Efficiency of Ipratropium Bromide and Albuterol Deposition in the Lung Delivered via a Soft Mist Inhaler or Chlorofluorocarbon Metered-Dose Inhaler.

The propellant-free Combivent Respimat Soft Mist Inhaler (CVT-R) was developed to replace the chlorofluorocarbon-propelled Combivent metered-dose inhaler (CVT-MDI). This steady-state pharmacokinetic (PK) substudy evaluated drug lung-delivery efficiency, using data from two phase III safety and efficacy trials. PK parameters were obtained from well-controlled population PK analyses. Area under the plasma concentration-time curve (AUC), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) showed systemic exposure to ipratropium bromide and albuterol delivered via the CVT-R was proportional to ex-mouthpiece delivered dose. Although the labeled dose of ipratropium bromide in the CVT-R was half that in the CVT-MDI, the systemic exposure was comparable. No PK interaction for the ipratropium bromide and albuterol Respimat drug components was demonstrated. Ipratropium bromide alone resulted in similar exposure to the combination of ipratropium bromide and albuterol. These results show that CVT-R delivers drug more efficiently to the lung than CVT-MDI.

Efficiency of a New Mesh-Type Nebulizer (NE-SM1 NEPLUS) for Intrapulmonary Delivery of Ipratropium Bromide in Surgical Patients.

This study was aimed to evaluate the efficiency of a new mesh-type nebulizer for the intrapulmonary delivery of ipratropium bromide in surgical patients under mechanical ventilation. A total of 20 patients were randomly allocated to receive 0.5 mg ipratropium bromide using either a control (Pariboy SX, Pari, Co., Starnberg, Germany, n = 10) or test (NE-SM1 NEPLUS, KTMED INC., Seoul, Korea, n = 10) nebulizer during general anaesthesia. Ipratropium bromide was nebulized continuously for 20 min. in each group. Plasma concentrations of ipratropium bromide were obtained from blood samples at preset intervals. Non-compartmental analysis of ipratropium bromide was performed to compare the efficiency of pulmonary drug delivery in both nebulizers. Population pharmacokinetic analysis of ipratropium bromide was performed. Additionally, the noise level during the nebulizer operation and the aerosol particle size for each device were measured. The dose-normalized AUC(last) was 0.10 min/L for both nebulizers. The pharmacokinetics of nebulized ipratropium bromide can be described best by a one-compartment model with first-order absorption. The apparent volume of distribution and metabolic clearance were 1340 L and 6.78 L/min, respectively. Type of nebulizer was a significant covariate for absorption rate constant. The equivalent sound level and median aerosol particle diameter were 35.0 dB and 4.52 µm for the test nebulizer, and 60.2 dB and 3.85 µm for the control nebulizer, respectively. From the standpoint of the dose-normalized AUC(last) , a new vibrating mesh-type nebulizer shows similar performance in the intrapulmonary delivery of ipratropium bromide to that of a jet-type nebulizer in surgical patients.

Quantitative analysis of a quaternary ammonium drug: ipratropium bromide by LC/ESI-MS(n) in horse plasma and urine.

A quantitative method, using LC/ESI-MS(n) with a quadrupole linear ion trap mass analyzer, has been developed for the analysis of ipratropium cation in horse plasma and urine. The method applies solid-phase extraction with WCX cartridges for plasma and MM2 cartridges for urine, prior to analysis by LC/ESI-MS(n). The efficiency of extraction combined with the sensitivity and the selectivity of MS(n) allows for the quantification of ipratropium cation at picogram per milliliter levels. The analytical capabilities of the method have been successfully checked by the quantitative analysis of ipratropium cation in post-administration samples collected from horses treated by nebulization.

Simultaneous determination of ipratropium and salbutamol in rat plasma by LC-MS/MS and its application to a pharmacokinetic study.

A novel, sensitive and specific LC-MS/MS method with silica-based solid-phase extraction was developed for simultaneous determination of ipratropium (IPR) and salbutamol (SAL) in rat plasma. Chromatographic separation was achieved on a Shiseido Capcell Pak CR column (SCX:C(18)=1:4, 150 mm × 2.0 mm, 5 µm) with a mobile phase consisting of methanol/water (85:15, v/v) containing 20 mmol/L ammonium formate and 0.1% formic acid at a flow rate of 0.3 mL/min. A tandem mass spectrometric detection with an electrospray ionization (ESI) interface was conducted via multiple reaction monitoring (MRM) under positive ionization mode. This method was validated in terms of specificity, linearity, accuracy (within ±115.4%), intra- and inter-day precision (<11.4%) over the concentration range of 8-1612 pg/mL for IPR and 50-10,000 pg/mL for SAL. In addition, stability and matrix effects of IPR and SAL in plasma were evaluated. This method has been successfully applied to the pharmacokinetic study of compound ipratropium bromide aerosol mainly containing ipratropium bromide (IB) and salbutamol sulphate (SS) after inhalation in rats.

LC/MS/MS analysis of quaternary ammonium drugs and herbicides in whole blood.

Quaternary ammonium drugs (atracurium, bretylium, edrophonium, ipratropium, mivacurium, neostigmine, pancuronium and rocuronium) and herbicides (difenzoquat, diquat and paraquat) in human whole blood were analysed by LC/MS/MS with positive electrospray ionisation (ESI), following extraction with Bond Elut LRC-CBA cartridges. Internal standards were benzyldimethylphenylammonium chloride monohydrate and ethyl viologen for drug and herbicide analysis, respectively. Ion-pair chromatography used heptafluorobutyric acid (15 mM)-ammonium formate (20 mM) buffer adjusted to pH 3.30 with formic acid and a linear gradient from 5 to 90% methanol run over 18 min. Recoveries ranged from 79.7 to 105.1%, detection limits were between 3.6 and 20.4 ng/ml and the intra- and inter-day precisions were less than 18.6% at a concentration of 10 ng/ml. The method was applied to a case of accidental paraquat poisoning in which the concentration of paraquat in blood was 0.64 mg/l, which is within the range associated with fatal paraquat poisoning.

Plasma kinetics of atropine and ipratropium in rats after different routes of administration evaluated by a radioreceptor assay.

Plasma kinetics of atropine and ipratropium was assessed in rat after i.v. (10 mg/kg), oral and i.p. (50 mg/kg) administration by a radioreceptor assay (RRA). The volume of the central compartment and the clearance of both drugs were very similar (about 3 L/kg and 3.5 L/h/kg respectively) while the steady state volume of distribution and the terminal half-life of atropine were higher than those of ipratropium. After i.p. administration the kinetics of ipratropium was very different from what was expected after the i.v. experiment.

Plasma terbutaline levels in nebulisation treatment of acute asthma.

A study was made of the effects of inhaling 5 mg of terbutaline and 0.5 mg of ipratropium bromide in 11 patients arriving at our emergency room with acute asthma (FEV1 less than or equal to 50% of the predicted). Measurable plasma levels of terbutaline before treatment were found in all patients who reported having taken oral terbutaline (mean value 30 nmol/l, range 11-89). A significant correlation was found between the reported terbutaline medication and the measured terbutaline plasma concentration (p less than 0.01). Plasma terbutaline had increased by 6-20 (mean 15) nmol/l 60 min after the start of treatment and by 6-45 (mean 14) nmol/l at 120 min, compared with the pre-treatment value. A highly significant decrease in dyspnoea and an increase in PEF and FEV1 was measured (p less than 0.01) after treatment, while no significant changes in respiratory rate, pulse rate, blood pressure or tremor were recorded. A significant positive correlation was found between delta plasma terbutaline and delta systolic blood pressure 120 min after treatment (p less than 0.05), but apart from this no statistically significant correlations were found between plasma terbutaline on arrival or delta plasma terbutaline and the other measurements of the effect of treatment. One of the advantages of adding ipratropium to nebulised beta-agonist treatment might be that it permits the use of lower doses of beta 2-agonist and thereby reduces the systemic side-effects of the treatment.

Radioreceptor assay for determination of the antimuscarinic drug ipratropium bromide in man.

A radioreceptor assay for the determination of ipratropium bromide in human plasma has been developed, using [3H] N-methyl-scopolamine as a radioligand to label muscarinic cholinergic receptors in a membrane preparation of rat cerebral cortex. There was no interference due to the cross-reactivity of 3 metabolites of ipratropium with the parent compound (5.2, 1.5 and 0.004%, respectively). The validity of the assay was checked between 20 pg/ml and 1000 pg/ml drug. In a pilot study plasma levels following a single oral dose of 30 mg were determined to examine the applicability of the radioreceptor assay to clinical and pharmacokinetic studies, and for measurement of plasma levels after therapeutic oral doses. The peak plasma concentration in three healthy volunteers (means = 322 pg/ml) occurred within 1-3 h.

New apparatus and method for the toxicological investigation of metered aerosols in rats.

A new apparatus and method for the toxicological investigation of metered aerosols in rats, which is also suitable for tests in other small laboratory animals, is described. It permits: 1. simultaneous treatment of 5 or more animals, 2. administration of metered aerosol doses to individual animals, 3. ventilation of the cages, 4. mechanical tilting of the metered aerosol packs to ensure thorough mixing of the content, and 5. continuous automatic tilting, administration and ventilatied under different ventilation conditions. Blood gases and fluorinated chlorohydrocarbons (abbreviation: fluorocarbons) in the arterial blood were also determined. In tests with spontaneous ventilation of the animal chambers without positive pressure, significant acidosis and hypoxia occurred after 40 puffs of metered aerosol. Where ventilation of the chambers was insufficient, the fluorocarbons led to dose-dependent toxic and lethal effects. The substance and the additives contained in the metered aerosol did not interfere with these effects. After active ventilation with 0.5 atm no symptoms of acidosis or hypoxia were observed. Up to 160 puffs of metered aerosol, no indications of toxic effects were established in the rats. Half-life of the fluorocarbons in the arterial blood after one puff of metered aerosol was 69 to 80 sec for fluorocarbon 11 and 57 to 67 sec for fluorocarbon 12.