Comparing weight method and oat method for pressurised metered dose inhaler as dose counting method.

INTRODUCTION Pressurised metered-dose inhalers (pMDIs) are not equipped with dose counters, so estimating the actuation remaining is dicult. We compared weight method and oat method in estimating the actuation remaining in discarded pMDIs. METHODOLOGY Used non-metered pMDIs were collected from Pharmacy department Hospital Seri Manjung from June to Dec 2018. Each of the returned canister was evaluated using oat and weight method to predict the balance actuation in the canister. For the oat test, the canister was placed in a container of water. Based on its position in the water, the pMDI was categorised as 1=empty, 2=¼ full, 3=½ full, 4=¾ full, or 5=full. For the weight method, canisters were weighed, and actuation remaining were calculated using a linear regression equation where the general equation is: Actuation remaining = Constant + β*pMDI weight, and further categorised as above. The percentage of empty pMDIs between the two methods were compared. RESULTS A total of 4517 pMDIs were returned to the pharmacy, of which 2131 (47%) were salbutamol, 1149 (25%) budesonide, 685 (15%) ipratropium/fenoterol, 340 (8%) innovator uticasone, 182 (4%) generic uticasone, and 30 (1%) beclomethasone. Overall, the oat method classied 75% pMDIs as empty, compared to 71% by the weight method. The percentage of empty salbutamol, generic uticasone, and beclomethasone pMDIs were similar between both methods. A higher percentage of budesonide pMDIs were classied as empty by the oat method compared to the weight method (62% vs 37%). For ipratropium/fenoterol pMDIs, the oat method did not identify any empty canisters, but 82% were classied as empty by the weight method. CONCLUSION This study produced a prediction equation that can be used to estimate remaining actuation in a pMDI based on its weight. There were differences in the identication of empty pMDIs between the oat test and the weight method, that oat test underestimate classication The results indicate that Float test classied canister lower than method. oat oat classication. The results indicate that oat test will show the canister to higher classication classication.


Introduction
Pressurized metered-dose inhalers (pMDI) are the basic method of drug delivery of asthma treatment. The pMDI is an economic and portable medication delivery system, but the device does not indicate how much medicine remains in the canister once a patient starts using it.
Studies have shown that patients are unable to gauge the amount of actuation remaining in their pMDI 1, 2, 3. Some of the reported measure by which patient estimate the balance actuation in pMDI are not reliable .Estimation based on patients perception on the weight of the inhaler, force of actuation, sounds, and taste are in uenced by the volume of remaining propellants and excipients and does not re ect the actual remaining active ingredients 2,4 .
In a study by Rubin 4 of paediatric asthma patients, 72% of the children (or their parents) reported using an MDI until they could no longer "hear" the MDI make a sound when it was actuated .In another study by Sander 1 , 25% of patients reported that they consider their inhaler to be empty "when it stopped spraying," unaware that propellant continues to spray long after the active ingredients has run out. Most patient report that they shake their MDIs to assess the amount of drug remaining in them, also unaware that it might just be propellants 2, 3, 6 . Holt 7 and colleagues asked patients receiving asthma treatment to return their MDIs, when deemed empty, to their physicians .Of 109 returned MDIs, 11% of "empty" MDIs still contained more than 20% (>40actuation) of the recommended metered actuation . A bronchodilator prescription typically requires re ll only a few times a year, yet almost 20% of patients reported re lling their inhaler at least once a month. The authors speculated that the excessive number of bronchodilator re lls might be due, in part, to throwing away partially used inhalers.
The design of metered dose inhaler makes it impossible for an MDI to cease delivering drug actuation at an exact point, and the number of actuations in an MDI need to be more than the recommended actuation. Once the recommended number of medication actuation is expelled, remaining actuations deliver decreasing concentrations of active medication and increasing concentrations of propellants and excipients 8 .Patients who are not tracking medication actuation either discard an MDI that may still contain actuation of drug, or continue to use a product that only contain propellants. The former is costly and the latter will be harmful for patient A method that usually taught to patient to determine the remaining amount is by " oats testing" (Figure 1). In oat testing, the canister is placed in glass water. If and how the canister oats re ects the relative weight and centre of gravity for the remaining drug solution 3  This study could be used as a base to determine if patient's pMDI could still be used or exchanged using weighing method. Exchanging pMDI when absolutely necessary could be a cost saving measure as well.

Aim of study
This study aimed to compare between oat method and weight method and to determine the balance actuation in canister exchanged by patient.

Methodology
This study was conducted in pharmacy department. Hospital Seri Manjung from June to Dec 2018 .Weighing scale Sartorius R200D (±0.001g) was be used to weigh the canister. Only the metal canister was weighted (the mouth piece was removed).
Among the collected pMDI , canister with illegible batch number or expiry date , canister which expired 1 month before or 1 month after data collection month , Different brand of pMDI other than used to prepare the linear regression and abnormal canister with damage or dent was excluded.
The minimum sample size required for this study was 488/month. This gure was arrived by using Raosoft sample size calculator by setting margin of error at 5% , con dence interval at 99% , population size at 1832 ( amount of pMDI dispensed on June 2018) and return rate at 50%. As the study period was for 6 month. 2928 canister need to be collected. To allow rejection rate of 10%, the researcher will collect 3221 canister or the total number of pMDI that during the study period.
The following linear regression equation was used to determine the balance actuation in returned or used canister : 1. Salbutamol : Actuation = 391.0244+ (-13.6 x canister weight). To determine if the oat test corresponds to the weight of canister All returned pMDI was segregated according to active ingredients and then subjected to inclusion and exclusion criteria. For each canister, the batch number and expiry date was recorded. Next the canister was weighed and the weight was recorded. Finally, the canister was subjected to oat test and the category was recorded according to the canister orientation in Figure 1 .The oat category was than compared to the weight of canister.
To determine the balance actuation in canister exchanged by patient.
The balance actuation in each canister was predicted and categorised according to the weight range using the line of best t that was built

Statistical analysis
All descriptive result was presented as number (n) and percentage (%) . A paired t-test was used to compare the difference between classi cations of the oat methods compared to weight method . For all test Two-tailed p-value <0.05 was considered as statistically signi cant. All statistical analyses were performed using SPSS for Windows version 22.0 (SPSS Inc., Chicago, Illinois, USA).

Results
A total of 4517 canister was collected and subjected to weight method and oat method. Each canister was weighted and subjected to oat and weight methods. Table 2 reports distribution of the canister according to balance category, Generally, there was difference in both method of classi cation. The amount of canister classi ed differs between oat method and weight method ( Table 2). The notable difference is with Budesonide, Ipratropium/Fenoterol and Fluticasone (Cipla) canister. For Budesonide canister there was no canister classi ed as 3/4full or full with oat method but 158 canisters was classi ed as 3/4full and 154 canisters was classi ed as full. For ipratropium/fenoterol, no canister was classi ed as empty with oat method but 563 were classi ed as empty with weight method.
Furthermore there was a reduction from 558 from 1/4full in oat method to only 52 in 1/4full classi cation with weight method. The same pattern was noticed with Fluticasone (Cipla) where there was no classi cation in 3/4full and full category but 4 canisters classi ed as 3/4full and 1 as full with weight method. Table 3 reports paired t-test between oat methods compared to weight method. 724 canister was classi ed higher with weight method classi cation compared with oat method classi cation.
Ipratropium/Fenoterol Canister was classi ed lower with weight method (0.38 ± 0.953) as opposed to oat method (0.53 ± 0.1135); a statistically signi cant decrease of 0.155 (95% CI, 0.125 to 0.184), t (648) = 10.211, p < .0001. The Mean between oat method and weight have been reduced from 0.53 to 0.38 which indicate that oat test method tend to overestimate the classi cation. The results indicate that oat test will show the canister to have higher content of solution in the canister Fluticasone Canister was classi ed lower with weight method (0.27 ± 0.715) as opposed to oat method (0.41 ± 0.817); a statistically signi cant decrease of 0.138 (95% CI, 0.1 to 0.177), t (339) = 7.035, p < 0 .000. The Mean between oat method and weight have been reduced from 0.71 to 0.27 which indicate that oat test method tend to overestimate the classi cation. The results indicate that oat test will show the canister to have higher content of solution in the canister.
Fluticasone (generic) Canister was classi ed higher with weight method (0.23 ± 0.674) as opposed to oat method (0.18 ± 0.499); a statistically signi cant increase of 0.049 (95% CI, -0.085 to -0.014), t (181) = -2.763, p =0 .006. The results indicate that weight method classi ed the canister higher than oat method.The mean have been increased from 0.18 to 0.23 which indicate that oat test method tend to underestimate the classi cation. The results indicate that Float test classi ed the canister lower than weight method.
30 Beclometasone canisters were weighed. There was no difference in classi cation between oat method and weight method and hence no statistical signi cant was found this study had been used well past the recommended number of actuations. This study also came to a similar nding which shows that about 70% of the returned canister was empty. Activating a nearly empty or an altogether empty MDI to deliver orally inhaled asthma medication appears to be a common occurrence when patients use an MDI without a dose counter 1, 2, 4 .
The amount of active ingredients in those additional actuations is variable as propellant and excipients form up to 99% of an asthma drug formulation 11 . Currently available MDI are formulated as suspensions. Suspensions comprise micronized drug substance suspended in propellant and other excipients. If the drug substance adheres to the walls of the container or valve components, dose delivery and particle size distribution could be inconsistent1 11,12 .
Actuating beyond the recommended number of actuation will cause the active ingredient delivery per actuation becomes unpredictable, a phenomenon known as "tail-off" 7 ( Figure 4). Tail-off is particularly problematic when the medication delivered by the MDI is formulated as a suspension rather than a solution. Tail-off may be rapid (e.g., within 5 actuations), or erratic, requiring 10-20 actuations before the canister is nally empty of its drug content 8.
Advising the patient top use the inhaler until its empty or more than the recommended actuation will not guarantee the accurate actuation of medication will be delivered to the patient. Although there might be some solution in the canister or visible puff could be seen after each actuation , the amount of recommended active ingredients will not be accurate .All manufacturer recommended that the accurate actuation of medication from MDI can only be ensured if patient uses the recommended number of actuation .
Actuating the canister until its empty might be patient an important contributor to poor asthma control. For example, patients may think they are taking their asthma medication when they actually inhaling excipients and sub-therapeutic active ingredients. This is potentially dangerous especially for rescue medication such as Salbutamol.

Conclusion
This study concludes that there is statistically signi cant difference between oat method and weight method in which oat test method tend to underestimate the content of the canister compared to weight. Weighing pMDI could be used as a dose counter at health care facilities; however it must be noted that the linear regression model may vary with pMDI product.