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

• US 6,514,518 B2
• Filed: 08/17/2001
• Issued: 02/04/2003
• Est. Priority Date: 10/18/1993
• Status: Expired due to Fees

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Therics Inc.
• Inventors: Cima, Michael J., Sherwood, Jill K., Yoo, Jaedeok, Monkhouse, Donald, Bornancini, Esteban
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/932,245
• Publication Number:
  US 20020018816A1
• Time in Patent Office: 536 Days
• Field of Search: 424/472, 424/484, 424/427, 424/428, 424/486, 424/487
• US Class Current: 424/427
• 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 method for forming a multiphasic dosage form containing at least two pharmaceutically active materials comprising:

preparing a first layer of pharmaceutically acceptable powder on a platform;

forming a first pattern of adhered particulates in the first layer by applying a binder to selected portions of the first layer wherein the pattern forms boundary walls within the layer;

incorporating a first pharmaceutically active material within a boundary formed in the first layer;

preparing a second layer of pharmaceutically acceptable particulates over the first layer;

forming a second pattern of adhered particulates which is the same or different from the first pattern by applying a binder to selected portions of the second layer, the second pattern being adhered to the first pattern along an interface thereof to thereby produce a three dimensional dosage form; and

incorporating a second pharmaceutically active material within a boundary formed in the second layer.

2. A method as claimed in claim 1, wherein the steps of forming the first and second patterns include forming first and second patterns having different release profiles for the first and second pharmaceutical materials.

3. A method as claimed in claim 1, wherein preparing the second layer of pharmaceutically acceptable particulates comprises preparing a second layer having a different composition than the first layer of pharmaceutically acceptable particulates.

4. A method as claimed in claim 1, wherein applying a binder to selected portions of the second layer comprises applying a binder that is different than the binder applied to the first layer.

5. A method as claimed in claim 1, wherein the active ingredient is contained in the binder.

6. A method as claimed in claim 1, wherein the pharmaceutically active materials are applied to the first and second layers with the respective binders.

7. A method as claimed in claim 1, wherein the at least two pharmaceutically active materials are incorporated into the first and second layers respectively.

8. A method as claimed in claim 1 further comprising preparing a third layer of pharmaceutically acceptable particulates over the second layer and forming a third pattern of adhered particulates which is the same or different from the second pattern by applying a binder to selected portions of the thirds layers to produce a three dimensional dosage form of at least three layers.

11. A multiphasic dosage form as claimed in claim 1, wherein the first pharmaceutically active material comprises 5-FU and is released in pulsatile form, and wherein the second pharmaceutically active material is diclofenac and is released in continuous form.

9. A method for forming a dosage form comprising the steps of:

preparing a three dimensional pattern of a soluble material having a variable surface topography;

spreading a layer of particulates over the soluble pattern, thereby partially filling in the variable surface topography;

applying binder to the layer, thereby effecting adherence of adjacent particulates of the layer;

repeating, preparing a pattern, spreading a layer and applying a binder to form a three dimensional structure comprising adhered particulates corresponding to the variable surface topography and the three dimensional pattern of soluble material; and

removing the soluble material by dissolution with a solvent in vitro or in vivo, thereby introducing at least one of a variable topography or channels in the dosage form.

10. A multiphasic dosage form comprising:

an intraocular implant for delivery of at least two pharmaceutically active materials comprising a first matrix of bound particulates incorporating a first pharmaceutically active material and having a first erosion or degradation rate for release of the first material, and

a second matrix of bound particulates incorporating a second pharmaceutically active material and having a second erosion or degradation rate for release of the second material, the second erosion or degradation rate being different than the first erosion or degradation rate.

12. A multiphasic dosage form for intraocular implant devices comprising:

a three dimensional matrix comprising pharmaceutically acceptable particulates adhered together, at least two pharmaceutically active materials incorporated into the matrix wherein the first pharmaceutically active material releases at a first rate and the second pharmaceutically active material releases at a second rate.

13. The intraocular dosage form of claim 12 wherein the matrix has two different three dimensional architectures, the first internal architecture having walls, micro chambers and a top and bottom lids, the second internal architecture comprising a homogenous matrix.

14. The intraocular dosage form of claim 12 wherein the walls are formed from chloroform combined with PLGA.

15. The intraocular dosage form of claim 12 wherein the micro chamber lids are formed from P(FAD:

SA).

16. The intraocular dosage form of claim 12 wherein the first active ingredient is contained in the micro chamber.

17. The intraocular dosage form of claim 12 wherein the second active ingredient is contained in the homogenous matrix.

18. The intraocular dosage form of claim 12 wherein the first active ingredient is 5-FU and the second active ingredient is diclofenac.