The Effect of Different Preparation Methods on the In Vitro and In Vivo Performance of Solid Dispersion Formulations (U01)

Background: Solid dispersion has been investigated extensively to enhance bioavailability through improving dissolution property of poorly water-soluble drugs. In spite of the great potential for enhancing bioavailability using solid dispersion, the commercial application is limited and only a few products have been marketed so far, such as Prograf (Tacrolimus), Sporanox (Itraconazole), Kaletra (lopinavir/ritonavir). There are more and more approved and pending abbreviated new drug applications (ANDAs) referencing these products. For example, Tacrolimus is a calcineurin-inhibitor immunosuppressant indicated for Prophylaxis of organ rejection in patients receiving allogenic liver, kidney or heart transplants. Tacrolimus is practically insoluble in water (2-3 g/mL) and several formulation approaches including solid dispersion, complexation with cyclodextrin, oily solution and others have been developed to improve drug availability. Of them solid dispersions succeeded in improving its delivery and led to commercialization. Itraconazole is a synthetic triazole antifungal agent, and is also practically insoluble in water. Itraconazole was formulated as amorphous solid dispersion in Sporanox, and there are two approved generic drug products. The concerns related to solid dispersion include but are not limited to drug substance crystallization during storage, drug substance precipitation from supersaturated solution during in vivo dissolution, and the impact of polymers on drug permeability in the gastrointestinal (GI) tract. Depending on how drug substance is converted from crystalline state to amorphous state, solid dispersion preparation can be roughly divided into two categories, i.e. solvent method and melting method. Solid dispersion carrier and manufacturing process for amorphous solid dispersion can affect not only solid dispersion stability, but also their in vivo or therapeutic performance. To keep drug substance from crystallization during storage as well as precipitation from supersaturated solution during dissolution, polymer carrier plays a critical role in solid dispersion formulation design. Different manufacturing processes impact not only the physical state of drug substance, but also the physical state of polymer carrier(s) including the miscibility of carrier with drug substance. Many techniques have been developed and applied on detecting the degree of crystallinity, such as powder x-ray diffraction (PXRD), infrared spectroscopy (IR), differential scanning calorimetry (DSC) as well as dissolution. However, it is still challenging to quantify the amorphous content in the formulation during manufacturing and storage, as the amount of amorphous material is generally measured indirectly through measuring the amount of crystalline material in the sample. It will be very valuable to identify and optimize analytical methods to detect solid dispersion quality changes during manufacturing and storage, and evaluate the impact of those changes on their in vivo performance. Regarding generic solid dispersion products, the FDA is interested in in vitro and in vivo performance of drug products made from different manufacturing processes, as well as their performance consistency during storage and among batches. This type of study would help establish optimal in vitro batch quality controls to ensure consistent batch to batch in vivo performance. Objectives: The objective of this study is to investigate the in vitro and in vivo performance for solid dispersion drug products made from different manufacturing processes or polymer carriers, as well as their performance consistency during storage and among batches. The investigation should identify critical process parameters and critical quality attributes for solid dispersion made from different preparation methods, and develop discriminating analytical methods. Detailed Descriptions: The following studies should be conducted for the purpose of this project: (1) Identify model drugs, and prepare amorphous solid dispersion using different preparation methods which include but not limited to solvent method and melting method. In addition, the impact of polymer miscibility with drug substance on the in vitro and in vivo performance of drug products should be taken into consideration when designing manufacturing processes. (2) Identify critical process parameters and critical quality attributes for solid dispersion made from different preparation methods, as well as discriminating analytical methods. The analytical methods should be able to detect drug product quality changes including crystalline content in amorphous solid dispersion and its impact on dissolution profiles, as well as precipitation of drug substance in the GI tract during dissolution. (3) Perform quality characterization on brand and generic solid dispersion drug products including assay, related substances, and dissolution in accordance with the United States Pharmacopeial (USP) standards (if available), and in discussion with the FDA (sponsor). (4) Determine stressed conditions that could result in significant quality changes including dissolution and precipitation changes. Evaluate the relationship between moisture content, crystalline content, and dissolution rate under stressed conditions and under long term storage. (5) Conduct a randomized, single dose, four-treatment, four-period cross-over in-vivo bioequivalence (BE) study in 24 normal healthy adult males and females (non-pregnant) (general population). Adverse events should be monitored and recorded through the study. Treatments including 1. RLD fresh 2. RLD aged (slower dissolution than RLD fresh) 3. Generic A fresh (slower dissolution than the RLD) 4. Generic A aged (much slower dissolution) Statistical analysis will be performed on the peak, partial and total exposure of drug product to determine if there are any significant pharmacokinetic differences among the RLD, generic drug products, and drug products from stability studies.