Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution

• US 5,858,410 A
• Filed: 06/19/1997
• Issued: 01/12/1999
• Est. Priority Date: 11/11/1994
• Status: Expired due to Term

• Current Assignee: Jagotec Ag (Vectura Group Ltd.)
• Original Assignee: Medac Gesellschaft Fur Klinische Spezialpraparate mbH (Medac GmbH)
• Inventors: Peters, Katrin, Muller, Rainer H., Becker, Robert, Kruss, Bernd
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Seidleck, Brian K.
• Application Number:
  US08/836,305
• Time in Patent Office: 572 Days
• Field of Search: 424/489, 424/491, 424/493, 424/494, 424/495, 424/499
• US Class Current: 424/489
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/145 with organic compounds

Abstract

Provided is a drug carrier comprising particles of at least one pure active compound which is insoluble, only sparingly soluble or moderately soluble in water, aqueous media and/or organic solvents, wherein said active ingredient is solid at room temperature and has an average diameter, determined by photon correlation spectroscopy (PCS) of 10 nm to 1,000 nm, the proportion of particles larger than 5 μm in the total population being less than 0.1% (number distribution determined with a Coulter counter), and, when introduced into water, aqueous media and/or organic solvents, the active compound has an increased saturation solubility and an increased rate of dissolution compared with powders of the active compound prepared using an ultrasonic probe, a ball mill or a pearl mill, the solid particles having been comminuted, without prior conversion into a melt, by using cavitation or shearing and impact forces with introduction of a high amount of energy.

Claims

1. Drug carrier comprising particles of at least one therapeutically active compound which is insoluble, only sparingly soluble or moderately soluble in water, aqueous media and/or organic solvents, wherein said active ingredient is solid at room temperature and has an average diameter, determined by photon correlation spectroscopy (PCS) of 10 nm to 1,000 nm, the proportion of particles larger than 5 μ

m in the total population being less than 0.1% (number distribution determined with a Coulter counter), and, when introduced into water, aqueous media and/or organic solvents, the active compound has an increased saturation solubility and an increased rate of dissolution compared with powders of the active compound prepared using an ultrasonic probe, a ball mill or a pearl mill, the solid particles having been comminuted, without prior conversion into a melt, by using a piston-gap homogenizer.

2. Carrier according to claim 1, wherein the particles of the main population have an average diameter of between 40 and 1,000 nm.

3. Carrier according to claim 1, wherein said carrier is prepared using the jet stream principle.

4. Carrier according to claim 1, wherein said carrier is prepared using synthetic, semi-synthetic or naturally occurring surfactants in concentrations of 0.001-30%.

5. Carrier according to claim 1, wherein said carrier is prepared with exclusion of the use of organic solvents.

6. Carrier according to claim 1, wherein said carrier is prepared without the use of ultrasonic probes or ball or pearl mills.

7. Carrier according to claim 1, wherein the proportion of the internal or drug phase, based on the total weight of said carrier, is 0.1 to 30 wt. %.

8. Carrier according to claim 1, wherein the drug carrier comprises an active compound or active compounds which are slightly soluble or insoluble in water or aqueous solutions.

9. Carrier according to claim 1, wherein the drug carrier comprises an active compound or active compounds which are slightly soluble or insoluble in organic solvents.

10. Carrier according to claim 1, wherein the drug carrier comprises an active compound or active compounds which are slightly soluble or insoluble in water or aqueous solutions and in organic solvents.

11. Carrier according to claim 1, wherein the drug carrier comprises an active compound or active compounds which have a moderate solubility in water or aqueous solutions and/or in organic solvents.

12. Carrier according to claim 1, wherein said carrier comprises one or more dispersion-stabilizing substances.

13. Carrier according to claim 12, wherein said carrier comprises the dispersion-stabilizing substances in an amount of 0.001 to 20 wt. %, based on the total weight of said carrier.

14. Carrier according to claim 12, wherein the dispersion-stabilizing substances are compounds from the series consisting of poloxamers, poloxamines, ethoxylated mono-and diglycerides, ethoxylated lipids and lipoids, ethoxylated fatty alcohols and alkylphenols, ethoxylated fatty acid esters, polyglycerol ethers and esters, lecithins, esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols, phospholipids and sphingolipids, sterols, esters or ethers thereof and mixtures of these compounds.

15. Carrier according to claim 12, wherein the stabilizing substance comprises egg lecithin, soya lecithin or hydrogenated lecithin, mixtures thereof or mixtures of one or both lecithins with one or more phospholipid components, cholesterol, cholesterol palmitate, or stigmasterol.

16. Carrier according to claim 1, further comprising charge stabilizers.

17. Carrier according to claim 16, further comprising charge stabilizers in an amount of 0.01 to 20 wt. %, based on the total weight of said carrier.

18. Carrier according to claim 16, wherein the charge stabilizers comprise dicetyl phosphate, phosphatidylglycerol, saturated or unsaturated fatty acids, sodium cholate, anti-flocculants or amino acids.

19. Carrier according to claim 1, further comprising one or more viscosity-increasing substances.

20. Carrier according to claim 19, further comprising viscosity-increasing substances in an amount of 0.1 to 20 wt. %, based on the total weight of said carrier.

21. Carrier according to claim 19 wherein the viscosity-increasing substances comprises cellulose ethers and esters, polyvinyl alcohol, alginates, xanthans, pectins, polyacrylates, poloxamers and poloxamines.

22. Carrier according to claim 19, further comprising a compound selected from the group consisting of sugars or sugar alcohols, glucose, mannose, trehalose, mannitol and sorbitol.

23. Carrier according to claim 19, further comprising charge carriers.

24. Carrier according to claim 1, characterized in that the particles are dispersed in distilled water or an aqueous medium or in an aqueous medium with additions of electrolytes, mono- and disaccharides, polyols or mixtures thereof.

25. Carrier according to claim 24, wherein the additions comprise sodium chloride, mannose, glucose, fructose, xylose, mannitol, sorbitol, xylitol and glycerol.

26. Carrier according to claim 1, wherein the particles are lyophilized or spray dried.

27. Carrier according to claim 1, further comprising one or several active compounds.

28. Carrier according to claim 27, wherein, in the case of several active compounds, one active compound or several active compounds are dissolved or dispersed in another or several others, adsorbed onto the surface thereof or dispersed as a solution in the particle.

29. Carrier according to claim 1, wherein said particles are dispersed in a non-aqueous medium.

30. Carrier according to claim 29, wherein said particles are dispersed in a liquid, semisolid or solid medium.

31. Carrier according to claim 30, wherein said particles are dispersed in a liquid oily medium.

32. Carrier according to claim 30, wherein the medium comprises lipids or lipoids or mixtures thereof.

33. Carrier according to claim 32, wherein the medium comprises mono-, di- or triglycerides, waxes, fatty alcohols and fatty alcohol esters, beeswax, oleyl oleate, isopropyl myristate, wool fat or mixtures thereof.

34. Carrier according to claim 30, wherein the medium comprises longer-chain organic molecules or polymers, of liquid, semisolid or solid polyethylene glycols, poloxamers, poloxamines or mixtures thereof.

35. Process for the preparation of the drug carrier according to claim 1, wherein it is produced by using cavitation, wherein the drug or the drug mixture is ground to a powder, dispersed in a dispersing agent and forced under pressure through a gap, where cavitation occurs.

36. Process for the preparation of the drug carrier according to claim 1, wherein it is produced by using shearing and impact forces, wherein the drug or the drug mixture is ground to a powder, dispersed in a dispersing agent and then ground in the wet state, in particular in a jet stream system.

37. Drug carrier comprising particles of at least one therapeutically active compound which is insoluble, only sparingly soluble or moderately soluble in water, aqueous media and/or organic solvents, wherein said active ingredient is solid at room temperature and has an average diameter, determined by photon correlation spectroscopy (PCS) of 40 nm to 100 nm, the proportion of particles larger than 5 μ

m in the total population being less than 0.1% (number distribution determined with a Coulter counter), the solid particles having been comminuted, without prior conversion into a melt, by using a piston-gap homogenizer.

38. A method of making a drug carrier comprising the steps of:

subjecting at least one solid therapeutically active compound dispersed in a solvent to high pressure homogenization in a piston-gap homogenizer to form particles having an average diameter, determined by photon correlation spectroscopy (PCS) of 40 nm to 100 nm, the proportion of particles larger than 5 μ

m in the total population being less than 0.1% (number distribution determined with a Coulter counter), without prior conversion into a melt, wherein said active compound is solid at room temperature and is insoluble, only sparingly soluble or moderately soluble in water, aqueous media and/or organic solvents.

39. Drug carrier comprising particles of at least one therapeutically active compound which is insoluble, only sparingly soluble or moderately soluble in water, aqueous media and/or organic solvents, wherein said active ingredient is solid at room temperature and has an average diameter, determined by photon correlation spectroscopy (PCS) of 10 nm to 1,000 nm, the proportion of particles larger than 5 μ

m in the total population being less than 0.1% (number distribution determined with a Coulter counter), and, when introduced into water, aqueous media and/or organic solvents, the active compound has an increased saturation solubility and an increased rate of dissolution compared with powders of the active compound prepared using an ultrasonic probe, a ball mill or a pearl mill, the solid particles having been comminuted, without prior conversion into a melt, by using cavitation or shearing and impact forces with introduction of a high amount of energy, and wherein said active compound comprises at least one compound selected from the group consisting of;

analgesics, anaesthetics, antirheumatics, antiallergics, antibiotics, antiepileptics, antimycotics, calcium metabolism regulators, chemotherapeutics, corticoids, cytokines, cytostatics, dermatics, hypnotics, immunotherapeutics, local anesthetics, metastasis inhibitors, migraine agents, ophthalmics, parathyroid hormones, psychotropics, sedatives, and sex hormones.

40. A drug carrier according to claim 39, wherein said active compound comprises an analgesic selected from the group consisting of morphine, codeine, piritramide, fentanyl, levomethadone, tramadol, diclofenac, ibuprofen, indomethacin, naproxen, and prioxicam.

41. A drug carrier according to claim 39, wherein said active compound comprises an antiallergic selected from the group consisting of pheniramine, dimethindene, terfenadine, astemizole, loratidine, dosylamine and meclozine.

42. A drug carrier according to claim 39, wherein said active compound comprises an antibiotic selected from the group consisting of rifampicin, ethambutol and thiacetazone.

43. A drug carrier according to claim 39, wherein said active compound comprises an antiepileptic selected from the group consisting of clonazepam, mesuximide, phenyltoin, and valproic acid.

44. A drug carrier according to claim 39, wherein said active compound comprises an antimycotic selected from the group consisting of natamycin, amphotericin B, miconazole, clotrimazole, econazole, fenticonazole, bifonazole, ketoconazole and tolnaftate.

45. A drug carrier according to claim 39, wherein said active compound comprises a corticoide selected from the group consisting of aldosterone, fludrocortisone, betamethasone, dexamethasone, triamcinolone, fluocortolone, hydroxycortisone, prednisolone, prednylidene, cloprednol and methylprednisolone.

46. A drug carrier according to claim 39, wherein said active compound comprises a dermatic selected from the group consisting of tetracycline, erythromycin, framyctin, tyrothricin, fusidic acid, vidarabine, amcinonide, fluprednidene, alclometasone, clobetasol, diflorasone, halcinonide, fluocinolone, clocortolone, flumethasone, diflucortolone, fludroxycortide, halmethasone, desocimetasone, fluoconolide, fluocortin butyl, fluprendidene, prednicarbate, and desonide.

47. A drug carrier according to claim 39, wherein said active compound comprises a hypnotic selected from the group consisting of cyclobarbital, pentobarbital, methaqualone and benzodiazepines.

48. A drug carrier according to claim 39, wherein said active compound comprises an immunotherapeutic selected from the group consisting of azathioprine and ciclosporin.

49. A drug carrier according to claim 39, wherein said active compound comprises a local anaesthetic selected from the group consisting of butanilicaine, mepivacaine, bupivacaine, etidocaine, lidocaine, articaine, oxybuprocaine, tetracaine, and benzocaine.

50. A drug carrier according to claim 39, wherein said active compound comprises a migraine agent selected from the group consisting of lisuride, methysergide, dihydroergotamine, and ergotamine.

51. A drug carrier according to claim 39, wherein said active compound comprises an anaesthetic selected from the group consisting of methohexital, propfol, etomidate, ketamine, thiopental, droperidol and fentanyl.

52. A drug carrier according to claim 39, wherein said active compound comprises dihydrotachysterol.

53. A drug carrier according to claim 39, wherein said active compound comprises an ophthalmic selected from the group consisting of cyclodrin, cyclopntolate, homatropine, trompcamide, pholedrine, edoxudine, aciclovir, acetazolamide, diclofenamide, carteolol, timolol, metipranolol, betaxolol, pindolol, bupranolol, levobununol, and carbachol.

54. A drug carrier according to claim 39, wherein said active compound comprises a psychotropic selected from the group consisting of benzodiazepines.

55. A drug carrier according to claim 39, wherein said active compound comprises a sex hormone selected from the group consisting of anabolics, androgens, antiandrogens, gestagens, oestrogens and antioestrogens.

56. A drug carrier according to claim 39, wherein said active compound comprises a cytostatic or metastasis inhibitor selected from the group consisting of alkylating agents, antimetabolites, alkaloids, antibiotics, taxol and decarbazine.

57. A method of making a drug carrier comprising the steps of:

subjecting at least one solid therapeutically active compound dispersed in a solvent to high pressure homogenization in a piston-gap homogenizer to form particles having an average diameter, determined by photon correlation spectroscopy (PCS) of 40 nm to 100 nm, the proportion of particles larger than 5 μ

m in the total population being less than 0.1% (number distribution determined with a Coulter counter), without prior conversion into a melt, wherein said active compound is solid at room temperature and is insoluble, only sparingly soluble or moderately soluble in water, aqueous media and/or organic solvents, wherein said active compound comprises at least one compound selected from the group consisting of;

analgesics, anaesthetics, antirheumatics, antiallergics, antibiotics, antiepileptics, antimycotics, calcium metabolism regulators, chemotherapeutics, corticoids, cytokines, cytostatics, dermatics, hypnotics, immunotherapeutics, local anesthetics, metastasis inhibitors, migraine agents, ophthalmics, parathyroid hormones, psychotropics, sedatives, and sex hormones.