Wei-Guo Dai, Janssen Research and Development, Johnson & Johnson

Wei-Guo Dai

Development of viable dosage forms for poorly water soluble compounds continues to be a significant challenge to the formulation scientists in pharmaceutical industry and insufficient bioavailability of such compounds due to poor formulation design may result in delays in development or cause them to be dropped from the pipeline (1,2). Various solubilization techniques such as using surfactants, co-solvents and cyclodextrins, adjusting the formulation pH, and screening salts have been developed, but these conventional techniques are not always effective enough to achieve the desirable solubility enhancement for an increasing amount of difficult-to-formulate compounds. Recently several new solubilization technologies have advanced significantly with commercial successes. This article only focuses on two excipient-enabling techniques: lipid-based formulations and solid dispersion approach, and discusses how excipients play a critical role in these innovative solubilization technologies. 

With several commercial successes including Sandimmune® and Neroal®(Cyclosporine A), Norvir® (Ritonavir) and Fortovase® (Saquinavir), lipid-based formulations have drawn considerable interest and attention in pharmaceutical industry as effective ways to improve oral bioavailability of poorly water soluble compounds (3,4). In principle, this approach is to dissolve the lipohilic drug in oils, emulsify the oil phase in water, and maintain the drug in the solubilized state in the gastrointestinal tract until absorption has occurred. Very often the lipid formulation is designed in such way that it tends to generate and maintain a supersaturated drug concentration in vivo for improved oral absorption (5). In some cases nanoparticulate emulsions are formed. Excipients definitely play a most critical role in the formulation performance.

One of the most critical criteria of the excipients used in lipid-based formulations is its solubilization capacity. The excipient or excipient blend must be able to fully solubilize the entire drug dose, preferably in a volume of a single oral dosage. This is often achieved by careful screening of appropriate oils, co-solvents and surfactants. 

Both long-and medium-chain triglyceride oils with different degrees of saturation have been extensively investigated for the design of lipid-based formulations. Co-solvents have been also used to help dissolve the drug or a large amount of the hydrophilic surfactant in the formulations. Examples of such co-solvents include ethanol, propylene glycol and polyethylene glycol. 

Surfactants with a relatively high hydrophilic/liphophilic balance (HLB) are often needed to provide a good dispersing/self-emulsifying performance. For example, polysorbates, Cremophor® (rebranded to Kolliphor® EL/ RH40) and Solutol® HS15 (rebranded to Kolliphor® HS15) are used as the surfactants due to their relatively low toxicity and excellent performance. 

In addition to the solubilization capacity, excipients in the lipid-based formulations must maintain the drug in the solubilized state in the gastrointestinal tract, preferably in supersaturable high concentration, until absorption has occurred. Therefore excipient type/composition and excipient/drug ratio are the critical factors. For supersaturable lipid-based formulations, the metastable supersaturated drug concentration has to be maintained for a long enough time period sufficient for adsorption before drug precipitation occurs. This is often achieved by temporary inhibition of drug precipitation using excipients as precipitation inhibitors (6). For example cellulose derivatives and vinyl polymers have been widely studied as precipitation inhibitors. Examples of such polymers include hydroxypropyl methylcellulose (HPMC), methyl cellulose (MC), hydroxypropyl cellulose (HPC), hypromellose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), Polyvinyl alcohol (PVA), and vinylpyrrolidone/vinylacetate copolymers (PVPVA). The studies showed that HPMC and PVP were the effective precipitation inhibitors to prolong the supersaturable drug concentration for the significantly improved bioavailability of poorly water soluble compounds (7,8). 

Some Poloxamers also exhibit precipitation inhibitory effect in the tested compounds. Studies showed that Poloxamer 407 (rebranded to Kolliphor® P407) and Poloxamer P338 (rebranded to Kolliphor® P338)  inhibited the compound precipitation in the simulated intestinal fluid (SIF) at concentrations below their CMCs 9. Combinations of Kolliphor® P407 or Kolliphor® P338 with Vitamin E TPGS (rebranded to Kolliphor® TPGS) showed significantly stronger inhibitory effects on the tested compound than the individuals, indicating synergistic effects on inhibition of drug precipitation 10. The lead formulation comprising Kolliphor® P407 maintained the tested compound concentration at 300 μg/mL upon dilution in SIF for at least two hours compared with the compound alone at  less than1 μg/mL of its concentration, and increased oral bioavailability significantly (11). 

Despite much effort on lipid-based formulations, the success of commercial products is limited to a few active pharmaceutical ingredients. The complexity of such formulation and product development requires extra efforts. Also, the effect of excipients on the bioavailability of the lipid based formulations is highly complex; the in vivo performance of such formulations is poorly predictable. Furthermore, excipients with both acceptable toxic profile and high solubilization capacity for lipophilic drugs are limited. Very often a large amount of surfactants and co-solvents are needed in order to achieve the targeted dose level and to form stable microemulsions. Such a large quantity of excipients might raise safety concerns or compromise shelf-life stability of the products in the lipid base formulations. 

A solid dispersion is a homogeneous mixture of one or more active ingredients in an inert carrier at the solid 12. It can be classified into simple eutectic mixtures, solid solutions and glass solutions. Solid dispersion approach, in particular, formation of glass solutions of poorly soluble compounds using amorphous excipients with high glass transition temperatures (T

), has been used to increase dissolution rate and solubility of low solubility compounds for improved oral absorption. Recently several poorly water soluble drugs with solid dispersion formulation approach have been successfully launched in the market. 

The strategy of solid dispersion approach is to a) convert crystalline drug into to amorphous one, b) disperse the drug in a hydrophilic excipient carrier at molecular level. Such transformation leads to generation of amorphous glass solution, improved wetting, and reduced particle size of the components to the molecular level, which contributes to increased drug dissolution rate and solubility. To achieve this goal, selection of excipients is crucial.

First of all, excipient miscibility with the drug is important. Excipients must be miscible with the drug in such that the drug can be either molecularly dispersed or form an amorphous precipitate into its excipient matrix. A glass solution will not form if the drug and excipient are immiscible at the tested ratio. The drug/excipient miscibility can be assessed by DSC or predicated with Hansen solubility parameters in some cases. In addition to type of excipients, miscibility of the drug with excipients is dependent on the excipient/drug ratio in the formulation. 

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 T

, 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. 

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. 

Another key aspect of excipient selection in new solubilization technologies is the structure-property correlation in the formulation. Current excipient selection is often empirical or semi-empirical. The interaction of excipients with drug in the formulation is poorly understood and development of the in vitro/in vivo correlation still remains an obstacle to the new solubilization technology based formulations. With more understanding of interactions of the drug with excipients in the formulation and the drug/excipients with the gastrointestinal tract environment, it could be possible in the future to establish structure-property correlation in the new techniques based formulations.

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Articles

Development of viable dosage forms for poorly water-soluble compounds continues to be a significant challenge for formulation scientists, and insufficient bioavailability of such compounds may result in development delays or failures.