The diacetylmorphine/caffeine sachets were shown to comply with the specifications for content and uniformity of mass. The finished product was found to be stable for 2 years when stored at 25 degrees C, 60% relative humidity and for 6 months when stored at 40 degrees C, 75% relative humidity.

Administration, Inhalation↗

PubMed2003

Pharmaceutical development of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum anticancer agent AP 5280.

AP 5280 is a novel polymer-conjugated platinum anticancer agent showing promising in vitro and in vivo activity against solid tumors. The aim of this study was to develop a parenteral pharmaceutical dosage form for phase I clinical trials. AP 5280 drug substance was characterized by using a wide range of analytical techniques and showed excellent solubility in water. However, as aqueous solutions of AP 5280 proved to be labile upon sterilization by moist heat, it was decided to develop a lyophilized dosage form. Initially, glass vials were used as primary packaging, but this led to a high breakage rate, which could be completely prevented by the use of CZ resin vials. Stability studies to date show that the lyophilized product in glass vials is stable for at least 12 months when stored at 2-8 degrees C in the dark and the lyophilized product in CZ resin vials is stable for at least 6 months under these conditions. Photostability testing revealed photolability of AP 5280 drug substance and lyophilized product in both types of primary container, necessitating storage in the dark. The first clinical experiences indicate that the proposed formulation is fully applicable for use in the clinical setting.

Acrylamides↗

PubMed2002

Pharmaceutical development of a parenteral lyophilized formulation of the antimetastatic ruthenium complex NAMI-A.

This paper describes the development of a stable pharmaceutical dosage form for NAMI-A, a novel antimetastatic ruthenium complex, for Phase I testing. NAMI-A drug substance was characterized using several spectrometric and chromatographic techniques. In preformulation studies, it was found that NAMI-A in aqueous solution was not stable enough to allow sterilization by moist heat. The effect of several excipients on the stability of the formulation solution was investigated. None of them provided sufficient stability to allow long-term storage of an aqueous solution of NAMI-A. Therefore, a lyophilized product was developed. Five different formulations were prepared and subjected to thermogravimetric (TG) analysis and stability studies at various conditions for 1 year. Minimal degradation during the production process is achieved with a formulation solution of pH 3-4. Of the acids tested, only hydrochloric acid (HCl 0.1 mM) both stabilized the formulation solution and was compatible with the lyophilized product. This product was stable for at least 1 year when stored at -20 degrees C, 25 degrees C/60% relative humidity (RH) and 40 degrees C/75% RH, and was also photostable.

Antineoplastic Agents↗

PubMed2002

Stability and compatibility of the investigational polymer-conjugated platinum anticancer agent AP 5280 in infusion systems and its hemolytic potential.

AP 5280 is a novel polymer-conjugated platinum anticancer agent currently undergoing phase I clinical trials. It is pharmaceutically formulated as a lyophilized product containing 200 mg platinum per dosage unit. The aim of this study was to determine the reconstitution and dilution fluid of choice, and to investigate the stability and compatibility of AP 5280 in solution under different storage conditions and with several container materials. Furthermore, the hemolytic potential of AP 5280 infusion solution was investigated. AP 5280 slowly released small platinum species in all solutions, although this release was enhanced in normal saline. Accordingly, 5% dextrose in water (D W) was selected for reconstitution and dilution of AP 5280. Container material [glass or polyvinylchloride (PVC)] did not influence the stability of AP 5280 in solution. Storage at refrigerated temperature (2-8 degrees C) marginally decreased the release rate of liberated platinum. The infusion solutions are compatible with the PVC infusion system and do not cause hemolysis. In conclusion, AP 5280 lyophilized product should be reconstituted and diluted to infusion concentration with D W, and administered within 8 h after preparation to ensure that less than 1.0% of the total platinum concentration is present as liberated platinum.

Acrylamides↗

PubMed2001

Compatibility and stability of the investigational polypeptide marine anticancer agent kahalalide F in infusion devices.

Kahalalide F is a novel marine-derived antitumor agent isolated from the marine mollusk Elysia rufescens, an organism living in the seas near Hawaii. The compound has shown highly selective in vitro activity against prostate tumors and phase I trials in patients with androgen independent prostate tumors incorporating a daily times five and weekly schedule have been initiated. Kahalalide F is pharmaceutically formulated as a lyophilized product containing 150 microg active substance per dosage unit. Prior to i.v. administration it is reconstituted with a solution composed of Cremophor EL, ethanol absolute and Water for Injection (CEW, 5/5/90% v/v/v) with further dilution in 0.9% w/v sodium chloride for infusion. The aim of this study was to investigate the compatibility and stability of kahalalide F with different infusion systems prior to the start of clinical trials with the compound. Due to the presence of Cremophor EL in the infusion solution, leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride infusion containers (PVC, Add-a-Flex) was found. Loss of kahalalide F as a consequence of sorption to contact surfaces was shown with an infusion container composed of low density polyethylene (LD-PE, Miniflac). We conclude that kahalalide F must be administered in a 3-h infusion in concentrations of 0.5 microg/mL to 14.7 microg/mL using an administration set consisting of a glass container and a low-extrables, DEHP-free extension set. Kahalalide F 150 microg/vial powder for infusion reconstituted with 5/5/90% v/v/v CEW is stable in the original container for at least 24 h at room temperature (+20-25 degrees C) and ambient light conditions. Infusion solutions stored in glass infusion containers at either room temperature (+20-25 degrees C, in the dark) or refrigerated conditions (+2-8 degrees C, in the dark) are stable for at least 5 days after preparation.

Absorption↗

PubMed2001

Progress in the development of alternative pharmaceutical formulations of taxanes.

The currently available taxanes paclitaxel (Taxol) and docetaxel (Taxotere) are clinically effective against advanced breast, ovarian and non-small cell lung cancer. Due to their low aqueous solubility, both taxanes posed difficulties to the pharmaceutical scientists with respect to the development of an intravenous dosage form. At present, paclitaxel is formulated in a mixture of 50:50% (v/v) Cremophor EL and dehydrated ethanol. However, this formulation vehicle is associated with a number of pharmacological, pharmacokinetic and pharmaceutical concerns amongst which serious hypersensitivity reactions. This review deals with the attempts made into the development of alternative dosage forms of paclitaxel devoid of the Cremophor EL/ethanol excipients and potential future taxane formulations.

Animals↗

PubMed2001

Development of a lyophilized parenteral pharmaceutical formulation of the investigational polypeptide marine anticancer agent kahalalide F.

Kahalalide F is a novel antitumor agent isolated from the marine mollusk Elysia rufescens; it has shown highly selective in vitro activity against androgen-independent prostate tumors. The purpose of this study was to develop a stable parenteral formulation of kahalalide F to be used in early clinical trials. Solubility and stability of kahalalide F were studied as a function of polysorbate 80 (0.1%-0.5% w/v) and citric acid monohydrate (15-15 mM) concentrations using an experimental design approach. Stabilities of kahalalide F lyophilized products containing crystalline (mannitol) or amorphous (sucrose) bulking agents were studied at +5 degrees C and +30 degrees C +/- 60% relative humidity (RH) in the dark. Lyophilized products were characterized by infrared (IR) spectroscopy and differential scanning calorimetry (DSC). Recovery studies after reconstitution of kahalalide F lyophilized product and further dilution in infusion fluid were carried out to select an optimal reconstitution vehicle. It was found that a combination of polysorbate 80 and citric acid monohydrate is necessary to solubilize kahalalide F. Lyophilized products were considerably less stable with increasing polysorbate 80 and citric acid monohydrate concentrations, with polysorbate 80 being the major effector. A combination of 0.1% w/v polysorbate 80 and 5 mM citric acid monohydrate was selected for further investigation. Lyophilized products containing sucrose as a hulking agent were more stable compared to the products containing mannitol. The glass transition temperature of the sucrose-based product was determined to be + 46 degrees C. The amorphous state of the product was confirmed by IR analysis. A solution composed of Cremophor EL, ethanol, and water for injection (5%/5%/90% v/v/v CEW, kept kahalalide F in solution after reconstitution andfurther dilution with 0.9% w/v sodium chloride (normal saline) to 1.5 microg/m. A stable lyophilized formulation was presented containing 100 microg of kahalalide F, 100 mg sucrose, 2.1 mg citric acid monohydrate, and 2mg polysorbate 80 to be reconstituted with a vehicle composed of 5%/5%/90% v/v/v CEW and to be diluted further using normal saline.

Algorithms↗

PubMed2000

In vitro biocompatibility studies with the experimental anticancer agent BIBX1382BS.

The novel anticancer agent BIBX1382BS is a representative of the human epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. BIBX1382BS, for parenteral use, is formulated pharmaceutically as a lyophilized product containing 100 mg BIBX1382BS per dosage unit. This in vitro study was performed to establish the optimal intravenous administration conditions (infusion concentration and infusion rate) for the forthcoming clinical absolute oral bioavailability study of BIBX1382BS. BIBX1382BS infusion solutions have a low pH in order to keep the substance in solution. We therefore decided to investigate the hemolytic and precipitation potential of the drug in vitro. Also, the ratio of formulation (F) solution volume and a blood simulans (B) volume necessary to reach the physiological pH, expressed as the FB-ratio, was determined in vitro. On the basis of the results obtained, it is advised to administer BIBX1382BS infusion at a concentration of 1 mg/ml and a maximum infusion rate of 10 ml/min. This article describes the in vitro biocompatibility screening program.

Antineoplastic Agents↗

PubMed2000

Pharmaceutical development of anticancer agents derived from marine sources.

The marine ecosystem is more and more acknowledged as a source of potential anticancer agents. After the identification of a potential substance several hurdles have to be overcome before a marine candidate can enter the clinic. Amongst these are the establishment of a method which ensures sufficient supply and, which is the focus of this review, the development of a clinically useful pharmaceutical formulation. General issues with respect to the pharmaceutical development of marine anticancer agents will be discussed, which will be illustrated by highlighting aspects of the pharmaceutical development and clinical use of some representative compounds.

Animals↗

PubMed1999

Compatibility and stability of aplidine, a novel marine-derived depsipeptide antitumor agent, in infusion devices, and its hemolytic and precipitation potential upon i.v. administration.

Aplidine is a novel marine-derived antitumor agent isolated from the Mediterranean tunicate Aplidium albicans. The compound is pharmaceutically formulated as a lyophilized product containing 500 microg active substance per dosage unit. Prior to i.v. administration it is reconstituted with a solution composed of Cremophor EL, ethanol absolute and Water for Injection (15/15/70% v/v/v) with further dilution in 0.9% w/v sodium chloride for infusion (normal saline). The aim of this study was to investigate the compatibility of aplidine infusion solutions with polyvinyl chloride (PVC)-containing and PVC-free administration sets, and to determine the stability of aplidine after reconstitution and further dilution in infusion solutions. Furthermore, in vitro biocompatibility studies to estimate the hemolytic and precipitation potential of aplidine infusion solutions upon i.v. administration were conducted. In this study we show that sorption of aplidine to PVC and to a lesser extent to PVC-free administration set materials occurs. Also, most probably due to the presence of Cremophor EL in the infusion solution, significant leaching of diethylhexyl phtalate (DEHP) from the PVC administration set occurs. After reconstitution and dilution the drug is stable for at least 24 and 48 h, respectively, in glass containers when stored at room temperature (20-25 degrees C) and ambient light conditions. We found that aplidine should be administered in infusion concentrations equal or above 28.8 microg/ml using a PVC-free administration set consisting of a glass container and PVC-free infusion tubing. After reconstitution it must be diluted further with normal saline within 24 h after preparation and subsequently administered to the patient within 48 h. Additionally, results from the biocompatibility studies show that neither hemolysis nor precipitation of aplidine is expected upon i.v. administration.

Antineoplastic Agents↗

PubMed1997

Alternative formulations of paclitaxel.

Paclitaxel, a novel antitumour agent, is active clinically against advanced ovarian and breast cancer and under investigation for various other cancers. One of the problems associated with the intravenous administration of paclitaxel is its low solubility in water. The current pharmaceutical formulation consists of a 1:1 (v/v) mixture of ethanol and Cremophor EL. This formulation, however, has been demonstrated to cause some severe hypersensitivity reactions. Therefore the development of a safer intravenous formulation devoid of Cremophor EL is an important investigational issue. This review deals with some of the most promising formulation alternatives.

Antineoplastic Agents, Phytogenic↗

PubMedDate not supplied

Pharmaceutical development of a parenteral lyophilized formulation of the novel antitumor agent aplidine.

Aplidine is a naturally occurring cyclic depsipeptide isolated from the Mediterranean tunicate Aplidium albicans. Aplidine displays promising in vitro and in vivo antitumor activities against various solid human tumor xenografts and is therefore developed now for clinical testing. The aim of this study was to develop a stable parenteral pharmaceutical dosage form for clinical Phase I testing. Aplidine raw material was characterized by using several chromatographic and spectrometric techniques. These experiments showed that aplidine exists as two isomers. A stability-indicating HPLC assay was developed. Solubility testing showed that aplidine exhibits very poor aqueous solubility. Because solubilized aplidine showed substantial degradation under heat and light stress testing conditions, it was decided to develop a lyophilized dosage form. Freeze-drying was carried out with a 500 micrograms/mL solution of aplidine in 40% (v/v) tert-butanol in Water for Injection (WfI) containing 25 mg/mL D-mannitol as a bulking agent. Differential scanning calorimetry was applied to determine the optimal freeze-drying cycle parameters. The prototype, containing 500 micrograms aplidine and 25 mg D-mannitol per vial, was found to be the optimal formulation in terms of solubility, length of lyophilization cycle, and dosage requirements in the forthcoming Phase I clinical studies. Quality control of the freeze-dried formulation demonstrates that the manufacturing process does not affect the integrity of aplidine. The optimal reconstitution solution was found to be 15/15/70% (v/v/v) Cremophor EL/ethanol/WfI (CEW). Both reconstituted product and dilutions of the reconstituted product with normal saline (up to 1:100 v/v) appeared to be stable for at least 24 hours after preparation. Shelf-life data, available thus far, show that the lyophilized formulation is stable for at least 1 year when stored at +2-8 degrees C in the dark.

Antineoplastic Agents↗

PubMedDate not supplied

In vitro hemolysis and buffer capacity studies with the novel marine anticancer agent kahalalide F and its reconstitution vehicle cremophor EL/ethanol.

An in vitro biocompatibility study was performed with the pharmaceutical formulation of the investigational, marine-derived anticancer agent kahalalide F developed for early clinical studies. The pharmaceutical formulation consists of a lyophilized product containing 150 micrograms kahalalide F, 3 mg citric acid, 3 mg polysorbate 80, and 150 mg of sucrose per dosage unit, to be reconstituted with 3 mL of a mixture composed of Cremophor EL, ethanol, and water (5/5/90% v/v/v), resulting in a solution of pH 3 and to be further diluted in normal saline for infusion. The reconstituted product, infusion solutions, and Cremophor/ethanol (CE) vehicle were tested for hemolytic potential and buffer capacity. No significant hemolysis due to the kahalalide F formulation as well as the CE vehicle was found using both a static and dynamic test model. FB-ratio's (ratio of formulation solution (F) and volume of blood simulant (B) necessary to maintain physiological pH) as a measure of the buffer capacity of the kahalalide F infusion solutions examined indicated that no vascular irritation due to pH effects is expected in the intended administration schedule in the forthcoming Phase I study.

Animals↗