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The authors evaluated the effect of alcoholic beverages on the release profiles of sustained-release dosage forms containing metformin and diclofenac.
More and more people who suffer from chronic diseases such as high blood pressure, diabetes, and disorders of the central nervous system are developing the habit of alcohol consumption. The United States ranks 40th among nations in alcohol consumption, and alcohol use is particularly common in tribal, rural, and poor urban areas of the country. The consumption of alcoholic beverages varies considerably between different countries and between different ethnic groups within a country (1).
Extended-release dosage forms are the drug-delivery systems of choice for managing chronic diseases. Such formulations typically contain a higher dose of drug than instant-release formulations and generally are based on matrix principles or the barrier-membrane coating principle. Excipients such as hypromellose (i.e., hydroxypropyl methylcellulose) and ethyl cellulose control the drug's release rate. Alcohol affects the solubility of these excipients, and consuming alcohol after taking extended-release drug products that contain these excipients may lead to dose dumping.
Depending on the therapeutic indication and the therapeutic index of a drug, dose dumping can raise safety concerns or diminish a drug's efficacy, thus posing a significant risk to patients. Some modified-release oral dosage forms contain drugs and excipients that exhibit higher solubility in ethanolic solutions than they do in water. Such products may exhibit rapid drug dissolution in the presence of ethanol. Therefore, the consumption of alcoholic beverages along with these products might be expected to induce dose dumping.
This potential for dose dumping from an oral modified-release dosage form has not attracted much attention in the pharmaceutical literature for many reasons. One possible reason is the general assumption that a clinically insignificant difference in drug-release rate would be expected with ethanol consumption in vivo. A study conducted more than 20 years ago, and the absence of a clear postmarketing signal pointing to alcohol-induced dose dumping, may have reinforced this assumption (2).
Although various drug–drug interactions and drug–food interactions have been discussed widely, no research has evaluated the influence of various alcoholic beverages on the performance of drug products-specifically sustained-release dosage forms. A review of the literature indicates the gap in this field of research. The objective of the present study was to evaluate the influence of alcoholic beverages on the drug-release profile of sustained-released dosage forms.
The authors used standard reagent-grade ethanol (40% v/v, Avantor Performance Materials, Selangor, Malaysia) for their analysis. Kingfisher Strong beer (8% alcohol, Bombay Breweries, Taloja, India), Kingfisher Mild beer (5% alcohol), and rum (40–55% alcohol, South Seas Distilleries and Breweries, Mumbai) were the alcoholic beverages.
The authors studied instant- and sustained-release formulations of metformin (Glycomet 500, Batch No. 13003812, USV, Mumbai, and Glycomet 500 S.R., Batch No. 28002510, USV) and of diclofenac (Voveran 50, Batch No. 107015AD, Novartis, Basel, and Voveran S.R. 100, Batch No. 98033 A, Novartis). The authors chose metformin and diclofenac because they are the most frequently prescribed drugs for diabetes and pain management in India.
Metformin. The dissolution study for both metformin formulations was carried out with 900 mL of demineralized water (maintained at 37 ± 0.5 °C) in a US Pharmacopeia Type I dissolution apparatus at 100 rpm. The tablets were used as received. Six tablets from the same batch of each product were tested. A suitable volume of medium was withdrawn, filtered, and diluted with demineralized water, and the amount of metformin released from the dosage form was determined using a UV–vis spectrophotometer (Model No.1700 E, Shimadzu, Kyoto) at a wavelength of 233 nm.
For the alcoholic dissolution study, the designated volume of alcoholic beverages was included in medium for 1 h (the volume was increased to 900 mL using demineralized water) to simulate in vivo conditions. After 1 h, the medium was replaced with the fresh demineralized water at 37 ± 0.5 °C. The same procedure was followed for the determination of drug release in all solutions.
The designated volumes of various alcoholic beverages were the following:
The data obtained were analyzed using software (PCP-DISSO, Bharati Vidyapeeth College of Pharmacy, Pune, Maharashtra, India).
Diclofenac. The dissolution study for both diclofenac formulation was carried out with 900 mL of demineralized water (maintained at 37 ± 0.5 °C) in a USP Type I dissolution apparatus. The apparatus ran at 50 rpm for instant-release diclofenac and at 100 rpm for sustained-release diclofenac.
The tablets were used as received. Six tablets from the same batch of each product were tested. The amount of diclofenac released from the dosage form was determined using a UV–vis spectrophotometer (Model No.1700 E, Shimadzu) at a wavelength of 277 nm.
For the alcoholic dissolution study, the designated volume of alcoholic beverages was included in medium for 1 h (the volume was increased to 900 mL using demineralized water) to simulate in vivo conditions. After 1 h, the medium was replaced with the fresh demineralized water at 37 ± 0.5 °C. The same procedure was followed for the determination of drug release.
The designated volumes of various alcoholic beverages were the same as for the metformin study. The data obtained were analyzed using PCP-DISSO software.
Results and discussion
The release of drug from instant-release metformin tablets depended on the volume of alcoholic beverage present. Drug release was fastest in Kingfisher Strong beer. Release was progressively slower in Mild beer, rum, and 40% alcohol. The release was slowest in water (see Figure 1). Both the strength and the volume of the alcoholic beverage affected the release rate. A similar trend was observed for instant-release diclofenac tablets (see Figure 2). Thus, the authors concluded that the volume and strength of the alcoholic beverage affected that drug's release as well.
The release of sustained-release metformin was similar in 40% alcohol and rum. Drug release was slower in the Strong and Mild beers and slowest in water (see Figure 3). These results indicate that the drug release was affected by the strength of the alcoholic beverages rather than by their total volume. This conclusion suggests that drug release is strongly influenced by alcohol's ability to disrupt the sustained-release mechanism. The similar release profiles obtained for the sustained-release diclofenac formulation confirmed this proposition (see Figure 4).
The consequences of the changes in the dissolution profiles observed in sustained-release formulations depend on the drug. Dose dumping of metformin could result in anaphylactic reactions and lactic acidosis, among other effects. In addition, metformin is excreted unchanged by the renal route. Therefore, dose dumping of metformin also could result in renal impairment. Dose dumping of diclofenac could cause allergic reactions, fluid retention, and impairment of renal function (4).
The significant changes in release pattern are further confirmed by low F2 values. The similarity factor F2, as defined by the US Food and Drug Administration, is a logarithmic reciprocal square-root transformation of one plus the mean squared (i.e., the average sum of squares) differences of drug percent dissolved between the test and reference products (5). Table I compares the F2 values for all dissolutions in alcoholic beverages with those in water. The results clearly indicate the effect of alcoholic beverages on in vitro drug release.
The authors concluded that the release of the instant-release formulations was faster in Kingfisher Strong beer, Mild beer, rum, and 40% alcohol than it was in water. The difference may be attributable to the volume of the alcoholic beverages, rather than to their strength. The drug release of the sustained-release formulations was faster in 40% alcohol and in rum than it was in water. The authors concluded that the consumption of alcoholic beverages should be avoided during treatment with sustained-release formulations of metformin and diclofenac to prevent dose dumping.
Anagha Joshi* is a doctoral student at Bharati Vidyapeeth University's Poona College of Pharmacy and assistant professor of pharmaceutical chemistry at Indira College of Pharmacy, Pune, Maharashtra, India, firstname.lastname@example.org. Shivajirao S. Kadam is vice-chancellor of Bharati Vidyapeeth University Pune, Maharashtra,India, and Aatmaram P. Pawar is a professor of pharmaceutics at Bharati Vidyapeeth University Pune, Maharashtra, India.
*To whom all correspondence should be addressed.
Submitted: Feb. 13, 2010. Accepted: Apr. 5, 2010.
1. L.A. Bennett et al., Alcohol Health Res. World 22 (4), 243–252 (1998).
2. R.J. Meyer and A.S. Hussain, Proceedings of FDA's Advisory Committee For Pharmaceutical Science meeting (Rockville, MD, 2005), p. 2.
3. Indian Pharmacopoeia (Controller of Publications, New Delhi, India, 2007), p. 1020.
4. Goodman and Gilman's The Pharmacological Basis of Therapeutics, J.G. Hardman, L.E. Limbird, and A.G. Gilman, Eds. (McGraw-Hill, New York, 10th ed., 2001), pp. 644–646.
5. M.C. Gohel and M.K. Panchal, Dissol. Technol. 9 (1), 1–5 (2002).