Parameters that determine dissolution and efficacy of itraconazole and its relevance to recalcitrant dermatophytoses

ABSTRACT

Introduction: Recalcitrant dermatophytoses is on the rise. Though myriad factors contribute to recalcitrance including terbinafine resistance, itraconazole largely remains sensitive. However, there are increasing instances of patients not responding adequately to itraconazole despite low MICs, probably due to issues plaguing the pelletization process, resulting in suboptimal quality.

Data on this topic was searched on pubmed using the search items: itraconazole, MIC, MFC, quality, assay, pharmacokinetics, pharmacodynamics, dermatophytoses, and recalcitrance.

Areas covered: A detailed analysis of the manufacturing process of itraconazole with emphasis on pelletization and parameters affecting the dissolution and bioavailability is presented. Important formulation factors including drug-polymer ratio, polymer type, coating thickness, bead size, and number are discussed. Also covered is the rationale of dosimetry of itraconazole in dermatophytoses based on the skin pharmacokinetics and MIC of the organism.

Expert opinion: The process of pelletization has multiple components aiming to achieve maximum dissolution of the drug. Variations in the process, pellet quality, number, and polymer determine absorption. Morphometric analysis of pellets is a simple method to quantify quality of the drug. Once the process has been standardized, dosimetry depends on the route of secretion and site of infection, accounting for the variation of doses from 100 mg to 400 mg/day.

KEYWORDS:

• Dose
• itraconazole
• layering
• nanosuspension
• pelletization
• pellet size
• polymer type
• recalcitrant dermatophytoses
• resistance
• tinea

Article highlights

• Though rising MICs and clinical failures to terbinafine have been reported, itraconazole largely remains sensitive and is being increasingly prescribed for recalcitrant dermatophytoses.

• Failure of the drug with low MICs points to quality issues that plague the process of pelletization of itraconazole, impacting the bioavailability and ultimately the results of treatment.

• Formulation scientists are facing challenges because of the increasing number of poorly water-soluble drugs such as itraconazole which is a BCS II model drug with poor solubility. The ultimate goal of the manufacturing process is to the achieve maximum possible solubility and bioavailability of the drug.

• The manufacturing process of itraconazole is complex and several formulation and processing factors involved in the pelletization process have an impact on the dissolution and bioavailability of itraconazole.

• Small bead size (35/40 mesh), optimum drug polymer ratio (1:4), sugar beads, more number of pellets, HPMC VLV as film-forming polymer, and thinner coating layer result in faster dissolution rate and thus higher bioavailability.

• The ultimate dose depends on skin levels and not serum levels, as the drug achieves higher levels in skin than plasma, and the drug persists in skin for a longer time after cessation of therapy

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.