Are lipid emulsions the drug delivery solution?Lipophilic compounds have great potential in the discovery process. BY LYNN COLLINS-GOLD, With the introduction of new automated synthesis methods, combinatorial libraries, and high-throughput screening, the capacity for screening new drug compounds has soared. However, the ability to handle this wealth of molecules could be improved. More than likely, many potential blockbusters have been lost because of inadequate formulation strategies during different stages of evaluation. In many cases, the loss could have simply been due to solubility problems.
Appropriately formulated and processed nutritional emulsions stabilized by phospholipids tend to be stable for long periods. The approved shelf life is normally 18 or 24 months at room temperature, but emulsions could remain physically stable for much longer. In clinical nutrition practice, emulsions are used under circumstances that would put a severe strain on the stability profile of most formulations. At the hospital, other nutrients are often added to the emulsion, including amino acids, glucose, electrolytes, trace elements, and vitamins. In spite of the change in pH and the high electrolyte load due to these nutrients, the emulsion will remain intact for a prolonged period. For selected admixtures prepared aseptically as an industrial product, a shelf life of up to eight months can be attained in cold storage. To maximize the drug potential of all molecules, there has been a renewed effort to find formulation strategies for compounds inadequately soluble in water. Many different drug delivery vehicles for lipid-soluble compounds have been suggested, but few have been executed on a large scale. For most compounds, the lack of information about manufacturing cost, stability, regulatory acceptance, and safety hinders their use. In the early 1960s, Arvid Wretlind and his colleagues developed the first safe parenteral fat emulsion for clinical nutrition, called Intralipid. This product provides concentrated energy and essential fatty acids to patients who cannot eat. By focusing on the formulation technology and the selection and purification of the lipid raw materials, Wretlind’s group overcame several adverse clinical reactions that had caused extensive problems for earlier investigators, including withdrawal of products from the market. The clinical use of parenteral fat emulsions is now globally accepted as a part of nutrition therapy. Formulation and manufacturing A prominent example in the field of anesthesia is the propofol-containing drug emulsion Diprivan. This product, introduced in the mid 1980s, now has a large market for the induction and maintenance of anesthesia, and has been the most successful example of lipid emulsions applied to drug delivery so far. Improved solubility is critical to propofol’s success. Propofol readily dissolves in soybean oil and gives a low concentration of the drug in the water phase. Because the concentration determines the pain on injection, this adds to the benefits of an emulsion formulation. Propofol emulsions are now available as a generic product. Compounds such as cyclosporine and Amphotericin B have been formulated both in admixtures with nutritional emulsions as ex tempore preparations (prepared just before administration), and in drug emulsions. Several cytotoxic compounds with a lipophilic character have also been formulated in this manner, including taxol. Polar triglycerides Much attention has been paid to perfluorocarbons as alternative carriers for active substances in disperse systems. The most prominent example is perfluorocarbon emulsions used as injectable oxygen carriers (e.g., as blood substitutes). Although the solubility of oxygen in perfluorocarbons makes such systems good candidates for this purpose, stability issues have hampered their exploitation. The interest in perfluorocarbons, however, points out that weakly or strongly lipophilic gases also may be solubilized into parenteral emulsions. As with any drug formulation, lipid emulsions must be manufactured to strict specifications. The emulsions must have a droplet size distribution that is appropriate, stable, and highly reproducible. High-pressure homogenization—the preparation procedure used for most commercial products—is adaptable to small-scale and large-scale manufacture. Another prerequisite is sterility. Heat sterilization is preferred because of its advantages with respect to manufacturing ease and product safety, but alternative sterilization methods are feasible. Under certain circumstances, sterile filtration has proved to be feasible for emulsions with a small mean droplet size. Advantages of emulsions The lipid emulsions that have been used for parenteral (i.e., not through the intestines) nutritional use have a composition and droplet size distribution that are much like those of chylomicrons, the endogenous aggregates that distribute lipids in the bloodstream. Indeed, Intralipid’s developers intended for their product to mimic chylomicrons. The mean droplet size of nutritional emulsions and chylomicrons is similar, although the droplet size distribution is wider for chylomicrons. In both systems, phospholipids are the emulsifier. It is generally agreed that parenteral lipid emulsion is taken up along similar routes as natural chylomicrons (see MDD, September/October 1999, p 67). It was early shown that the rate of elimination is similar for fat emulsions and chylomicrons. However, more detailed studies show differences in the molecular mechanisms of elimination from the bloodstream. In chylomicrons, the triglyceride substrate is cleared by two processes: removal of triglyceride from the particle through lipolysis, and then removal of the particle itself. For emulsions, the second route is somewhat predominant. For drug delivery purposes, it may be necessary to control and modify the uptake of the droplets. Adding block copolymers of ethylene oxide and propylene oxide to stabilize an emulsion prolongs circulation time. Another strategy for avoiding rapid clearance uses phospholipids modified with polyethylene glycol or the addition of surfactants containing polyethylene glycol. The decrease in toxicity and the concomitant increase in therapeutic window are other potential advantages. In the case of Amphotericin B, for example, several studies have suggested that toxicity significantly decreases when the compound is added ex tempore to a lipid emulsion. The mechanism for this decrease in toxicity remains to be explained. Other lipid drug carrier systems have been used or reported in the literature. Although the range of formulation types is vast, few have any track record, and those most commonly encountered have seldom gained any application beyond a single product. Because of some similarities in the processing and excipients used, a comparison with liposomes should highlight the capabilities of popular lipophilic delivery systems. Liposomes consist of bilayered structures that are commonly built up by using phospholipids, with one or several bilayers surrounding a water core (see MDD, July/August 1999, p 41). Although most pharmaceutical research with liposomes has focused on water-soluble drugs entrapped in the aqueous core, preparations containing Amphotericin B are based on their amphiphilic character. Like parenteral fat emulsions, liposomes can solubilize or complex amphiphilic or lipophilic drugs, but there are significant differences between the pharmaceutical properties of the resulting products. Drug loading of lipophilic drugs is normally substantially lower for liposomes than for emulsions. The concentration of an active component in liposomes would, at equal drug concentrations, be closer to that of solubilized formulations, which could have substantial clinical disadvantages. Parenteral lipid emulsions are normally ready-to-use formulations stored at room temperature, unless the stability of the formulated drug itself limits this type of formulation. Liposome formulations normally are lyophilized because of stability issues and require reconstitution before use. The lack of a lyophilization step during manufacture is another advantage of lipid emulsions. Delivering the future The eventual success of this technology, however, will depend on the extent to which industry will allow lipid-soluble compounds to be explored in detail. If the full potential of lipid emulsions is to be realized, they need to be used as a tool in the earlier stages of lead evaluation. Although not necessarily applicable to the earliest stages of the screening procedure, it should be realized that whole classes of components may be evaluated more readily if lipid emulsions are added to the repertoire of the formulation scientist and to the entire development chain.
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An emulsion is a liquid system in which one liquid is dispersed in a second, immiscible liquid (with or without emulsifiers), usually in droplets. A parenteral lipid emulsion, such as Intralipid, consists of a water phase with droplets composed of a triglyceride core (diam 250–400 nm) stabilized with a phospholipid monolayer (2–3 nm). The phospholipid monolayer stabilizes the emulsion by long-range repulsive electrostatic forces and short-range repulsive hydration forces. Any excess phospholipid exists as dispersed liposomes, unilamellar closed aggregates with a water core (diam 60–90 nm). Detailed structures can be obtained by electron microscopy and indirect techniques such as NMR. Submicrometer droplet emulsions are typically characterized by using light-scattering and light-diffraction methods.