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MEGGLE highlights role of excipient properties in alcohol-induced dose dumping AIDD
A new briefing white paper from pharmaceutical lactose specialist MEGGLE underlines the importance of excipients in combating the problem of alcohol-induced dose dumping or AIDD that affects some modified-release tablet formulations.
AIDD describes the phenomenon of modified release oral solid dose (OSD) drugs that have higher overall API content prematurely dumping rather tailored/modified manner into patient bloodstream when ingested with alcohol compared with dosage release when taken with water.. This fact is leading to potentially lethal overdosing. AIDD has become a subject of increasing concern to the pharmaceutical industry and regulators that has led to the withdrawal of some products (e.g. Palladone capsules) from the market and regulatory ‘black box’ warnings on others.
The MEGGLE White Paper The importance of Excipient selection for modified-release formulations –prevent the risk for alcohol-induced dose dumping specifically addresses the current state of AIDD in modified-release OSD formulations, as well as the need for regulatory harmonization in dealing with this issue.
The paper reviews the basic scientific factors affecting the AIDD phenomenon, the varying stances of international regulators and proposes mitigation measures available to combat the problem as highlighted in recent research.
The white paper is authored by a team from MEGGLE´s Business Unit Excipients comprising Research & Development Head Ricarda Leister with South Asia Regional Head Pawan Zade and Technical Application Manager Prasad Gunjal.
Ms. Leister commented: “We are glad to provide this comprehensive review on alcohol induced dose dumping that also shows how use of co-processed lactose excipient can create a more alcohol-resilient matrix system for modified-release formulations.”
The paper identifies the three properties of powdered matrix tablet and capsule formulations that are most influential in determining the interaction with alcohol:
- Wettability: the contact angle between solid and liquid interfaces that determine penetration of solvents into the polymeric system
- Solubility: Typically, polar molecules being more soluble in polar solvents (e.g. water), while non-polar molecules are soluble in non-polar solvents (e.g. ethanol/alcohol).
- Swellability: the use of hydrogel or hydrophilic polymers that swell in contact with aqueous solutions to form a gel layer delaying API release, with Hypromellose particularly liable to form non-uniform layers in presence of alcohol.
In addition, research identifies Tablet Hardness as a further key factor in resisting AIDD, indicating preference for co-processed excipients that possess functionalities not achievable through simple blending.
Ms. Leister explains: “We proposed a sustained release direct compressible co-processed excipient in this white paper which may help in formulating alcohol resistant matrix system, which depends upon several physiological and physicochemical parameters.”
The paper highlights MEGGLE RetaLac® as the first hypromellose/lactose-based, co-processed excipient specifically designed for direct compression (DC) and dry granulation of modified-release formulations.
“The monoparticulate structure of RetaLac® helps in providing alcohol resistance in dissolution media, as lactose solubility decreases with increase alcohol concentration and Hypromellose is insoluble in ethanol. Despite their distinct solubility profile, Hypromellose and lactose monohydrate act synergistically to retard the drug release in hydroalcoholic dissolution media,” Ms. Leister notes.
Call for harmonization
The White Paper concludes:
“The selection of appropriate excipients including a polymeric system is a vital step to assure protection from AIDD.”
“Clinical implications should be considered during formulation development to develop formulations and dosages that tolerate dose dumping and failure mode analysis should be performed early in development.” say the authors.
The paper ends with a call for regulatory agencies guidelines to be harmonized concerning AIDD in vitro testing regimes, reflecting physiologically relevant alcohol concentrations and exposure times.