Solid dosage forms from self-emulsifying lipidic formulations

There has been growing interest in the use of lipidic excipients in formulations and, in particular, in self-emulsifying lipid formulations (SELFs) because of their ability to solubilize poorly water-soluble 'lipophilic' drugs and overcome the problem of poor drug absorption.

These formulations have also attracted interest because they can improve the bioavailability of compounds that fall into Class II of the biopharmaceutical classification system (BCS). Class II compounds are poorly water soluble and highly permeable.¹ This bioavailability enhancing property has been associated with a number of in vivo properties of lipidic formulation including:

• The formation of fine dispersions and micellar suspensions to prevent precipitation and recrystallization of the drug compound.

• The ability of certain lipid compounds and their metabolites to initiate changes in the gastrointestinal fluid to favour improved drug absorption.

• The inhibition of cellular efflux mechanisms, which keep drugs out of the circulation.

• Certain lipidic excipients are associated with selective drug uptake into the lymphatic transport system, thereby reducing the effect of first-pass drug metabolism in the liver.²

The mechanisms by which lipids influence drug delivery, digestion and absorption are complex and not yet fully understood. Nevertheless, it is well known that lipidic excipients provide a safe and effective way of enhancing bioavailability, and offer an additional approach to 'mechanical' or 'chemical' strategies for dealing with poorly water-soluble compounds (i.e., techniques such as nanomilling and altering the physicochemical properties of the compound).

Provided the formulator succeeds in addressing the challenges of drug solubility and absorption, the next big challenge is the delivery of the drug in an acceptable dosage form. It is an undisputed fact that oral dosage forms are the preferred drug administration route, and lipid formulations offer versatility for oral dosage forms because they can be formulated as solutions, and semi-solid and solid forms.

Within these oral dosage forms, lipids are formulated as simple emulsions, self-emulsifying and self-micro-emulsifying formulations. SELF systems comprise a defined mixture of lipid excipients, including simple oils, nonionic surfactants and cosurfactants. SELF systems act as carriers for drugs by forming fine emulsions, or micro-emulsions, under gentle stirring when diluted in water or physiological media with physiological motion. Drug molecules are either dissolved or suspended in the SELF system, which maintains the drug in very fine dispersion droplets inside the intestinal lumen, providing optimal conditions for absorption.

Figure 1 Schematic diagram of SEDDS and SMEDDS.

Two types of SELF systems exist: self-emulsifying drug delivery systems (SEDDSs) and self-micro-emulsifying drug delivery systems (SMEDDSs). Both SEDDSs and SMEDDSs have distinct features associated with improved drug delivery properties. SEDDS formulations can be simple binary systems: lipophilic phase and drug, or lipophilic phase, surfactant and drug. The formation of a SMEDDS requires the use of a cosurfactant to generate a micro-emulsion. SEDDS formulations are characterized by in vitro lipid droplet sizes of 200 nm–5 mm and the dispersion has a turbid appearance.

SMEDDSs, however, have a smaller lipid droplet size (<200 nm) and the dispersion has an optically clear-to-translucent appearance. Both systems are associated with the generation of large surface area dispersions that provide optimum conditions for the increased absorption of poorly soluble drugs. The choice of whether a SEDDS or a SMEDDS is the preferred formulation option often depends on the interplay between the intrinsic properties of the drug compound and its solubility and dissolution profile during in vitro screening with a number of excipients. The two systems are illustrated schematically in Figure 1.

In terms of dosage form, SELFs are principally liquid or semi-solid formulations and, therefore, ideal for soft or hard capsule filling. Currently, drugs that utilize SEDDs are exclusively developed in soft or hard gelatin capsules (Table 1). This is because, until recently, getting a SELF into tablet form was a formulation challenge because of the nature of excipients and formulation techniques. That is not to say that formulating for a solid dosage form that utilizes a SELF is impossible, but the starting point for such a formulation requires the use of semi-solid excipients.

Table 1 Examples of pharmaceutical products formulated as self-emulsifying systems.

SELFs have been transformed into solid dosage forms using techniques such as melt granulation, where the lipid excipient acts as a binder and solid granules are produced on cooling. Solvents or supercritical fluids can be used with semi-solid excipients, which are solubilized and then the solvent evaporated to produce a waxy powder. Spraying techniques can be used to produce powder form formulations. These techniques enable the production of granules or powders that can then be compressed into a tablet form or filled into capsules. In all cases, the lipidic excipients used must be semi-solid at room temperature.

However, in many cases, because of the nature of lipidic excipients, the SELF system is a liquid-based formulation rather than a semi-solid formulation and, therefore, an alternative approach is required. This article describes the development and optimization of a solid SELF system to produce a tablet from a liquid SELF.

The concept works by the adsorption/absorption of a liquid SELF onto a neutral carrier (i.e., neutral silicate). Although surprisingly straightforward, developing this solid dosage form technique has required extensive investigation of critical success parameters including:

• Extensive screening of different neutral carriers to evaluate their ability to adsorb maximum levels of the liquid SELF.

• Maximum loading value of the carrier and effect on tablet compression.

• Absorption onto the carrier and effect on flowability — an essential feature for tablet compression.

• Evaluation of the integrity of the system with a poorly soluble API to examine the effect of transforming a liquid into a powder on drug solubility and dissolution rate.

Performance criteria

This case study describes the development of Piroxicam tablets using a liquid SELF. The resulting tablets were analysed for key performance criteria, including dissolution testing, tablet cohesion (hardness) and stability.

Piroxicam was selected as model drug: it is a very poorly soluble, BCS Class II molecule with a LogP value of 1.5. The formulation consisted of 10% w/w Piroxicam to obtain a 20 mg per unit dose and 90% SELF. Although Piroxicam is only partially soluble in the SELF, it emulsifies completely on dilution in large amounts of water (900 mL) at 20 mg per unit dose. The liquid SELF was adsorbed onto a selected silicate by a simple mixing process in a traditional high shear mixer (loading from 60–70%). The resulting powder was then filled into hard gelatine capsules or formulated with additional excipients and compressed into a tablet. To make a tablet, the powder was mixed with a diluent — microcrystalline cellulose — and a super-disintegrant, and then compressed.

Figure 2 Dissolution properties of solid SELF Piroxicam formulations in tablet and capsule form.

The integrity and performance of the Piroxicam tablets and capsules was evaluated by performing dissolution studies that compared the dissolution profiles of pure Piroxicam, the liquid SELF Piroxicam formulation (SMEDDS), the solid tablet form and the capsule form (SMEDDS; Figure 2).

The tablets contained 50% of the loaded silicate and the amount of liquid SELF corresponded to 30% in the tablet formulation. The tablet contained 3% Piroxicam and its hardness was 80 N.

Stability testing is currently underway using the Piroxicam tablets. The initial 3-month results are promising, with demonstrable stability for 3 months at 25 °C and 40 °C.

Optimizing product performance

As with any formulation, certain parameters need to be optimized to deliver the end-product performance required. Important points to consider when developing a solid SELF from a liquid SELF starting point are:

• If tablet cohesion properties are not satisfactory, the ratio of silicate to diluent can be adjusted and/or a binder can be added.

• The dose requirement of active in the final form of the solid SELF because the active compound is diluted during each step of creating the final dosage form.

Conclusions

This straightforward solid SELF approach enables the development of tablets using a liquid SELF for a poorly water-soluble API. A high content of liquid SELF was loaded (up to 70%) onto a carrier (up to 70%), which maintained good flowability, and enabled the production of tablets with good cohesive properties and good content uniformity in both capsules and tablets. Both the tablet and hard capsules produced good dissolution profiles. The tablets have proven stability for 3 months with positive results for 6 months anticipated.

SELF systems have been developed for liquid and semi-solid dosage forms and it is now feasible to develop solid dosage forms using a liquid SELF as the starting material. This clearly expands the options available to the formulator. Naturally, the development of the optimal SELF system requires an in-depth level of understanding of the properties of lipidic excipients, and particularly an understanding of the behaviour of the formulation system created when two or more excipients are mixed together (i.e., SEDDS and SMEDDS), as well as the properties of the API.

In addition to providing the obvious in vivo benefits of a SELF system in tablet dosage form (improved drug absorption, etc.), the benefits of developing a solid SELF system are that a high content of liquid SELF can be loaded onto a carrier and the process gives good content (granule) uniformity. In terms of functionality and performance, the solubilizing properties of the final solid dosage form should remain unaffected by both the adsorption of the liquid SELF on to a carrier and the state of the drug in the lipid formulation (solubilized versus suspended). The formulation and process is remarkably straightforward and few challenges can be envisaged at the industrial scale. This technique offers formulators an additional option in the quest to achieve product performance, product design and manufacturability.

Delphine Marchaud is a technical manager for Gateffosse Pharmaceutical Products. She has been with the company for 10 years , during which she has developed proprietary techniques with Gateffosse liquids, including self-micro-emulsifying lipid formulations (SMEDDS). Her aim and that of her laboratory team is to improve understanding of how lipid-based drug delivery works in vitro and in vivo, and how formulation techniques can be applied to address the drug development challenges faced by the pharmaceutical and healthcare industries.

Sophie Hughes is marketing manager for Gateffosse Pharmaceutical Products. She is responsible for new product development, communication and the development of training programmes about the use of Gateffosse lipidic excipients and lipid-based drug delivery.

References

1. C.Y. Wu. et al., Pharmaceutical Research 22(1), 11–23 (2005).

2. C.J.H. Porter et al., Nature Reviews Drug Discovery 6(3), 231–248 (2007).