Title:  Pharmaceutical compositions comprised of stabilized peptide particles

United States Patent:  6,447,806

Issued:  September 10, 2002

Inventors:  Gassmann; Peter (Weil, DE); Sucker; Heinz (Basel, CH)

Assignee:  Novartis AG (Basel, CH)

Appl. No.:  668889

Filed:  September 25, 2000

Particles of a substantially water insoluble biologically active substance, such as Cyclosporin, are loaded with a charged glyceryl ester as an electrostatic stabilizer which imparts to the particles a zeta potential and having an active substance:stabilizer weight ratio of 1:1 to 400:1 and an average particle diameter of 1 nanometer to 10 micrometers. Compositions having such particles are found to be useful delivery systems.

Description of the Invention

This invention relates to particles of biologically active substances that are electrostatically protected against coagulation when they are dispersed in water, e.g. producing colloids, and pharmaceutical compositions containing them.

Biologically active substances are understood to include those active substances, i.e. pharmacologically active substances, which may be used in medicine as medicaments or in the agricultural industry e.g. as pesticides. The term "biological compositions" therefore also includes compositions which are employed in the agricultural industry. However, the invention relates in particular to pharmaceutical compositions for medicinal usage.

Colloids produced on dispersing the particles may have in general a particle size of between 1 and 10000 nanometers (=0.001 to 10 micrometers). These colloidal particles in compositions of the present invention are believed to consist only of active substance in amorphous form. The small size of the particles, especially less than 2 micrometers, enables intravenous application of the colloidal drug particles to take place without any danger of blocking the finest blood capillaries.

The colloidal state in itself is generally regarded as unstable and liable to collapse since this finely-dispersed state is associated with a large surface area. The colloidal system attempts to;reduce the surface area in the dispersion medium by coagulation,: e.g. aggregation, flocculation or crystallization. Addition of stabilizers is necessary to prevent this.

Basically, there are two known principles of stabilization. The first is steric stabilization. Polymer molecules are adsorbed on the surface of the particles and prevent aggregation or flocculation through their chains which reach into the dispersion medium.

The second principle is based on charging particles positively or negatively and on the resulting reciprocal repulsion of the particles. The stabilizer is charged and contains a lipophilic moiety which is suitable for adsorption onto the lipophilic surface of the particles. Since the potential prevailing at the particle surface is poorly accessible for technical measurement, the so-called zeta potential has become is a well known characteristic used e.g. to indicate the stability of electro-statically stabilized particles. The zeta potential of an electrostatically stabilized particle may be regarded as the electric potential prevailing at its boundary surface, corresponding to a layer at a certain distance from the particle up to which electrolyte ions in solution are brought or from which they are removed by thermal motion.

The zeta potentials may be determined in conventional manner.

The present invention provides in one aspect particles of a substantially water insoluble biologically active substance having on the surface thereof charged glyceryl ester, the particles having an active substance: ester weight ratio of from 1:1 to 400:1.

In another aspect the invention provides pharmaceutical compositions comprising particles of a biologically active substance which is very poorly soluble in water and which are free from polymeric or cross linked nucleus, wall or matrix material, but loaded with a negatively or positively charged glyceryl ester as an electrostatic stabilizer which imparts to the particles a zeta potential of -1.5 to -100 or from +1.5 to +100 mV when in an aqueous 0.01 molar KCl solution, the particles having an active substance: stabilizer weight ratio of 1:1 to 400:1 and having diameters of 1 nanometer to 10 micrometers when measured in a liquid medium.

The present invention also provides a process for the production of particles according to the invention which comprises mixing a) an organic solution containing 1 to 100 mg/ml pharmacologically active substance and the glyceryl ester or electrostatic stabilizer and b) an aqueous medium are under conditions such that in the corresponding mixture the weight ratio of active substance to ester or stabilizer corresponds to that given above.

In a further aspect the present invention provides a process for the production of a pharmaceutical composition according to the invention wherein in a first step the particles are produced, with subsequent isolation of the resultant colloidal particles.

The glyceryl esters preferably have organic and inorganic acid moieties. The organic acid moiety is preferably of a fatty acid. The inorganic acid moiety is preferably derived from a polybasic acid, e.g. phosphoric acid. Additionally, the glyceryl esters may contain amino residues, e.g. amino alcohol ester residues, or hydroxyl residues, e.g. glycerol.

The organic acid moiety is the lipophilic moiety of the glyceryl ester; the inorganic acid moiety may, if in salt form, give the glyceryl ester molecule its negative charge; the amino moiety, if present, may, if quaternized, give the glyceryl ester molecule a positive charge.

A preferred class of glyceryl esters are the negatively and positively charged phospholipids.

The biologically active substances are preferably those which may be employed in medicine.

Preferably their water solubility is less than 1 part by weight of substance per 1000 parts by volume of water (=0.1% or 1 mg /ml at room temperature).

Such substances are classified according to USP XXII (1990) as very poorly (slightly) soluble.

The water solubility is preferably at least 1 part by volume of substance per 10000 parts by volume of water (=0.01% or 0.1 mg /ml).

The active substances may belong to any of a wide variety of chemical classes. One example of an active substance are the imidazoles. Another Example is FK 506. This compound has been described in Merck Index, Eleventh Edition, Appendix, A5. Analogues of FK 506 are also generally known. The active substances are preferably very poorly soluble peptides, especially cyclopeptides, such as those having cyclosporin structure, such as the cyclosporins, especially those having a water solubility of at most 400, especially at most 40, micro-grams per ml of water. The cyclosporins comprise a known class of pharmacologically active substances, which are described extensively together with their medicinal uses in the literature see e.g. GB 2,222,770 A (the contents of which are incorporated by reference). Preferred cyclosporins are cyclosporin A (=ciclosporin), cyclosporin G, cyclosporin D.

Claim 1 of 46 Claims

What is claimed is:

1. Particles of a substantially water insoluble biologically active peptide having on the surface thereof a negatively or positively charged glyceryl ester which is a charged phospholipid obtained by extraction from natural lecithin or partially or completely by synthesis, the particles having a peptide charged ester weight ratio of from 30:1 to 50:1.
 

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