Ipratropium Bromide and Albuterol Sulfate

IPRATROPIUM BROMIDE AND ALBUTEROL SULFATE — ipratropium bromide and albuterol sulfate solution
Aurobindo Pharma Limited

DESCRIPTION

The active components in ipratropium bromide and albuterol sulfate inhalation solution, USP are albuterol sulfate USP and ipratropium bromide USP.
Albuterol sulfate, is a salt of racemic albuterol and a relatively selective β2 -adrenergic bronchodilator chemically described as α1 -[(tert-butylamino)methyl]-4-hydroxy-m-xylene-α, α’-diol sulfate (2:1) (salt). It has a molecular weight of 576.7 and the molecular formula is (C13 H21 NO3 )2 •H2 SO4 . It is a white to practically white crystalline powder, freely soluble in water and slightly soluble in alcohol, chloroform and ether. The World Health Organization recommended name for albuterol base is salbutamol.

Figure 1: Chemical structure of albuterol sulfate.
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Ipratropium bromide is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo [3.2.1]-octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8methyl-8-(1-methylethyl)-, bromide, monohydrate (endo, syn)-, (±)-; a synthetic quaternary ammonium compound, chemically related to atropine. It has a molecular weight of 430.4 and the molecular formula is C20 H30 BrNO3 •H2 O. It is a white to off white crystalline powder, soluble in water, freely soluble in methanol and slightly soluble in ethanol, insoluble in isopropyl alcohol, chloroform, methylene chloride and benzene.
Figure 2: Chemical structure of ipratropium bromide.
(click image for full-size original)

Each 3 mL vial of ipratropium bromide and albuterol sulfate inhalation solution, USP contains 3 mg (0.1%) of albuterol sulfate USP (equivalent to 2.5 mg (0.083%) of albuterol base) and 0.5 mg (0.017%) of ipratropium bromide USP in an isotonic, sterile, aqueous solution containing edetate disodium (a chelating agent), sodium chloride and hydrochloric acid to adjust to pH 4.
Ipratropium bromide and albuterol sulfate inhalation solution, USP is a clear, colorless solution. Practically free from visible particles and foreign matters packed in natural BFS LDPE vial. It does not require dilution prior to administration by nebulization. For ipratropium bromide and albuterol sulfate inhalation solution, USP, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the Pari-LC-Plus™ nebulizer (with face mask or mouthpiece) connected to a PRONEB™ compressor system, under in vitro conditions, the mean delivered dose from the mouth piece (% nominal dose) was approximately 46% of albuterol and 42% of ipratropium bromide at a mean flow rate of 3.6 L/min. The mean nebulization time was 15 minutes or less. Ipratropium bromide and albuterol sulfate inhalation solution, USP should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces (see DOSAGE AND ADMINISTRATION).

CLINICAL PHARMACOLOGY

Ipratropium bromide and albuterol sulfate inhalation solution is a combination of the β2 -adrenergic bronchodilator, albuterol sulfate, and the anticholinergic bronchodilator, ipratropium bromide.
Albuterol Sulfate
Mechanism of Action
The prime action of β-adrenergic drugs is to stimulate adenyl cyclase, the enzyme that catalyzes the formation of cyclic-3’,5’-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The cAMP thus formed mediates the cellular responses. In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on β2 -adrenergic receptors compared with isoproterenol. While it is recognized that β2 -adrenergic receptors are the predominant receptors in bronchial smooth muscle, recent data indicated that 10% to 50% of the β-­receptors in the human heart may be β2 -receptors. The precise function of these receptors, however, is not yet established. Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other β-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients.
Pharmacokinetics
Albuterol sulfate is longer acting than isoproterenol in most patients by any route of administration, because it is not a substrate for the cellular uptake processes for catecholamine nor for the metabolism of catechol-O-methyl transferase. Instead the drug is conjugatively metabolized to albuterol 4’-O-sulfate.
Animal Pharmacology/Toxicology
Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of plasma concentrations. In structures outside of the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those found in whole brain.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrythmias and sudden death (with histological evidence of myocardial necrosis) when beta-agonists and methyl-xanthines are administered concurrently. The clinical significance of these findings is unknown.

Ipratropium Bromide

Mechanism of Action
Ipratropium bromide is an anticholinergic (parasympatholytic) agent, which blocks the muscarinic receptors of acetylcholine, and, based on animal studies, appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cGMP), resulting from the interaction of acetylcholine with the muscarinic receptors of bronchial smooth muscle.
Pharmacokinetics
The bronchodilation following inhalation of ipratropium is primarily a local, site-specific effect, not a systemic one. Much of an inhaled dose is swallowed as shown by fecal excretion studies. Following nebulization of a 1 mg dose to healthy volunteers, a mean of 4% of the dose was excreted unchanged in the urine.
Ipratropium bromide is minimally (0% to 9% in vitro) bound to plasma albumin and α1 -­acid glycoproteins. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half is excreted unchanged in the urine. The half-life of elimination is about 1.6 hours after intravenous administration. Ipratropium bromide that reaches the systemic circulation is reportedly removed by the kidneys rapidly at a rate that exceeds the glomerular filtration rate. The pharmacokinetics of ipratropium bromide and albuterol sulfate inhalation solution or ipratropium bromide have not been studied in the elderly and in patients with hepatic or renal insufficiency (see PRECAUTIONS).
Animal Pharmacology/Toxicology
Autoradiographic studies in rats have shown that ipratropium does not penetrate the blood-brain barrier.

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution

Mechanism of Action
Ipratropium bromide and albuterol sulfate inhalation solution is expected to maximize the response to treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms: sympathomimetic (albuterol sulfate) and anticholinergic/parasympatholytic (ipratropium bromide). Simultaneous administration of both an anticholinergic and a β2 -sympathomimetic is designed to produce greater bronchodilation effects than when either drug is utilized alone at its recommended dosage.
Animal Pharmacology/Toxicology
In 30-day studies in Sprague-Dawley rats and Beagle dogs, subcutaneous doses of up to 205.5 mcg/kg of ipratropium administered with up to 1000 mcg/kg albuterol in rats and 3.16 mcg/kg ipratropium and 15 mcg/kg albuterol in dogs (less than the maximum recommended daily inhalation dose for adults on a mg/m2 basis) did not cause death or potentiation of the cardiotoxicity induced by albuterol administered alone.
Pharmacokinetics
In a double blind, double period, crossover study, 15 male and female subjects were administered single doses of ipratropium bromide and albuterol sulfate inhalation solution or albuterol sulfate inhalation solution at two times the recommended single doses as two inhalations separated by 15 minutes. The total nebulized dose of albuterol sulfate from both treatments was 6 mg and the total dose of ipratropium bromide from ipratropium bromide and albuterol sulfate inhalation solution was 1 mg. Peak albuterol plasma concentrations occurred at 0.8 hours after dosing for both treatments. The mean peak albuterol concentration following administration of albuterol sulfate alone was 4.86 (± 2.65) mg/mL and it was 4.65 (± 2.92) mg/mL for ipratropium bromide and albuterol sulfate inhalation solution. Mean AUC values for the two treatments were 26.6 (± 15.2) ng·hr/mL (albuterol sulfate alone) versus 24.2 (± 14.5) ng·hr/mL (ipratropium bromide and albuterol sulfate inhalation solution). The mean t1/2 values were 7.2 (± 1.3) hours (albuterol sulfate alone) and 6.7 (± 1.7) hours (ipratropium bromide and albuterol sulfate inhalation solution). A mean of 8.4 (± 8.9)% of the albuterol dose was excreted unchanged in urine following administration of two vials of ipratropium bromide and albuterol sulfate inhalation solution which is similar to 8.8 (± 7.3)% that was obtained from albuterol sulfate inhalation solution. There were no statistically significant differences in the pharmacokinetics of albuterol between the two treatments. For ipratropium, a mean of 3.9 (± 5.1)% of the ipratropium bromide dose was excreted unchanged in urine following two vials of ipratropium bromide and albuterol sulfate inhalation solution, which is comparable with previously reported data.
Clinical Trials
In a 12 week, randomized, double-blind, positive-control, crossover study of albuterol sulfate, ipratropium bromide, and ipratropium bromide and albuterol sulfate inhalation solution, 863 COPD patients were evaluated for bronchodilator efficacy comparing ipratropium bromide and albuterol sulfate inhalation solution with albuterol sulfate and ipratropium bromide alone.
Ipratropium bromide and albuterol sulfate inhalation solution demonstrated significantly better changes in FEV1, as measured from baseline to peak response, when compared with either albuterol sulfate or ipratropium bromide. Ipratropium bromide and albuterol sulfate inhalation solution was also shown to have the rapid onset associated with albuterol sulfate, with a mean time to peak FEV1 of 1.5 hours, and the extended duration associated with ipratropium bromide with a duration of 15% response in FEV1 of 4.3 hours.

Figure 3
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This study demonstrated that each component of ipratropium bromide and albuterol sulfate inhalation solution contributed to the improvement in pulmonary function, especially during the first 4 to 5 hours after dosing, and that ipratropium bromide and albuterol sulfate inhalation solution was significantly more effective than albuterol sulfate or ipratropium bromide alone.

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