Nanoparticulate inclusion and charge complex for pharmaceutical formulations

• US 20070149479A1
• Filed: 09/01/2006
• Published: 06/28/2007
• Est. Priority Date: 09/02/2005
• Status: Abandoned Application

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: General, Sascha, Fischer, Katrin
• Application Number:
  US11/514,323
• Publication Number:
  US 20070149479A1
• Time in Patent Office: Days
• US Class Current: 514/58
• CPC Class Codes: A61K 31/724 Cyclodextrins
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08B 37/0012 Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
• CPC Class Codes: C08B 37/0015 Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Abstract

A Nanoparticulate inclusion and charge complex that comprises at least two complex partners, whereby a complex partner is an anionic inclusion-forming agent and another complex partner is a cationic active ingredient.

Claims

1. Nanoparticulate inclusion and charge complex, comprising at least two complex partners, whereby a complex partner is an anionic inclusion-forming agent and another complex partner is a cationic active ingredient.

3. Nanoparticulate inclusion and charge complex according to claim 1, whereby the basic active ingredient is in the protonated state.

4. Nanoparticulate inclusion and charge complex according to claim 1, whereby the cationic active ingredient is a low-molecular active ingredient.

5. Nanoparticulate inclusion and charge complex according to claim 1, whereby the inclusion-forming agent is an anionically modified cyclodextrin.

6. Nanoparticulate inclusion and charge complex according to claim 5, whereby the anionically modified cyclodextrin is selected from the group that consists of cyclodextrin phosphate, cyclodextrin sulfate, cyclodextrin carboxylate and cyclodextrin succinate.

7. Nanoparticulate inclusion and charge complex according to claim 5, whereby the anionically modified cyclodextrin is a beta-cyclodextrin phosphate.

8. Nanoparticulate inclusion and charge complex according to claim 5, whereby the anionically modified cyclodextrin is heptakis-(2,3-dimethyl-6-sulfato)-beta-cyclodextrin or heptakis-(2,6-diacetyl-6-sulfato)-beta-cyclodextrin.

9. Nanoparticulate inclusion and charge complex claim 1, whereby the active ingredient is selected from the group that consists of pynalin, vatalanib succinate, imipramine, apomorphine, atropine, scopolamine, bamipine, astemizole, diphenhydramine, quinidine, quinine, chloroquine, chlorpromazine, chlorprothixene, codeine, ephedrine, naphazoline, oxedrine, isoprenaline, salbutamol, fenoterol, hydromorphone, hydrocodone, morphine, haloperidol, imipramine, lidocaine, loperamide, methadone, levomethadone, metoclopramide, cimetidine, naphazoline, perazine, pethidine, procaine, benzocaine, lidocaine, mepivacaine, promazine, chlorpromazine, propanolol, scopolamine, perazine, thioridazine, trimethoprim, bromhexine, clotrimazole, nitroflurantoin, diazepam, oxazepam, nitrazepam, diphenhydramine, haloperidol, imipramine, isoniazid, loperamide, metronidazole, nicotinamide, papaverine, pethidine, phenazone, ambroxol, bamipine, diphenhydramine, bromocriptine, clonidine, propanolol, metoprolol, phentolamine, sulfaguanidine, ergotamine, verapamil, diltiazem, neostigmine bromide, pilocarpine, physostigmine, ketotifen, thiamin, pyridoxine, imiquimod, irinotecan, raloxifene, tirofiban, mercaptamine bitartrate, brimonidine, tolterodine, mizolastine, abacavir, zaleplon, emedastine, amisulpride, sibutramine, levacetylmethadol, rizatriptan, lercandipine, rosiglitazon, buproprion, quetiapin, brinzolamide, lomefloxacin, almotriptan, galanthamine, desloratadine, levocetirizine, levodropropizine, oxaprozin, voriconazole, tiotropium bromide, ziprasidone, ebastine, eletriptan, imantinib, gatifloxacin, olmesartan, frovatriptan, solifenacin, manidipine, epinastine, olopatadine, escitalopram, duloxetine, a therapeutically active protein, a therapeutically active peptide, and salts thereof.

10. Nanoparticulate inclusion and charge complex according to claim 9, whereby the active ingredient is vatalanib succinate.

11. Nanoparticulate inclusion and charge complex according to claim 1, whereby the complex is meta-stable.

12. Nanoparticulate inclusion and charge complex according to claim 1, whereby the complex dissociates from inclusion-forming agents and active ingredients in the presence of another charged compound or another salt.

13. Nanoparticulate inclusion and charge complex according to claim 12, whereby the additional compound or the additional salt is contained endogenically in the gastrointestinal tract and/or is fed exogenically.

14. Nanoparticulate inclusion and charge complex according to claim 12, whereby the inclusion-forming agent and the additional charged compound or the additional salt accompany a complex and the dissociated active ingredient diffuses.

15. Nanoparticulate inclusion and charge complex according to claim 1, whereby in the range of pH 4 to pH 9, the stability of the complex is independent of pH.

16. Nanoparticulate inclusion and charge complex according to claim 1, whereby in the range of pH 5 to pH 7.5, the stability of the complex is independent of pH.

17. Nanoparticulate inclusion and charge complex according to claim 1, whereby the complex is stable in a simulated intestinal fluid, selected from FaSSIF and FeSSIF.

18. Nanoparticle comprising an inclusion and charge complex according to claim 1.

19. Nanoparticle according to claim 18, which comprises a surface modifying the inclusion and charge complex.

20. Nanoparticle according to claim 18, which has a size in the range of 10 nm to 1.2 μ

m.

21. Nanoparticle according to claim 20, which has a size in the range of 10 nm to 500 nm.

22. Nanoparticle according to claim 21, which has a size in the range of 10 nm to 300 nm.

23. Nanoparticle according to claim 1, whereby the surface has a negative surface potential in the range of −

10 mV to −

70 mV.

24. Nanoparticle according to claim 23, whereby the surface has a negative surface potential in the range of −

20 mV to −

60 mV.

25. Nanoparticle according to claim 1, which comprises at least one compound that modifies the surface.

26. Nanoparticle according to claim 25, whereby the compound that modifies the surface is covalently bonded or non-covalently-bonded to the surface of the nanoparticle.

27. Nanoparticle according to claim 25, whereby the compound that modifies the surface has a charge that is opposite to the charge of the surface of the nanoparticle.

28. Nanoparticle according to claim 25, whereby the compound that modifies the surface is a positively charged compound.

29. Nanoparticle according to claim 28, whereby the positively charged compound is a block co-polymer.

30. Nanoparticle according to claim 29, whereby the block co-polymer is a cationically modified polyethylene glycol.

31. Nanoparticle according to claim 18, whereby the surface has modified terminal functional groups.

32. Nanoparticle according to claim 18, which comprises a target structure.

33. Nanoparticle according to claim 32, whereby the target structure is a part of an antibody, ligands, aptamers or a fragment thereof.

34. Process for the production of a nanoparticle according to claim 18, comprising an inclusion and charge complex comprising at least two complex partners, whereby a complex partner is an anionic inclusion-forming agent and another complex partner is a cationic active ingredient, whereby the process comprises the following steps:

(a) Dissolving a cationic active ingredient in a solvent;

(b) Bringing the active ingredient into contact with an anionic inclusion-forming agent;

(c) Producing an inclusion and charge complex with the formation of a nanoparticulate dispersion;

(d) Recovering the nanoparticle from the dispersion.

35. Process according to claim 34, whereby the process, in addition, comprises the following step:

(c′

) Modifying the surface of the nanoparticle.

36. Process according to claim 35, whereby the modification in step (c′

) is a formation of non-covalent electrostatic and/or covalent bonds.

37. Use of a nanoparticle according to claim 18 for the production of a pharmaceutical preparation.

38. Use according to claim 37, whereby the pharmaceutical preparation comprises a controlled-release preparation.

39. Use according to claim 37, whereby the pharmaceutical preparation comprises a formulation that is insoluble in gastric juice.

2. Nanoparticulate inclusion and charge complex according to the claim, whereby the cationic active ingredient is a basic active ingredient.