Development and evaluation of a tampering resistant transdermal fentanyl patch
Graphical abstract
Introduction
The misuse and abuse of prescription opioid products have been medical concerns for many years. Fentanyl is one of the most abused opioids: a survey published in 2010 revealed that the number of emergency visits related to the non-medical use of the fentanyl has increased 105% during 2004–2008 in United States (Anonymous, 2010a). Although the transdermal fentanyl gained a lot of patient compliance for its non-invasive and around-the-clock treatment, the number of abuse cases on these patches increase significantly, causing dose dumping and thus serious side effects (Carson et al., 2010, Moon and Chun, 2011, Prosser et al., 2010, Woodall et al., 2008). Commonly, abusers override the controlled release mechanisms of the patches in order to obtain fast on-set euphoria by oral ingestion, injection and inhalation (Butler et al., 2011, Mastropietro and Omidian, 2013). To address the growing problem of the nonmedical use of fentanyl, there is a need for transdermal formulations that could reduce abuse potential and the risk of dose dumping (Howard and Reidenberg, 2004, Kugelmann and Bartholomaeus, 2006, Tavares et al., 2011).
Several tamper-resistant patches have been designed to solve this problem. Patent documents WO2004098568 A2, US7182955 B2 and US8790689 B2 describe transdermal dosage forms with a separated compartment containing antagonist/aversive agent (Hart et al., 2007, Howard and Reidenberg, 2004, Howard and Reidenberg, 2005). The antagonists or aversive agents are not liberated if the patch is correctly used but will release along with the opioids if the patch formulation is tampered. US7511054 B2 illustrates a dosage form that contains opioid pro-drugs and a form of antagonist poorly absorbed through the skin (Stinchcomb et al., 2009). The antagonist would be minimally delivered transdermally but would take effect when the dosage form is tampered with. As the tamper-resistance of the product will never be absolute, researchers are endeavoring to find better formulations that will further reduce the abuse potential without compromising the efficacy of drug administration.
Geopolymers, a type of ceramic materials, are composed of three-dimensional networks of SiO4 and AlO4. Previous studies have suggested that geopolymers could be used as a drug carrier for controlled-release for oral formulation with better tamper-resistance than the compared commercial tablet (Cai et al., 2014, Jämstorp et al., 2010). For the geopolymer-based drug carrier, diffusion is the main rate-limiting step of drug release (Jämstorp et al., 2010, Jämstorp et al., 2011). The physical properties of geopolymer, such as porosity and mechanical strength, could be adjusted by changing its composition and synthesis condition. Our previous study showed that these geopolymer-based formulations could maintain controlled drug release even after milled into fine granules (Cai et al., 2014). Moreover, in comparison to the commercial tablet based on a polymer matrix, these formulations had better resistance against the extraction in heated water. In Cai et al. (2014), geopolymer showed its ability to increase the resistance of oral dosage forms against some common tampering methods and reduce the risk of dose dumping.
This study aims to evaluate geopolymer-integrated transdermal patch in its resistance to tampering. To our knowledge, this is the first attempt to integrate ceramics into the matrix of transdermal patches to reduce their abuse potential. The transdermal patch formulation that contains geopolymer granules in the matrix layer was expected to have better tamper-resistance against some common abuse methods without compromising the efficiency of drug delivery, as schematically illustrated in Fig. 1.
Section snippets
Materials
Kaolin (Al2Si2O5(OH)4), fumed silica (SiO2, 7 nm particle size), reagent grade sodium hydroxide (NaOH), monopotassium phosphate (KH2PO4), 37% fuming hydrochloric acid (HCl) and 99.5% ethanol were purchased from Sigma–Aldrich. Fentanyl base (MacFarlan and Smith, Edinburgh, UK) was donated by Orexo AB, Sweden. DuroTak® 87-4098 were obtained from National Starch Chemicals (Bridgewater, U.S.). A commercially available fentanyl patch, Durogesic® (Janssen-Cilag, Belgium) was used for comparison.
Synthesis
The
Evaluation of resistance to tampering and in vivo drug absorption from geopolymer granules
The drug extraction from Patch C and geopolymer granules with particle size ranges of 315–710 μm was estimated in phosphate buffer and 50% ethanol solution at 37 °C (Fig. 2). In both media, the drug releases from geopolymer granules with particle size range of 315–710 μm were slower than that from commercial patch: Patch C released all drug content within 1 h (Fig. 2). It suggested that geopolymer, as an inert and unswellable matrix, had better resistance to extraction than commercial patch. The
Conclusion
As the abuse problems related to transdermal opioid formulation increases, new solution to increase resistance to tampering is needed. In this paper, a patch technology with drug loaded geopolymer granules incorporated into the adhesive matrix is presented. To our knowledge, this is the first attempt to blend ceramic materials into the adhesive to improve the resistance to tampering. The geopolymer granules showed a better resistance to extraction and gave a similar in vivo response as a
Acknowledgements
This work has received support from Orexo AB for kind contribution of the materials and Sweden’s Innovation Agency (VINNOVA) and the Swedish Research Council (2011-3399 and 2011-4444) for financial contributions. Karin Söderkvist, Anders Sågström, Cecilia Coupland, Sari Öbrink, Ulrica Roos are acknowledged for some of the experimental works.
References (25)
- et al.
Evaluation of the resistance of a geopolymer-based drug delivery system to tampering
Int. J. Pharm.
(2014) - et al.
A fatality involving an unusual route of fentanyl delivery: chewing and aspirating the transdermal patch
Legal Med. (Tokyo, Japan)
(2010) - et al.
Mechanically strong geopolymers offer new possibilities in treatment of chronic pain
J. Controlled Release
(2010) - et al.
Modeling structure–function relationships for diffusive drug transport in inert porous geopolymer matrices
J. Pharm. Sci.
(2011) - et al.
Polymer excipients enable sustained drug release in low pH from mechanically strong inorganic geopolymers
Results Pharm. Sci.
(2012) - et al.
Transdermal drug delivery: principles and opioid therapy
Contin. Educ. Anaesth. Crit. Care Pain
(2007) - et al.
Fentanyl intoxication caused by abuse of transdermal fentanyl
J. Emerg. Med.
(2011) - et al.
Validated GC–MS analysis for the determination of residual fentanyl in applied Durogesic reservoir and Durogesic D-Trans matrix transdermal fentanyl patches
J. Chromatogr. B: Anal. Technol. Biomed. Life Sci.
(2007) The DAWN Report: Trends in Emergency Department Visits Involving Nonmedical Use of Narcotic Pain Relievers
(2010)Guidance for Industry Assessment of Abuse Potential of Drugs
Guidance for Industry Abuse-Deterrent Opioids – Evaluation and Labeling, Draft Guidance
Abuse risks and routes of administration of different prescription opioid compounds and formulations
Harm Reduct. J.
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