Research PaperAlcohol dose dumping: The influence of ethanol on hot-melt extruded pellets comprising solid lipids
Introduction
Alcohol-induced dose dumping of controlled-release oral dosage forms containing opioid and non-opioid drugs with narrow therapeutic ranges is a significant challenge in the formulation development. Since alcohol may alter the release-rate-controlling mechanism of the formulation, possibly resulting in an immediate and uncontrolled drug release, the concomitant intake of alcoholic beverages together with such dosage forms poses a serious safety concern. This phenomenon, known as alcohol-induced dose dumping (ADD), can have dangerous effects [1]. Particularly susceptible are controlled-release formulations that contain a high total amount of API in order to reduce the dosing frequency and prolong the therapeutic effect. In 2005, Palladone™, a hydromorphone modified-release capsule formulation, was withdrawn from the US market, since taking it together with alcohol drastically increased the peak plasma concentrations of hydromorphone by causing failure in the release-rate-controlling mechanism [2]. Such opioid-overdose may lead to respiratory depression followed by hypoxia and even death [3]. To test for possible alcohol dose dumping effects, the Food and Drug Administration (FDA) recommends to conduct in vitro drug release studies in ethanolic media of controlled-release dosage forms containing opioid and non-opioid drugs with a narrow therapeutic range [1], [4].
To date, only a limited number of robust single unit dosage forms [5], such as osmotic drug delivery devices [6], [7] and controlled-release matrix systems [8], [9], [10], [11], [12], [13], [14], [15] that can withstand the effect of alcohol, are available. For the former one, a controlled-release tablet formulation of oral hydromorphone was developed using a patented oral osmotic (OROS®) Push–Pull delivery system [6]. It was shown that the controlled-release properties remained unchanged in the presence of alcohol and no dose dumping of hydromorphone occurred [6]. The same effect was reported by Koziara et al. [7]: although increasing ethanol concentrations up to 60% caused a slight increase in the drug release of OROS® systems, controlled-release properties of the drug delivery system remained unaffected and no dose dumping occurred. This could be attributed to the specific OROS® technology, which is designed such that the drug release rate is actively controlled by the dosage form, regardless of such environmental factors as gastrointestinal motility, surrounding pH and presence of food and alcohol [16]. In the field of matrix systems and alcohol-robust controlled-release matrix tablets, hydrophilic polymers (e.g., polyethylene oxide [8], cross-linked high amylose starch [9], carbomer [10] and hypromellose [11], [12], [13], [14], [15]) can be used. Insoluble in EtOH, they are expected to remain unaffected when consumed together with alcohol.
Currently, only one multiple unit dosage form is available that can withstand the influence of alcohol and remain intact in the course of the drug release process. It comprises theophylline pellets coated with Aquacoat® ARC (Alcohol Resistant Coating), which consists of guar gum blended with Aquacoat® ECD (Ethylcellulose Aqueous Dispersion) [17]. Insoluble in alcohol, guar gum acts as a protective layer for the alcohol-soluble ethylcellulose, leaving the controlled-release film intact. Similar controlled-release drug rates were obtained at all tested EtOH concentrations levels (10%, 20%, 40%), confirming the robustness of the coating system [17].
However, to our knowledge, no literature exists concerning the development of uncoated alcohol-resistant multiple unit dosage forms with sustained-release. To fill this gap, in this study we investigated the influence of ethanol on the in vitro drug release behavior of hot-melt extruded pellets. Hot-melt extrusion (HME) is a promising technology for the preparation of alcohol-resistant controlling dosage forms. For example, Roth et al. developed the innovative sustained-release Verapamil Meltrex® formulation [18]. The in vitro dissolution studies indicated that ethanolic media (5%, 20% and 40% (v/v)) did not affect the drug release rate after 8 h in dissolution media. The authors concluded that the melt-extruded tablets remained intact in the in vitro environment and no dose dumping occurred [18].
The hot-melt extruded pellets prepared in our study were composed of the well-characterized analgesic and antipyretic drug paracetamol and the opioid analgesic drug codeine phosphate as model active pharmaceutical ingredients (APIs) and vegetable calcium stearate (CaSt) as a matrix carrier. Being a mixture of water-insoluble calcium salts of stearic and palmitic acid, CaSt is primarily used as a lubricant in tablet and capsule formulations [19]. However, Roblegg et al. demonstrated that CaSt could be used as a pelletisation matrix carrier for spherical slow-release pellets using the wet extrusion/spheronisation technique [20]. Another study by Roblegg et al. established that controlled-release spherical CaSt pellets could be produced via HME [21]. It was demonstrated that CaSt retarded the drug release to a significant extent and by adding plasticizers the in vitro release profile could be tailored as desired [21]. Due to its hydrophobic nature, CaSt is insoluble in water and ethanol and is a promising matrix system for alcohol-resistant formulations.
In the current study, two ethanol- and water-insoluble solid lipids (Compritol® and Precirol®), which are suitable for hot-melt extrusion [22], [23] were incorporated to form a robust/compact multiple unit dosage form resistant to ethanol. As calcium stearate shows a very high melting point, it is not expected to melt during HME. Hence, the low melting lipids Compritol® and Precirol® were incorporated which melt during the process and therefore, act as binders. All formulations were tested regarding their release characteristics in the presence of ethanol. The main goal was to achieve a better understanding of how alcohol interacts with the formulation, which is the basis for a rational formulation design. To that end, media uptake and wetting behavior upon exposure to ethanolic media were examined. Furthermore, the pellet surface properties and internal morphology were studied via scanning electron microscopy (SEM).
Section snippets
Materials
Paracetamol and codeine phosphate hemihydrates donated by G.L. Pharma GmbH, Lannach, Austria were used as model APIs. The matrix carrier system was vegetable calcium stearate (stearic acid 44% and palmitic acid 54%, EP) purchased from Werba-Chem GmbH, Vienna, Austria. The solid lipids Precirol® ATO 5 (glycerol distearate) and Compritol® 888 ATO (glycerol dibehenate) were supplied by Gattefossé, Weil am Rhein, Germany. The in vitro drug release studies were carried out with 0.1 N hydrochloric
Preparation of pellets via HME
The CaSt/paracetamol blend was extruded at a temperature ranging from 100 to 130 °C, and the evaluated torque value was 16%. The temperature profile was chosen according to the softening temperature of CaSt (i.e., around 120 °C) as it was previously shown that paracetamol does not act as plasticizer in this system [21]. At this temperature range cuttable extrudates with a suitable melt viscosity were obtained. For the CaSt/codeine phosphate blend, however, the extrusion temperature had to be
Conclusions
Alcohol-induced dose dumping of controlled-release oral dosage forms is a significant challenge in formulation development. Thus, the objective of this study was to investigate the interaction between ethanol and a multiple-unit pellet formulation, using various hydrophobic lipids (i.e., pure CaSt, CaSt with either Compritol® or Precirol®) as matrix carriers for HME. Highly ethanol-soluble paracetamol and codeine phosphate, having a lower solubility in alcoholic media than in acidic media, were
Conflict of interest
The authors report no conflicts of interest.
Acknowledgements
This work was funded under the Austrian COMET Program by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry of Economy, Family and Youth (BMWFJ) and by the State of Styria (Styrian Funding Agency SFG).
The authors would like to thank G.L. Pharma GmbH (Lannach, Austria) for providing the model drug paracetamol, the extrusion team at the RCPE GmbH, Graz, Austria for their assistance with the hot-melt extrusion process and Ing. H.
References (51)
- et al.
The design of controlled-release formulations resistant to alcohol-induced dose dumping – a review
Eur. J. Pharm. Biopharm.
(2014) - et al.
Aqueous and hydro-alcoholic media effects on polyols
Colloids Surf. B. Biointerfaces
(2013) - et al.
Influence of ethanol on aspirin release from hypromellose matrices
Int. J. Pharm.
(2007) - et al.
Ethanol effects on drug release from Verapamil Meltrex, an innovative melt extruded formulation
Int. J. Pharm.
(2009) - et al.
Development of lipophilic calcium stearate pellets using ibuprofen as model drug
Eur. J. Pharm. Biopharm.
(2010) - et al.
Development of sustained-release lipophilic calcium stearate pellets via hot melt extrusion
Eur. J. Pharm. Biopharm.
(2011) - et al.
In-line implementation of an image-based particle size measurement tool to monitor hot-melt extruded pellets
Int. J. Pharm.
(2014) - et al.
Drug release mechanisms of compressed lipid implants
Int. J. Pharm.
(2011) - et al.
Characterisation of solid dispersions of paracetamol and EUDRAGIT® E prepared by hot-melt extrusion using thermal, microthermal and spectroscopic analysis
Int. J. Pharm.
(2008) - et al.
Characterization of ibuprofen as a nontraditional plasticizer of ethyl cellulose
J. Pharm. Sci.
(2002)
A new pure paracetamol for direct compression: the orthorhombic form
Int. J. Pharm.
Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution
J. Pharm. Sci.
An investigation into the effects of thermal history on the crystallisation behaviour of amorphous paracetamol
Eur. J. Pharm. Biopharm.
Solid-state transformation of the pseudopolymorphic forms of codeine phosphate hemihydrate and codeine phosphate sesquihydrate monitored by vibrational spectroscopy and thermal analysis
J. Mol. Struct.
Physical and thermal characterisation of Precirol® and Compritol® as lipophilic glycerides used for the preparation of controlled-release matrix pellets
Int. J. Pharm.
Solid lipid extrudates as sustained-release matrices: The effect of surface structure on drug release properties
Eur. J. Pharm. Sci.
Solid lipid extrusion of sustained release dosage forms
Eur. J. Pharm. Biopharm.
Understanding the solid-state behaviour of triglyceride solid lipid extrudates and its influence on dissolution
Eur. J. Pharm. Biopharm.
Solubility of organic solutes in ethanol/water mixtures
J. Pharm. Sci.
Correlation between wettability and dissolution rate of pharmaceutical powders
Int. J. Pharm.
Wetting properties of bile salt solutions and dissolution media
J. Pharm. Sci.
The effect of the drying temperature on the properties of wet-extruded calcium stearate pellets: Pellet microstructure, drug distribution, solid state and drug dissolution
Int. J. Pharm.
Mechanisms of fatal opioid overdose
Addiction
Cited by (18)
Ethanol-induced dose dumping from sodium alginate matrix tablets: Investigation of the effects of medium viscosity and pH
2023, International Journal of PharmaceuticsCitation Excerpt :Thus, the ruggedness towards ethanol-induced dose dumping has become essential for developing safe and effective MR excipients and formulations for oral delivery. Several studies have investigated the effect of ethanol on the release of drugs from matrix systems (Ali et al., 2020; Asare-Addo et al., 2013; Butreddy et al., 2020; Jedinger et al., 2015; Kozak et al., 2019; Lazzari et al., 2018; Levina et al., 2007; Lochař et al., 2020; Mawla et al., 2020; Nep et al., 2018; Palmer et al., 2011; Rahim et al., 2013; Roberts et al., 2007; Schrank et al., 2016), film-coated dosage (Al-Zoubi et al., 2019; Endres et al., 2021; Jedinger et al., 2016; Rosiaux et al., 2013a, 2013b), and different marketed oral solid dosage forms (Barkin et al., 2009; Fiske et al., 2012; Friuli et al., 2018; Grady et al., 2018; Johnson et al., 2008; Karunasena et al., 2017; Roth et al., 2009; Smith et al., 2010; Traynor et al., 2008). The US FDA has issued general draft guidance requiring in vitro dissolution of MR products in media comprising ethanol at concentrations up to 40% in 0.1 N HCl for 2 hours (Anand et al., 2011).
Lipids for Taste masking and Taste assessment in pharmaceutical formulations
2021, Chemistry and Physics of LipidsCitation Excerpt :In this case paracetamol or codeine phosphate were taken as active agents along with Compritol® and Precirol®which were added in the matrix and pellets were prepared using hot-melt extrusion method. However, alcohol induced dose dumping was observed from the matrix formulation (Jedinger et al., 2015). Lipids are generally more compatible with most of the drugs and other excipients in the pharmaceutical formulations (Silva et al., 2015; Kumar et al., 2013).
Extended release pellets prepared by hot melt extrusion technique for abuse deterrent potential: Category-1 in-vitro evaluation
2020, International Journal of PharmaceuticsThe effect of alcohol on ionizing and non-ionizing drug release from hydrophilic, lipophilic and dual matrix tablets
2020, Saudi Pharmaceutical JournalThe influence of hydroalcoholic media on the performance of Grewia polysaccharide in sustained release tablets
2017, International Journal of PharmaceuticsPore blocking: An innovative formulation strategy for the design of alcohol resistant multi-particulate dosage forms
2016, International Journal of PharmaceuticsCitation Excerpt :Thereby, the final pellet pore structure and the corresponding porosity are modified, which strongly affects the drug release. As COP-h is soluble in water/ethanol mixtures (Jedinger et al., 2015b) (i.e., the granulation liquid), it can be assumed that a certain amount of COP-h was dissolved during wet massing. Most likely, this amount was rather low, since CaSt, which was present to a far higher content, competed for liquid absorption (Schrank et al., 2012).