Hydrophilic matrices are a popular and extensively used strategy for oral extended-release (ER) drug delivery. Hypromellose (hydroxypropyl methylcellulose, HPMC) is the polymer of choice as the rate-controlling carrier (1). In addition to HPMC, polyethylene oxide (PEO) has been used as a matrix-forming polymer (2, 3). These excipients are nontoxic and have pH-independent hydration and swelling, good compressibility and lubricity, and versatility due to a wide range of molecular weights. PEO polymers have global regulatory acceptance and can be utilized for modulating the release of drugs at various solubilities and doses (1–13).
When in contact with water, PEO hydrates rapidly, swells to a large extent and forms a gelatinous barrier layer around the tablet (15). Drug release from the PEO matrices is generally controlled by diffusion of the drug through the swollen gel at the surface of the tablet and/or gel erosion (9, 16). The rates of wetting, swelling and erosion are controlled by polymer molecular weight and other ingredients within the matrix (17).Rapid polymer hydration and uniform gel formation are critical to the performance of hydrophilic matrix systems (18). It is also crucial to take into account the type of dissolution media the tablets are exposed to, because it may affect polymer hydration and gel formation.
Alcoholic beverages have been consumed for thousands of years, and a United Kingdom National Health Service survey indicated that 73% of men and 57% of women (aged 16 and over) had alcoholic drinks on at least one day per week (19). In another report, US statistical data showed that around 50% of the American population routinely consumed alcoholic beverages (20).
The potential effect of alcoholic drinks in significantly accelerating drug release from ER oral formulations has been of some concern (21). It is known that alcohol has an influence on the absorption, metabolism and excretion of drugs, which can potentially lead to adverse side effects (22). Toxicity is most often associated with acute intake rather than longer-term consumption of alcohol, but both patterns can impact the toxico-kinetics of concomitantly administered medicines (23).
ER formulations, which are intended for once or twice daily administration, are designed with a higher unit dose of the drug than conventional formulations. Therefore, it is imperative that retardation properties are tightly controlled to ensure that a rapid release of the drug, or dose dumping, cannot occur.
In July 2005, FDA published an alert for healthcare professionals regarding the negative effect of alcoholic drinks on drug release from Palladone (hydromorphone). Alcohol breaks down the ER formulation, and, as a result, increases peak plasma concentration causing potentially lethal dose dumping (24). Several publications have outlined the influence of hydro-alcoholic media on the performance of solid oral ER systems in the years since the FDA alert.
According to Fadda et al., vulnerable formulations are likely to cause adverse pharmacokinetic and therapeutic outcomes in patients on exposure to alcoholic solutions. The extent of the adverse reaction depends on the drug, polymer, and excipients in the formulation (25, 26). Some oral ER dosage forms contain drugs and excipients that exhibit a higher solubility in aqueous solutions containing ethanol. Accordingly, such products may be expected to exhibit more rapid drug dissolution and release in the presence of ingested ethanol (27).
Koziara et al. reported an increased permeability, elasticity, and swelling of cellulose acetate semipermeable membranes used for osmotic drug delivery in 0-60% ethanol solutions (28). Although drug release from the analyzed osmotic-controlled release oral deilvery systems increased slightly, it was fully controlled, and no morphological changes to the dosage form occurred. The system maintained its functionality, and no potential for dose dumping was reported.
Roberts et al. studied the influence of alcohol on the release of aspirin from HPMC matrix tablets (29). They found that ethanol retarded hydration of the polymer and produced a more rapid initial drug dissolution but overall did not result in dose-dumping.
The influence of ethanol on the in vitro release of opioid drugs from various ER formulations (e.g., tablets, capsules, and suspensions) was examined by Walden et al. An extrapolation of the findings to the likely outcome in vivo indicated no risk of dose dumping (27).
Traynor et al. studied the potential for dose dumping in hydro-alcoholic media from three commercially available opioid analgesic (tramadol) formulations. The formulations provided 24-h dissolution using release-controlling coatings (30). The authors found that for two products (Ultram ER tablets and T-long capsules), the release of tramadol significantly increased in the presence of alcohol. Conversely, a decrease in the rate of drug release in hydro-alcoholic media was recorded for Tridural ER tablets.
Skalsky et al. analyzed the effect of alcoholic beverage concentrations up to 40% (v/v) on model highly water-soluble drugs, diltiazem hydrochloride (HCl) and metoprolol succinate, using both methacrylic copolymers and HPMC in matrix formulations (22). Drug- release behavior was unchanged in all media. However, the authors suggested a significant difficulty in correlating in vitro data to potential in vivo results due to the unpredictable effect of alcohol on absorption, metabolism, and excretion from the human body.
Levina et al. investigated the effect of hydro-alcoholic solutions on hydration, gel formation, and drug release from HPMC ER tablets and reported that hydro-alcoholic media containing up to 40% ethanol did not affect the performance of the matrices (18). Investigation of the effect of hydro-alcoholic solutions on textural and rheological properties of various controlled-release grades of hypromellose was also described by Missaghi et al. (31).
According to Ager et al., the effect of ethanol on pseudoephedrine HCl from HPMC ER matrix systems depended on the qualitative and quantitative composition of the tablets (32). The authors claimed that the drug release may be affected when using a filler with decreased solubility in ethanol (e.g., lactose or starch) and formulations containing fillers that have both poor aqueous and ethanol solubility (e.g., microcrystalline cellulose) might have no effect on drug release.
The influence of hydro-alcoholic media on PEO ER matrices has not yet been investigated. This research studies the influence of hydro-alcoholic media on the hydration and swelling properties of pure PEO compacts manufactured using different viscosity grade of Polyox, and drug release from ER matrices using two model drugs with different aqueous solubilities.