METHODS, COMPOSITIONS AND SYSTEMS FOR LOCAL DELIVERY OF DRUGS

• US 20110195123A1
• Filed: 06/28/2009
• Published: 08/11/2011
• Est. Priority Date: 06/30/2008
• Status: Active Grant

• Current Assignee: Silenseed Ltd.
• Original Assignee: Silenseed Ltd.
• Inventors: Shemi, Amotz
• Granted Patent: US 8,999,945 B2
• Time in Patent Office: Days
• US Class Current: 424/484
• 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 prolonged period is provided, including several types of such a device, the treatment modes of implementation and methods of implantation. The device comprising of polymeric substrate, such as a matrix for example, that is used as the device body, and drugs, and in some cases additional scaffolding materials, such as metals or additional polymers, and materials to enhance visibility and imaging. The selection of drug is based on the advantageous of releasing drug locally and in prolonged period, where drug is released directly to the extracellular matrix (ECM) of the diseased area such as tumor, inflammation, degeneration or for symptomatic objectives, or to injured smooth muscle cells, or for prevention. One kind of drug is the gene silencing drugs based on RNA interference (RNAi), including but not limited to si RNA, sh RNA, or antisense RNA/DNA, ribozyme and nucleoside analogs. The modes of implantation in some embodiments are existing implantation procedures that are developed and used today for other treatments, including brachytherapy and needle biopsy. In such cases the dimensions of the new implant described in this invention are similar to the original implant. Typically a few devices are implanted during the same treatment procedure.

Claims

1-48. -48. (canceled)

49. A millimeter scale Drug Delivery System (DDS) comprising:

a nucleotide based agent; and

a solid matrix comprising at least one biocompatible polymer and at least one additive, the solid matrix arranged to carry the nucleotide based agent, to sustainedly release the nucleotide based agent into a surrounding of the DDS during a release period at a controlled rate and to shield the nucleotide based agent from degradation, during the entire release period,

wherein the at least one additive comprises at least one homogenizing additive selected to homogenize a dispersion of the nucleotide based agent within the at least one polymer, and

wherein at least one of;

the at least one additive; and

the at least one polymer, is selected to reduce at least one of;

swelling; and

nucleotide based agent-matrix polymer hydrophilic-hydrophobic interaction.

50. The DDS of claim 49, wherein the biocompatible polymer is at least one of PLA, and PGA.

51. The DDS of claim 49, wherein the at least one biocompatible polymer is a biodegradable polymer and the DDS is configured to release the nucleotide based agent substantially by bulk erosion to maintain the dimensions of the DDS substantially constant during the entire release period.

52. The DDS of claim 49, wherein the solid matrix comprises at least one of:

a polymer cast, electrospun polymer fibers;

a polymer film;

a polymer mold;

a polymeric sponge;

a polymer fiber;

a polymer fiber mat;

a coating layer;

a multi-layer structure; and

a core-shell structure.

53. The DDS of claim 49, wherein the at least one polymer comprises an elastomer that is vulcanized at room temperature using at least one of:

RTV-1 methods; and

RTV-2 methods.

54. The DDS of claim 49, wherein the at least one polymer comprises at least one of:

Fibrin;

Collagen;

Gelatin;

Hyaluronan;

Casein;

Silk;

Wool;

Lignin;

Shellac;

Starch;

Cellulose;

Alginate;

Chitosan;

poly caprolactone (PCL);

Poly(trimethylene carbonate) (PTMC);

Poly(pdioxanone) (PPDO);

polylactic acid (PLA) and its copolymers;

polyglycolic acid (PGA) and its copolymers;

polyglycolic acid (PGA) and its copolymers with polylactic acid (PLA) (PLGA);

polyglycolic acid (PGA) and its copolymers with trimethylene carbonate (TMC) (poly (glycolide-co-trimethylene carbonate));

polyglycolic acid (PGA) and its copolymers with caprolactone (PCL) (poly(glycolide-co-caprolactone));

polylactic acid (PLA) and its copolymers with (poly caprolactone) (PCL);

polyethylene glycol (PEG) and its derivatives;

polyvinyl alcohols (PVA);

polyvinyl acetate (PVAc);

PCL and its copolymers with (tri calcium phosphate) (TCP);

poly(3-hydroxybutanoic acid) (P(3HB)) or 3-hydroxyvaleric acid(3HV);

polyalkylene esters;

polyorthoesters (POE);

poly ester urethanes (PEU);

Hydroxybutyric Acids (HB);

polyethers (PE);

polyvinyl alcohols (PVA);

polyvinyl esters (PVE);

polyvinyl acetate (PVAc);

polyamide esters;

polyanhydrides (PA);

poly(anhydride-co-imides);

poly(alkylcyanoacrylate) (PACA);

polyphosphazenes (PPA);

Polyphosphoesters (PPE);

Polysaccharides (PSAC);

poly(organophosphazene) (POPs);

poly(amidoamine) (PAMAM);

poly(L-glutamic acid) (PGA);

poly(ethyleneimine) (PEI);

poly(propylene imine) (PPI) and its derivatives;

polymethyl methacrylate (PMMA);

natural biodegradable polymers;

PolyEthyleneTerephthalate (PET);

silicone and polydimethylsiloxane (PDMS);

Ethylene vinyl acetate (EVA);

Poly(2-hydroxyethyl methacrylate) (pHEMA);

Polyethylene (PE);

Spermin;

Phosphatidylethanolamine;

L-α

-Cephalin;

DOPE;

DOTAP;

poly(ethylene glycol) (PEG) and PEG-modified polycations;

PEGylated particles;

PEGylated polyion complexes (PICs);

poly(amidoamine) (PAMAM);

poly[2-(N;

N-diethylaminoethyl)methacrylate] (PDEAMA);

polyethyleneimine (PEI) and mixtures and/or copolymers and/or blends and their derivatives thereof.

55. The DDS of claim 49, wherein the at least one homogenizing additive comprises mannitol.

56. The DDS of claim 49, wherein the at least one polymer and the at least one additive are selected to allow manufacturing the DDS substantially at, or below, room temperature.

57. The DDS of claim 49, configured to have a volume between 0.1 mm³ and 1000 mm³.

58. The DDS of claim 49, wherein an amount of the nucleotide based agent in the DDS is larger than 20 microgram.

59. The DDS of claim 49, arranged to carry the nucleotide based agent at a w/w agent:

polymer load ratio above 1;

20.

60. The DDS of claim 49, arranged to carry the nucleotide based agent at a w/w agent:

polymer load ratio above 1;

9.

61. The DDS of claim 49, wherein the nucleotide based agent comprises a siRNA with at least one of:

no modification (naked), a 2′

modification, a termini and overhang modification.

62. The DDS of claim 49, wherein the nucleotide based agent comprises at least one of:

RNA interfering (RNAi) agents that perform gene knockdown of mRNA, small interfering RNA (siRNA), short hairpin RNA (shRNA), non-coding RNA, Short RNAs active on DNA, Dicer-substrate siRNAs (DsiRNAs), UsiRNAs, Self-delivering RNA (sdRNA), siNA, nucleotide based agents inhibiting the pre-mRNA maturation step of polyA tail addition, U1 adaptors, microRNA, aptamers, triple-helix formation, antisense, Morpholinos (PMO, phosphorodiamidate morpholino oligo);

locked nucleic acid (LNA), peptide nucleic acid (PNA), DNAzymes, Ribozyme and chimeroplast.

63. The DDS of claim 49, wherein the nucleotide based agent is modified in at least one of:

a base;

a phosphate group; and

a sugar of the nucleotide based agent,

64. The DDS of claim 49, wherein the nucleotide based agent is conjugated with at least one of:

lipid moieties;

cholesterol;

protein transduction domains;

membrane-penetrating peptides;

multi-component polymer systems including membrane-active polymer and charge masking polymer and/or targeting polymer; and

lipophilic groups.

65. The DDS of claim 49, wherein the nucleotide based agent is complexed with at least one of:

a polyamine;

a cationic polymer;

a cationic peptide;

a lipid;

a non-cationic polymer; and

a natural polymer.

66. The DDS of claim 49, wherein the release period is at least three weeks.

67. The DDS of claim 49, wherein the release period is at least eight weeks.

68. The DDS of claim 49, wherein the sustained release comprises an initial burst of less than 10% of an overall amount of the nucleotide based agent.

69. The DDS of claim 49, wherein the sustained release comprises an intermediate phase of enhanced release, wherein a peak release rate is achieved between two days and three weeks after a commencement of the release.

70. The DDS of claim 49, configured and shaped for placing in at least one of:

a tumor;

pancreas;

breast;

prostate;

liver;

gallbladder;

spleen;

kidney;

lymph nodes;

salivary glands;

peridontal tissue;

intra-vaginal;

endocrine gland;

brain;

joint;

bone;

oral cavity;

gastro-intestinal system;

biliary system;

respiratory systems;

artery;

uterine cervix;

vein;

ureter or urethra;

the basal ganglia;

white and gray matter;

the spine;

active and chronic inflammatory joints;

the dermis;

sympathetic and sensoric nervous sites;

intra osseous;

acute and chronic infection sites;

ear;

Intra-cardiac;

cardiovascular system;

epicardiac;

urinary bladder;

parenchymal tissues;

Brain tissue;

Brain ventricles;

a cavity;

intra ocular; and

an eye.

71. The DDS of claim 49, integrated in a medical device selected from:

a contact lens;

a female gynecological device;

an IUD;

a cervical ring;

a knee joint; and

a stent.

72. The DDS of claim 49, configured to be implantable using a brachytherapy procedure and cylindrically shaped having a diameter between 17 gauge and 19 gauge.

73. The DDS of claim 49, further comprising at least one additional drug.

74. The DDS of claim 49, further comprising at least one imaging visibility enhancing component.

75. Use of the DDS of claim 49, for treating at lease one of:

high abnormal proliferation of cells, and cancer in specified tissues, tumors, degenerative sites, inflammatory sites, pain generating sites.

88. The DDS of claim 49, wherein the nucleotide based agent is a siRNA targeted at a mutated KRAS gene.

89. The DDS of claim 49, wherein the nucleotide based agent is a siRNA against KRASG12D.

76. A composition for administration from a local site of a nucleotide based agent, comprising a formulation adapted for insertion to a site inside the body for administration from that local site, substantially without significant diffusion from said local site, for extended release of said nucleotide based agent,

wherein said nucleotide based agent comprises one or more of RNA interfering (RNAi) agents that perform gene knockdown of message (mRNA) by degradation or translational arrest of the mRNA, inhibition of tRNA and rRNA functions;

small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA and non-coding RNA or the like, and Short RNAs activity on DNA, and Dicer-substrate siRNAs (DsiRNAs), and UsiRNAs and Self-delivering RNA (sdRNA), siNA, nucleotide based agents inhibiting the pre-mRNA maturation step of polyA tail addition, Ul adaptors, microRNA, aptamers, tripel-helix formation, DNAzymes, antisense, Morpholinos (PMO, phosphorodiamidate morpholino oligo);

or ribozyme;

or a chimeroplast;

or a combination thereof,

wherein said nucleotide based agent comprises a modification or a plurality of modifications,

wherein said modification comprises conjugation and/or complexation with another molecule or plurality of molecules,

wherein said molecule comprises one or more of a polymer, lipid, peptide or carbohydrate,

wherein said molecule comprises cholesterol and/or other transfection reagents and/or complexation reagents, and

wherein said reagents comprise polyamins, polycations, cationic peptides, non-cationic polymers, or natural polymers.

77. A millimeter scale Drug Delivery System (DDS) comprising:

a nucleotide based agent comprising a siRNA with at least one of;

no modification (naked), a 2′

modification, a termini and overhang modification; and

a solid matrix comprising at least PLGA and at least one additive, the solid matrix arranged to;

carry the nucleotide based agent at a w/w agent;

polymer load ratio above 1;

20;

sustainedly release the nucleotide based agent into a surrounding of the DDS during at least three weeks at a controlled rate comprising an initial burst of less than 20% of an overall amount of the nucleotide based agent and an intermediate phase of enhanced release; and

shield the nucleotide based agent from degradation, during the entire release period,

wherein the at least one polymer and the at least one additive are selected to allow manufacturing the DDS substantially at, or below, room temperature,

wherein the at least one additive comprises;

mannitol selected to homogenize a dispersion of the nucleotide based agent within the at least one polymer, and

an additional additive selected to reduce at least one of;

swelling; and

nucleotide based agent-matrix polymer hydrophilic-hydrophobic interaction, and

wherein the DDS is configured and shaped to be inserted and placed in a pancreatic tumor.

78. A method of manufacturing a nucleotide based agent drug delivery system, comprising:

associating the nucleotide based agent with at least one polymer to create a solid matrix of a millimeter scale, the association configured to sustainedly release the nucleotide based agent from the solid matrix into a surrounding thereof at a controlled rate, upon placement in the body and during a period of at least three weeks, and to shield the nucleotide based agent from degradation, during the entire release period, the associating comprising;

adding at least one homogenizing additive selected to homogenize a dispersion of the nucleotide based agent within the at least one polymer; and

reducing at least one of;

swelling; and

nucleotide based agent-matrix polymer hydrophilic-hydrophobic interaction, by at least one of;

selecting the at least one polymer, and adding at least one additive, and

configuring and shaping the solid matrix with the associated nucleotide based agent for placing in the human body.

79. The method of claim 78, wherein the associating the nucleotide based agent with at least one polymer comprises:

mixing siRNA dissolved in aqueous solution with the at least one additive to yield a mixture fluid;

lyophilizing the mixture fluid to yield a powder; and

adding a polymer solution and the powder by at least one of;

stirring;

vortexing;

mixing;

shaking; and

spraying, to yield a resultant homogenized fluid material,

wherein the configuring and shaping is carried out by drying the resultant homogenized fluid material.

80. The method of claim 78, wherein the at least one polymer is at least one of PLA, and PGA, and wherein the at least one homogenizing additive comprises mannitol.

81. The method of claim 78, wherein the associating the nucleotide based agent with at least one polymer comprises creating a polymeric fiber carried out by at least one of:

single needle electrospinning, core-shell two needle electrospinning, and melt spinning.

82. The method of claim 78, wherein the associating is carried out substantially at, or below, room temperature.

83. The method of claim 78, wherein the at least one polymer comprises an elastomer, and further comprising vulcanizing the elastomer using at least one of:

RTV-1 methods; and

RTV-2 methods.

84. The method of claim 78, further comprising at least one of:

modifying the nucleotide based agent, by modifying at least one of;

a base;

a phosphate group; and

a sugar of the nucleotide based agent; and

conjugating the nucleotide based agent with at least one of;

lipid moieties, cholesterol protein transduction domains;

membrane-penetrating peptides; and

lipophilic groups.

85. The method of claim 78, further comprising complexing the nucleotide based agent with at least one of:

a polyamine;

a cationic polymer;

a cationic peptide;

a lipid;

a non-cationic polymer; and

a natural polymer.

86. The method of claim 78, further comprising placing the solid matrix into a specified location in a body.

87. The method of claim 86, wherein the placing is carried out by at least one of:

brachytherapy methods;

direct methods;

biopsy;

endoscopy;

ultrasound endoscopy;

ERCP;

stereotactic methods into the brain tissue;

laparoscopy; and

implantation with a laparoscope into at least one of;

joints;

abdominal organs;

bladder wall;

stenting, and body cavities.