Dosage forms exhibiting multi-phasic release kinetics and methods of manufacture thereof

• US 6,280,771 B1
• Filed: 02/20/1998
• Issued: 08/28/2001
• Est. Priority Date: 02/20/1997
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology, Therics Inc.
• Inventors: Bornancini, Esteban, Cima, Michael J., Sherwood, Jill K., Yoo, Jaedeok, Monkhouse, Donald
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/027,290
• Time in Patent Office: 1,285 Days
• Field of Search: 424/484, 424/485, 424/486, 424/487, 424/488, 424/422, 424/443, 424/451, 424/464, 424/465, 424/468, 424/469, 424/457
• US Class Current: 424/484
• CPC Class Codes: A61F 2/02 Prostheses implantable into the body closure means for urethra or rectum or for artificial body openings therefor A61F2/0004
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2/3094 Designing or manufacturing processes
• CPC Class Codes: A61F 2002/009 for hindering or preventing attachment of biological tissue of bone tissue onto implantable joints A61F2002/30932
• CPC Class Codes: A61F 2002/30032 differing in absorbability or resorbability, i.e. in absorption or resorption time
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/3028 polyhedral different from parallelepipedal and pyramidal
• CPC Class Codes: A61F 2002/30677 Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
• CPC Class Codes: A61F 2002/30932 for retarding or preventing ingrowth of bone tissue
• CPC Class Codes: A61F 2002/30962 using stereolithography
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2230/0063 Three-dimensional shapes
• CPC Class Codes: A61F 2240/001 Designing or manufacturing processes
• CPC Class Codes: A61F 2250/003 differing in adsorbability or resorbability, i.e. in adsorption or resorption time
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• 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 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/20 : Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2086 : Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/2095 : Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: B29C 64/165 : using a combination of solid and fluid materials, e.g. a powder selectively bound by a liquid binder, catalyst, inhibitor or energy absorber
• 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

Abstract

Dosage forms prepared by solid free form fabrication (SFF) provide release of medicament in multiple phases.

Claims

1. A multiphasic dosage form comprising a three dimensional matrix including pharmaceutically acceptable particulates adhered together;

at least one pharmaceutically active material incorporated into the matrix; and

at least one complexing agent incorporated into the matrix and in contact with the pharmaceutically active material.

2. A multiphasic dosage form as claimed in claim 1, wherein the complexing agent comprises a substance that forms micelles.

15. The multiphasic dosage form of claim 1 further including, at least one of the pharmaceutically active material on the complexing agent having a non linear concentration gradient along an axis of the dosage form.

3. A multiphasic dosage form comprising a three dimensional matrix including pharmaceutically acceptable particulates adhered together;

at least one pharmaceutically active material incorporated into the matrix; and

at least one complexing agent incorporated into the matrix and in contact with the pharmaceutically active material wherein the complexing agent comprises a cylcodextrin or a derivative thereof.

4. A non-compressed drug delivery system comprising one or more active ingredients and a solid matrix harboring said one or more active ingredients, said matrix having a three dimensional architecture suitable for administration to a subject and which matrix comprises a bulk material and a binder, and which binder causes adhesion between the bulk materials and the binder, said bulk material being a biocompatible compound in a powder form and said binder comprising a pharmaceutically acceptable substance that together with said bulk material permits said matrix to maintain its three-dimensional architecture such that said pharmaceutical composition is released in a multiphasic pattern and said composition exhibits hardness and friability characteristics adequate to permit storage and handling of said composition.

5. A drug delivery system as claimed in claim 4, wherein the drug delivery system comprises at least two active ingredients and wherein the second active ingredient is released in a continuous pattern.

6. A drug delivery system as claimed in claim 4, wherein the drug delivery system comprises at least two active ingredients and wherein the second active ingredient is released in a multiphasic pattern.

7. A drug delivery system as claimed in claim 4, wherein the drug delivery system is an oral dosage form comprising a pill, tablet, or capsule.

8. A drug delivery system as claimed in claim 4, wherein the drug delivery system comprises a tissue scaffold, an implantable device or a patch.

9. A drug delivery system as claimed in claim 4, wherein the active ingredient is present in sub-milligram quantities.

10. A drug delivery system as claimed in claim 9, wherein the active ingredient comprises a natural or synthetic hormone, growth factor, a cytokine or a lymphokine.

11. A drug delivery system as claimed in claim 9, wherein the active ingredient is present in an amount of less than about 100 μ

g.

12. A drug delivery system as claimed in claim 4, wherein the content uniformity of the active ingredient is controlled within a factor of no more than 15% between systems.

13. A drug delivery system as claimed in claim 4, wherein the content uniformity of the active ingredient is controlled within a factor of no more than 5% between systems.

14. A drug delivery system as claimed in claim 4, wherein the release of the active ingredient is accurately controlled.