A Comparison of Pharmaceutical Product Performance of Albuterol Inhalers Available in the United States and Those Obtained in a Mexican Border Town – PMC

Abstract

Background: american residents travel to Mexico to purchase medications for a fraction of US cost and frequently without prescription requirements. A previous bioequivalence study found differences in lung function measures between 2 brands of Mexican-manufactured albuterol inhalers ( both 100 µg/puff ). An probe of the pharmaceutical operation of different inhalers available may illuminate why different clinical results may be observed and offer insight to consumer and provider expectations of such products. Objective: The determination of this report is to provide some reasonable expectations for a aesculapian tourist who shops in Mexico for albuterol metered dose inhalers ( MDIs ) or for their health care providers by comparing pharmaceutical intersection performance of the consumer-available brands. Methods: Five unlike albuterol MDI products were purchased in Nogales, Mexico. The albuterol content was quantified through high-performance fluid chromatography. The inhalers were analyzed to determine the measure of the albuterol venereal disease that can be considered respirable and compared with the findings from 2 US pioneer products. Results: The mean respirable mass for each brand of albuterol MDI was compared with that of the other 4 brands and the 2 US pioneer products using Student ’ s thymine screen. All evaluations showed significant differences ( P < .05 ) except for 3 comparisons ( Sacrusyt five Assal, P = .89 ; Xeneric-S five non-US Ventolin, P = .98 ; Victory vs US Proventil HFA, P = .06 ). Conclusion: Since pharmaceutical unevenness was found among the albuterol MDIs evaluated in this study, consumers and clinicians should appreciate possible differences in merchandise operation of albuterol MDIs obtained in Mexico. Keywords:

asthma, β-2-adrenergic agonists, international medicine/issues, medication safety, pharmaceutics, inhalers

“ Medical tourism ” is a term describing the international border-crossing for health caution products and services. 1 The medical tourism industry is estimated to contribute $ 45 to 95 billion to the ball-shaped economy, and it accommodates the checkup treatment for more than 1.2 million Americans every year. 2, 3 Mexico is a lead region for medical tourism and attracts american residents for cheap, more accessible medical and dental procedures, services, products, and medications. 3 many prescription-only drugs in the United States are available for leverage at bound township Mexican pharmacies without prescription drug requirements and, frequently, for lower price. In late years, the transition in the United States to the more environmentally friendly hydrofluoroalkane ( HFA ) propellant systems has led to raw branded albuterol metered dose inhaler ( MDI ) products. This transition has besides led to an increase in the cost of albuterol inhalers in the United States. 4, 5 While it is expected that generic products will finally enter the market, the impression on the consumer price is unknown at this time. 6 indeed, the out-of-pocket cost of albuterol inhalers in Mexico has been reported to be one one-third of distinctive US copays ( and even less than the cash price for the uninsured or underinsured ). Since lower monetary value is the chief reason for aesculapian tourists to purchase medications outside of the United States, it would appear probably that this vogue will continue. 4, 7 – 9 Yet, the question remains : “ What do you get when you cross the edge and buy medications, such as albuterol MDIs, for cheaper prices ? ” several studies have compared pharmaceutical quality of medications that were available to patients in other countries and showed varying results. For case, 2 classify studies performed by Karlage and colleagues, both of which analyzed capacity uniformity for several products obtained in Mexico, found that while the majority of the products fell within the average US Pharmacopeia ( USP ) limits for active pharmaceutical ingredient, individual capsules/tablets demonstrated a considerable amount of unevenness within the products. 10, 11 Furthermore, 2 of the 12 products tested were found to contain significantly less active pharmaceutical ingredient than the pronounce total. 10, 11 A product quality study that compared simvastatin tablets purchased from canadian manufacturers using the Internet with the US pioneer products found like blend uniformity between the 2 groups. 12 however, a subsequent Internet simvastatin report that included a variety of external manufacturers discovered nonequivalent drug total, tablet hardness, and weights among the samples compared with the US standard. 13 With esteem to albuterol inhalers, a bioequivalence analyze by Leon-Molina et aluminum of 2 brands of albuterol inhalers available in Mexican pharmacies, Ventolin ( “ non-US Ventolin ” ) and Assal, demonstrated clinical differences and bioinequivalence between the 2 brands despite that both were expected to deliver 100 µg of drug per puff. 14 Non-US Ventolin exhibited higher push expiratory volume in 1 moment ( FEV1 ) values, higher maximum consequence ( Emax ), higher time to Emax ( tmax ), and higher area under the share of response–time curvature ( AUC ) than Assal. A project explanation for the unwrap inequivalence in lung affair tests was that there may be unaccounted pharmaceutical differences between the 2 products. 14 apposite pharmaceutical operation factors might include the aerosol particle size deviation and actual amount of drug delivered to the lungs. The aim of this study is to provide some fair expectations for a checkup tourist who shops in mexican border towns for albuterol MDIs or for providers who encounter such a patient by comparing pharmaceutical quality and intersection operation of these inhalers with one another and with those available in US pharmacies .

Methods

Study Samples and Equipment

This study compared the pharmaceutical performance of albuterol MDIs obtained in the boundary line town of Nogales, Mexico, with each other and with those available in US pharmacies. A assortment of trade name identify products were obtained during multiple visits to Nogales pharmacies including Victory, non-US Ventolin, Assal, Xeneric-S, and Sacrusyt. Two or more units were purchased for each brand, depending on retail obtainability ( more than 2 were purchased when they came in multi-packs ). The samples included 5 units Xeneric-S, 2 units Victory, 3 units non-US Ventolin, 2 units Assal, and 2 units Sacrusyt, totaling 14 units. For each brand, 2 singular draw numbers were tested, with the exception of Sacrusyt, for which a second lot was unavailable at the purchase times. An evaluation of study sample product pronounce is offered in, and the units are depicted in. Two US pioneer products, US-purchased Ventolin HFA ( “ US Ventolin HFA ” ) and US-purchased Proventil ( “ US Proventil HFA ” ), were included for comparison .

Table 1.

Brand (# Units Tested) Product Manufacturing Country Pregnancy Warning Labeled Weight Labeled Amount of Drug Delivered per Dose
(µg)
Out-of-Pocket Unit Cost (US$)
Victory (2) China Yes 20 g 100 4.25
Non-US Ventolin (3) Spain No 18 g 100 10.00
Assal (2) Mexico No 20 mg 100 4.25
Xeneric-S (5) India No 17 g 100 3.00-4.00
Sacrusyt (2) China Yes 20 mg 100 3.00-5.00
US Proventil (3) United States Yes 6.7 g 108 of albuterol sulfate; 90 of albuterol 20.00-50.00
US Ventolin (3) United Kingdom Yes 18 g 108 of .albuterol sulfate; 90 of albuterol 20.00-50.00

Open in a separate windowAn external file that holds a picture, illustration, etc.
Object name is 10.1177_8755122515595052-fig1.jpgOpen in a separate window Mean full acid, respirable mass, and nonrespirable bulk were determined using the TSI Model 3306 Impactor Inlet ( TSI Inc, Shoreview, MN ). In brief, an MDI is actuated into a USP initiation port ( “ throat ” ), which is coupled to the TSI 3306. The TSI 3306 is a single-stage impactor with a 4.7 µm cutpoint while the USP throat collects particles that likely would deposit in a patient ’ randomness throat. A high-performance liquid chromatography ( HPLC ) arrangement utilized for albuterol analysis was a 2690 legal separation module combined with a 996 photodiode array ( Waters Corporation, Milford, MA ). pharmaceutical parameters used for comparison include the comply :

  • Mean Total Dose is the modal albuterol batch that could reach the patient per propulsion. This includes all particles deposited on the TSI 3306 trickle ( which would reach a affected role ’ second lungs ) equally well as particles deposited in the throat and impactor plate of the TSI 3306 ( which would deposit in the patient ’ s mouth, throat, and trachea ) .
  • Mean Respirable Mass is the average mass of albuterol that could reach a affected role ’ sulfur lungs per propulsion. only aerodynamic particles of diameter of 4.7 µm or smaller are likely to reach a patient ’ mho lungs. Mean respirable mass is measured by finding the average albuterol batch deposited on the TSI 3306 filter after each test play .
  • Mean Nonrespirable Mass is the average mass of albuterol that could not reach a patient ’ s lungs per propulsion. Nonrespirable particles have streamlined diameter greater than 4.7 µm diameter and think of nonrespirable multitude is measured by finding the average albuterol mass deposited on the TSI 3306 throat and impactor plate after each test run .

Procedure

Every inhaler to be tested was prepared for test runs by priming with 3 actuations, washing the inhaler root with methanol, and allowing fourth dimension to dry before recording an initial weight unit. The TSI 3306 was prepared by adjusting the airflow to reach the manufacturer ’ s stated calibration menstruate rate of 28.3 L/min. Three examination runs were completed for each MDI unit and the results composited to find base entire dose, mean respirable multitude, and mean nonrespirable multitude per single propulsion. For every trial run, a standard protocol was followed in which the inhaler was actuated 5 times ( shaken before each propulsion ) into the throat over 60 seconds. Each component of the inhaler and of the TSI 3306 that could have aerosol on it was rinsed with an appropriate book of dilutant ( 23:77 methanol–water ), and samples were collected for the HPLC assay. These components included the throat, annex, home plate, and filter from the TSI 3306 and the stem and actuator from the MDI. HPLC analysis of albuterol was performed using an Apollo C18 column ( 5 µm, 150 × 4.6 millimeter ) maintained at 30 ± 2°C. The mobile phase consisted of 1 % phosphorous acid–methanol ( 77:23 ), the menstruate rate was 0.75 mL/min, and the injection bulk was 40 µL. UV detection was set at 225 nm .

Statistical Analysis

To grasp what differences, if any, there were from one consumer-available intersection to the next, each of the 5 mexican edge town MDI brands were compared one-on-one ( Victory vanadium non-US Ventolin, Victory vanadium Assal, Victory vs Xeneric-S, etc ). The continuous data of total dose and respirable mass included in each one-to-one comparison were analyzed using student ’ s triiodothyronine tests. To compare the respirable bulk data of each of the border town samples against each of the 2 US pioneer MDI products, 1-sample thyroxine tests were performed .

Results

Visual Inspection

All 5 mexican boundary line town inhaler brands were sold in a Spanish-labeled box containing a single-page instructions insert. Every inhaler label displayed a visible fortune total, passing date, the international generic drug name for albuterol ( salbutamol ), and stated a drug of 100 µg. US Ventolin and US Proventil label the dose as 108 µg of albuterol sulfate, which correlates to 90 µg of albuterol per propulsion. As illustrated in, the package labels of the 5 mexican border township products exhibit a venereal disease of 100 µg but do not specify if it is albuterol sulfate or not. Some of the inhaler units were short-dated, list passing dates that were only 1 month from the purchase date ( non-US Ventolin ), while other units expired up to 26 months from date of acquisition ( Victory ). Listed manufacture locations included China, Mexico, India, and Spain ( ). Two brands showed a pictorial pregnancy-related warn label on the box. Most of the MDIs were purchased for about $ 3 to $ 5 each, with non-US Ventolin being the most expensive ; the non-US Ventolin units used in the learn were purchased for $ 10 each but they were priced american samoa much as $ 15 or $ 20 each depending on the pharmacy placement. The inhaler labels all exhibited what appeared to be total merchandise weight. notably, some products listed slant in grams ( Victory, Xeneric-S, and non-US Ventolin ) while others listed milligrams ( Assal and Sacrusyt ). It was not always clear on the packaging what component of the intersection the weight regarded ( eg, total canister weight, conceptualization fill weight, albuterol weight ) .

Comparison of Total Dose and Respirable Mass Among Mexican Border Town
Inhalers

The active drug found in all cogitation samples was albuterol, as labeled on the packaging. however, there were pharmaceutical performance differences discovered between the Mexican edge town–purchased inhalers. illustrates the average sum dose, mean respirable mass, and mean nonrespirable aggregate measured for each of these MDIs. The mean full acid was an sphere of significant variability among the mexican bound township products. Assal ( average sum venereal disease of 57.9 µg ) tested the lowest among the other 4 Mexican-purchased MDI brands ( Xeneric-S 75.2 µg ; Sacrusyt 66.9 µg ; non-US Ventolin 66.6 µg ; Victory 61.1 µg ) and exhibited the widest unevenness ( ). When comparing the mean sum dose, lone 2 comparisons showed no meaning dispute ( Sacrusyt vanadium non-US Ventolin, P = .84 ; Victory vs Assal, P = .28 ). All remaining comparisons showed significant inconsistencies between the brands, suggesting that patients may encounter sum acid differences from one product to the next ( P < .05 ).

Read more : ‎Photo Editor

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Object name is 10.1177_8755122515595052-fig2.jpgOpen in a separate window A key circumstance when evaluating inhaler operation is how much of the entire acid is respirable ( what could reach a affected role ’ second lungs ). Differences in respirable mass were besides found between the Mexican frame township inhaler samples. The beggarly respirable aggregate measurements of non-US Ventolin ( 28.0 µg ) and Xeneric ( 28.1 µg ) were the lowest compared with any of the other inhalers ( Victory, 41.0 µg ; Sacrusyt, 36.8 µg ; Assal, 37.0 µg ). When the base respirable mass measurements of the non-US brands of albuterol MDIs were compared with one another ( the think of of each sword compared with that of each of the other 4 brands ), all comparisons were significantly different ( P < .05 ) except for 2 brands ( Sacrusyt volt Assal, P = .89 ; Xeneric-S v non-US Ventolin, P = .98 ). Regarding the measure of albuterol one could expect to reach the lungs in a single puff, most of the brands tested show significant differences from one another, far highlighting another aspect of product variability that a patient may encounter .

Respirable Mass: Comparison Between US Available Products and Study
Samples

To examine how well a venereal disease from a mexican boundary line town–purchased albuterol inhaler would reach a patient ’ south lungs in relation to US counterpart products, respirable bulk measurements of each were compared. The intend respirable batch and mean total dose of each Mexican border town–purchased MDI is displayed in junction with the measurements from US-purchased MDI products ( ). A 1-sample thymine test was used to find differences between edge town inhaler results and corresponding data from US Ventolin HFA and US Proventil HFA. 15 Among the mexican boundary line town MDIs, all except Victory ( 41.0 µg ) offered lower respirable mass than that of US Proventil HFA ( 41.5 µg ) and US Ventolin HFA ( 37.8 µg ). The respirable mass values of non-US Ventolin, Xeneric-S, and Victory were significantly different from the US Ventolin HFA ( P < .001 ), and the values for all but Victory were different from US Proventil HFA ( P < .05 ). More explicitly, no remainder was found between Victory and US Proventil HFA ( P = .06 ), Sacrusyt and US Ventolin HFA ( P = .35 ), or Assal and US Ventolin HFA ( P = .61 ). Furthermore, Victory compared significantly higher in hateful respirable mass than a US branded product ( Victory > US Ventolin HFA, P < .001 ) .An external file that holds a picture, illustration, etc.
Object name is 10.1177_8755122515595052-fig3.jpgOpen in a separate window

Clinical Implications

A medical tourist who obtains rescue MDIs from Mexican molding towns may face differences from one product to the next or differences between the border town products and the US counterparts. passing dates are a particular area of concern since some ( but not all ) inhaler units acquired in this study were short-dated deoxyadenosine monophosphate humble as 1 calendar month from purchase date. Some label inconsistencies among mexican boundary line town–purchased inhalers could be confusing for consumers, that is, some products showing condom warnings and some not. The pharmaceutical product operation examination revealed differences among the mexican border town MDIs in full acid and respirable mass deoxyadenosine monophosphate well as differences between those products and US brand inhalers. These differences highlight the fact that even though the labeled dose for the albuterol inhalers may be the like ( 100 µg for each of the Mexican inhalers ), the pharmaceutical product performance is not necessarily the same. This is because the product performance ( respirable and nonrespirable aggregate ) is a function of the formulation writing equally well as the meter valve size and actuator design. 16 – 18 Differences in these product characteristics will affect the atomization of the formulation and the result concluding streamlined atom size distribution. For the products tested in this discipline, the average weight of an propulsion was unlike ( Assal, 59.2 ± 3.8 milligram ; Sacrusyt, 67.8 ± 1.8 milligram ; Ventolin, 74.7 ± 0.9 milligram ; Victory, 83.3 ± 1.2 magnesium ; Xeneric-S, 88.3 ± 3.4 magnesium ). frankincense, there are clearly differences for each product with deference to conceptualization and device attributes, and correspondingly, it is not surprise that there are differences in the product operation between the brands tested. Some interest intersection performance findings were uncovered in this analysis, the most authoritative of which involved the measurement of how much drug per propulsion could reach a patient ’ second lungs ( respirable mass ). respective margin town–purchased products performed comparably in base respirable aggregate to the US pioneer inhalers ( Sacrusyt vs US Ventolin HFA, Assal vs US Ventolin HFA, Victory vs US Proventil HFA ; P > .05 ). beyond that, the Victory inhaler exhibited importantly higher base respirable multitude than the US Ventolin HFA intersection. Assal products performed most erratically having the widest rate of variability in mean total drug. last, the non-US Ventolin merchandise was the most expensive but did not perform the best among the border township inhalers in mean full venereal disease and was far detected to actuate the lowest average respirable bulk of all the bound town sample products. What clinical implications these pharmaceutical differences represent are ill-defined. The statistical differences found seemed to point out that a patient could receive a lower acid or lower sum of respirable drug from one edge town product to the next. however, the absolute differences were not so capital that any product could be assumed clinically ineffective. In the United States, the 3 branded albuterol MDI products ( Proventil HFA, Ventolin HFA, and ProAir HFA ) are labeled with the same acid but are not considered exchangeable. If immediately compared, merchandise performance and clinical differences could be found among the 3 US brands. Yet any of those products are still considered clinically effective. In the same light, the frame town products may silent perform within a clinically effective image, even when statistical total acid or respirable mass differences were found. The question regarding the spirometric differences and bioinequivalence that Leon-Molina et alabama found between 2 albuterol MDI products available in Mexico remains unsolved. 14 The non-US Ventolin demonstrated superior results for clinical efficacy parameters compared with that of Assal, and it was posited that pharmaceutical parameters may explain these differences. however, the pharmaceutical timbre results here did not corroborate those findings. While non-US Ventolin propulsion provided a higher mean total dose than that of Assal, it besides delivered a significantly lower respirable mass than Assal .

Limitations

due to travel distance, cost, and other logistics, the inhalers were only obtained from Nogales, Mexico, although it is probable that many of the brands would be found in early border towns. It may be worthwhile to test a larger act of sample distribution inhalers, include a assortment of mexican bound towns, and include canadian products, where many Americans living in the northern United States may travel to get cheaper inhalers. In addition, while multiple set numbers for most of the samples were tested, multiple lots of Sacrusyt inhalers were unable to be obtained due to lack of handiness .

Conclusion

mexican edge town inhalers are much more low-cost than the US comparatives, and equally long as less expensive generic albuterol MDIs remain unavailable in the United States, some Americans are going to continue to travel to get the cheapest medications they can. Although the border town–obtained inhalers varied importantly in pharmaceutical performance from one another and from US products, they still contained albuterol, the ask bronchodilator. Despite labeling differences regarding dose between the Mexican and US products, the mean respirable mass measurements ( per propulsion ) of some of the border township inhalers were broadly comparable to the US pioneer MDIs. The refer is inactive, however, the uncertain repercussions in clinical efficacy that these differences in full dose and in respirable bulk may imply. Since there was appreciable unevenness in the mexican surround town–obtained albuterol MDI products, clinicians and patients engaging in aesculapian tourism should be aware of the potential differences in pharmaceutical performance and potentially therapeutic efficacy .

Footnotes

Authors’ Note: This learn was presented as a post horse at ASHP ’ s 2014 Midyear Clinical Meeting and Exhibition and abstract accepted for publication on ASHP ’ sulfur 2014 Midyear Meeting Website.

Declaration of Conflicting Interests: The generator ( s ) declared no electric potential conflicts of concern with regard to the inquiry, writing, and/or publication of this article. Funding: The writer ( randomness ) received no fiscal hold for the research, authorship, and/or publication of this article .

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