Alcohol resistant enteric pharmaceutical compositions

Our pharmacokinetics department offers the clients a broad spectrum of high quality of services in the areas of in vitro ADME, in vivo pharmacokinetics studies and bioanalysis services, ranging from small molecules to large molecules, such as protein and antibody. The animal species involved in our services are non-human primate, canine, mice, rat, rabbit and hamster. Meanwhile, non-human primate experimental platform and isotope platform for protein/antibody are certified by the Shanghai Government.Email:marketing@medicilon.com.cn Web:www.medicilon.com

Unintended, rapid drug release in a short period of time of the entire amount or a significant portion of the drug contained in a dosage form is referred to as "dose dumping" . Dose-dumping poses a significant risk to patients because of safety issues and/or diminished efficacy, particularly in controlled release dosage form where the active drug may be present in relatively high amounts. In these controlled release dosage forms, the rate of drug released from the dosage form is controlled by the release-rate-controlling mechanism. Typical release-rate-controlling mechanisms include swellable polymers, gel matrixes and polymeric coatings, to name a few. A compromise or failure of the release-rate-controlling mechanism is a likely cause of dose dumping. The likelihood of dose-dumping for certain controlled release products when administered with food has been recognized for more than twenty years. See Hendeles L, Wubbena P, Weinberger M. Food-induced dose dumping of once-a-day theophylline. Lancet. 22: 1471 (1984).

In addition to food, the presence of alcohol can compromise release-rate-controlling mechanisms of controlled release dosage forms. Certain controlled release dosage form employing release-rate-controlling mechanisms are more susceptible to dose dumping in the presence of alcohol than other release-rate-controlling mechanisms .

In 2005, the United States Food and Drug Administration (FDA) required the withdrawal of several drugs from the market or required a change in the warning labels because of the effects of ethanol on the controlled release formulations of the drug. For example, the FDA asked Purdue Pharma of Stamford, CT to withdraw Palladone® (hydromorphone hydrochloride) extended release capsules from the market because a pharmacokinetic study showed that when Palladone® was taken with alcohol, its extended release formulation was compromised and resulted in dose dumping (cf . FDA Press Release of Jul. 13, 2005) . The FDA concluded that the overall risk versus benefit profile of the Palladone® drug product was unfavorable due to its alcohol induced dose dumping susceptibility. The FDA decision was based, in part, on an a pharmacokinetic study in healthy subjects (utilizing a naltrexone block) , which demonstrated that co-ingestion of Palladone® with 240 mL (8 ounces) of 40% (80 proof) alcohol resulted in an average peak hydromorphone concentration approximately six times greater than when taken with water. Furthermore, one subject in this study experienced a 16-fold increase when the drug was ingested with 40% alcohol compared with water. This study also showed that 8 ounces of 4% alcohol (equivalent to 2/3 of a typical serving of beer) could in some subjects result in almost twice the peak plasma hydromorphone concentration than when the drug was ingested with water. FDA Alert for Healthcare Professionals (July 2005) : Hydromorphone Hydrochloride Extended- Release Capsules (marketed as Palladone®) .

An in vivo alcohol dose dumping resistance test is not the preferred approach due to potential harm the test could pose to a human subject. The preferred approach, according to the FDA, is an in vitro dissolution test in the presence of 40% ethanol. At the Pharmaceutical Sciences Advisory Committee Meeting of Oct. 26, 2005, OPS (Office of Pharmaceutical Science) personnel from CDER (Center for Drug Evaluation and Research) presented data showing that in an alcohol susceptible controlled release dosage form, a higher concentration of ethanol (e.g., 40%) is likely to trigger faster drug release than a lower concentration of ethanol (e.g., 20% or 4%). This may or may not be the case depending on the specifics of the controlled release formulation. (See Presentations at the Pharmaceutical Sciences Advisory Committee Meeting Oct. 26, 2005). Accordingly, the Division of Bioequivalence - 2, Office of Generic Drugs CDER/FDA on 13 May 2009 at the AAPS workshop, Physical Pharmacy and Biopharmaceutics issued proposed dissolution testing for alcohol- induced dose-dumping of generic MR oral drug products. The proposed dissolution study is designed to compare dissolution performance of the generic (test) product and the corresponding reference listed drug. Conditions for dissolution include 0. IN HCL media with differing amounts of ethanol (v/v) added to give the following percentages of ethanol in the media: 0.0%, 5.0%, 20%, and 40%. Protocols similar to these prescribed dissolution studies were adopted to ascertain the robustness of the alcohol resistant pharmaceutical composition of the present invention.