Manufacturing process, such as three dimensional printing, including binding of water-soluble material followed by softening and flowing and forming films of organic-solvent-soluble material

• US 20070009606A1
• Filed: 05/12/2005
• Published: 01/11/2007
• Est. Priority Date: 05/12/2004
• Status: Abandoned Application

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Serdy, James, Saini, Sunil, Sharobiem, John, Sachs, Emanuel, Cai, Jie, West, Thomas, Caruso, Andrea, Materna, Peter
• Application Number:
  US11/127,298
• Publication Number:
  US 20070009606A1
• Time in Patent Office: Days
• US Class Current: 424/497
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30224 cylindrical
• CPC Class Codes: A61F 2002/30225 Flat cylinders, i.e. discs
• CPC Class Codes: A61F 2002/30785 parallel
• CPC Class Codes: A61F 2002/30985 using three dimensional printing [3DP]
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2230/0069 cylindrical
• CPC Class Codes: A61F 2310/00293 containing a phosphorus-containing compound, e.g. apatite
• CPC Class Codes: A61F 2310/00353 Bone cement, e.g. polymethylmethacrylate or PMMA
• CPC Class Codes: A61L 2300/412 Tissue-regenerating or healing or proliferative agents
• CPC Class Codes: A61L 2300/434 of enzymes
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: B33Y 10/00 Processes of additive manufacturing
• CPC Class Codes: B33Y 70/00 Materials specially adapted for additive manufacturing
• CPC Class Codes: B33Y 80/00 Products made by additive manufacturing
• CPC Class Codes: Y10T 428/15 Sheet, web, or layer weakened to permit separation through thickness
• CPC Class Codes: Y10T 428/24273 including aperture
• CPC Class Codes: Y10T 428/31504 : Composite [nonstructural laminate]

Abstract

The invention includes biostructures which may be characterized as having substantially all of the organic-solvent-soluble material in the form of a network of irregularly shaped perforated films. The biostructure may further include particles of a substantially-insoluble material, which may be a member of the calcium phosphate family. The biostructure may be osteoconductive. The biostructure may further contain an Active Pharmaceutical Ingredient or other bioactive substance. The API may be a substance which stimulates the production of bone morphogenetic protein, such as Lovastatin or related substances, thereby making the biostructure effectively osteoinductive. One or more of the polymers may have a resorption rate in the human body such as to control the release of the API. Methods of manufacture are also disclosed.

Claims

1. A biostructure which comprises an organic-solvent-soluble network comprising organic-solvent-soluble material at least some of which is in the form of irregularly shaped perforated films, and wherein the organic-solvent-soluble material comprises an Active Pharmaceutical Ingredient and an organic-solvent-soluble material which is not an Active Pharmaceutical Ingredient.

2. The biostructure of claim 1, wherein the organic-solvent-soluble network defines pores which have a size scale less than approximately 1000 micrometers.

3. The biostructure of claim 1, wherein the organic-solvent-soluble network further defines macroscopic internal features which are free of the organic-solvent-soluble material, the macroscopic internal features having a cross-sectional dimension greater than approximately 100 micrometers.

4. The biostructure of claim 1, wherein all of the organic-solvent-soluble material is in the form of irregularly shaped perforated films.

5. The biostructure of claim 1, wherein the organic-solvent-soluble material which is not an Active Pharmaceutical Ingredient comprises a polymer or copolymer or terpolymer, and wherein the Active Pharmaceutical Ingredient is co-located with the polymer or copolymer or terpolymer, and wherein the polymer or copolymer or terpolymer has a resorption time in the bodily environment which provides a desired release characteristic for the Active Pharmaceutical Ingredient.

6. The biostructure of claim 1, wherein the organic-solvent-soluble material comprises a copolymer or terpolymer comprising caprolactone and an appropriate number of additional monomers.

7. The biostructure of claim 6, wherein the additional monomer(s) are selected from the group consisting of glycolide, L-lactide, D-L-lactide, trimethylene carbonate and ethylene glycol.

8. The biostructure of claim 1, wherein the organic-solvent-soluble material comprises at least one substance selected from the group consisting of polylactones;

polyamines;

polymers and copolymers of trimethylene carbonate with any other monomer;

vinyl polymers;

acrylic acid copolymers;

polyethylene glycols;

polyethylenes;

Polylactides;

Polyglycolides;

Epsilon-caprolactone;

Polylacatones;

Polydioxanones;

other Poly(alpha-hydroxy acids);

Polyhydroxyalkonates;

Polyhydroxybutyrates;

Polyhydroxyvalerates;

Polycarbonates;

Polyacetals;

Polyorthoesters;

Polyamino acids and their esters;

Polyphosphoesters;

Polyesteramides;

Polyfumerates;

Polyanhydrides;

Polycyanoacrylates;

Poloxamers;

Polysaccharides;

Polyurethanes;

Polyesters;

Polyphosphazenes;

Polyacetals;

Polyalkanoates;

Polyurethanes;

Poly(lactic acid) (PLA);

Poly(L-lactic acid) (PLLA);

Poly (DL-lactic acid);

Poly-DL-lactide-co-glycolide (PDLGA);

Poly(L-lactide-co-glycolide) (PLLGA);

Polycaprolactone (PCL);

Poly-epsilon-caprolactone;

Polycarbonates;

Polyglyconates;

Polyanhydrides;

PLLA-co-GA;

PLLA-co-GA 82;

18;

Poly-DL-lactic acid (PDLLA);

PLLA-co-DLLA;

PLLA-co-DLLA 50;

50;

PGA-co-TMC (Maxon B);

Polyglycolic acid (PGA);

Poly-p-dioxanone (PDS);

PDLLA-co-GA;

PDLLA-co-GA (85;

15);

aliphatic polyester elastomeric copolymer;

epsilon-caprolactone and glycolide in a mole ratio of from about 35;

65 to about 65;

35;

epsilon-caprolactone and glycolide in a mole ratio of from about 45;

55 to about 35;

65;

epsilon-caprolactone and lactide selected from the group consisting of L-lactide, D-lactide and lactic acid copolymers in a mole ratio of epsilon-caprolactone to lactide of from about 35;

65 to about 65;

35;

Poly(L-lactide and caprolactone in a ratio of about 70;

30);

poly (DL-lactide and caprolactone in a ratio of about 85;

15);

poly(DL-lactide and caprolactone and glycolic acid in a ratio of about 80;

10;

10);

poly(DL-lacticde and caprolactone in a ratio of about 75;

25);

poly(L-lactide and glycolic acid in a ratio of about 85;

15);

poly(L-lactide and trimethylene carbonate in a ratio of about 70;

30);

poly(L-lactide and glycolic acid in a ratio of about 75;

25);

Gelatin;

Collagen;

Elastin;

Alginate;

Chitin;

Hyaluronic acid;

Aliphatic polyesters;

Poly(amino acids);

Copoly(ether-esters);

Polyalkylene oxalates;

Polyamides;

Poly(iminocarbonates);

Polyoxaesters;

Polyamidoesters;

Polyoxaesters containing amine groups;

Poly(anhydrides); and

mixtures, copolymers, and terpolymers thereof.

9. The biostructure of claim 1, wherein the not-Active-Pharmaceutical-Ingredient has a solubility in at least one organic solvent of at least approximately one part in 100 by weight at room temperature.

10. The biostructure of claim 1, wherein the not-Active-Pharmaceutical-Ingredient has an aqueous solubility of less than approximately 1 part in 100 by weight at room temperature.

11. The biostructure of claim 1, wherein the Active Pharmaceutical Ingredient is capable of stimulating bone repair.

12. The biostructure of claim 1, wherein the Active Pharmaceutical Ingredient is capable of stimulating the production of bone morphogenetic proteins.

13. The biostructure of claim 1, wherein the Active Pharmaceutical Ingredient is an HMG-CoA reductase inhibitor.

14. The biostructure of claim 1, wherein the Active:

Pharmaceutical Ingredient is a member of the statin family.

15. The biostructure of claim 1, further comprising particles of tricalcium phosphate or another substantially-insoluble substance.

16. The biostructure of claim 1, wherein the biostructure further comprises, in at least some space not occupied by any other materials, a biologically useful material.

17. A preform which comprises a water-soluble structure forming a network, and, partially attached to the water-soluble structure, particles of an organic-solvent-soluble material, the preform having macroscopic channels therethrough, wherein the organic-solvent-soluble material comprises an Active Pharmaceutical Ingredient.

18. The preform of claim 17, wherein the preform further defines macroscopic internal features which are free of any material, the macroscopic internal features having a cross-sectional dimension greater than approximately 100 micrometers.

19. A preform which comprises a water-soluble structure forming a network, and an irregularly-shaped perforated film of organic-solvent-soluble material conforming to surfaces of the water-soluble structure, wherein the organic-solvent-soluble material comprises an Active Pharmaceutical Ingredient.

20. The preform of claim 19, wherein the preform further defines macroscopic internal features which are free of any material, the macroscopic internal features having a cross-sectional dimension greater than approximately 100 micrometers.

21. A method of manufacturing a biostructure, the method comprising:

forming at least one powder mixture by mixing particles of an organic-solvent-soluble material and particles of a water-soluble material;

manufacturing a preform by causing particles of the water-soluble material in the powder mixture to join or adhere to other particles of the water-soluble material to form a water-soluble structure which also contains or holds particles of the organic-solvent-soluble material;

forming a film of the organic-solvent-soluble material by causing particles of the organic-solvent-soluble material to soften and at least partially flow to conform to surfaces of the water-soluble structure; and

causing or allowing the organic-solvent-soluble material to harden, wherein forming the film of the organic-solvent-soluble material comprises exposing the preform to a fluid in a supercritical or critical state or at a pressure greater than half the critical pressure of the fluid, under suitable conditions and for a suitable time duration to cause organic-solvent-soluble material in the preform to soften and at least partially flow.

22. The method of claim 21, wherein the fluid comprises a substance selected from the group consisting of:

carbon dioxide;

nitrous oxide;

sulfur hexafluoride;

alkanes;

hydrofluoroalkanes; and

a mixture of carbon dioxide and an alcohol.

23. (canceled)

24. A method of manufacturing a biostructure, the method comprising:

forming at least one powder mixture by mixing particles of an organic-solvent-soluble material and particles of a water-soluble material;

manufacturing a preform by causing particles of the water-soluble material in the powder mixture to join or adhere to other particles of the water-soluble material to form a water-soluble structure which also contains or holds particles of the organic-solvent-soluble material;

forming a film of the organic-solvent-soluble material by exposing the preform to a vapor of an organic solvent in which the organic-solvent-soluble material is soluble, under suitable conditions and for a suitable time duration to cause organic-solvent-soluble material in the preform to soften and at least partially flow to conform to surfaces of the water-soluble structure;

causing or allowing enough of the organic solvent to escape from the preform so that the organic-solvent-soluble material hardens; and

exposing the preform to a clean-up solvent suitable to remove residual organic solvent,

wherein the clean-up solvent comprises carbon dioxide in a pressurized liquid, pressurized gas, critical or supercritical state.

25. A method of manufacturing a biostructure, the method comprising:

forming at least one powder mixture by mixing particles of an organic-solvent-soluble material and particles of a water-soluble material;

manufacturing a preform by causing particles of the water-soluble material in the powder mixture to join or adhere to other particles of the water-soluble material to form a water-soluble structure which also contains or holds particles of the organic-solvent-soluble material;

forming a film of the organic-solvent-soluble material by causing particles of the organic-solvent-soluble material to soften and at least partially flow to conform to surfaces of the water-soluble structure; and

causing or allowing the organic-solvent-soluble material to harden, wherein the organic-solvent-soluble material comprises an Active Pharamaceutical Ingredient.

26. The method of claim 25, wherein the particles of the organic-solvent-soluble material comprise discrete particles of Active Pharmaceutical Ingredient.

27. The method of claim 25, wherein the particles of the organic-solvent-soluble material comprise particles which contain, co-located with each other, both Active Pharmaceutical Ingredient and a polymer or copolymer or terpolymer.

28. The method of claim 25, wherein the particles of the organic-solvent-soluble material comprise particles which contain, located in identifiable places within particles, Active Pharmaceutical Ingredient and a polymer or copolymer or terpolymer.

29. The method of claim 25, further comprising, after all of the above steps, infiltrating a biologically useful substance into the biostructure.

30. The method of claim 25, wherein the powder mixture further comprises particles of tricalcium phosphate or another substantially-insoluble substance.

31. The method of claim 25, wherein the particles of organic-solvent-soluble material contain an Active Pharmaceutical Ingredient which is not soluble in an organic solvent.

32. The method of claim 25, wherein film-forming comprises exposing the preform to vapor of an organic solvent in the presence of air.

33. The method of claim 25, wherein film-forming comprises exposing the preform to vapor of an organic solvent substantially in the absence of air.

34. The method of claim 25, wherein film-forming comprises exposing to vapor of acetone, ethyl acetate, acrylonitrile, tetrahydrofuran, or another non-chlorinated organic solvent.

35. The method of claim 25, wherein the powder mixture further comprises particles which contain at least two out of the following three categories of substances:

organic-solvent-soluble substances, water-soluble substances, and substantially-insoluble substances.

36. The method of claim 25, wherein manufacturing the preform comprises three dimensional printing.

37. The method of claim 25, wherein manufacturing the preform comprises manufacturing the preform containing empty macroscopic internal features having a cross-sectional dimension greater than approximately 100 micrometers.