Drug delivery system for hydrophobic drugs - Patents

Drug delivery system for hydrophobic drugs

Agent: Morrison & Foerster LLP - San Diego, CA, US
Inventors: Ronald Erwin Boch, Dev Mitra Ranji Singh, Iman Karmadi
Class: 424450000 (USPTO)
Related Patents: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Liposomes
#20060039965
02/23/06
Compositions comprising microaggregates containing hydrophobic drugs, as well as methods for their production, are described. Such microaggregates may include micelle structures or combinations thereof with liposomes, and constitute an effective delivery vehicle for a hydrophobic agent. Methods for microaggregate production include the use of preferred lipid compounds and processing conditions favo the production of small aggregates for improved filter sterilization.
FIELD OF THE INVENTION
[0002] The invention relates to water soluble microaggregates of water insoluble, poorly soluble or otherwise hydrophobic agents and phospholipids or lipids which may be used pharmaceutically, agriculturally or industrially. These microaggregate compositions may be used to deliver hydrophobic drugs as a pharmaceutical formulation, hydrophobic compounds related to plant growth as an agricultural product, and hydrophobic reagents as an industrial material. Moreover, the microaggregates of the invention comprise combinations of natural and/or synthetic phospholipids which permit aggregation with the hydrophobic agents to result in micelles, liposomes, and mixtures thereof. Particular combinations of hydrophobic agents and phospholipids or lipids produce microaggregates that are effective delivery vehicles of said compounds.
[0003] Additionally, the invention relates to processes for the production of said microaggregates as delivery systems. These processes include microfluidization (liquid jet milling), high shear mixing, and sonication. Particular processes, involving the use of specific combinations of hydrophobic agents and phospholipids or lipids, permit the large scale preparation of effective delivery vehicles for hydrophobic agents.
SUMMARY OF THE INVENTION
[0015] The present invention provides a phospholipid composition into which hydrophobic photosensitizers may be incorporated that could be processed into a stable liposome product small enough to be sterile filtered, lyophilized for storage, and would rapidly dissolve in an aqueous medium for administration, while maintaining the small particle size. It was initially believed that the phospholipids of choice would contain only saturated lipids, because saturated lipids are more stable, eliminating the need for anti-oxidants in pharamaceutical preparation. The initial attempts for a composition using saturated phospholipids failed. Surprisingly, it was found that the presence of at least some unsaturated lipid in the composition was essential for a stable, robust product that would survive the lyophilization process intact. Additionally, it was found that the presence of at least some phospholipids having negatively charged polar headgroups contributed to the stability of the composition.
[0016] Another totally unexpected finding was that bilayer forming phospholipids comprising a proportion of unsaturated charged lipids were capable of assuming a micellular structure (with or without the incorporation of a hydrophobic molecule) if the material was subjected to a high energy process, such as microfluidization. The production of micelles from bilayer forming lipids is believed to be completely novel, and would not have been predicted from the literature on bilayer forming lipids.
[0017] The present invention relates to microaggregates of lipids and hydrophobic agents. In particular, the microaggregates are produced by combining phospholipids and active hydrophobic compounds. Such compositions may be used in any therapeutic, agricultural or industrial setting, and as such, they are delivery vehicles for the active hydrophobic agents. Preferably, the microaggregates comprise micelles and/or small liposomes containing a therapeutically acceptable amount of a hydro-monobenzoporphyrin photosensitizer. The lipids used for microaggregate production comprise unsaturated lipids, and may be stabilized by the presence of antioxidants. Preferably, the microaggregates comprise a mixture of saturated and unsaturated lipids. Preferably, the microaggregates comprise phospholipids having a headgroup that is negatively charged over the pH range of 5-7. Alternatively, the microaggregates may comprise both micelles and liposomes produced from, or containing, the same combination of phospholipids.
[0018] The present invention also relates to methods of producing microaggregates comprising lipids and hydrophobic agents. It has been discovered that with appropriate selection of lipids, salt conditions, temperature, and size reduction process, microaggregates comprising differing amounts of liposomes and micelles can be produced. Appropriately selected combinations of lipids, low salt conditions, and a high energy process such as microfluidization can result in the production predominantly micelle comprising microaggregate compositions.
[0019] The microaggregates of the invention provide nearly 100% incorporation of a hydrophobic agent such as a hydro-monobenzoporphyrin photosensitizer, which can be expensive and usually requires a complicated synthetic procedure to produce. Thus, there is little reworking necessary and very little waste of the photosensitizer. In addition, due to their small particle size, the present microaggregates exhibit the improved filterability important in producing large quantities of photosensitizer-containing delivery vehicles. Further, the microaggregates retain their small size following lyophilization and reconstituion with an aqueous medium for pharmaceutical delivery. Such photosensitizing microaggregate compositions are useful in mediating the destruction of unwanted cells or tissues or other undesirable materials, or to detect their presence through fluorescence, upon appropriate irradiation. Particularly preferred hydro-monobenzoporphyrin photosensitizers used in the practice of this invention include those having one or more light absorption maxima in the range of 670-780 nm.
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