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High-throughput platforms can be used to develop tertiary phase diagrams, which can be leveraged to identify the most stable SEDDS formulations and excipients for lipid-based drug delivery systems.
Most published estimates state that greater than 70% of drugs in the small-molecule pipelines are considered poorly water soluble. Because the human body requires that a drug essentially be solubilized in an aqueous environment, this poor water solubility poses an enormous challenge to effective drug delivery. Drugs may be poorly water soluble for a number of reasons, such as molecules with strong crystal lattices and high melting points or, on the other end of the spectrum, drugs exhibiting extremely high hydrophobicity that simply do not interact physico-chemically with water. If these drugs are not solubilized, they cannot be absorbed and are thus not producing a therapeutic effect. As the “easy” molecules (i.e., both water soluble and readily absorbed) become more rare in modern pharmaceutical pipelines, effective technological and formulation strategies need to be developed to effectively deliver the poorly water soluble molecules (i.e., APIs in BCS Class II and IV).
One key aspect for these formulations and technologies is that they need to be practical; formulations must be straightforward to manufacture, as well as pragmatic for the patient to consume. Thus, techniques such as amorphous solid dispersions (ASDs), which are made using hot melt extrusion and spray drying, and lipid-based drug delivery systems (LBDDS) are effectively used in the majority of the poorly water-soluble drugs brought to market. ASDs can be easily formulated into tablets, which are a widely accepted dosage form to be manufactured and ultimately consumed. LBDDS, with formulations that are often liquid or semi-solid, may be produced into hard or softgel capsules, which are also highly accepted from a patient compliance standpoint, and the knowledge base to manufacture these and scale them up exists within the industry. Despite the ease of manufacturing, however, the challenge remains of how to properly formulate LBDDS, and more specifically, self-emulsifying drug delivery systems (SEDDS), which are notoriously difficult to formulate from scratch.
LBDDS use the body’s own mechanisms to effectively deliver drugs. As an example, when the body digests a fatty meal, the lipids and fats are dispersed through the gastrointestinal tract (GIT), where they are emulsified and subsequently absorbed. During the digestion process, lipophilic solubilized vitamins and nutrients are absorbed. LBDDS and more specifically, SEDDS, work using this same mechanism. The encapsulated formulation releases from the capsule in the stomach or intestine (which may be targeted through enteric or sustained release coatings); the oils are emulsified and stabilized by the surfactant phase to form small droplets, which consequently allow for rapid absorption of the drug into the body. Once dispersed, these are effectively an oil/water (O/W) emulsion. One could start with a predispersed O/W emulsion; however, a formulator cannot encapsulate an O/W emulsion effectively because it is inherently unstable from a thermodynamic perspective, and over a relatively short amount of time it will fully separate. To overcome this tendency and to formulate a truly stable system requires creating a microemulsion, which no longer has a defined oil and water phase, but rather a bicontinuous phase. Unlike traditional O/W or water/oil (W/O) emulsions, these are thermodynamically stable, clear, low viscosity, and exhibit a high capacity for drug solubilization. The stable region is drawn theoretically in Figure 1.
Microemulsion regions are also drawn using the classic fishtail diagram (see Figure 2), where the Winsor Type IV emulsions have the right blend of oil, water, and surfactant to maintain an equilibrium bicontinuous system. In these systems, there are no true droplets, but rather single digit nanoscale structures that coexist. The Y-axis on the diagram in Figure 2 may be the surfactant blend (hydrophilic surfactant and hydrophobic surfactant) or the temperature of the system.
It is these Winsor Type IV microemulsions that may be encapsulated effectively. Once these stable microemulsion systems inside of the capsules meet with the aqueous environment of the GIT, the system shifts to an O/W emulsion. Depending on the formulation, droplets can range from tens of nanometers to millimeters in diameter. These droplets encapsulate the poorly water-soluble drug and allow for absorption of the API as the oil is digested, forming micelles and other complex colloidal structures. In theory, this approach works well, but in reality, it can be challenging to isolate stable microemulsion regions within a given system in order to build formulations.
SEDDS, which create tiny nano-scale droplets upon contact with the GIT, are highly effective, and a number of APIs have been recently approved that use this formulation approach (e.g., Rydapt, Neoral, Avodart, Norvir). However, what is yet to be comprehensively studied is the effect of excipients on the formulations. Although it is generally accepted that an oil-phase, primary surfactant, and secondary surfactant are required to effectively formulate these products, scientists must often work with existing formulations. Otherwise, they must start from scratch, which can require hundreds if not thousands of experiments.
With the aim of reducing the amount of experimentation and the time required to evaluate the applicability of SEDDS for different formulations, the author and his colleagues developed an approach that may be useful in future work. Their research, summarized in this article, used a high-throughput robotic system to establish tertiary phase diagrams (Figure 3) to determine stable regimes within these surfactant, oil, and water phase diagrams. Then different formulations using different surfactants, oils and aqueous phases were evaluated within this stable range to determine their applicability.
Within the stable region indicated by the green dots in Figure 3, a series of formulations were crafted to comprehensively study the effect of excipients on the formulations by varying the oil phase, aqueous phase, and surfactant/blend phase. An aqueous phase was studied because, in most encapsulations (particularly with softgels), moisture ultimately enters the system and reaches an equilibrium with the non-ionic surfactants, sometimes at concentrations greater than 5% w/w. The approach of formulating with an aqueous phase of 10% (either as water, ethanol, or others) builds robustness into the formulation and enhances the ability to maintain stability in the future. This phase may be either water or ethanol; ethanol allows for higher levels of drug solubility and better miscibility between the phases but may pose additional formulation challenges, such as the handling of flammable solvents during manufacturing.
Next, the oil phase, which is primarily responsible for solubilization of the drug and is the primary ingredient that is digested, was designed to be varied based on the solubility of the drug, rate of digestion (e.g., medium chain triglycerides digest faster than long chain), and the concentration, which further affects the digestion rate.
Finally, the surfactant phase was designed. This phase is primarily responsible for the stability of the system as a microemulsion as well as the size and stability of the droplets after the microemulsion “breaks” to form an O/W emulsion. Typically, and in the case of these examples, one would use a hydrophilic and a hydrophobic surfactant to balance the phases and enable the formation of a true microemulsion; this case was also tested by high-throughput screening. The results of these efforts were 10 stable formulations that can be used at multiple temperatures, aqueous/moisture levels, and different applications, as shown in Table I (see next page).
Formulations were tested using model drug compounds and studied for stability, robustness, dispersibility, and digestibility using in vitro models (1). These were further corroborated by observing in vivo absorption using a rat model.
Each of the formulations listed in Table I exhibits unique properties. The use of ethanol, in the case of F1 and F6, allows for higher drug solubility and rapid dispersibility in aqueous media. Those using potent concentrations of surfactant, such as a non-ionic oil-in-water solubilizer and emulsifying agent (Kolliphor RH 40, BASF) used in formulas F2 and F3, exhibit very small droplet sizes upon release (10s of nanometers) and highly stable micellar systems once the oil is digested, although it is important to note that they generally require a few minutes to fully disperse from the capsules. Similarly, those made with a non-ionic oil-in-water emulsifier and solubilizer (Kolliphor EL, BASF) used in formulas F4 and F5, exhibit small droplet dispersions, but a slightly faster digestion due to the faster digestibility of the surfactant. Formula F6 uses a liquid poloxamer surfactant (Kollisolv P124, BASF), which allows for rapid dispersion, but sacrifices stability of the oil droplets. By using other oils, such as soybean and corn oil (formulas F7 and F8, respectively), digestion rates may be varied (MCT being the fastest typically, soybean the slowest), and the solubility of the API may be tailored. Finally, co-surfactants, while a minor component, are key to maintaining the microemulsion. Several formulations are shown using glyceryl monooleate (formulas F2, F3, F4, F5, F6, F7, F8) and glyceryl monocaprylocaprate (formulas F9 and F10), offering different droplet sizes and digestion rates.
In order to test one of these formulations, it is generally recommended that the API be first saturated into the oil phase, which can be done by stirring overnight and filtering and testing API content by ultraviolet (UV) spectroscopy or high-performance liquid chromatography. Oil phases (oil + hydrophobic surfactant) and water phases (aqueous + hydrophilic surfactant) should be heated to approximately 60 °C and lightly mixed by hand; the microemulsions self-assemble. The resulting mircoemulsion may then cool and be dispensed into soft- or hard-shell capsules. Generally, the oil phase will be preloaded with API for formulation. It is recommended that approximately 80% of saturation in the total formulation be used for the final formulation to maintain API stability.
Testing of these formulations can be challenging, because in a standard dissolution bath with UV filter it is often too difficult to parse the API concentration from the droplets, micelles, and other phases in the bath. Therefore, it is recommended that formulators test these using lipolysis, membrane-based absorption models (macroFlux, Pion) or cell-based methods, such as Caco-2. Using a lipolysis mode and the model drug Danazol (synthetic steroid, MP 224.2°C, 337.46 g/mol, LogP = 3.62), the varied digestion rates of the 10 formulations can be clearly noted, as shown in Figure 4.
Those formulations with a higher oil content, particularly those with medium chain triglycerides (Kollisolv MCT 70, BASF) exhibit the fastest digestion over one hour in intestinal media. Comparing the digestibility as well as the solubility of the API, one can compare formulations more succinctly. As an example, formulation F2, with high concentrations of Polyoxyl 40 hydrogenated castor oil (Kolliphor RH 40, BASF), disperses into nanoscale droplets and is digested slowly. Formulation F3, with the same ingredients but a much higher oil concentration, exhibits a much faster digestion rate and higher API capacity but sacrifices the size of the resulting oil droplets. Over a 90-minute digestion, these differences can be seen as graphed in Figure 5: the orange line is the titrated free fatty acid (digestion rate); the grey is solubilized and available API; and the black, precipitated unavailable API.
In summary, the formation of microemulsions is a challenge that can be overcome using modern methods such as robotic high throughput screening. These identified regions can then be utilized to craft functional pharmaceutical formulations capable of varied API loading, digestion rates, and dispersibility. The ten new formulations described in Table I are available for formulators to place “on the shelf” as more challenging APIs come through the pipeline.
1. S.D.S Jorgensen, et. al. Eur. J. Pharmaceutics and Biopharmaceutics124, 116-124 (2018).
Frank Romanski, PhD is head of Global Marketing, Pharma Solutions, BASF Corp, Florham Park, NJ, email@example.com.
Supplement: APIs, Excipients, and Manufacturing
When referring to this article, please cite it as F. Romanski, “How Excipient Type Influences Self-Emulsifying Drug Delivery," Pharmaceutical Technology APIs, Excipients, and Manufacturing Supplement (October 2019).