Method of producing microscopic particles made of hydrolytically

Details Method of producing microscopic particles made of hydrolytically Method of producing microscopic particles made of hydrolytically

1993-06-22

1995-06-13

Page, Thurman K.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

424451, 424452, 424455, 424462, 424489, 514963, 264 46, 42840221, 42840222, A61K 950, A61K 914, B01J 1302, B32B 516

Patent

active

054240760

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a method for manufacturing microparticles containing active substances from hydrolyrically decomposable polymers.
It has been known from numerous publications that resorbable polyesters, in particular those with a lactic acid base or glycolic acid base, and especially their copolymers, are completely decomposed into endogenous compounds in human or animal tissue or in human or animal fluids, wherein, depending on the purpose of use, the decomposition rates of the polymers can be varied from a few hours up to several months.
The decomposition products reach the normal biochemical metabolism and are either directly excreted or finally metabolized into water and carbon dioxide.
Of particular interest and importance are the applications of resorbent polyesters in galenic preparations with delayed release of active substances for the manufacture of stock forms.
However, these kinds of polyesters can only then be used in human or animal organisms, if they are free of impurities, which possibly may cause irritations. These impurities are, for example, nonconverted residual monomers, molecular weight regulators, or polymerization catalysts.
The present state of the art is represented in
Sustained release (drug) formulations, which are manufactured by using these types of resorbent polyesters that are suitable for subcutaneous injections or implantations into the body, have been manufactured up to now according to the following processes:
microencapsulation with organic solvents (L. M. Sanders et al., J. Contr. Release, 2 (1985) 187, or P. B. Deasy, Microencapsulation and Related Drug Processes, M. Dekker Inc., New York 1984);
emulsification and subsequent solvent evaporation, T. R. Tice & R. M. Gilley, J. Contr. Release, 2 (1985) 343);
spray drying (D. L. Wise et al., Life Sci., 19 (1976) 867;
extrusion (A. J. Schwope et al., Life Sci., 17 (1975) 1877);
fusion embedding (A. J. Schwope et al., Life Sci., 17 (1975) 1877); or
boundary surface polymerization (G. Birrenbach & P. Speiser, J. Pharm. Sci., 65 (1976) 1763).
The above-mentioned processes either have the disadvantage of requiring large amounts of toxic organic solvents, wherein the resulting sustained releae (drug) formulations have high solvent residual concentrations in the form of polymer embeddings (see, J. P. Benoit et al., Int. J. Pharmaceutics, 29 (1986) 95); or, the mentioned processes require high temperatures or pressures, which, in particular, lead to high localized temperature increases and can damage the incorporated medicaments (see L. M. Sanders et al., J. Pharm. Sci., 75 (1986) 356). If such a medicament type remains under the skin or in the tissue over an extended period of time, toxic tissue reactions can be expected locally from the organic solvents. Therefore, the solvent residues must be removed as thoroughly as possible from the mentioned products.
A detailed description of the above-mentioned manufacturing process of the present state of the art is found in DE-OS 37 44 329.
Finally, a process described as "Aerosol Solvent Extraction System" (ASES) for the manufacture of drug-containing microparticles loaded with active substance is known from EP P 322 687 A2. In this process, active substance-loaded microparticles are manufactured with the aid of fluid gases. Microparticles are formed in a supercritical atmosphere from a solution of polymers and active substance, wherein the solvent is removed by absorption into the gas phase.
Although this method is suitable for manufacturing auto-sterile active drug-containing microparticles with a minimum of organic solvents (below 10 ppm) without residual monomers, molecular weight regulators, or polymerization catalyzers, it is, however, disadvantageous in that, with larger batches, no reliable constant particle size distribution can be achieved and in that not all hydrolytically decomposable polymers can be reliably processed into microparticles.
Therefore, it is the object of this invention to manufacture active substance-containing microparticles with constant particle

REFERENCES:
patent: 5232707 (1993-08-01), Lokensgard
patent: 5271945 (1993-12-01), Yoshioka et al.

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