Metered-dose Inhaler Canisters Research Articles

Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension.

Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.

Are we handling used metered dose inhaler canisters safely? – A call for action to address an environmental hazard

Background: Metered dose inhalers (MDI) are preferred treatment for asthma and chronic obstructive pulmonary disease. The used MDI canisters are to be disposed off in appropriate manner to prevent environmental pollution. In this study, the disposal methods followed by the patients were investigated. Methodology: This study was conducted in out-patient setting in departments of pulmonary medicine of a tertiary care teaching hospital in south Kerala. The Any patient who was using MDI for at least past one year was enrolled into the study. Exhaustive sampling was done over a period of six months to obtain interviews of 883 patients. Age, gender and educational status of participants, disposal methods they followed for MDI canisters and the source of information for the disposal methods were enquired. Results: Among the 883 patients who were interviewed, 46% were females and 54% were males and 57% were older persons (age above 60 years). All of them were using MDI for at least past one year. None of them were informed about the correct methods of disposal of used MDI canisters (recycle or incineration or plasma pyrolysis). Majority (79%) of the participants disposed them in the waste bins or into the general waste heaps, 13.7% of the participants burned them in their courtyard and 7 (0.8%) participants stored them and 3 (0.4%) used to flush down them in the toilet. Conclusions: MDI canister disposal is an unaddressed environmental hazard. Take back programs need to be initiated to recycle them or at least to incinerate them safely according to Biomedical Waste Management and Handling Rules. ‘Complete the Cycle’ scheme in United Kingdom can be a model for a recycling project venture. Incineration is currently possible through IMAGE project (IMA Goes Eco-friendly) which is currently run in Kerala. Keywords: Biomedical waste management; Metered dose inhaler; Inhalational therapy; Recycle, Take back program.

Design and Development of a Non-volatile Counter for Metered Dose Inhaler (MDI)

In 2014, Global Asthma Report 2014 stated there were 334 million of people in the worldwide suffering of asthma and the population was increased 99 million compared in 2011. Asthma is the leading chronic childhood disease with albatross on affected children and their families. It occurs when the pulmonary airway is blocked or the airways become narrowed and result in difficult breathing. When asthma under attack, asthma patients normally use metered dose inhaler (MDI) to inhale the salbutamol to restore normal breathing. Therefore, MDI currently available in market unable to monitor the remaining amount of puffs available in the MDI canister and may lead problems for the user due to inability to monitor the amount of salbutamol in the MDI canister. Besides this, some manufacturers developed MDI with counter but it had the limitation such as unable to store memory of the last counting value if power failure occurs, uses non-rechargeable battery and are disposable. Hence, this paper is to present the development of a device consist of a non-volatile counter. It is designed using EEPROM to save the memory of the last counting value and to prevent data loss due to power failure. The MDI was installed with the limit switch for counter and the MDI press is attached to MDI canister so that when the user presses both simultaneously then it provides enough pressure to the limit switch to update the counter. The MDI cover is developed to protect the internal connection and to prevent the user from accidently pressing the limit switch. 7.4V Li-ion rechargeable battery was employed to supply power source for system operation. Arduino UNO (ATmega328P) act as microcontroller to control the system operation of this device. The device is capable of displaying the number of used salbutamol puff on the liquid crystal display (LCD). Furthermore, RGB LED is integrated into the device as visualization to indicate the level of salbutamol in the MDI canister. It consists of four levels indication which is high, medium, low and empty canister of used puff. The high level of used puffs is between 0 to 120 puffs with green colour indicator, medium level is between 121 to 160 puffs with yellow/orange colour indicator, low level is between 161 to 199 puffs with red colour indicator and empty canister without any colour of indicator when the used puffs reached to 200. This device could remind the user to prepare a new MDI canister since it had indicated of low level of salbutamol in the MDI canister. Besides this, it also could reduce the deaths from asthma due to the user would prepare a new MDI canister before attacked by asthma.

Design and Development of a Salbutamol Intake Detector for Low Respiratory Treatment

This paper proposed a new salbutamol intake detector design using asthma spacer and gas sensor. The device enable real time monitoring of propellant level inhaled by the infant which will decrease the recovery time of the asthma attack. Microcontroller Arduino UNO is program to control the input and output of the system. MQ6 gas sensor detecting the propellant Hydrofluoroalkane from the metered dose inhaler (MDI) canister and demonstrated the level of propellant inhaled on the LCD in real time. MQ6 gas sensor suitable used to detect concentration of propellant inside the asthma spacer due to it is low sensitive to natural gas where include the carbon dioxide exhaled by the infant. Besides this, MQ6 gas sensor also highly sensitive to propane and the preview aerosol inventor mentioned propane as propellant which used for MDI to push the salbutamol out from MDI canister. Therefore, MQ6 gas sensor is suitable to detect propellant inside asthma spacer. The output voltage of MQ6 in initial state where no propellant inside asthma spacer is between 0.55V and 0.65V. Furthermore, when the MDI canister is been pressed, the concentration of propellant is increased and the output voltage of MQ6 gas sensor also increased in ranged between 1.1V and 1.2V.

Effect of Heliox on Albuterol Delivery by Metered-Dose Inhaler in Pediatric In Vitro Models of Mechanical Ventilation

To determine the effect of varying concentrations of heliox, a mixture of helium and oxygen, on albuterol delivery administered by metered-dose inhaler (MDI) in pediatric mechanically ventilated models. Prospective in vitro laboratory study. University-affiliated research laboratory. The lungs of a 10-kg infant and 30-kg child receiving humidified pressure-regulated volume-controlled ventilation were simulated. The infant settings were an endotracheal tube (ETT) of 4.0 mm, tidal volume of 150 ml, positive end-expiratory pressure of 2 cm H(2)O, rate of 20 breaths/minute, inspiratory time of 0.7 second; the child settings were an ETT of 6.0 mm, tidal volume of 450 ml, positive end-expiratory pressure of 2 cm H(2)O, rate of 16 breaths/minute, and inspiratory time of 0.8 second. Ten albuterol MDI canisters with chlorofluorocarbon propellants were each actuated once sequentially (total dose 1000 mug) with a commercially available aerosol holding chamber. Albuterol was collected onto a filter proximal to a lung simulator. The filter was rinsed, and concentrations were determined by high-performance liquid chromatography. In the infant model, heliox mixtures of 70:30, 60:40, and 50:50 were compared with nitrogen:oxygen (N(2):O(2)) mixtures in the same ratios. The effect of the 70:30 mixtures was also explored in a child model. Each gas mixture was tested 5 times. At all three ratios, albuterol delivery to the end of the ETT was improved with heliox compared with N(2):O(2) (approximately 7% vs 3-4%, p<0.0001, one-way analysis of variance [ANOVA] with a Bonferroni correction for multiple comparisons). No significant difference was noted in mean percentage albuterol delivery among the varying ratios of heliox studied. By two-way ANOVA, significantly greater albuterol delivery was noted with 70:30 heliox compared with 70:30 N(2):O(2) (7-8% vs 3%, p<0.0001), with no significant difference between the infant and child model (p=0.21). The gas mixture, model, and interaction of the two explained 88% of the variability in mean percentage albuterol delivery. Heliox increased albuterol delivery administered by MDI to the end of the ETT in these in vitro pediatric models of mechanical ventilation. Further studies are needed to determine if the improved albuterol delivery with heliox enhances clinical response in infants and children needing mechanical ventilation.

Metered dose inhalers: A need for dose counters

This study investigated the ability of patients to assess when a metered dose inhaler (MDI) is empty. A total of 17 patients assessed, by shaking, the number of doses remaining in a salbutamol MDI that had been partially emptied. Another 100 patients were asked to collect all salbutamol MDIs they considered to be empty and would have thrown away. These MDI canisters were weighed and the number of doses that had been used was estimated. Using the 'shaking method', patients overestimated the amount remaining by around 40 doses. The mean number of doses delivered from an MDI labelled to contain 200 doses before it was discarded was 224 (range, 155-289). These findings confirm that patients are unable to determine when an MDI should be discarded, resulting in insufficient drug delivery at the end of the life of an MDI for the majority of patients, and wastage of the drug for others.

What's New: Newly Approved Drugs for Children

What's New: Newly Approved Drugs for Children

Association Between Inhaled β-Agonists and the Risk of Unstable Angina and Myocardial Infarction

beta-Adrenoceptor agonists (beta-agonists) are commonly used to treat obstructive lung diseases, and preliminary studies have suggested they are associated with an increased risk of adverse cardiovascular outcomes. We further examined the association between acute coronary syndromes and inhaled beta-agonist therapy. We performed a nested, case-control study using data that were collected as part of a larger, ongoing, prospective study of quality improvement in the primary care clinics of seven Veterans Administration Medical Centers. We identified 630 patients with unstable angina or acute myocardial infarction hospitalized between 1996 and 1999. We frequency matched these case patients to 10,486 control subjects according to clinic location, and randomly assigned each an "index date." The computerized pharmacy database at each center was used to ascertain beta-agonist use. Cardiovascular risk factors were assessed from mailed questionnaires and electronic medical records, which included inpatient and outpatient diagnoses, medications, and laboratory results. In comparison with patients who had not filled a beta-agonist prescription during the 90 days prior to their index date, patients who had filled a beta-agonist prescription had an increased risk of experiencing an acute coronary syndrome. The increased risk of an acute coronary syndrome persisted after adjusting for age and cardiovascular risk factors, including hypertension, diabetes, and smoking history. Moreover, there was a dose-response relationship with an adjusted odds ratio (OR) of 1.38 for one to two metered-dose inhaler (MDI) canisters (95% confidence interval [CI], 0.86 to 2.23), an OR of 1.57 for three to five MDI canisters (95% CI, 1.01 to 2.46), and an OR of 1.93 for six or more MDI canisters (95% CI, 1.23 to 3.03). After stratifying for receipt of a beta-blocker prescription, the adjusted OR in subjects who did not receive a beta-blocker was 1.55 for one to two MDI canisters (95% CI, 0.60 to 3.99), an OR of 4.07 for three to five canisters (95% CI, 2.17 to 7.64), and an OR of 3.83 for six or more canisters (95% CI, 2.02 to 7.29). Subjects who had received both beta-blockers and beta-agonists had no increase in risk in acute coronary syndromes unless they had filled six or more beta-agonist MDI canisters. A prescription for inhaled beta-agonists may increase the risk of myocardial infarction and unstable angina in patients with COPD.

Albuterol delivery by metered-dose inhaler in a pediatric high-frequency oscillatory ventilation model.

To assess albuterol delivery by metered-dose inhaler (MDI) in a pediatric lung model ventilated by high-frequency oscillatory ventilation (HFOV). The percentage albuterol dose lost in the circuit's expiratory limb and the effects of operating frequency, inspiratory time, and use of a spacer were also determined. Prospective in vitro laboratory study. Research laboratory. A model consisting of a HFOV and circuit, 4.5-mm endotracheal tube, and lung simulator was assembled. Ventilator settings were the following: humidified FIO2 of 1.0; mean airway pressure of 28 cm H2O; operating frequency of 10 Hz; pressure amplitude of 55 cm H2O; bias gas flow to maintain mean airway pressure; 30% inspiratory time; and temperature of 35 degrees C (95 degrees F). Lung simulator compliance and resistance values were consistent with pediatric patients with pulmonary disease. A total of ten MDI canisters were used to administer 2000 microg of albuterol with a spacer. Circuit filters placed proximal to the lung simulator and in the circuit's expiratory limb collected albuterol exiting the endotracheal tube and any albuterol lost, respectively. Filters were rinsed with water and albuterol concentrations determined by high performance liquid chromatography. Albuterol administration was repeated at operating frequencies of 5 and 15 Hz, inspiratory times of 40% and 50%, and with an actuator instead of a spacer. Each test condition was repeated ten times. Analysis of variance or Student's t-test was used to determine significant differences in albuterol delivered or lost among the operating frequencies and inspiratory times, and between the spacer and actuator. Albuterol delivery to the lung simulator was <1% of the administered dose regardless of the operating frequency, inspiratory time, or use of a spacer or actuator. Albuterol lost in the expiratory limb ranged from 3.28% to 14.89% of the administered dose. These in vitro results suggest albuterol delivery by MDI in a pediatric model of HFOV is negligible, regardless of the operating frequency, inspiratory time, or use of a spacer or actuator.

Reservoir design and dose availability with long-term metered dose inhaler corticosteroid use.

The effect of reservoir design and long-term use with inhaled metered dose inhaler (MDI) corticosteroids on aerosol dose availability was examined. Beclomethasone dipropionate (Vanceril) was delivered by MDI with three brands of available reservoir devices: the AeroChamber, the OptiHaler, and the Aerosol Cloud Enhancer (ACE). An in vitro lung model simulated inspiration. Long-term use was simulated by exhausting five MDI canisters of beclomethasone through each sample of reservoir tested. Each canister exhausted through a reservoir represented approximately 1 month of use with one drug. Total inhaled dose was collected at the reservoir mouthpiece and measured using a spectrophotometric assay. Dose delivery was measured before simulated use and after each MDI canister was exhausted through the reservoir. Three samples of each brand were tested with cleaning and three samples were tested without cleaning. With cleaning, the AeroChamber, OptiHaler, and ACE delivered significantly different average doses of 16.6, 10.3, and 8.7 micrograms per MDI actuation, respectively, (P = 0.0017) over time of use. Changes in dose delivery over time of use were not significant (P = 0.2011). Without cleaning, the same three brands averaged 21.1, 9.7, and 7.8 micrograms per MDI actuation, respectively, (P = 0.0019), and changes in dose delivery over time were not significant (P = 0.3265). Reservoir design can affect the delivery of an inhaled corticosteroid, although the delivery over 4 to 5 months remained stable.

Dosing Efficiency and Particle-size Characteristics of Pressurized Metered-dose Inhaler Aerosols in Narrow Catheters

An experimental in vitro model was used to determine the effects of intraluminal catheter diameter and length on the delivered dose and particle-size characteristics of salbutamol (albuterol) aerosol delivered by metered dose inhaler (MDI) (Ventolin, 100 micrograms per puff). The dose of aerosolized drug that exited a 16-cm-long tracheal tube with an inner diameter (ID) of 6 mm was compared with that from 4 catheters of differing diameters and lengths that were inserted individually into the tracheal tube. The salbutamol MDI canister was actuated ten times into each delivery system, and the effluent aerosol was trapped onto a filter. The filtrate was dissolved in methanol, and the salbutamol concentration was determined using high-performance liquid chromatography. For the 3 22-cm-long catheters, the delivered dose (mean +/- SD) of salbutamol per actuation for the 22-standard wire gauge (SWG) catheter was 97.5 +/- 3.9 micrograms, which was similar to that for the 19-SWG catheter (102.3 +/- 2.5 micrograms) but was significantly less than that for the 14-SWG catheter (108.2 +/- 4.2 micrograms) (p < 0.05). These delivered doses exceeded those of the 6.0-mm-ID tracheal tube alone (2.33 +/- 0.76 micrograms) and the 13-cm-long 19-SWG catheter (2.17 +/- 0.29 micrograms) (p < 0.001). In a second experiment using a cascade impactor, the distribution of aerosol particle diameters that exited the 6-mm-ID tracheal tube was compared with that exiting a 13-cm-long 19-SWG catheter that extended halfway down the tracheal tube and with that exiting a 22-cm-long 19-SWG catheter inserted into the distal end of the 6-mm-ID tracheal tube. The mass median aerodynamic diameter (mean +/- SD) of the salbutamol aerosols delivered through both the 6.0-mm-ID tracheal tube (1.1 +/- 0.1 microns) and that of the 13-cm-long 19-SWG catheter (1.2 +/- 0.2 microns) were significantly less than that delivered through the 22-cm-long 19-SWG catheter (2.0 +/- 0.1 microns) (p < 0.05). The authors conclude that delivery of respirable aerosol can occur through narrow catheters that function as extended nozzles for MDIs. Optimal dosing will be obtained when the catheter extends the full length of the tracheal tube.