Lipid-Based Formulations - Pharmaceutical Technology

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PharmTech Europe

Lipid-Based Formulations
A new solubilization technology

Pharmaceutical Technology Europe
Volume 24, Issue 9

Also, the physical stability of amorphous solid dispersion is one of the most critical considerations during excipient selection. The amorphous solid dispersion is metastable, and the drug will re-crystallize inevitably with time. In order to stabilize amorphous solid dispersion, polymer excipients with high Tg, such as PVP and HPMC, have been selected so that Tg of the dosage form is well above ( more than 500C) the storage temperature (13). As a result, the amorphous drug in the solid dispersion is “immobilized” in a hard, brittle glassy matrix, which prevents or slows down drug recrystallization with time (14). In addition to miscibility and physical stability requirements, the excipients for solid dispersion must be non-toxic and pharmacologically inert, and stable during manufacturing processes.

Various excipients have been extensively studied to the formation of glass solutions in solid dispersion approach (15). They are usually hydrophilic polymers. Examples include sugars, such as dextrose, fructose, galactose, trehalose, and sucrose, or amorphous polymers such as PVP, Polyvinylpyrrolidone- co-vinylacetate (PVPVA) and HPMC. Among them PVP, PEG, HPMC have received increasing attention, and been successfully used in commercial products including Sporanox®, Intelence®; Certican®; Nivadil®; Prograf® (HPMC), Cesamet®; Kaletra® (PVPVA) and Gris-PEG® (PEG 8000). The excipient type, molecular weight, and excipient/drug ratio can affect drug/excipient miscibility, chemical and physical stability during manufacturing process and shelf-life of the solid dispersion formulations.

Despite the huge efforts and commercial product successes, this approach is limited by the number of excipients that are able to stabilize metastable amorphous formulation for acceptable shelf-life stability. Very often a significant amount of excipients have to be added in order to achieve such physical stability of the formulation, but this might also result in unacceptable large dosage form size. In addition, even current excipients are not always effective in stabilizing the formulation for acceptable shelf-life stability, and selection of excipients is drug specific. As a result, the physical stability of amorphous solid solutions is still one of the main reasons why only a few amorphous solid solutions have made it to the market. Therefore development of new excipients that are able to achieve physical stability of the formulation is of significance to the solid dispersion approach.

Future perspective

The success of novel solubilization techniques such as lipid base formulation and solid dispersion approach has been demonstrated with the launch of commercial products for improving oral bioavailability of poorly water-soluble compounds. Excipients have played an essential role in such excipient-enabling technologies. Nevertheless, the number of effective solubilization techniques is limited to the increasing amount of difficult-to-formulate compounds. In particular, it still remains a significant obstacle and challenge to formulate poorly water soluble compounds with high dose requirements even with current solubilization technologies. Future efforts may involve exploring and developing new excipients for high-dose drug formulations. For example new oils with high solubilization capacity are much needed to dissolve more lipophic drugs in a lipid based formulation approach, while a novel potent excipient for stabilizing physical stability of solid dispersion will reduce the amount of excipients to achieve high drug loading. The toxicity and regulatory consideration are the critical aspects of such new excipient development.

In addition to the development of new excipients, it is worth exploring combining widely used excipients in formulation screening to produce a synergistic effect for an optimized product performance. Using high throughput and automation techniques, scientists can screen rapidly thousands of excipient combination in various formulations such as lipid formulation, and solid dispersion using small quantities of compounds (16), something that would be difficult to do manually. It is an efficient and cost-effective way to find new applications of currently used excipients in solubilization technologies.


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