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PubMed2001

Ointment is evenly spread on the skin, in contrast to creams and solutions.

BACKGROUND: The efficacy of topical therapy depends on the patient spreading the topical drug in an even layer to give a standard dose. Ointments are believed to be more effective than creams and solutions. OBJECTIVES: To compare the application and spreading of four different pharmaceutical vehicles. METHODS: Twenty-nine healthy volunteers applied a fixed amount (0.1 g) of solution (S), ointment (O), cream (C) and low-viscosity cream (LVC) to the abdominal skin. Area of spread, skin surface lipids (dependent on formulation) and changes in skin surface temperature (cooling due to evaporation of formulation water/alcohol) were measured. RESULTS: Area of spread: O = C = LVC = S. Skin surface lipids: O > C > LVC > S. Difference in skin surface lipids between centre and periphery: O < C = LVC = S. Cooling: O < C = LVC < S. CONCLUSIONS: The four formulations were spread to similar areas. The ointment was spread evenly in the treated area while the other formulations were unevenly spread, with a lower dose in the periphery. Creams and solutions have disadvantages as vehicles, as rapid evaporation of formulation water/alcohol, measured as cooling, influences spread, resulting in an uneven topical dose within the treated area. In contrast, ointment is evenly spread and is thus a more appropriate formulation. Patients should be instructed to apply creams and solutions to multiple sites and to spread them quickly.

Administration, Topical↗
PubMed1981

2,5-Diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone II: Isolation and characterization of degradation products.

A direct high-performance liquid chromatographic (HPLC) method was applied to monitor 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (I) and its degradation products in pharmaceutical vehicles at 25 +/- 0.1 degrees. At the optimal pH for stability of I, an increase in buffer concentration [phosphate and tris(hydroxymethyl)-aminomethane] or ionic strength accelerated degradation. The reaction rate in the solutions studied followed pseudo-first-order kinetics. Degradation products were characterized by mass spectrometry after isolation by semipreparative HPLC. Different degradation pathways prevailed in acidic and basic media. The acid-catalyzed reaction resulted in consecutive aziridine ring opening, while the base-catalyzed reaction led to nucleophilic displacement of thie aziridine ring(s).

Antineoplastic Agents↗
PubMed1998

Quantitation of Cremophor EL in human plasma samples using a colorimetric dye-binding microassay.

This paper describes an analytical procedure for the quantitative determination of the pharmaceutical vehicle Cremophor EL in human plasma samples. The procedure is based on rapid binding of Coomassie brilliant blue G-250 to Cremophor EL following plasma protein precipitation with acetonitrile and analyte extraction with n-butylchloride. The binding of the dye to Cremophor EL causes a shift in the absorption maximum from 465 to 624 nm, which is monitored using an automated microplate-absorbance reader. The assay permits estimation of Cremophor EL concentrations in the range 0.05-1.00% (v/v) in 50 microL of human plasma, with percentage deviation and precision of < or = 12 and < or = 15%, respectively. The assay was subsequently used to measure Cremophor EL concentrations in plasma samples in support of a project to develop a pharmacokinetic model for this compound in patients receiving paclitaxel.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Drug interactions in oncology.

Drug interactions are an ongoing concern in treatment of cancer, especially when cytotoxic drugs are being used. However, the clinical relevance of these interactions is not always investigated. Drug interactions can be pharmaceutical, pharmacokinetic, or pharmacodynamic. They can also be wanted (eg, use of ciclosporin to enhance the oral bioavailability of paclitaxel); unwanted (eg, combination of the antiviral agent sorivudine and oral fluorouracil analogues can lead to fatal complications); between cytotoxic drugs, cytotoxic drugs and non-cytotoxic drugs; or with pharmaceutical vehicles. Potential interactions between anticancer drugs and over-the-counter or alternative medicines and herbs should not be underestimated. More attention should be given to the recognition of potential drug interactions in the preclinical and early clinical development phase of a new anticancer drug. Here, we provide a comprehensive overview of drug interactions, with selected examples.

Antineoplastic Agents↗
PubMed1991

Cosolvency of dimethyl isosorbide for steroid solubility.

Dimethyl isosorbide (DMI), which is currently under investigation for its potential use as a pharmaceutical vehicle and drug permeation enhancer, is a water-miscible liquid with relatively low viscosity. The solubilization behavior of DMI as a cosolvent for nonpolar drugs was characterized via dielectric constant measurements of binary solvent systems containing DMI and either water, propylene glycol (PG), or polyethylene glycol (PEG). Evidence from the dielectric constant profiles and NMR studies suggest that DMI undergoes complexation with water and PG, but not with PEG, through hydrogen bonding interactions. The solvent complexation exhibited a major effect on the solubilities of prednisone, dexamethasone, and prednisolone in the mixed solvent systems. Maximum solubility of each drug was found to occur near a DMI/water or DMI/PG concentration ratio of 1:2. In the DMI-PEG mixed system, while there is no apparent interaction between DMI and PEG molecules, the solubility of prednisone was found to increase with decreasing dielectric constant.

Dexamethasone↗
PubMed2000

Milk depletion of dicloxacillin residues in cows and sheep following intramammary administration.

The excretion rate of dicloxacillin from milk was studied after intramammary administration of a suspension of the drug active in vegetable oil. Eight cows and eight sheep, four of each group in low and four in high milk production, were dosed with 200 mg dicloxacillin/quarter in cows and 100 mg dicloxacillin/quarter in sheep, three times at 12 h intervals. The dicloxacillin concentrations in milk were quantified by high performance liquid chromatography (HPLC). In cows, time until dicloxacillin was undetectable was 48 h and no difference was observed between the groups. In sheep, dicloxacillin was undetectable 72 h and 84 h after the treatment in low and in high milk production groups, respectively. The implications of several factors affecting the possible milk withdrawal period were studied. The results indicated that the pharmaceutical vehicle and the coefficient of lipid solubility exerted major effects on depletion time.

Animals↗
PubMed2001

Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel.

Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m(2), as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m(2), at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.

Adult↗
PubMedDate not supplied

Cyclosporine-induced anaphylaxis.

OBJECTIVE: To describe a case of an anaphylactic reaction after first ingestion of oral cyclosporine capsules (Neoral). CASE SUMMARY: A 73-year-old white woman was admitted for the treatment of metastatic breast carcinoma with an experimental oral paclitaxel solution in combination with cyclosporine capsules. After ingestion of the cyclosporine capsules, the patient collapsed within one hour. She initially experienced severe hypotension and bradycardia. After a few minutes, she developed severe tachycardia, dyspnea, and decreased consciousness. Administration of epinephrine, dexamethasone, clemastine, oxygen, and gelofusine (succinylated gelatin 4% in NaCl 0.9%) infusion resulted in complete recovery after several hours. The planned oral paclitaxel administration was canceled. Intravenous paclitaxel was given the next day, preceded by standard premedication with dexamethasone, clemastine, and cimetidine, without complications. DISCUSSION: To our knowledge, this is the first report in the literature of an anaphylactic reaction after oral ingestion of cyclosporine capsules. Earlier reports of anaphylaxis concerned intravenous cyclosporine or oral solutions of cyclosporine (both Sandimmune). These anaphylactic reactions were considered to be due to the pharmaceutical vehicle Cremophor EL or related substances, which are well-known causes of anaphylaxis. The capsules used in this case contain the Cremophor EL-related polyoxyl 40 hydrogenated castor oil as a base; our patient's anaphylactic shock may have been due to this substance. CONCLUSIONS: In addition to earlier reports about anaphylactic reactions after administration of an intravenous or oral solution of cyclosporine, this case shows that anaphylactic shock can occur after ingestion of cyclosporine capsules.

Administration, Oral↗
PubMed1999

Coadministration of oral cyclosporin A enables oral therapy with paclitaxel.

i.v. paclitaxel is inconvenient and associated with significant and poorly predictable side effects largely due to the pharmaceutical vehicle Cremophor EL. Oral administration may be attractive because it may circumvent the use of Cremophor EL. However, paclitaxel, as well as many other commonly applied drugs, has poor bioavailability caused by high affinity for the mdrl P-glycoprotein drug efflux pump, which is abundantly present in the gastrointestinal tract. Consequently, inhibition of P-glycoprotein by oral cyclosporin A (CsA) should increase systemic exposure of oral paclitaxel to therapeutic levels. A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral paclitaxel of 60 mg/m2 with or without 15 mg/kg CsA and with i.v. paclitaxel in subsequent courses. The pharmacokinetics of paclitaxel and its major metabolites were determined during the first two courses. In addition, levels of CsA, Cremophor EL, and ethanol were measured. Bioavailability of oral paclitaxel in combination with CsA was 8-fold higher than after oral paclitaxel alone (P<0.001). Therapeutic concentrations were achieved on average during 7.4 h, which is comparable with an equivalent i.v. dose. The oral combination was well tolerated and did not induce gastrointestinal toxicity or myelosuppression. Cremophor EL plasma levels after oral drug administration were undetectable. In conclusion, coadministration of oral CsA increased the systemic exposure of oral paclitaxel from negligible to therapeutic levels. The combination enables treatment with oral paclitaxel. Undetectable Cremophor EL levels after oral administration may have a very beneficial influence on the safety of the treatment with oral paclitaxel.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Effect of various vehicles on diclofenac sodium and indomethacin pharmaceutical availability.

The aim of the study was to determine the pharmaceutical availability of various ointment systems containing antirheumatic substances and to establish an optimal system for cutaneous application. Topical application permits elimination or at least reduction of side effects connected with oral administration. Three systems were evaluated: emulsion W/O (ointment), emulsion O/W (cream) and gel, all of them containing diclofenac sodium or indomethacin. The investigated systems are characterized by proper rheological parameters and long physicochemical stability. Studies on diclofenac and indomethacin pharmaceutical availability show a good release of the substances from cream and hydrogel bases, but a very poor release from the ointment base.

Biological Availability↗
PubMed1999

A novel percolation method for determining solubilities of pharmaceutical agents in semisolid vehicles.

A novel technique was developed to quantify the solubility of pharmaceutical actives in semisolid formulations. Ointments and emulsions of increasing potencies were sheared to disrupt their internal microcrystalline networks. These sheared materials were held in taut cheesecloth pouches, and the bleed that percolated out was collected and assayed for active potency. The solute concentration in the bleed was proportional to the concentration of the solute in solution in the formulation. Plots of bleed active potency against total formulation potency rose linearly to the point of formulation saturation. Above saturation, bleed potencies remained constant, producing plateaus on the solubility plots. The formulation potency at the onset of plateau quantified the saturation solubility of the active in each formulation. This technique was demonstrated with butylparaben in three ointment bases, and with hydrocortisone in an emulsion formulation. The solubility estimates thus obtained were confirmed experimentally by optical microscopy. This novel technique permits saturation solubilities to be determined for a range of semisolid formulations, with much greater accuracy than was previously possible.

Anti-Inflammatory Agents↗
PubMed1987

Chimeric peptides as a vehicle for peptide pharmaceutical delivery through the blood-brain barrier.

A new strategy for peptide delivery through the brain capillary wall, i.e., the blood-brain barrier (BBB), is the synthesis of chimeric peptides which are formed by the covalent coupling of a non-transportable peptide (e.g., beta-endorphin) to a transportable peptide that undergoes receptor- or absorptive-mediated transcytosis at the BBB. beta-endorphin was covalently coupled via disulfide linkage to cationized albumin (pI greater than or equal to 9) which, owing to it's highly basic charge, undergoes rapid absorptive-mediated transport into brain from blood. The [3H]labeled beta-endorphin-cationized albumin chimera was rapidly taken up by isolated brain capillaries in vitro and by rat brain in vivo; conversely, the BBB uptake of native [3H]beta-endorphin was negligible. The synthesis of chimeric peptides is a new strategy for solving the problem of peptide delivery through the BBB.

Animals↗
PubMed1990

Patient tolerance study of topical chlorhexidine diphosphanilate: a new topical agent for burns.

Effective topical antimicrobial agents decrease infection and mortality in burn patients. Chlorhexidine phosphanilate (CHP), a new broad-spectrum antimicrobial agent, has been evaluated as a topical burn wound dressing in cream form, but preliminary clinical trials reported that it was painful upon application. This study compared various concentrations of CHP to determine if a tolerable concentration could be identified with retention of antimicrobial efficacy. Twenty-nine burn patients, each with two similar burns which could be separately treated, were given pairs of treatments at successive 12-h intervals over a 3-day period. One burn site was treated with each of four different CHP concentrations, from 0.25 per cent to 2 per cent, their vehicle, and 1 per cent silver sulphadiazine (AgSD) cream, an antimicrobial agent frequently used for topical treatment of burn wounds. The other site was always treated with AgSD cream. There was a direct relationship between CHP concentration and patients' ratings of pain on an analogue scale. The 0.25 per cent CHP cream was closest to AgSD in pain tolerance; however, none of the treatments differed statistically from AgSD or from each other. In addition, ease of application of CHP creams was less satisfactory than that of AgSD. It was concluded that formulations at or below 0.5 per cent CHP may prove acceptable for wound care, but the vehicle system needs pharmaceutical improvement to render it more tolerable and easier to use.

Administration, Topical↗
PubMedDate not supplied

Comparison of the relative toxicity of travoprost 0.004% without benzalkonium chloride and latanoprost 0.005% in an immortalized human cornea epithelial cell culture system.

The purpose of this study was to compare the relative toxicity of a new topical ophthalmic glaucoma medication, travoprost 0.004% without benzalkonium chloride (BAK), with that of commercially available latanoprost 0.005% (preserved with 0.02% BAK) in immortalized human corneal epithelial cells (HCEs). Tissue culture plates (96 well) containing HCEs were divided into 6 groups. Two groups served as negative controls (70% methanol and gentamicin). Another 2 groups--1 in corneal epithelial culture media and the other in a hydroxypropyl (HP)-Guargellable lubricant eyedrop--served as live controls. The travoprost 0.004% without BAK and latanoprost 0.005% groups were exposed to 100 microL of the undiluted solutions. Cells were incubated for 25 min at 37 degree C. A live/dead assay was used to measure the effects of travoprost without BAK and of latanoprost on HCEs compared to 70% methanol and culture medium. Between the 2 glaucoma medications tested, travoprost 0.004% preserved without BAK showed significantly less toxicity on HCEs than did latanoprost 0.005%. This difference may have ramifications in terms of tolerability for patients who use these topical glaucoma drugs on a long-term basis.

Antihypertensive Agents↗
PubMed1985

Controlled release technology for the control of helminths in ruminants.

Release rates from controlled release devices are determined by the device itself and thus are accurate, reproducible and predictable, whereas in general, prolonged or slow release systems are sensitive to environmental conditions. Diffusion and dissolution are the principal means of achieving controlled release. A diffusion system is specific for the active ingredient and release rate decreases proportionately to the square root of time because of a decreasing concentration gradient or an increasing diffusion path. In dissolution systems, the choice of matrix determines the rate of dissolution and release rates are linearly related to the area of dissolution which can be maintained constant. Consequently, this system has general application, a sharp cut-off point and can be used for more than one ingredient simulatenously. Potential disadvantages of controlled release technology centre on unacceptable tissue residues and parasite resistance to the chemicals used. Advantages include, the ability to programme the release of compounds to achieve specific effects for various periods, decreasing the frequency of dosage and increasing the choice of compounds for the control of parasitic infections. Sufficient epidemiological information should be available before controlled release technology is implemented. Existing anthelmintics and control strategies can be used to achieve an enhanced, but expected result, e.g., prolonged reduction in pasture contamination to protect both ewes and lambs. In future it should be possible to devise compounds and strategies appropriate to the unique features of controlled release technology, e.g., compounds which interrupt or inhibit the growth and development of parasites. Environmental impact should be low because of the specific effect and low dosage of the chemical used.

Animals↗