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IMPROVING COMPLIANCE AND ACCESS TO NITROGLYCERIN AND ASPIRIN IN PEOPLE WITH CORONARY ARTERY DISEASE: DEVELOPMENT AND VALIDATION OF THE SMHEARTCARD SYSTEM

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Abstract

Nitroglycerin is a potent vasodilatory drug used to alleviate chest pain. The American Heart Association Guidelines recommend patients with coronary artery disease (CAD) carry and use both aspirin (ASA) and nitroglycerin at the onset of chest pain. However, a recent Canadian survey revealed only 20% of patients with CAD carried the recommended medication. A novel pill holder, SMHeartCard, was developed to provide a convenient way to immediately access nitroglycerin tablets and ASA in wallets, pockets, and purses. We demonstrate that throughout a 12 week testing period, Nitrostat® pills stored in the SMHeartCard system with complete PTFE or borosilicate glass enclosure performed similarly to those stored in the original packaging across a range of temperatures relevant to on person carriage in a pocket or wallet. In contrast, enclosing Nitrostat® pills in Polyethylene significantly reduced nitroglycerin release. These results validate the SMHeartCardTM storage system for use in constant temperatures ranging from 4 to 35°C, and show that short (<1 week) exposure to temperatures of up to 60°C do not impair SMHeartCardTM stored Nitrostat® performance.
Figure 1: SMHeartCardTM.
Improving Compliance and Access to Nitroglycerin and Aspirin in People with Coronary Artery Disease:
Development and Validation of the SMHeartCardTM System
Tyson Le MSc1, John R. Mackey MD2, Ian Paterson MD2, and Neal M. Davies PhD1
University of Alberta, Faculties of 1) Pharmacy and Pharmaceutical Sciences and 2) Medicine and Dentistry
Heat Flow
A microcalorimeter was used to measure the heat flow of the Nitrostat® pills in various temperatures.
Storage Conditions
Nitrostat® pills were stored as in the original Pfizer packaging (control), SMHeartCardTM with inserts made from
polytetrafluoroethylene (PTFE; a synthetic fluoropolymer), borosilicate glass, and polyethelene (PE). Temperatures
tested were 4°C, room temperature (22°C), and 35°C, stored with and without N2 gas to replace atmospheric
oxygen. Pills were stored for 1, 2, 4, 8, and 12 weeks before subjected to release tests to evaluate the
performance.
Release Test
A 0.45 µm synthetic hydrophobic PVDF membrane was briefly soaked in octanol to create a partition replicating a
mucosal membrane. The membrane was assembled in a Franz cell with a Nitrostat® pill and 1 mL of water in the
sample holder. The water jacket of the Franz cells were kept at 37.4°C with the magnet stirrer spinning at 600 rpm.
Samples are collected through a sampling port with a needle at 2, 5, 10, 20, 30, and 60 min.
Analytical Method
The HPLC method was adapted from USP3 with some slight modifications. A C18 column was used with a mobile
phase of methanol in water 45:55 on a Shimadzu HPLC with a UV detector at 210 nm. An injection volume of 50
µL was used with a flow rate of 0.75 mL/min.
The purpose of this study was to evaluate the materials used to construct the SMHeartCardTM and to investigate
the performance of Nitrostat® pills in various storage conditions.
Results
Hypothesis
Nitrostat® pills stored within the SmHeartCardTM do not degrade significantly faster than those stored in
their original borosilicate glass packaging container at room temperature.
Conclusions
We demonstrate that throughout a 12 week testing period, Nitrostat® pills stored in the SMHeartCardTM system with complete
PTFE or borosilicate glass enclosure performed similarly to those stored in the original packaging across a range of
temperatures relevant to on person carriage in a pocket or wallet. In contrast, enclosing Nitrostat® pills in Polyethylene
significantly reduced nitroglycerin release. These results validate the SMHeartCardTM storage system for use in constant
temperatures ranging from 4 to 35°C, and show that short (<1 week) exposure to temperatures of up to 50°C do not impair
SMHeartCardTM stored Nitrostat® performance.
References
1.O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. J
Am College Cardiol 2013;61:e78-140.
2.Horseman C, Frederick T. Poor compliance with carrying nitroglycerin and aspirin in patients with coronary artery disease. Can J
Cardiol 2018;34:945.e1.
3.“The United States Pharmacopeia,” 37th rev., The United States Pharmacopeia Convention., Rockville, MD., 2014, p. 4009.
Introduction
Purpose
Materials and Methods
Nitroglycerin is a potent vasodilatory drug used to alleviate chest pain. The American Heart Association
Guidelines1 recommend patients with coronary artery disease (CAD) to carry and use both aspirin (ASA) and
nitroglycerin at the occurrence of pain. However, a recent Canadian survey revealed only 20% of patients with
CAD carried the recommended medication2. A novel pill holder, SMHeartCardTM (figure 1), was developed to
provide a convenient way to immediately access nitroglycerin tablets and ASA in wallets, pockets, and purses.
HPLC
Analysis
Figure 2: Release test work flow.
Figure 4: Heat flow of Nitrostat® at various temperatures for 1
week from the microcalorimeter.
Figure 6: Release profiles of Nitrostat® in original glass packaging, SMHeartCardTM enclosed with PTFE or PE at room temperature (22°C),
or 35°C at week 1 (a), week 4 (b), and week 12 (c). (n=6 mean±SEM).
Figure 5: Release profiles of Nitrostat® at various temperatures from the
microcalorimeter. (n=6 mean±SEM).
Figure 3: Minimum and maximum pocket temperature measured
with ThermPro -TP50 Digital LCD Indoor Thermometer
Hygrometer Humidity Meter.
Table 1 : F2 values comparing mean cumulative percent release of Nitroglycerin from the original glass packaging (OG) at room temperature
(RT) and different test conditions. Glass = borosilicate glass enclosed. (n=6 mean±SEM).
a) b)
c)
On person carriage of SMHeartCardTM in shirt and pant
pockets in winter and summer experienced temperature
extremes ranging from 17.2°C to 32.4°C. Nitrostat® pills performed similarly to original packaging at room temperature for all storage conditions, except when enclosed in
PE. N2 packing made no difference in Nitrostat® performance.
TM
TM
T e m p e r a tu r e ( ° C )
Winter
Summer
0
1 0
2 0
3 0
4 0
Nitrostat ® was chemically stable for one week at 45°C and
50°C, and N2 packaging did not improve stability. At 60°C
Nitrostat ® demonstrated time dependent chemical changes.
0
20
40
60
80
100
120
0 20 40 60 80
Normalized Cumulative Release
(%)
Time
(min)
Week 1
original glass
packaging
room
temperature
Week 1 PTFE
enclosed
room
temperature
Week 1 PTFE
enclosed
35°C
Week 1 PE
enclosed
35°C
0
20
40
60
80
100
120
0 20 40 60 80
Normalized Cumulative Release
(%)
Time
(min)
Week 4 original
glass packaging
room
temperature
Week 4 PTFE
enclosed room
temperature
Week 4 PTFE
enclosed 35°C
Week 4 PE
enclosed 35°C
0
20
40
60
80
100
120
0 20 40 60 80
Normalized Cumulative Release
(%)
Time
(min)
Week 12 original
glass packaging room
temperature
Week 12 PTFE
enclosed room
temperature
Week 12 PTFE
enclosed 35°C
Week 12 PE enclosed
35°C
0.000# 2.000# 4.000# 6.000# 8.000# 10.000#
230#nm#
Comparison
Similarity factor (f2)
Week 1 Week 2 Week 4 Week 8 Week 12
OG vs PTFE RT
64.6 SIMILAR 69.4 SIMILAR 84.6 SIMILAR 86.6 SIMILAR 87.6 SIMILAR
OG vs Glass RT
46.9
NOT
SIMILAR 59.8 SIMILAR 66.1 SIMILAR 69.5 SIMILAR 85.8 SIMILAR
OG vs PTFE 4°C
68.5 SIMILAR 76.1 SIMILAR 67.4 SIMILAR 68.9 SIMILAR 80.1 SIMILAR
OG vs Glass 4°C
53.2 SIMILAR 59.6 SIMILAR 75.6 SIMILAR 85.0 SIMILAR 73.5 SIMILAR
OG vs PTFE 35°C
62.3 SIMILAR 78.2 SIMILAR 71.1 SIMILAR 95.1 SIMILAR 64.8 SIMILAR
OG vs PE 35°C
77.4 SIMILAR 82.3 SIMILAR 44.3
NOT
SIMILAR 46.3
NOT
SIMILAR 45.0
NOT
SIMILAR
OG vs Glass 35°C
46.7
NOT
SIMILAR 71.4 SIMILAR 64.1 SIMILAR 82.2 SIMILAR 58.1 SIMILAR
OG vs PTFE + N2
35°C
58.8 SIMILAR 78.7 SIMILAR 65.1 SIMILAR 75.7 SIMILAR 84.2 SIMILAR
OG vs Glass + N2
35°C
55.0 SIMILAR 61.2 SIMILAR 75.8 SIMILAR 62.0 SIMILAR 77.1 SIMILAR
-0.001
-0.0008
-0.0006
-0.0004
-0.0002
0
0.0002
-20 30 80 130 180
Heat Flow
(W)
Time
(Hr)
45°C -N2 for 1
week
45°C +N2 for
1 week
50°C for 1
week
60°C for 1
week
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70
Cumulative Nitroglycerin Release
(%)
Time
(min)
45°C - N2 for 1 week
45°C + N2 for 1 week
50°C for 1 week
60°C for 1 week
®