Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-12-22
2003-09-23
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S497000, C424S009400, C514S951000
Reexamination Certificate
active
06623761
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to nanoparticles of substantially water insoluble materials, methods of preparation, and use thereof. In particular, the invention relates to nanoparticles of therapeutic and diagnostic agents, method of preparation thereof, and pharmaceutically useful dispersions containing these nanoparticles. This invention further relates to methods of treatment using these nanoparticles.
BACKGROUND OF THE INVENTION
Nanoparticles of substantially water insoluble materials (i.e. materials that have water solubility of less than 0.1%) have a wide variety of applications, including therapeutic and diagnostic agents, paints, inks, dyes, and semiconductors. In most cases, performance of these nanoparticles dramatically improves as the nanoparticle size is reduced to 200 nanometers or less. Nanoparticles of therapeutic and diagnostic agents, in particular of a pharmaceutical compound (“drug”) are customarily delivered with a solid or liquid carrier. Liquid containing nanoparticles such as emulsions, microemulsions and liposomes, however, usually suffer from the inherent physical instability of fluids resulting from globule dissociation. Solid polymeric or lipid nanoparticles have more structural stability, yet the rate of biodegradation of the nanoparticles and/or controlled release of the agent in the nanoparticles may not take place as intended, thereby adversely affecting optimal agent delivery and targeting. In addition, only a relatively small amount of the agent or drug can be encapsulated in fluid or solid carriers, requiring large, and sometimes impractical size dosages.
Carrier-free nanoparticles, made entirely of a water insoluble therapeutic agent or drug, have been introduced as an alternative solution for the above limitations and drawbacks. There are two major techniques described in the prior art, to produce solid drug nanoparticles. These techniques are known as wet grinding, and antisolvent precipitation. Other general techniques for nanoparticle formation, such as solvent evaporation and emulsion polymerization, are either not suitable or have not proved to be successful in making carrier-free drug nanoparticles.
Wet grinding involves the mechanical crushing of brittle crystalline drug particles, using hard beads made of glass, porcelain, zirconium oxide, or similar materials (of about 1-2 mm diameter), and aqueous solution of a hydrophilic material. The hydrophilic solution, which can be a surface active agent, surface modifier, or surface stabilizer, prevents aggregation or caking of the ground particles. An aggregate or a cake of drug particles is usually elastic in nature due to entrapped air or liquid within the void spaces between the particles and is not susceptible to further size reduction by bead bombardment. Accordingly, the wet grinding technique is not suitable for making nanoparticles from elastic materials. In addition, because the hard grinding beads can erode during grinding, remnants of the grinding beads can become incorporated in the nanoparticles, causing particle contamination.
The liquid antisolvent technique involves dissolving the water insoluble compound in suitable organic solvent, and diluting that solution with a non-solvent, which is miscible in the solution. The non-solvent neither dissolves the compound nor causes its precipitation from the original solvent. Solid nanoparticles are then generated by carefully controlling the precipitation step by addition of an antisolvent liquid (usually water or an aqueous solution). Since the formation of the nanoparticles is solely dependent on the diffusion of totally miscible liquids under non-structural geometry, or boundaries, resultant particle size, surface, and shape are critically sensitive to minimal changes in the precipitation conditions. The drawbacks of this process are that it is difficult to control and requires considerable preparation. Recently, the use of a supercritical fluid antisolvent, such as pressurized carbon dioxide, gained considerable attention because of the simpler clean up and recovery of the nanoparticles. However, supercritical fluid precipitation requires high pressure, which greatly increases the difficulty in controlling the process.
It would be desirable to have an alternative method for the preparation of substantially water insoluble nanoparticles without the drawbacks of the prior art methods.
SUMMARY OF THE INVENTION
According to one aspect, this invention provides a method of making nanoparticles of substantially insoluble water compounds and more specifically, nanoparticles of a water insoluble pharmaceutical compound (or “drug”) from an emulsion in which a solution of said material forms the globules of the dispersed phase. These emulsions are readily transformed into a single uniform liquid phase, in which nanoparticles of the diagnostic or therapeutic agent are suspended, upon further dilution with the external or continuous phase. The resulting dispersed solid nanoparticles are generally less than 200 nm average diameter.
An advantageous feature of this invention is that therapeutic or diagnostic nanoparticles so produced can be utilized for intravascular injections to treat or diagnose local or systemic diseases. Another advantageous feature is that extravascular injections containing these particles can provide controlled release of the drug at the site of injection for prolonged drug effects, and minimize multiple dosing. Yet another advantage of this invention is improved drug transport across absorption barriers such as mucosal gastrointestinal barriers, nasal, pulmonary, ophthalmic, and vaginal membranes, and other distribution barriers, such as the blood—tissue and blood—tumor barriers of various organs and tissues. For example, anti-cancer nanoparticles of less than 50 nm diameter can migrate through the compromised, more permeable vascular bed to reach tumor tissues. Once the nanoparticles are inside the tumor tissue they will provide local cytotoxic action against the tumor cells. In the case of highly protected organs such as the brain, with its tight vascular bed surrounding the normal tissues, drug nanoparticles will preferentially concentrate in the tumor tissue, with minimal or no toxicity to the healthy brain tissue. A further advantage of this invention is the improved oral bioavailability of poorly absorbed drugs.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
The formation of oil-in-water or water-in-oil emulsions is a well-known process. Emulsions suitable for generating nanoparticles of therapeutic or diagnostic agent in accordance with this invention comprise a dispersed or internal phase in which the agent is totally soluble, an appropriate emulsifier, e.g., a surfactant, and a continuous or external phase with limited solubilizing affinity to the dispersed phase.
While not intending to be confined by a particular theory, the nanoparticles described above appear to be formed by the following mechanism. After emulsification, the system comprises generally spherically shaped globules of agent surrounded by a protective sheath of emulsifier molecules. Those globules are dispersed throughout a bulk of the external phase. The emulsion will be intact as long as the protective sheath is intact and the external phase cannot dissolve the molecules of agent in the dispersed phase. Further dilution of the emulsion with the external phase will cause the sheath to become thinner, allowing the external phase to dissolve some or all of the internal phase globules. The dissolution of the internal phase globules in the external phase results in the production of nanometer-sized particles of the therapeutic or diagnostic agent. Aside from the novel procedure by which these nanoparticles are formed, a fundamental and unique feature of this invention is that precipitation of solid drug nanoparticles from the emulsion globules provides ultimate control over nanoparticle size because the resulting nanoparticles are less than or at least similar to the globule size of the initial emulsion.
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Child, Jr. John S.
Kam Chih-Min
Low Christopher S. F.
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