Lipid Based Drug Formulation
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Lipid-based delivery systems are an accepted, proven, commercially viable strategy to formulate pharmaceuticals, for topical, oral, pulmonary or parenteral delivery. Whether in the form of liposomes, micelles, or emulsions, formulations can be tailored to meet a wide range of product requirements dictated by disease indication, route of administration, and considerations of cost, product stability, toxicity, and efficacy.
One of the earliest applications of liposome technology has been to improve drug solubility (AmBisome®, Visudyne®). NLI has established manufacturing processes designed for the preparation of large scale batches of sparingly soluble compounds, often at drug concentrations that are several orders of magnitude higher than the nominal aqueous solubility of the compound.
Sophisticated “next generation” formulations (e.g. DOXIL®, Myocet®) focus on controlled delivery of small molecules, peptides, proteins or nucleic acids. There has been particular excitement generated by recent published preclinical data demonstrating the effectiveness of liposome formulations of siRNA. Another recent trend is the increased use of liposome technology to control the bioavailability of small molecules and peptides following localized administration e.g. to the lungs, subcutaneous tissue or brain.
Liposome technology has also been commercially proven as a vaccine adjuvant. There are several marketed liposome products (Epaxal®, Inflexal®), and a growing number of products under clinical development.
The proven safety and efficacy of lipid-based carriers make them attractive candidates for the formulation of pharmaceuticals, as well as vaccines, diagnostics and nutraceuticals.
Lipid-Based Drug Formulations
The most frequent role for lipid-based formulations has traditionally been to improve the solubility of sparingly soluble drugs. However, the number of applications for lipid-based formulations has expanded as the nature & type of active drugs under investigation has become more varied. The observation that particulates such as “long-circulating” emulsions and liposomes can “passively” accumulate at sites of disease or inflammation provides a strong rationale for using lipid-based systems to increase drug bioavailability at the disease site. Lipid-based formulations may also protect active compounds from biological degradation or transformation, that in turn can lead to an enhancement of drug potency. In addition, lipid-based delivery systems have been shown to reduce the toxicity of various drugs by changing the biodistribution of the drug away from sensitive organs thereby reducing the accumulation of otherwise toxic drugs in the heart, kidney and muscle. This reduction in toxicity may allow for more drug to be administered and forms the basis for the current success of several marketed lipid based formulations of amphotericin B (AmBisome®, ABELCET®) and doxorubicin (Doxilâ, Myocetâ).
Liposomes, a termed coined by Alex Bangham, describes artificial membranes composed of lipids arranged in a bilayer that surrounds an aqueous interior. For the last twenty five years, there has been widespread interest in the application of liposome technology to the development of pharmaceuticals. In all cases, the primary rational for introducing liposome formulations into the market was to achieve a significant reduction in the toxicity of the drug, while maintaining or improving the efficacy of the active compound. That these products have been successfully brought to the market is a testament that this approach to formulation of pharmaceuticals has reached a higher level of maturity and market acceptance than ‘rival” drug delivery technologies.
Liposome formulations of drugs are not suitable for all diseases or drugs. However, a number of principals have been established for these specialized drug delivery systems. First, lipid excipients are generally considered as safe and have proven to be minimally toxic even in applications where they have been employed at very high concentrations. Moreover, not only are the expients themselves non-toxic, but liposomes gave been shown to buffer the toxicity of many drug classes. This buffering of toxicity can be attributed to a retention of the drugs in the carrier, which can significantly alter tissue biodistribution, as well as reduction in the tendency of hydrophobic molecules to precipitate, or lyse membranes. Thus, liposome formulations can decrease the tendency of drugs to cause necrosis at their site of injection. It is perhaps not surprising that one of the most popular applications of liposome technology is in the area of dissolution of sparingly soluble compounds. In contrast to approaches that use co-solvents, liposome formulations are stable to dilution. Moreover, since many drug candidates are selected on the basis of their ability to cross biological membranes, almost all of these drugs classes show some tendency to dissolve in liposome formulations. The utility of this approach has recently been validated by the successful introduction of a liposome formulation of a benzoporphyrin (Visudyneâ) for the treatment of age-related macular degeneration.
It is well established that intravenous administration of particulate carriers such as liposomes and long-circulating emulsions, leads to their accumulation in extravascular sites that exhibit leaky vasculature. The extent of this accumulation can be remarkable, and lead to an increase in tissue specific delivery of active molecules corresponding to several orders of magnitude higher than free compounds. This passive delivery to sites of therapeutic activity undoutedly accounts for the proven efficacy of marketed liposome formulations, Doxilâ and Myocetâ. Liposome formulations can also protect fragile molecules from chemical degradation or transformation. There are numerous examples, where molecules such as nucleic acids, recombinant proteins, peptides as well as small molecular weight drug candidates exhibit stability in biological fluids that is several orders of magnitude greater than the free molecule. This protection of the active molecule can lead to a significant increase in bioavailability. Applications of liposome technology to the delivery of bioactive compounds is now widespread, and encompasses delivery of small molecules, nucleic acids, antisense molecules, recombinant proteins, peptides and bioactive lipids.
Principals associated with Northern Lipids Inc. (NLI) have been at the forefront of designing lipid-based formulations for many years. This group is recognised for making a number of significant contributions to current practices and underlying concepts associated with the formulation of lipid-based pharmaceuticals: (i) application of extrusion to prepare homogenous preparations of unilamellar vesicles; (ii) inclusion of disaccharides to improve drug retention following lyophilization of liposome formulations; (iii) the use of “remote loading” to encapsulate antibiotics and antineoplastic agents into liposomes; (iv) the demonstration that drug/lipid ratio plays a critical role in determining the efficacy and toxicity of liposome formulations of antineoplastic and antifungal agents; (v) the application of ion gradients to increase the retention of weak acids and bases in liposome delivery systems; (vi) the use of pegylated lipids to control the release of active compounds from lipid delivery systems; (vii) the use of liposomes to dissolve sparingly soluble compounds; and (viii) the use of pegylated lipids to control the circulating half-life of emulsions.
Taken together, these contributions reflect a wealth of experience and ability to solve formulation problems, as they arise during product development. Adaptation of liposome technology to the dissolution of sparingly soluble compounds, complements emulsion and micellar delivery systems that we work with at NLI. NLI staff have experience covering early stage research and development through scale and GMP production of these formulations.
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