Process and device for the production of liquid, disperse systems

• US 6,241,967 B1
• Filed: 07/10/1995
• Issued: 06/05/2001
• Est. Priority Date: 10/16/1992
• Status: Expired due to Fees

• Current Assignee: Andreas Sachse, Georg Rossling
• Original Assignee: Andreas Sachse, Georg Rossling
• Inventors: Schneider, Thomas, Sachse, Andreas, Rossling, Georg
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US08/416,842
• Time in Patent Office: 2,157 Days
• Field of Search: 424/1.11, 424/1.29, 424/1.65, 424/9.1, 424/9.3, 424/9.321, 424/9.4, 424/9.5, 424/450, 424/9.51, 424/9.52, 264/4.3, 264/13, 252/314
• US Class Current: 424/9.321
• CPC Class Codes: A61K 49/0466 Liposomes, lipoprotein vesicles, e.g. HDL or LDL lipoproteins, phospholipidic or polymeric micelles
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/1812 liposomes, polymersomes, e.g. immunoliposomes
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: Y10S 977/801 Drug
• CPC Class Codes: Y10S 977/907 Liposome
• CPC Class Codes: Y10S 977/927 Diagnostic contrast agent
• CPC Class Codes: Y10S 977/928 X-ray agent
• CPC Class Codes: Y10S 977/929 Ultrasound contrast agent

Abstract

A continuous process for the production of liquid, disperse systems is described, which is characterized in that a predispersion is extruded under a high pressure of 6.6 to 250 MPa sequentially over 1 to 8 filter stages of decreasing pore size between 0.01 and 35 μm, and up to 20 passages per filtration stage can be used.

Further, a device is described which can be used for implementing the process according to the invention.

Claims

1. A process for the production of a liquid, disperse system, comprising continuously not batchwise extruding a predispersion comprising water and lipids, liposomes or both under a pressure of 7 to 250 MPa sequentially through 1 to 8 filter stages each stage having a pore diameter of from 0.01 to 35 μ

m wherein at least one filter in a filter stage is a membrane filter.

2. The process according to claim 1, wherein at least one filter in a filter stage is made of an inorganic material.

3. The process according to claim 1, wherein each filter stage contains 2 to 4 membrane filters, placed one above the other.

4. The process according to claim 3, wherein the filters placed one above the other have different pore sizes.

5. The process according to claim 1, wherein there is more than one filter stage and the filter stages are sequentially of decreasing pore size.

6. The process according to claims 1, wherein extruding is conducted for 1 to 20 passages through the filter stages.

7. The process according to claim 1, wherein the amount of liquid, disperse system product produced in one operation is above 100 ml.

8. The process according to claim 1, wherein the flow of liquid, disperse system product is more than 150 ml per minute.

9. The process according to claim 1, wherein the liquid, disperse system is an emulsion.

10. The process according to claim 1, wherein the liquid, disperse system is a liposome suspension.

11. The process according to claim 10, wherein the liposomes contain x-ray contrast media.

12. The process according to claim 11, wherein the liposomes contain iotrolan, iopromide, or 3-carbamoyl-5-[N-(2-hydroxyethyl)-acetamido]-2,4,6-triiodobenzoic acid-[(1RS,2SR)-2,3-dihydroxy-1-hydroxymethylpropyl]-amide, as the x-ray contrast media.

13. The process according to claim 10, wherein the liposomes contain NMR contrast media.

14. The process according to claim 13, wherein the liposomes contain Gd-DTPA, Gd-EOB-DTPA, or gadobutrol as the NMR contrast media.

15. The process according to claim 9, wherein the emulsion is sterile.

16. The process of claim 10, wherein the liposome suspension is sterile.

21. The process of claim 1, wherein the pressure is 7 to 80 MPa.

22. The process according to claim 1, wherein the predispersion is extruded through at least one PTFE filter.

23. The process according to claim 1, wherein the liquid, disperse system contains liposomes prepared from a predispersion containing lipids.

24. The process of claim 23, wherein the lipid concentration in the predispersion is 400 mg/ml or higher.

25. The process of claim 23, wherein the lipid concentration in the predispersion is 500 mg/ml or higher.

26. The process of claim 1, wherein the liquid, disperse system produced has a gel-like consistency.

27. The process of claim 10, wherein the liposome suspension contains contrast medium encapsulated in liposomes and contrast medium unencapsulated in suspension and the unencapsulated contrast medium is not separated from the liposome suspension.

28. The process of claim 27, wherein the contrast medium contains iopromide.

29. A process for the production of pharmaceutical substance-containing liposomes comprising mixing a liposome suspension prepared according to the process of claim 10, wherein the liposomes contain no pharmaceutical substance, with a lipophilic pharmaceutical substance.

30. The process of claim 29, wherein the lipophilic pharmaceutical substance is methylprednisolone aceponate.

32. The process of claim 1, wherein the membrane filter is of a polymer membrane material.

17. A device for the production of a liquid, disperse system comprising a storage vessel having a drainpipe leading to a high-pressure pump, said pump providing a working pressure of from 7 to 250 MPa, and said pump being in communication with a filter holder for 1 to 8 filter stages, each with a pore diameter of 0.01 to 35 μ

m, at least one filter in a filter stage being a membrane filter, such that material from the storage vessel is continuously not batchwise pumped through the filter stage(s), and means by which the product liquid, disperse system can be recirculated to the filter stage(s), removed from the device, or both.

18. A device according to claim 17, wherein the high-pressure pump provides a working pressure of from 7 to 80 MPa.

19. The device according to claim 17, additionally comprising a prefilter holder mounted between the high-pressure pump and filter holder for filters with an average pore size of 2 to 35 μ

m.

20. A device according to claim 17, additionally comprising a ventilating device, a temperature and pressure gauge or both.

31. A process for the production of a liposome suspension wherein the liposomes contain a contrast medium, which comprises continuously, not batchwise extruding a predispersion comprising water and lipids, liposomes or both and the contrast medium under a pressure of 7 to 250 MPA sequentially through 1 to 8 filter stages each stage having a pore diameter of from 0.01 to 35 μ

m.