WO1996040075B1

WO1996040075B1 - Large scale production process with instantaneous component mixing and controlled sequential mixing characteristics

Info

Publication number: WO1996040075B1
Application number: PCT/US1996/008782
Authority: WO
Filing date: 1996-06-05
Publication date: 1997-01-16
Anticipated expiration: 1997-12-07

Abstract

A method and apparatus for large scale production of a product of in vivo medicine carriers for medicine administration. The reagents are prepared in solution and contained in respective bags. A series pumps and mixing chambers are connected to the reagent bags. The pumps are set at pre-determined rates and activated in a pre-determined sequence within respective pre-determined delay periods, to achieve instantaneous component mixing and controlled sequential mixing characteristics.

Claims

AMENDED CLAIMS

[received by the International Bureau on 2 December 1996 (02.12.96); original claims 2, 20, 35, 39 and 44-48 amended; remaining claims unchanged (6 pages)] mixing chamber; and iv) after said third delay time, deactivating said sixth pump to stop sending said post-treatment agent from said sixth reagent bag into said fourth mixing chamber; and

j . as soon as said third pump is deactivated, activating said first pump to rinse said mixing chambers, delay coils and connection tubings again with said rinse solution from said first reagent bag, rinsing residuals of said product from said mixing chambers, delay coils and connection tubings into said product collection bag;

k. whereby said large scale production method produces said product of stabilized, monodispersed and medicine coated albumin microspheres which are useful as in vivo medicine carriers for medicine administration.

2. The method as defined in Claim 1 wherein said step of sterilizing said large scale production system is performed by gamma radiation rays.

3. The method as defined in Claim 1 wherein said step of preparing said solutions further includes the step of dilution.

4. The method as defined in Claim 1 wherein said step of preparing said solutions further includes the step of filtration.

5. The method as defined in Claim 1 wherein said rinse solution is normal saline.

6. The method as defined in Claim 1 wherein said albumin is Heman Serum Albumin (HSA) .

7. The method as defined in Claim 1 wherein said surfactant is Sodium Tetradecyl Sulfate (STS) . solution of post-treatment agent to said solution of medicine-coated stabilized protein microspheres for post-production stabilization.

17. The method as defined in Claim 13 further including the step of rinsing said large scale production system after using it to produce said product.

18 The method as defined m Claim 13 wherein said protein is selected from a group including albumin and hemoglobin

19. The method ac defined m Claim 13 nerem said alcohol is Ethanol

20. The metnoα as defined m Claim 13 .nerem said stabilizer _ selecteα from a group consisting of Glutaraldehyαe Glutathione, Sodium Sulfite, Sodium Bisulfite, I.icotinamide Adenine Dinucleotide Phosphate

(NADP) , Ditn-othereitol (DTT) , Polyethylene Glycol (PEG) , 2-Mercaptoethanol, 1-Ketogiutarιc Acid, Gamma- aminolevulm c Acid, N-acetylneuraminic Acid, DL Lactic Acid, Thioctic Acid, Succinic Acid, Ascorbic Acid, Stannous Chloride, Manganese Chloride, Magnesium Chloride, Gentamycm, Poly-L-lysin , Cysteine and Dimethyl Sulfoxide

21. The method as defined m Claim 13 wnerem said medicine is fmrinogen.

22. The method as defined in Claim 16 wherein said post- treatment agent is dextrose.

23. A device produced by the method as defined in Claim

13. 24. A method for large scale production of a product of in vivo carriers, comprising the steps of: a. assembling a large scale production system including: i) a protein unit including a protein bag and a protein pump 31. The method as defined in Claim 24 further including the step of mixing a solution of post-treatement agent to said solution of stabilized protein spheres for post-production stabilization.

32. The method as defined in Claim 24 further including the step of rinsing said large scale production system after using it to produce said product.

33. The method as defined in Claim 24 wherein said protein is selected from a group including albumin and hemoglobin.

34. The method as defined in Claim 24 wherein said alcohol is Ethanol .

35. The method as defined in Claim 24 wherein said stabilizer is selected from a group consisting of Glutaraldehyde, Glutathione, Sodium Sulfite, Sodium bisulfite, Nicotinamide Adenine Dinucleotide Phosphate (NADP) , Dithiothreitol (DTT) , Polyethylene Glycol (PEG) , 2-Mercaptoethanol, 1-Ketoglutaric Acid, Gamma- aminolevulinic Acid, N-acetylneuraminic Acid, DL Lactic Acid, Thioctic Acid, Succinic Acid, Stannous Chloride, Manganese Chloride, Magnesium Chloride, Genta ycin, Poly-L-lysine, Cysteine and Dimethyl Sulfoxide .

36. The method as defined in Claim 27 wherein said medicine is fibrinogen.

37. The method as defined in Claim 31 wherein said post- treatment agent is dextrose.

38. A device produced by the method as defined in Claim 24.

39. An appartus for large scale production of a product of in vivo medicine carriers for medicine administration, comprising: o o a. a large scale production system including: i) a protein unit including a protein bag and a protein pump connected downstream from said protein bag; ii) an alcohol unit including an alcohol bag and an alcohol pump connected downstream from said alcohol bag; and iii) a stabilizer unit including a stabilizer bag and a stabilizer pump connected downstream from said stabilizer bag; iv) a first mixing chamber connected downstream from said protein and alcohol pumps; v) a second mixing chamber connected downstream from said stabilizer pump and first mixing chamber; vij a product collection bag connecting to said medicine mixing chamber for collection said product; and vii) connection tubings interconecting said bags, pumps, mixing chambers and collection bag;

b. said bags filled with respective solutions of a group of reagents including a protein, an alcohol, and a stabilizer, where i) said protein bag is filled with a prepared solution of said protein; ii) said alcohol bag is filled with a prepared solution of said alcohol; and iii) said stabilizer bag is filled with a prepared solution of said stabilizer;

c. said pumps set at respective pump rates for mixing pre-determined amounts of said reagents;

d. said pumps activated in sequence for mixing said reagents in a pre-determined order within a pre¬ determined time period to produce said product, where i) said protein pump is activated to send said solution of said protein from said protein bag to said first mixing chamber, then said alcohol pump is activated to send said solution of said alcohol from said alcohol bag to said first mixing chamber, to thereby mix therein said solution of said protein with said solution of said alcohol, resulting in a solution containing protein spheres; and said stabilizer

ii) pump is activated to send said solution of said stabilizer from said stabilizer bag to said second mixing chamber, to thereby mix therein said solution of protein spheres with said solution of said stabilizer, resulting in said product which is a solution of stabilized protein spheres;

e. whereby said large scale production apparatus produces said product of medicine coated cross¬ linked protein microspheres which are useful as in vi vo medicine carriers for medicine administration.

40. The apparatus as defined in Claim 39 wherein said mixing chambers each has two inlet nozzles arranged 180 degrees opposite to each other to enhance the mixing.

41. The apparatus as defined in Claim 39 wherein said mixing chambers are static mixers.

42. The method as defined in Claim 39 further comprising means for sterilizing said large scale production system before using it to produce said product.

43. The method as defined in Claim 39 further comprising means for rinsing said large scale production system before using it to produce said product.

44. The apparatus as defined in Claim 39 further comprising means for mixing a solution of medicine to said solution of said protein for producing a solution of stabilized protein spheres carrying medicine. 45. The apparatus as defined in Claim 39 further comprising means for mixing a solution of medicine to said solution of protein spheres for producing a solution of stabilized protein spheres carrying medicine.

46. The apparatus as defined in Claim 39 further comprising means for mixing a solution of medicine to said solution of stabilized protein spheres for producing a solution of stabilized protein spheres carrying medicine.

47. The apparatus as defined in Claim 39 further comprising means for mixing a solution of post- treatment agent to said solution of stabilized protein spheres for post-production stabilization.

48. The apparatus as defined in Claim 39 further comprising means for rinsing said large scale production system after using it to produce said product.