Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1995-11-27
1998-07-14
Schofer, Joseph L.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424489, A61K 916
Patent
active
057800626
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with the formation of small particles of organic compounds upon precipitation when a solution of such an organic compound in a water-miscible solvent is added to an aqueous medium containing polymer and an amphiphilic compound (surfactant or lipid) at a concentration at which polymer/amphiphile complexes are formed. At said concentrations, the system is a solution below the critical concentration at which free micelles are formed. Upon addition of the organic compound, the compound interacts with the polymer/amphiphile complexes, thus increasing their hydrophobicity and leading to precipitation of organic compound/polymer/amphiphile aggregates.
According to the present invention, a small particle refers to a particle size of less than 2 .mu.m.
The object of the invention is to provide a process for the formation of small particles of organic compounds, especially pharmaceutically active compounds, where such process does not involve emulsification or water-immisicible solvents.
The process is preferably used to prepare a readily soluble pharmaceutically active compound.
BACKGROUND OF THE INVENTION
From a pharmaceutical point of view, the smaller the particle size of a relatively insoluble drug, the grater is its rate of solution and as a rule, the greater is its bioavailability (J. H. Fincher, J. Pharm. Sci., 57, 1825 (1968)). To this end, small particles are conventionally formed by mechanical subdivision of bulk matter or by aggregation of small molecules or ions (D. J. Shaw, "Introduction to Colloid and Surface Chemistry", 3rd Ed., Butterworths, London, 1980, Chapter 1).
Studies of polymer/amphiphile systems in aqueous media have shown that interactions of polymers with charged amphiphiles occur in different stages. Ionic polymers and charged amphiphiles of opposite charge precipitate accordingly by electrostatic interactions. On the other hand, interactions between non-ionic polymers and amphiphiles occur in three stages. In the most dilute solutions, very little physical biding occurs. At concentrations of amphiphile higher than the critical micelle concentration, true micelles form. However, between these two concentrations, complexation or binding of polymer to amphiphile occurs (M. L. Fishman and F. R. Eirich, J. Phys. Chem., 75(20), 3135-40 (1971)). Small polymer/amphiphile aggregates or sub-micelles are thus formed. The presence of the amphiphile introduces an effective attraction between different polymer molecules since the formed aggregates could involve more than one polymer molecule. This attraction, together with the binding of the amphiphile to the polymer would lead to an increase in the hydrophobicity of the polymer. If the aggregate is sufficiently hydrophobic it will precipitate. The addition of a polar water-soluble compound (e.g. NaCl) to a polymer/amphiphile system will further enhance the precipitation of the polymer/amphiphile aggregates because there will be an increased difference in polarity between the solvent and the polymer/amphiphile aggregates and because the polar compound will tend to decrease the number of water molecules available for the hydration of the polymer/amphiphile aggregates. Also, precipitation occurs on increasing the temperature of systems containing polymers for which solubility is inversely related to temperature, such as cellulosic derivatives. The cloud point of hydroxypropylmethylcellulose (HPMC) has been shown to be lowered by addition of amphiphiles, the effect being more pronounced in the presence of salt (J. E. Lofroth, L. Johansson, A. C. Norman, and K. Wettstrom, Progr. Colloid. Polym. Sci., 84, 73-77 (1991)).
On the other hand, if a hydrophobic compound is added, it will tend to interact with the polymer/amphiphile aggregates, thus increasing the hydrophobicity of these polymer/amphiphile aggregates and facilitating their precipitation.
SUMMARY OF THE INVENTION
A method has now been found which surprisingly involves the formation of small particles, the growth of which is limited by the adsorption and/or
REFERENCES:
patent: 4606940 (1986-08-01), Frank et al.
patent: 4826689 (1989-05-01), Violanto et al.
Derwent Abstract Accession No. 95-06706, Bostonian et al., "Characterization of Small Particles of Probucol," Pharm. Res. 11, No. 10, Suppl., S326, 1994.
Lofroth et al. "Interactions between surfactants and polymers. I:HPMC," Prog. Colloid Polym. Sci., 84:73-77 (1991).
M. L. Fishman et al., "Interactions of Aqueous Poly (N-vinylpyrrolidone) with Sodium Dodecyl Sulfate," J. Phys. Chem., vol. 75, No. 20, 1971, p. 3135.
Fincher, J.H. "Particle Size of Drugs and Its Relationship to Absorption and Activity" J. Pharm. Sciences 57(11): 1825-1835, 1968.
Shaw, D.J. "Introduction to Colloid and Surface Chemistry" 3rd Ed. Butterworths Pub. pp. 1-18, 1980.
Derwent Abstract Accession No. 93-14549, Bostonian et al. "Formation of Small Particles of a Relativly Insoluble Drug," Pharm. Res. 9, No. 10, Suppl., S224, 1992.
Bostanian Levon
Frank Sylvan
Lofroth Jan-Erik
Cheng Wu C.
Schofer Joseph L.
The Ohio State University Research Foundation
LandOfFree
Small particle formation does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Small particle formation, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Small particle formation will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1879409