Telmisartan Tablets Repackaged into Dose Administration Aids: Physicochemical Stability under Tropical Conditions

Abstract

Dose administration aids (DAAs) are commonly used to assist patients with chronic disease to manage multiple medications and thus improve adherence. Several brands of telmisartan, commonly prescribed for hypertension, are available in Australia. Manufacturer’s storage advice is to leave tablets in the blister strip until administered to patients. This study aimed to investigate the stability of telmisartan tablets when repackaged and stored in DAAs, to identify a brand, which is sufficiently stable to be repackaged. All available brands of telmisartan tablets in Australia, which contain different excipients, were repackaged into DAAs and stored at 30 °C, 75% RH for 28 days before screening, using visual inspection and physical testing. A candidate brand was then selected for physicochemical and photostability testing using pharmacopoeial methods. Repackaged Mizart^® tablets were shown to be sufficiently stable, when repackaged and stored under tropical conditions (30 °C, 75% RH) for 28 days. Several of the other brands were deemed inappropriate for repackaging, due to physical instability, highlighting the importance of considering not only the drug, but also excipients to ensure the stability of repackaged medicines. Although the repackaging of telmisartan tablets is not advised, this study provides evidence to support the Mizart^® brand as an option for pharmacists to recommend for repackaging.

1. Introduction

Dose administration aids (DAAs) are often recommended in the management of chronic disease, to improve the adherence to multiple medications and thus health outcomes for patients. The repackaging of medications into DAAs, involving their removal from original packaging, results in exposure to environmental conditions, which may adversely affect their stability [1]. The environmental conditions of elevated temperature and relative humidity (RH) can be problematic for medication storage in tropical areas [2]. DAAs provide varying levels of protection from humidity for repackaged medicines, due to lack of hermeticity [3,4], and in tropical areas there is potential for exposure to higher levels of temperature and humidity.

There is a lack of product-specific physicochemical stability data to guide pharmacists and other health professionals when repackaging medications [5]. The removal of medications from original packaging and repackaging into DAAs voids the original expiry dates provided by manufacturers [5]. Although available guidelines provide some general advice on the practice of repackaging medications, the lack of information on specific medications can limit pharmacists’ ability to make informed judgements [5,6].

Several studies have demonstrated the risks of both physical and chemical instability in environments of elevated temperature and humidity. Repackaged atenolol tablets stored at 40 °C, 75% RH for 28 days [7], sodium valproate immediate release (IR) tablets stored at 40 °C, 75% RH for 14 days [8], and warfarin tablets stored at 40 °C, 75% RH for 56 days [9] all failed dissolution tests. The increased dissolution time of a drug is directly associated with reduced bioavailability and may affect therapeutic efficacy [10]. Repackaged dabigatran capsules, stored at 30 °C, 75% RH for 28 days [11] and aspirin tablets, stored at 40 °C, 75% RH [12] failed chemical content tests, and were deemed unsuitable for repackaging into DAAs, due to the potential impact on therapeutic efficacy.

Varying stability has also been demonstrated for different brands of medications that contain the same active pharmaceutical ingredient (API). A study on different brands of repackaged atenolol tablets found that physicochemical response to storage conditions varied across brands of tablets, with the author [7] attributing this to differing formulations and coating, although no mention was made of specific excipients. Investigation into two brands of repackaged clozapine tablets also demonstrated varying API levels between different brands of tablets subjected to identical repackaging and storage conditions [13].

Although once considered inert, excipients are now recognized as impacting therapeutic efficacy [14] and product stability [15], as well as causing adverse reactions in patients [16] and incompatibilities with APIs [17]. Although excipients in compounded products have been studied less, it has been demonstrated for example that the lactose content of commercial tablets compromises the stability of isoniazid in compounded mixtures [18]. A field that remains unexplored is the role excipients play in the stability of repackaged medicines, particularly in humid environments, where moisture permeability of DAAs is generally unknown [19]. Since a wealth of knowledge on the hygroscopicity of excipients exists [20,21,22], these data might enable brand selection, where problems with physical stability have been identified in repackaged medicines, which may not be attributed to the API.

Telmisartan is an antihypertensive and represents 11.5% of the 213,568,055 prescriptions subsidized in the 2020–2021 financial year by the Pharmaceutical Benefits Scheme in Australia [23], with AUD 105.5 million of allocated government funding provided for DAA services for the same period [24]. The manufacturers of telmisartan tablets recommend that their products be stored below 30 °C (some below 25 °C), be protected from light and moisture, and that tablets should not be removed from their foil pack until required for administration [25]. The various brands of telmisartan tablets available in Australia contain different excipients (Table 1) in their formulations. There is currently no data to inform the safe repackaging of telmisartan tablets into DAAs, especially in hot and very humid (30 °C, 75% RH) tropical areas. This study aims to screen brands of telmisartan tablets available in Australia to identify a candidate brand of telmisartan for repackaging and physicochemical stability testing and to make recommendations to pharmacists about repackaging of telmisartan tablets.

Table 1. Comparison of different excipients present in telmisartan tablet brands (NB: all brands also contained povidone, meglumine, sodium hydroxide, and magnesium stearate) [25].

Tablet Brand	Excipient
Micardis®	Sorbitol
DRLA®	Mannitol, Polysorbate 80
APO®	Mannitol, Sodium stearyl fumarate
Mizart®	Mannitol, Sodium stearyl fumarate
GH®	Mannitol, Sodium stearyl fumarate
Teltartan®	Mannitol, Sodium stearyl fumarate
Sandoz®	Lactose, Ludipress
Pharmacor®	Lactose, Crospovidone, Colloidal anhydrous silica

Download the full study as PDF here Telmisartan Tablets Repackaged into Dose Administration Aids: Physicochemical Stability under Tropical Conditions

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Ma, A.P.; Robertson, S.G.; Glass, B.D. Telmisartan Tablets Repackaged into Dose Administration Aids: Physicochemical Stability under Tropical Conditions. Pharmaceutics 2022, 14, 1667. https://doi.org/10.3390/pharmaceutics14081667

excipients formulation