Methods, compositions and systems for local delivery of drugs

• US 8,999,945 B2
• Filed: 06/28/2009
• Issued: 04/07/2015
• Est. Priority Date: 06/30/2008
• Status: Active Grant

• Current Assignee: Silenseed Ltd.
• Original Assignee: Silenseed Ltd.
• Inventors: Shemi, Amotz
• Primary Examiner(s): Marvich, Maria
• Application Number:
  US13/000,656
• Publication Number:
  US 20110195123A1
• Time in Patent Office: 2,109 Days
• Field of Search: None
• US Class Current: 514/44.A
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders

Abstract

Implantable medical device eluting drug locally and in a prolonged fashion are provided.

Claims

1. A method of treating a solid tumor in a subject, the method comprising the step of implanting an implant within said solid tumor or into a tumor bed thereof, wherein said implant is a solid matrix that has a volume between 0.1-1000 mm³, and said solid matrix comprises:

A. a biocompatible polymeric matrix, comprising a polymer selected from the group consisting of poly(glycolide-co-lactide) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), and polycaprolactone (PCL); and

B. an RNAi (RNA interference) agent that targets an oncogene or a tumor-promoting factor within said tumor, wherein said RNAi agent is incorporated within said biocompatible polymeric matrix and treats said tumor,

wherein the amount of said RNAi agent is at least 1;

20 weight/weight of the amount of said polymer in said biocompatible polymeric matrix.

2. The method according to claim 1, wherein said implant further comprises mannitol.

3. The method according to claim 1, wherein said RNAi agent is selected from the group consisting of a small interfering RNA (siRNA), a short hairpin RNA (shRNA), a Dicer-substrate siRNA (DsiRNA), a locked nucleic acid (LNA), a microRNA, and a non-coding RNA.

4. The method according to claim 1, wherein said oncogene is a mutated K-ras gene.

5. The method according to claim 4, wherein said mutated K-ras gene is K-ras G12D.

6. The method according to claim 1, wherein said RNAi agent is conjugated to a substance selected from the group consisting of cholesterol, palmitate, α

-tocopherol (Vitamin E), a protein transduction domain, a membrane-penetrating peptide, a multi-component polymer system, and a lipophilic moiety.

7. The method according to claim 1, wherein said RNAi agent is complexed with a substance selected from the group consisting of a cationic peptide, spermin, phosphatidylethanolamine (cephalin), L-α

-cephalin, DOTAP, DOPE, polyethyleneimine (PEI), a derivative of PEI, a polyamine, a cationic polymer, a lipid, a non-cationic polymer, and a natural polymer.

8. The method according to claim 1, wherein said implant is configured to be implantable using a needle and cylindrically shaped having a diameter between 17 gauge and 19 gauge.

9. The method according to claim 1, wherein the amount of said RNAi agent in said implant is at least 4 μ

g.

10. The method according to claim 1, wherein said implant further comprises polymeric fibers encapsulating said RNAi agent.

11. The method according to claim 1, wherein said biocompatible polymeric matrix comprises nanoparticles.

12. The method according to claim 1, wherein said implant further comprises a polymeric envelope.

13. A method of treating a solid tumor in a subject, the method comprising the step of implanting an implant within said solid tumor or into a tumor bed thereof, wherein said implant is a solid matrix that has a volume between 0.1-1000 mm³, and said solid matrix comprises:

A. a biocompatible polymeric matrix comprising poly(glycolide-co-lactide) (PLGA) and mannitol; and

B. an RNAi (RNA interference) agent that targets an oncogene or a tumor-promoting factor within said tumor, wherein said RNAi agent is incorporated within said biocompatible polymeric matrix;

wherein the amount of said RNAi agent is at least 1;

20 weight/weight of the amount of said PLGA in said biocompatible polymeric matrix,

and wherein said implant, when implanted into a subject'"'"'s body tissue, treats said tumor and has an effective release period comprising 10 weeks.

14. The method according to claim 13, wherein said PLGA has a ratio of polylactic acid (PLA) and polyglycolic acid (PGA) of greater than 75:

25.