Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1997-06-19
1999-01-12
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424491, 424493, 424494, 424495, 424499, A61K 914
Patent
active
058584102
DESCRIPTION:
BRIEF SUMMARY
This application claims benefit of international application PCT/EP95/04401, filed Nov. 9, 1995 published as WO96/14830 May 23, 1996.
1. Field of the Invention
The invention relates to a drug carrier of pure active compound of high saturation solubility and high rate of dissolution, physical stabilization--in particular also using very low surfactant and stabilizer concentrations--and processes and process parameters for its preparation, which produce drug carriers having an average diameter of 10-1,000 nm with simultaneously such a low content of microparticles in the particle population that, in addition to other ways of administration, intravenous injection is also possible.
2. Definition and Advantages of Nanosuspensions
DEFINITION OF THE NANOSUSPENSION IN THE CONTEXT OF THE INVENTION
Disperse system of solid-in-liquid or solid-in-semisolid, the dispersed phase comprising pure active compound or an active compound mixture. The average diameter of the dispersed phase is between 10 nm and 1,000 nm (determined by photon correlation spectroscopy), the distribution of the population being quite narrow, that is to say the proportion of microparticles in the particle population is very low. The nanosuspension can be surfactant-free, but can also comprise surfactants or stabilizers or both. The nanosuspension can also be lyophilized or spray dried, and the nanoparticles of a nanosuspension can also be incorporated into a solid carrier matrix.
ADVANTAGES OF NANOSUSPENSIONS
The preparation of medicament particles having a size in the nanometer range has many advantages from the pharmaceutical technology, biopharmaceutical, pharmacological and medical aspect.
Some of these are:
1. The dissolution rate increases as the particle surface area increases in accordance with the Noyes-Whitney law. As a result, the rate of flooding of active compounds increases, and the maximum plasma level is reached faster (e.g. oral or i.v. administration of a nanosuspension). The preparation of nanosuspensions is therefore of interest for all substances with which the dissolution rate is the determining factor for the bioavailability.
2. Intravenous administration of sparingly soluble active compounds can be rendered possible by nanosuspensions. More and more newly developed medicaments have a very low solubility or are almost insoluble, specifically in water and, at the same time, in organic solvents. Pharmacological testing following oral or i.m. administration is not possible because of the low bioavailability due to the low solubility. Intravenous injection is excluded because of the lack of a suitable solvent mixture. As a nanosuspension, the active compound can be injected without blockade of blood capillaries. In the relatively large volume of blood compared with the injection volume (e.g. 20 ml to 6l ), the active compound then dissolves, the blood proteins often additionally having a solubilizing action.
3. Via formulation as a nanosuspension, a reduction in the injection volume of drugs can be achieved. If the water-solubility is low, the result is a relatively large volume to be administered if an active compound is administered as a solution. Alternatively, the active compound can be formulated as a nanosuspension, the medicament particles being dispersed in a saturated solution of the active compound. Infusion could thus be replaced by a bolus injection.
4. Nanosuspensions can be employed for controlled drug delivery. After oral administration, oral immunization could take place via the M cells in the gastrointestinal tract, and selective concentration in the absorption windows of the gastrointestinal tract could be achieved via bioadhesives.
5. Nanosuspensions are delivery systems for drug targeting. After intravenous injection, particles accumulate specifically in certain organs, e.g. liver, spleen or bone marrow, as a function of their surface properties (R. H. Muller, Colloidal Carriers for Controlled Drug Delivery and Targeting, Wissenschaftliche Verlagsgesellschaft Stuttgart, 1991). After parenteral administr
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Becker Robert
Kruss Bernd
Muller Rainer H.
Peters Katrin
Medac Gesellschaft Fur Klinische Spezialpraparate
Melcher Jeffrey S.
Page Thurman K.
Seidleck Brian K.
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