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Research shows that both drug prescription and alcohol consumption increase within the elderly population. It is, therefore, necessary to fully understand the impact of alcohol consumption on solid oral dosage forms, especially extended release formulations.
People have consumed alcoholic drinks for thousands of years and this tradition continues to occupy an important place in many cultures. According to a survey in 2002,1 7–28% of adults in the UK drink alcohol on five or more days a week. US statistical data indicates that a significant proportion of the American population also routinely consumes alcoholic beverages.2
The UK survey shows that older people drink alcohol more frequently than younger people: 21% of men and 11% of women aged 65 years and over had consumed alcohol every day during the week prior to the survey, compared with only 4% of men and 2% of women aged 16–24 years for the same time period. As the prevalence of chronic conditions increase with age, the elderly also consume more drug prescriptions as a percentage of the population for treating cardiovascular, pain management, arthritis and central nervous system conditions. The elderly are also likely to consume more specialized dosage forms because of the continued trend towards extended release (ER) formulations.
These trends make it imperative to understand the impact of alcohol consumption on modified release or ER dosage forms.
Hydrophilic matrix systems are a popular and widely used approach to extending drug release in tablets. Hypromellose (hydroxypropyl methylcellulose [HPMC]) is the most widely used rate-controlling polymer in these systems because of its safety, availability, global compliance and physicochemical/mechanical characteristics.3–6
Upon contact with aqueous media, HPMC polymer hydrates quickly to form a protective gel layer on the matrix surface. Soluble drugs are released primarily by diffusion through this gel layer while actives with low solubility are released primarily by gel erosion. Drug release typically occurs through a combination of these two mechanisms.7,8 Rapid polymer hydration and uniform gel formation are critical to the integrity and subsequent performance of HPMC matrix systems.
Drug release rate from HPMC ER tablets depends on many factors including:
Drug release rate may also be significantly affected by the medium parameters to which the matrix is exposed, prior to, or upon ingestion, including pH, electrolytes, surfactants and enzymes.16–23
Taking into account the impact of dissolution medium on gel formation and, therefore, drug release from HPMC matrices, the influence of hydro-alcoholic media for cases when the dosage may be taken with, shortly before or after an alcoholic drink has been recently investigated in a number of studies.
Accidental poisoning with ER dosage forms, although infrequent, poses special treatment problems that are often not seen with immediate release medication, as failure of an ER product can subject the body to a toxic drug level. Any unintended release of the total or a significant fraction of the active substance from an ER dosage form during a short period of time is referred to as 'dose dumping'.
The likelihood of dose dumping for certain ER products when administered with food has been investigated previously,24–27 and FDA has also issued a report to address the issue.28 However, some limited in vivo studies conducted in the 1980s showed that pharmacokinetics and the release properties of ER dosage forms were not influenced by alcohol.29
Pharmaceutical products and alcohol
Labels warning against the concomitant use of alcohol and products that contain alcohol-interactive (AI) drugs are used where appropriate. For other actives (non-AI) that do not have a pharmacokinetic or pharmacodynamic interaction with alcohol, a warning on the adverse consequence of alcohol consumption caused by the potential for dose dumping may not be present on a product label.30 The study conducted by Pringle et al. found that 19% of AI and 26% of non-AI drug users reported concomitant alcohol consumption.31
In 2005, FDA issued an alert to healthcare professionals regarding an alcohol-Palladone (Purdue Pharma, CT, USA) interaction.32 This alert cited an increase in the peak plasma concentration of the drug, hydromorphone, to potentially lethal levels because of the breakdown of the dosage form when ingested with significant amounts of alcohol (240 mL of 4, 20 or 40% ethanol). A pharmacokinetic study of healthy volunteers showed that co-ingestion of a Palladone capsule with 240 mL of 40% alcohol caused an average peak drug concentration that was approximately six times greater than when taken with water. One subject also experienced a 16-fold increase when the capsule was ingested with 40% alcohol compared with water. In a few volunteers, 240 mL of 4% alcohol (equivalent to two thirds of a typical serving of beer) resulted in almost twice the peak drug plasma concentration compared with when the capsule was ingested with water.
Shortly after the FDA alert, Meyer and Hussain reported an overall lack of attention in pharmaceutical science literature and the regulatory assessment process regarding consumption of alcoholic beverages with certain dosage forms, including ER tablets and capsules.30 FDA has subsequently issued advice to minimize the risk of alcohol-induced dose dumping. Therefore, potential effects on the release characteristics of an active substance by alcohol have to be thoroughly evaluated for currently marketed products and new drug applications that utilize an ER mechanism.
Since the FDA alert, there have been a number of reports on the influence of hydro-alcoholic media on the performance of ER systems.
Koziara et al. claimed increased permeability, elasticity and swelling of cellulose acetate (CA): polyethylene glycol (99:1 w/w) semipermeable membranes used for osmotic ER drug delivery in 0–60% ethanol solutions.33 Although a slight increase in drug release from the OROS (ALZA Corp., CA, USA) ER systems was recorded, the CA membrane maintained its functionality and no dose dumping was observed.
Fadda et al. studied the influence of hydro-ethanolic media on the release of mesalamine from Pentasa (Ferring, Switzerland) tablets comprising ethylcellulose coated granules.34 The time required for releasing 50% of the drug (T50%) was 120 min and 170 min in the absence and presence of ethanol, respectively. This was explained by the lower solubility of mesalamine in the presence of ethanol.
Roberts et al. studied the influence of hydro-ethanolic media on the dissolution rate of aspirin from HPMC (METHOCEL K4M; Dow Chemical Co., MI, USA) matrix tablets.35 They found that aspirin release increased with increasing alcohol concentration in the dissolution media, correlating with the drug's solubility, but did not result in dose dumping. In 40% ethanol, an initial rapid aspirin dissolution rate was reported that was explained by a slower initial interaction between alcohol and HPMC. Using cloud point study results, the authors indicated that ethanol retarded the hydration of the polymer.
Vuong et al. investigated the influence of hydro-alcoholic media on the swelling properties and drug release from HPMC ER matrices.36 The influence of media composition (0–50% v/v ethanol) on the swelling and erosion properties of HPMC (METHOCEL K100 LV CR, K4M CR and K100M CR) compacts was determined using a modified version of the method described by Tahara et al., and Kavanagh and Corrigan.37,38 It was shown that in water and hydro-alcoholic solutions, all compacts underwent swelling and gelation without any disruption to the matrix integrity. The compact wet weight appeared to be similar in water and aqueous ethanol solutions for the METHOCEL grades studied (Figure 1), but the extent of their relative swelling was found to increase with increasing viscosity of HPMC from 100 cps (K100 LV CR) to 4000 cps (K4M CR).
No significant difference in compact swelling was observed for METHOCEL K4M CR and K100M CR, which was further supported by the findings of Missaghi et al. who reported little effect of hydro-alcoholic media (0–40% v/v ethanol) on the textural and rheological performance of HPMC matrices.39,40
Levina et al. (2007) investigated the effect of hydro-alcoholic media on three HPMC ER matrix (12 h release) formulations (metformin HCl 500 mg, felodipine 5 mg and gliclazide 30 mg).41 The manufactured matrices were subjected to 5% or 40% v/v ethanol aqueous solutions for 1 or 12 h. The results were compared with drug release in non-hydro-alcoholic media. The tablets retained their hydrated structural integrity when exposed to 5 and 40% v/v ethanol solutions, respectively, for 12 h without any failure of the matrices resulting in dose dumping.
For felodipine and gliclazide, despite increased solubility in hydro-alcoholic media, drug release profiles remained similar to those in water with f2 values greater than 50, indicating statistical similarity.42,43
When metformin HCl tablets were exposed to 40% v/v ethanol solution for 12 h, a slower drug release was observed compared with exposure to water (Figure 2). This can be explained by a change in drug solubility in the various media. However, when the metformin HCl matrices were exposed to hydro-alcoholic media for only 1 h, the change in drug release profile was not significant.
Following the advice from FDA to minimize the risk of alcohol-induced dose-dumping from modified release dosage forms, the effect of hydro-alcoholic media on HPMC matrices was evaluated. None of the published papers reported dose dumping from HPMC ER tablets in hydro-ethanolic media. The results of the studies reviewed here indicate that well-designed, robust HPMC ER matrix formulations are safe in situations when the dosage form is taken with, shortly before or after the consumption of alcohol.
Marina Levina is Global Technical Manager, Modified Release Technologies, at Colorcon Ltd (UK).
Ali R. Rajabi-Siahboomi is Global Technical Director at Colorcon Inc. (PA, USA).
1. National Statistics, "Living in Britain General Household Survey 2002" (2002). www.statistics.gov.uk/
2. M.K. Serdula et al., Am. J. Prev. Med., 26(4), 294–298. (2004).
3. M.A. Longer and J.r. Robinson, "Sustained-release drug delivery systems," in A.R. Gennaro, Ed., Remington's Pharmaceutical Sciences (Mack Publishing, Easton, PA, USA, 1990) pp 1676–1693.
4. P. Colombo et al., Pharm. Sci. Tech. Today, 3(6), 198–204 (2000).
5. A.R. Rajabi-Siahboomi and M.P. Jordan, Eur. Pharm. Rev., 5(4), 21–23 (2000).
6. C.L. Li et al., J. Pharm. Pharmacol., 57(5), 533–546 (2005).
7. M.V. Velasco et al., J. Contr. Rel., 57(1), 75–85 (1999).
8. J. Siepmann and N.A. Peppas, Adv. Drug. Deliv. Rev., 48(2–3), 139–157 (2001).
9. H. Lapidus and N.G. Lordi, J. Pharm. Sci., 57(8), 1292–1301 (1968).
10. J.L. Ford, M.H. Rubinstein and J.E. Hogan, Int. J. Pharm., 24(2–3), 327–338 (1985).
11. J.L. Ford et al., Int. J. Pharm., 40(3), 223–234 (1987).
12. R. Bettini et al., Eur. J. Pharmaceut. Sci., 2(3), 213–219 (1994).
13. M.E. Campos-Aldrete and L. Vallafuerte-Robles, Eur. J. Pharm. Biopharm., 43(2), 173–178 (1997).
14. R Espinoza, E. Hong and L. Villafuerte, Int. J. Pharm., 201(2), 165–173 (2000).
15. C.F. Rodrigues et al., "Hydrophilic cellulose derivatives as drug delivery carriers: Influence of substitution type on the properties of compressed matrix tablets," in D. L. Wise, Ed., Handbook of Pharmaceutical Controlled Release Technology (Marcel Dekker, Inc., New York, NY, USA, 2000) pp 1–30.
16. D.A. Alderman, Int. J. Pharm. Tech. Prod. Manuf., 5(3), 1–9 (1984).
17. S.N. Pagay, Drug Dev. Ind. Pharm., 14(7), 875–894 (1988).
18. C. Doherty and P. York, Int. J. Pharm., 50(3), 223–232 (1989).
19. P.V. Wilder, M.R. Detaevernier and Y. Michotte, Drug Dev. Ind. Pharm., 17(1), 141–148 (1991).
20. M.T. Sheu et al., Int. J Pharm., 85(1–3), 57–63 (1992).
21. K. Mitchell et al., Int. J. Pharm., 66(1–3), 233–242 (1990).
22. A.R. Rajabi-Siahboomi et al., "Particle swelling and the mechanism of failure of HPMC matrices" at the Proc. 3rd Assoc. UK Academy of Pharmaceutical Sciences Conference (London, UK, 1994).
23. J.L. Johnson, J. Holinej and M.D. Williams, Int. J. Pharm., 90(2), 151–159 (1993).
24. L. Hendeles, P. Wubbena and M. Weinberger, Lancet, 22(2), 1471 (1984).
25. L. Hendeles et al., Chest, 87(6), 758–765 (1985).
26. G. Steffensen and S. Pedersen, Br. J. Clin. Pharmacol., 22(5), 571–577 (1986).
27. B. Schug et al., Eur. J Clin. Pharm., 58(2), 119–125 (2002).
28. Guidance for Industry: Food Effect Bioavailability and Fed Bioequivalance Studies (FDA, December 2002).
29. R.J. Wills et al., J. Clin. Pharmacol., 22(11), 557–561 (1982).
30. R.J. Meyer and A.S. Hussain, "Awareness Topic: Mitigating the Risk of Ethanol Induced Dose Dumping from Oral Sustained/Controlled Release Dosage Forms," at FDA's ACPS Meeting (October, 2005).
31. K.E. Pringle et al., J. Am. Geriatr. Soc., 53(11), 1930–1936 (2005).
32. FDA Alert for Healthcare Professionals - Hydromorphone hydrochloride extended-release capsules (marketed as Palladone), Alcohol-Palladone interaction, (July 2005).www.fda.gov/
33. J. Koziara, J. So and N. Agarwal, "The effect of ethanol on semipermeable cellulose acetate-based membranes," at AAPS Annual Meeting and Exposition (San Antonio, TX, USA), 29 October–2 November 2006.
34. H.Fadda, Y. AlBasarah and A. Basit, "Impairment of modified release formulations by alcohol in dissolution media and influence on drug release," at AAPS Annual Meeting and Exposition (San Antonio, TX, USA), 29 October–2 November 2006.
35. M. Roberts et al., "The influence of ethanol on aspirin release from hypromellose matrix tablets," at the British Pharmaceutical Conference & Exhibition (Manchester, UK), 4–6 September 2006.
36. H. Vuong, M. Levina and A.R. Rajabi-Siahboomi, "The influence of hydro-alcoholic media on hypromellose matrix systems," at AAPS Annual Meeting and Exposition (San Antonio, TX, USA), 29 October–2 November 2006.
37. K. Tahara, K. Yamamoto and T. Nishihata, J. Contr. Rel., 2910(35) 59–66 (1995).
38. N. Kavanagh and O.I. Corrigan, Int. J. Pharm., 279(1–2), 141–152 (2004).
39. S. Missaghi, K. Fegely and A.R. Rajabi-Siahboomi, "Evaluation of the Effect of hydro-alcoholic Media on Textural and Rheological Characteristics of Hypromellose Matrices," at CRS Annual Meeting and Exposition, (Long Beach, CA, USA, 7–11 July 2007).
40. S. Missaghi, K. Fegely and A.R. Rajabi-Siahboomi, "Investigation of the Effect of Hydro-Alcoholic Media on Rheological and Textural Properties of Various Grades of Hypromellose," at AAPS Annual Meeting and Exposition, San Diego, CA, USA, 11–15 November).
41. M. Levina, H. Vuong and A.R. Rajabi-Siahboomi, Drug Dev. Ind. Pharm., 33(10), 1125–1134 (2007).
42. FDA, Federal Register, 60(230) 61642 (1995).
43. J.W. Moore and H.H. Flanner, Pharmaceut. Tech., 20(6), 64–74 (1996).