The invention refers to a nanoparticle with a diameter which is the maximum in the nanoparticle size distribution, in the range of 10-300 nm, comprising a) a calcium phosphate nanoparticle core a), b) an active ingredient coating b) on the calcium phosphate nanoparticle core a), c) a lactic acid polymer coating c) on the active ingredient coating b), d) a cationic polymer coating d) on the lactic acid polymer coating c) selected from the group of polyethylene-imines, chitosan and human lactoferrin-derived peptides with a length of 14 to 30 amino acids.
1. A nanoparticle with a diameter, which is the maximum in the nanoparticle size distribution, in the range of 10-300 nm, the nanoparticle comprising:
a calcium phosphate nanoparticle core a),
an active ingredient coating b) on the calcium phosphate nanoparticle core a),
a lactic acid polymer coating c) on the active ingredient coating b), and
a cationic polymer coating d) on the lactic acid polymer coating c) selected from the group consisting of a polyethylene-imine, chitosan, and a human lactoferrin-derived peptide with a length of 14 to 30 amino acids.
2. The nanoparticle according to claim 1 , wherein the active ingredient is a peptide, a protein, or a nucleic acid.
3. The nanoparticle according to claim 1 , wherein the active ingredient is a siRNA.
4. The nanoparticle according to claim 1 , wherein the human lactoferrin-derived peptide is a peptide with the amino acid sequence according to SEQ. ID. NO:1 KCFQWQRNMRKVRGPPVSCIKR or a sequence that does not differ in more than 8 amino acid positions from SEQ. ID. NO:1.
5. The nanoparticle according to claim 4 , wherein, in the amino acid sequence of the human lactoferrin-derived peptide, at least two cysteine residues are present.
6. A pharmaceutical composition, comprising a nanoparticle according to claim 1 .
7. A process for preparing the nanoparticle according to claim 1 , the process comprising:
mixing an aqueous solution comprising calcium ions and an aqueous solution comprising phosphate ions and adding an active ingredient, to give a calcium phosphate nanoparticle core a) with the active ingredient coating b) in the form of an inner water phase (WI) for a water-in-oil-in water (WI/O/W2) emulsion;
adding the lactic acid polymer for the polymer coating c) in an organic solution to the water phase (W1) to give a water-in-oil emulsion (W1/O);
adding the water-in-oil emulsion (W1/O) to a further water phase (W2) to give the water-in-oil-in-water (W1/O/W2) emulsion;
removing an organic solvent to give a first dispersion;
collecting, re-dispersing in water, and drying a solid content of the first dispersion to obtain dried solid particles;
re-dispersing the dried solid particles in water to obtain re-dispersed solid particles;
adding a cationic polymer to the re-dispersed solid particles under stirring to obtain a second dispersion which comprises the nanoparticle as a solid content;
collecting, by centrifugation or tangential flow filtration a solid content of the second dispersion; and
re-dispersing or drying the solid content of the second dispersion to result in an aqueous dispersion or a dry preparation comprising the nanoparticle.
8. A method of preparing a pharmaceutical composition, the method comprising:
adding the nanoparticle according to claim 1 to a composition, thereby forming the pharmaceutical composition that comprises the nanoparticle, wherein
said pharmaceutical composition is suitable for oral or parenteral delivery to a subject in need thereof.
9. The nanoparticle according to claim 1 , which has a polydispersity index in the range of 0 to 0.8.
10. The nanoparticle according to claim 1 , wherein the lactic acid polymer of the lactic acid polymer coating c) has at least 10 mol % of polymerized lactic acid or lactide units.
11. The nanoparticle according to claim 1 , wherein the lactic acid polymer of the lactic acid polymer coating c) is a lactide-glycolide copolymer.
12. The nanoparticle according to claim 1 , wherein the lactic acid polymer of the lactic acid polymer coating c) is a poly(D,L-lactide-co-glycolide) copolymer with an inherent viscosity IV from 0.1-2.0 [dL/g].
13. The nanoparticle according to claim 1 , wherein the lactic acid polymer of the lactic acid polymer coating c) is a poly(D,L-lactide-co-glycolide) copolymer with a proportion of D,L-lactide:glycolide in the poly(D,L-lactide-co-glycolide) copolymer from 80:20 to 20:80 parts by weight, where the parts D,L-lactide:glycolide add up to 100 parts (100%).
14. The nanoparticle according to claim 1 , wherein the cationic polymer of the cationic polymer coating d) is a polyethylene-imine having a molecular weight (M w ) of from 5,000 to 50,000.
15. The nanoparticle according to claim 1 , wherein the cationic polymer of the cationic polymer coating d) is chitosan having a molecular weight (M w ) of from 20,000 to 250,000 and is acetylized to a degree of 50 to 100%.
16. The nanoparticle according to claim 1 , wherein the human lactoferrin-derived peptide is a peptide with the amino acid sequence according to SEQ. ID. NO:1 KCFQWQRNMRKVRGPPVSCIKR or a sequence that does not differ in more than 8 amino acid positions from SEQ. ID. NO:1, provided that the cysteine residues in positions 2 and 19 of SEQ. ID. NO:1 are present.