Drug delivery devices, and methods of use

• US 6,444,217 B1
• Filed: 04/25/2001
• Issued: 09/03/2002
• Est. Priority Date: 04/25/2000
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: University of Washington
• Inventors: Ratner, Buddy D., Kwok, Connie Sau-Kuen, Crum, Lawrence A., Mourad, Pierre D.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US09/844,659
• Time in Patent Office: 496 Days
• Field of Search: 424/423, 424/447, 424/486, 514/772.3
• US Class Current: 424/423
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• 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: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence

Abstract

The present invention provides biomedical devices, such as implantable drug delivery devices that possess a surface layer adapted to retain, and controllably release, drug molecules for administration to a subject. The present invention also provides methods of delivering a drug to a subject, the methods utilizing biomedical devices of the invention.

Claims

1. A biomedical device comprising:

(a) a polymeric or hydrogel substrate; and

(b) a surface layer comprising a multiplicity of C₁₀ to C₂₂ unbranched alkyl molecules, wherein;

(1) the multiplicity of alkyl molecules define a multiplicity of spaces therebetween;

(2) each member of the multiplicity of alkyl molecules possesses a proximal end and a distal end, the proximal end being covalently linked to the substrate; and

(3) the surface layer has an ordered state and a less ordered state, the surface layer being reversibly convertible to the less ordered state from the ordered state in response to an effective amount of sound or thermal energy.

2. The biomedical device of claim 1, wherein the device is capable of retaining a multiplicity of drug molecules within the multiplicity of spaces when the surface layer is in the ordered state, and wherein the surface layer releases at least some of the retained drug molecules when the surface layer is converted from the ordered state to the less ordered state in response to an effective amount of sound or thermal energy.

3. The device of claim 1, wherein the surface layer consists essentially of a multiplicity of C₁₀ to C₂₂ unbranched alkyl molecules, each of the C₁₀ to C₂₂ alkyl molecules being covalently attached to the substrate.

4. The device of claim 3, wherein the length of the unbranched alkyl molecules is from C₁₂ to C₁₈.

5. The device of claim 1, wherein the substrate consists essentially of poly (2-hydroxyethyl methacrylate), and the surface layer consists essentially of C₁₂ to C₁₈ unbranched alkyl molecules.

6. The device of claim 1 further comprising a multiplicity of drug molecules disposed in a location selected from the group of locations consisting of:

(a) within the substrate;

(b) within the multiplicity of spaces defined by the unbranched alkyl molecules; and

(c) within the substrate and within the multiplicity of spaces defined by the unbranched alkyl molecules.

7. The device of claim 6, wherein the multiplicity of drug molecules is disposed within the multiplicity of spaces defined by the unbranched alkyl molecules.

8. The device of claim 6, wherein said multiplicity of drug molecules comprises molecules of more thanone type of drug.

9. The device of claim 6, wherein said drug is selected from the group of drugs consisting of insulin, estrogens, androgens, hypnotics, antipsychotics, narcotics and diuretics.

10. The device of claim 1 further comprising a multiplicity of effector molecules wherein each member of the multiplicity of effector molecules is covalently attached to the distal end of a C₁₀ to C₂₂ unbranched alkyl molecule of the surface layer.

11. The device of claim 10, wherein the effector molecule is selected from the group of effector molecules consisting of protein, lipid, carbohydrate, nucleic acid and peptide.

12. The device of claim 1, wherein the device is an implantable medical device.

13. The device of claim 2, wherein the device is an implantable medical device.

14. The device of claim 1 or claim 2, wherein the ordered state of the surface layer forms a crystalline layer characterized by Fourier Infrared Peak Frequencies at 2850+/−

2 cm<sup>−

1</sup> and 2920+/−

2 cm<sup>−

1</sup>.

15. A method of making a biomedical device comprising a surface layer, said method comprising the steps of:

(a) disposing a multiplicity of drug molecules within a polymeric or hydrogel substrate; and

(b) covalently attaching a multiplicity of C₁₀ to C₂₂ unbranched alkyl molecules to the surface of the substrate by forming a covalent linkage between an end group on each member of the multiplicity of C₁₀ to C₂₂ unbranched alkyl molecules and a reactive group on the substrate, thereby forming a surface layer on the substrate wherein;

(1) the multiplicity of alkyl molecules define a multiplicity of spaces therebetween;

(2) each member of the multiplicity of alkyl molecules possesses a proximal end and a distal end, the proximal end being covalently linked to the substrate; and

(3) the surface layer has an ordered state and a less ordered state, the surface layer being reversibly convertible to the less ordered state from the ordered state in response to an effective amount of sound or thermal energy.

16. A method of delivering a drug to a subject, said method comprising the steps of:

(a) introducing into a subject a device comprising;

(1) a polymeric or hydrogel substrate comprising a multiplicity of drug molecules; and

(2) a surface layer comprising a multiplicity of C₁₀ to C₂₂ unbranched alkyl molecules, wherein;

(i) the multiplicity of alkyl molecules define a multiplicity of spaces therebetween;

(ii) a multiplicity of drug molecules are disposed within said spaces;

(iii) each member of the multiplicity of alkyl molecules possesses a proximal end and a distal end, the proximal end being covalently linked to the substrate; and

(iv) the surface layer has an ordered state and a less ordered state, the surface layer being reversibly convertible to the less ordered state from the ordered state in response to an effective amount of sound or thermal energy; and

(b) subjecting the device to an amount of sound or thermal energy effective to induce release of the drug molecules from the surface layer.

17. The method of claim 16, wherein the device is subjected to sound energy having a frequency in the range of from 20 kHz to 100 kHz for a period of from 1 minutes to 10 minutes.