METHODS, COMPOSITIONS AND SYSTEMS FOR LOCAL DELIVERY OF DRUGS
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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.
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Citations
89 Claims
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1-48. -48. (canceled)
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49. A millimeter scale Drug Delivery System (DDS) comprising:
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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. - View Dependent Claims (50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 88, 89)
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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.
- 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);
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77. A millimeter scale Drug Delivery System (DDS) comprising:
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a nucleotide based agent comprising a siRNA with at least one of;
no modification (naked), a 2′
modification, a termini and overhang modification; anda 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, andwherein the DDS is configured and shaped to be inserted and placed in a pancreatic tumor.
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78. A method of manufacturing a nucleotide based agent drug delivery system, comprising:
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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, andconfiguring and shaping the solid matrix with the associated nucleotide based agent for placing in the human body. - View Dependent Claims (79, 80, 81, 82, 83, 84, 85, 86, 87)
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Specification