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At least 19 recordsLinked to original sources
PubMed1981

Determination of delta 9-tetrahydrocannabinol in pharmaceutical vehicles by high-performance liquid chromatography.

A procedure for the determination of delta 9-tetrahydrocannabinol (delta 9-THC) in the presence of its degradation products in pharmaceutical vehicles by high-performance liquid chromatography (HPLC) is described. The method compares favorably with a standard gas-liquid chromatographic procedure used for the analysis of delta 9-THC in sesame oil USP. The HPLC method is suitable for quantitating delta 9-THC in the presence of several pharmaceutical vehicles and excipients including: sesame oil USP, polyvinylpyrrolidone, Emulphor EL620 and Cremophor EL. Extractions are not required and samples require little preparation. Only the addition of an internal standard in an appropriate solvent is necessary before injection. The procedure has been applied to stability studies of delta 9-THC in various pharmaceutical vehicles.

Chromatography, Gas↗
PubMed1996

Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL.

Studies in humans and mice have demonstrated a nonlinear pharmacokinetic behavior of paclitaxel. Because of its poor water solubility, the drug is formulated in a mixture of Cremophor EL and ethanol (1:1, v/v; Taxol). We hypothesized that the substantial amounts of concurrently administered Cremophor EL on the disposition of paclitaxel, female FVB mice received paclitazel by i.v. injection at does levels of 2, 10, and 20 mg/kg by appropriate (standard) dilution of the commercially available formulation of paclitaxel (Taxol) with saline. The drug was also given at 2 mg/kg with supplemental Cremophor EL-ethanol to achieve the same amount of vehicle as by standard administration of 10 mg/kg. Furthermore, paclitaxel formulations in Tween 80-ethanol (1:1, v/v) and dimethylacetamide were tested. Plasma samples were collected between 5 min and 48 h, and tissue specimens were sampled at 1, 4, and 8 h after drug administration. Paclitaxel and metabolites were quantified by high-performance liquid chromatography. Cremophor EL levels were determined by a novel high-performance liquid chromatography procedure. For comparative reasons, Cremophor EL was also assayed in plasma samples from three patients receiving a 3-h i.v. infusion of 175 mg/m2 of paclitaxel. A marked nonlinear pharmacokinetic behavior of paclitaxel was observed when the drug was formulated in Cremophor EL-ethanol. The clearance of 2.37 L/h/kg at 2 mg/kg was reduced to 0.33 and 0.15 L/h/kg at 10 and 20 mg/kg, respectively. When 2 mg/kg were given with an amount of Cremophor EL-ethanol matching that of the 10-mg/kg dose level, the clearance was 0.56 L/h/kg. If administered at 10 mg/kg in Tween 80-ethanol or at 2 and 10 mg/kg in dimethylacetamide, the clearances were 2.66, 2.57, and 2.62 L/h/kg, respectively. Despite the fact that much higher plasma levels of paclitaxel are reached when given in the Cremophor EL-ethanol formulation, the tissue levels were essentially similar with all tested drug preparations. The Cremophor EL levels in patients were in the same order of magnitude as those observed in mice after administration of 2 and 10 mg/kg. These data demonstrate that Cremophor EL has a profound effect on the pharmacokinetics of paclitaxel im mice. Because Cremophor EL also contributes substantially to the nonlinear pharmacokinetic behavior of paclitaxel observed in humans.

Animals↗
PubMed1975

Absolute concentrations of dithranol and triacetyl-dithranol in the skin layers after local treatment: in vivo investigations with four different types of pharmaceutical vehicles.

The pharmacokinetics of dithranol (anthralin) and its triacetate were investigated by employing a method which determines the quantity of the drug that penetrated into single layers of the human skin in vivo. For this purpose, tritium-labeled dithranol or triacetyl-dithranol was incorporated into four different ointments. The ointments were applied to the skin and biopsies were taken after 10, 30, 100, and 1000 min. The horny layer was removed before biopsy by Scotch tape stripping. The biopsies were sliced horizontally and the tritium determined in each sample. Dithranol as well as its triacetate penetrated best from more hydropholic ointments (Vaseline and aqueous wool-wax-alcohol ointment). From hydrophilic ointments (polyethylene glycol ointment and aqueous hydrophilic cream), only poor penetration was observed. Dithranol penetrated in far greater amounts than its triacetate, and the two compounds revealed fundamentally different penetration kinetics in epidermis and dermis. The data indicate that the triacetate was not split into its parent compound, dithranol, in substantial quantity, as the data obtained show the criteria of two independent substances.

Adult↗
PubMedDate not supplied

Use of affinity capillary electrophoresis for characterizing pharmaceutical colloidal vehicle systems thermodynamically.

This review offers a detailed discussion of the interaction between pharmaceutical compounds and vehicles using the affinity capillary electrophoresis and the microemulsion electrokinetic chromatography. Partition coefficients of drugs were calculated between a micelle and an aqueous phases from the measurement of the migration time, provided the critical micelle concentration and the phase ratio are known. Thermodynamic quantities such as enthalpy and entropy changes of micellar solubilization were calculated from the temperature dependence of the partition coefficients. Partial specific volumes were measured using dynamic light scattering. The logarithm of the partition coefficients and the capacity factor in the micellar system were correlated with the logarithm of the n-octanol/water partition coefficients.

Colloids↗
PubMed2002

Preclinical evaluation of alternative pharmaceutical delivery vehicles for paclitaxel.

New solubilizers, including Sorporol 230, Sorporol 120Ex, Aceporol 345-T, Aceporol 460 and Riciporol 335, as potential new delivery vehicles for paclitaxel were investigated, since recent studies have shown that the paclitaxel delivery vehicle Cremophor EL significantly alters the pharmacokinetics of paclitaxel. Cremophor EL and Tween 80 were used as a reference. As in the case of Cremophor EL, alteration of blood distribution of paclitaxel occurred in the presence of all tested vehicles. Also, no differences in the affinity of paclitaxel for the tested solubilizers was found during equilibrium dialysis experiments. The different vehicles could be distinguished by a different rate of esterase-mediated breakdown, which was correlated with the fatty acid content of the solubilizers. The activation of the complement cascade was less pronounced for all solubilizers, except Riciporol 335, compared to Cremophor EL. The strategies presented here provide the possibility to rapidly screen future candidate delivery vehicles with optimal characteristics for use as a solubilizer in clinical formulations of paclitaxel or other poorly water-soluble drugs.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Influence of Cremophor EL on the quantification of paclitaxel in plasma using high-performance liquid chromatography with solid-phase extraction as sample pretreatment.

For the quantitative determination of paclitaxel in human plasma reversed-phase high-performance liquid chromatographic (HPLC) methods with solid-phase extraction (SPE) as sample pretreatment procedure are frequently used. Recovery problems arose during the quantification of paclitaxel in plasma samples of patients. The major problems were a large batch-to-batch difference in performance of the SPE columns and the effects of the pharmaceutical vehicle Cremophor EL on the performance of the SPE. Cremophor EL concentrations exceeding 1.0% (v/v) had a great impact on the absolute recovery of paclitaxel from human plasma with the SPE procedure. The recoveries decreased approximately 10 to 40% depending on the quality of the batch SPE columns. The problems are avoided by using 2'-methylpaclitaxel as the internal standard. This study points out the importance of including the effects of a pharmaceutical vehicle, like Cremophor EL, in the validation programme of a bioanalytical assay and the use of an internal standard in HPLC paclitaxel assays preceded by SPE as sample pretreatment procedure.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Influence of pharmaceutical gel vehicles containing oleic acid/sodium oleate combinations on hairless mouse skin, a histological evaluation.

Aqueous gel preparations containing oleic acid/sodium oleate combinations were applied three times daily to hairless mice (CD1 strain). Six groups of animals (n = 9 or n = 10) were treated topically with six experimental vehicles containing 2, 3 and 4.5% oleic acid (OA) at two different pH values, 7.3 and 7.7. Sodium lauryl sulfate (5%) in a similar gel preparation was used as the positive control (n = 5), while untreated animals were used as the negative control (n = 6). After three treatment days, the skin samples were collected and processed for histological evaluation. It was seen that the severity and frequency of histological changes in the skin treated with OA-containing vehicles were directly correlated with increased pH/ionization (i.e. decreased OA/sodium oleate ratio) and with overall OA concentration.

Animals↗
PubMed1976

Hemolysis of erythrocytes by primary pharmacologic agents, part 2: influence of the vehicle.

The hemolytic activity in vitro of chlorpromazine hydrochloride, chlordiazepoxide hydrochloride and brompheniramine maleate was examined using various intravenous solutions as the vehicle. Fresh human blood was employed in the investigation which used a colorimetric method for the determination of hemolysis. Prior to the examination of the hemolytic activity of each drug in the various vehicles, the vehicles themselves were examined for their ability to protect erythrocytes from hemolysis. Little to no hemolysis occurred in normal saline solution (the standard), dextrose 2.5% in normal saline, dextrose 5% in normal saline, dextrose 10% in normal saline, and lactated Ringer's injection. Low levels of hemolysis occurred in dextrose 5% in water, invert sugar 10% in water, and M/6 sodium lactate in water. High levels of hemolysis occurred when red blood cells were suspended in dextrose 2.5% in water. Invert sugar 10% in normal saline and fructose 10% in water caused red cell denaturation resulting in brown cells and hemolysate rather than the characteristic red color. This denaturation was attributed to the hydrogen ion concentration of these two solutions, both having pH values less than 4.0. Vehicles of dextrose in saline, dextrose in water, lactated Ringer's, and invert sugar in water reduced the level of drug-induced hemolysis for the drugs tested compared to that which occurred in normal saline solution. The reduction of hemolysis was greater as the tonicity of the vehicle used was increased. It was concluded that the pharmaceutical vehicles examined have an influence on the cellular effects of drugs which only affects the erythrocyte but which could potentially affect the drugs' distribution from the blood to the sites of their action.

Brompheniramine↗
PubMed1997

Differential modulation of cisplatin accumulation in leukocytes and tumor cell lines by the paclitaxel vehicle Cremophor EL.

BACKGROUND: Several clinical studies have shown that polychemotherapy with the taxanes paclitaxel or docetaxel preceded or followed by cisplatin is associated with important schedule-dependent differences in toxicities, such as leukocytopenia. In general, the pharmacokinetics of both drugs during the combined treatment are unaltered, suggesting that a pharmacodynamic interaction might have occurred. MATERIALS AND METHODS: In order to gain insight into this pharmacologic interaction, we performed in vitro drug accumulation studies using peripheral blood leukocytes and a panel of tumor and non-malignant cell lines with paclitaxel and docetaxel, as well as with their respective formulation vehicles Cremophor EL and Tween 80. RESULTS: Our results show a significant reduction in the intracellular cisplatin concentration in leukocytes of up to 42% in the presence of Cremophor EL and Tween 80 as compared to the control. This pharmacodynamic interaction of these surfactants with cisplatin seems to be specific for haematopoietic cells, and does not occur in solid tumor cells. CONCLUSION: The present data suggest that the pharmaceutical vehicles Cremophor EL and Tween 80 might contribute to the reduced cisplatin-associated myelotoxicity observed in the clinical combination chemotherapy studies with paclitaxel and docetaxel.

Antineoplastic Agents↗
PubMed2005

First report on the efficacy of l-alanine-based in situ-forming implants for the long-term parenteral delivery of drugs.

The recent advent of biotechnologies has led to the development of labile macromolecular therapeutic agents that require complex formulations for their efficient administration. This work reports a novel concept for the systemic, sustained delivery of such agents. The proposed approach is based on the spontaneous self-assembly of low-molecular weight amphiphilic amino acid derivatives in a hydrophobic pharmaceutical vehicle. The injectable, in situ-forming organogels were obtained by mixing N-stearoyl l-alanine (m)ethyl esters with a vegetable oil and a biocompatible hydrophilic solvent. The gels' in vivo-delivering properties were evaluated in rats with leuprolide, a luteinizing hormone-releasing hormone agonist used in prostate cancer, endometriosis and precocious puberty treatment. Following subcutaneous injection, the gels degraded and gradually released leuprolide for 14 to 25 days. Drug release was accompanied by sustained castration lasting up to 50 days, as assessed by testosterone levels. This study demonstrates that in situ-forming implants based on l-alanine derivatives represent a novel injectable platform for the controlled delivery of hydrophilic compounds, which is simpler than currently available implant and microsphere technologies.

Alanine↗
PubMed1999

Phase II trial of topically applied miltefosine solution in patients with skin-metastasized breast cancer.

Skin deposits from breast cancer can present serious therapeutic problems, especially when resistant to conventional therapy. Topical application of a cytotoxic drug may represent an attractive new treatment modality devoid of major systemic toxicity. Miltefosine was selected because of its efficacy in breast cancer models. A mixture of alkylated glycerols of various chain lengths and water was used as the pharmaceutical vehicle to dissolve and to further facilitate tissue penetration of miltefosine. In our Institute a phase II study was performed to determine the efficacy and tolerability of topically applied miltefosine in patients with cutaneous metastases from breast cancer. Thirty-three patients in total entered the trial. A 6% miltefosine solution was applied once daily in the first week and twice daily in the following weeks. The planned minimum treatment duration was 8 weeks. We found an overall response rate of 43% for 30 evaluable patients, composed of 23% complete response and 20% partial response. The median response duration was 18 weeks, range 8-68. Toxicity consisted mainly of localized skin reactions, which could be controlled by a paraffin-based skin cream and, where appropriate, by dose modification. No systemic toxicities were observed. We conclude that topical miltefosine is an effective treatment modality in patients with skin metastases from breast cancer.

Administration, Topical↗