# US 2008/0187487 A1 · Methods for producing multilayered particles, fibers and sprays and methods for administering the same

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- Number: US 2008/0187487 A1
- Document ID: US20080187487A1
- Status: Published application
- Kind: A1
- Application number: 11/743,609
- Filed: 2007-05-02
- Published: 2008-08-07
- Earliest claimed: 2006-05-03
- Inventors: Gustavo LARSEN; Ruben SPRETZ; Raffet VELARDE-ORTIZ; David VU; Luis NUNEZ
- Web page: https://patentgrep.com/patent/US20080187487A1

## CPC

- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/5094: {Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting}
- A61K 9/5115: {Inorganic compounds}
- A61K 9/5192: {Processes}
- A61K 47/551: {one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid}
- A61K 47/642: {the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate}
- A61K 47/6425: {the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6925: {the form being a microcapsule, nanocapsule, microbubble or nanobubble}
- A61K 49/0043: {Fluorescein, used in vivo}
- A61K 49/0047: {Green fluorescent protein [GFP]}
- A61K 49/0056: {Peptides, proteins, polyamino acids}
- A61K 49/0065: {the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle}
- A61K 49/0093: {Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle}
- A61K 49/1878: {the nanoparticle having a magnetically inert core and a (super)(para)magnetic coating}
- A61K 51/1244: {microparticles or nanoparticles, e.g. polymeric nanoparticles}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- B01J 13/04: by physical processes, e.g. drying, spraying
- B05B 5/0255: {spraying and depositing by electrostatic forces only}
- B05B 7/061: {with several liquid outlets discharging one or several liquids}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B05B: SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES (spray-mixers with nozzles B01F25/72; processes for applying liquids or other fluent materials to surfaces by spraying B05D)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## Abstract

Capsules and particles with at least one encapsulated and/or entrapped agent, such as therapeutic agent, imaging agents, and other constituents may be produced by electrohydrodynamic processes. More particularly, the agent encapsulated in a vehicle, capsule, particle, vector, or carrier may maximize treatment and/or imaging of malignant cancers while minimizing the adverse effects of treatment and/or imaging.

## Claims

### Claim 1

A method of producing a capsule having at least one encapsulated agent, said method comprising:
supplying a core fluid to an interior of a hollow tube;
supplying a shell fluid flow;
generating a shell fluid flow to an external wall of the hollow tube;
subjecting the core fluid and the shell fluid to an electric potential so as to form a two-fluid electrified jet at an apex of the hollow tube;
forming a capsule having a core region and a shell region at the apex of the hollow tube.

### Claim 2 (depends on 1)

The method of claim 1, wherein the core fluid is supplied at a flow rate in the range of about 0.005 mL/hour to about 5 mL/hour.

### Claim 3 (depends on 2)

The method of claim 2, wherein the core fluid flow rate is about 0.025 mL/h.

### Claim 4 (depends on 1)

The method of claim 1, wherein the shell fluid is supplied at a flow rate in the range of about 0.05 mL/hour to about 5 mL/hour.

### Claim 5 (depends on 4)

The method of claim 4, wherein the core fluid flow rate is about 0.075 mL/h.

### Claim 6 (depends on 1)

The method of claim 1, further comprising the steps of:
supplying a collector electrode; and
depositing the formed capsules onto a surface of the collector electrode.

### Claim 7 (depends on 1)

The method of claim 1, wherein the electric potential is a positive electrical bias.

### Claim 8 (depends on 7)

The method of claim 7, wherein the positive electrical bias has a voltage in the range of about 5 kV to about 18 kV.

### Claim 9 (depends on 6)

The method of claim 6, wherein the collector electrode is at ground electric potential.

### Claim 10 (depends on 6)

The method of claim 6, further comprising the step of:
supplying an extractor body such that the electric potential is biased at an electrical potential between the two-fluid electrified jet and the collector electrode.

### Claim 11 (depends on 1)

The method of claim 1, further comprising the step of dispersing at least one species of a magnetite particle within the shell region of the capsule.

### Claim 12 (depends on 11)

The method of claim 11, wherein the magnetite particle species if Fe3O4.

### Claim 13 (depends on 11)

The method of claim 11, wherein the at least one species of magnetite particle has a size in the range of about 1 nm to about 300 nm.

### Claim 14 (depends on 1)

The method of claim 1, further comprising the step of dispersing at least one species of a photonic sensitive nanoparticle within the shell region of the capsule.

### Claim 15 (depends on 14)

The method of claim 14, wherein the species of photonic sensitive nanoparticle is a compound selected from the group consisting of silver, gold, palladium, and any combination thereof.

### Claim 16 (depends on 14)

The method of claim 14, wherein the photosensitive nanoparticle species has a size i the range of about 1 nm to about 50 nm.

### Claim 17 (depends on 1)

The method of claim 1, further comprising the step of dispersing a functional group on the outer perimeter of the shell of the capsule.

### Claim 18 (depends on 17)

The method of claim 17, wherein the function group is an entity selected from the group consisting of hydroxyl groups, amino groups, carboxyl groups, carboxylic acid anhydride groups, mercapto groups, hydrosilicon groups, thio groups, carboxylic groups, amine groups, and any combination thereof.

### Claim 19 (depends on 17)

The method of claim 17, wherein the functional group is capable of chemically or physically attaching to pancreatic cancer cells.

### Claim 20 (depends on 19)

The method of claim 19, wherein the functional group is one or more compounds selected from the group consisting of kinase receptors, fibroblast growth factor receptor, EGF, TGF, VEGF-A, urokinase receptor, interleukin-4 receptor, retinoic acid receptor, heparin-binding EGF-like growth factor, HB-EGF, amphiregulin, epireguin, neuregulins, and functional equivalents thereof.

### Claim 21 (depends on 20)

The method of claim 20, wherein the functional group has a content in the range of about 0 wt % to about 1 wt %.

### Claim 22 (depends on 17)

The method of claim 17, wherein the functional group is capable of chemically or physically attaching to glioma cells.

### Claim 23 (depends on 21)

The method of claim 21, wherein the functional group is epidermal growth factor and a functional equivalent thereof.

### Claim 24 (depends on 23)

The method of claim 23, wherein the functional group has a content on the capsule in the range of about 0 wt % to about 0.02 wt %.

### Claim 25 (depends on 17)

The method of claim 17, wherein the function group is capable of chemically or physically attaching to breast cancer cells.

### Claim 26 (depends on 25)

The method of claim 25, wherein the functional group is estrogen and functional equivalents thereof.

### Claim 27 (depends on 26)

The method of claim 26, wherein the functional group has a content on the capsule in the range of about 0.02 wt % to about 0.4 25 %.

### Claim 28 (depends on 17)

The method of claim 17, wherein the functional group is capable of chemically or physically attaching to at least one of lymphoma, myeloma and leukemia cancer cells.

### Claim 29 (depends on 28)

The method of claim 28, wherein the functional group is at least one compound selected from the group consisting of VEGR-2, tostumomab, antibodies capable of binding to a CD20 receptor, CD5, CD7, CD13, CD19, CD22, CD33, CD52, CD61, antimyeloperoxidase, and functional equivalents thereof.

### Claim 30 (depends on 29)

The method of claim 29, wherein the function group has a content on the shell of the capsule in the range of about 0.0 wt % to about 1.0 wt %.

### Claim 31 (depends on 1)

The method of claim 1, wherein the shell fluid is at least one biocompatible polymer.

### Claim 32 (depends on 31)

The method of claim 31, wherein the at least biocompatible polymer is a polymer selected from the group consisting of poly(lactic acid), poly(lactic-co-glycolic acid), citosan, alkyl metacrylates, polycaprolactone, starch, polyethylene glycol, and copolymers resulting from combination thereof.

### Claim 33 (depends on 1)

The method of claim 1, wherein the core fluid is at least one of a therapeutic agent and an imaging agent.

### Claim 34 (depends on 33)

The method of claim 33, wherein the therapeutic agent is one or more biological materials selected from the group consisting of nucleic acid, double stranded DNA, single stranded DNA, double stranded RNA, single stranded RNA, peptide nucleic acid(PNA), antisense DNA, antisense RNA, small interfering RNA, proteins, lipids, carbohydrates, and combination thereof.

### Claim 35 (depends on 33)

The method of claim 33, wherein the therapeutic agent is at least one abiological material.

### Claim 36 (depends on 33)

The method of claim 33, wherein the therapeutic agent is suitable for a treatment a patient afflicted with a condition.

### Claim 37 (depends on 36)

The method of claim 36, wherein the patient is afflicted with at least one condition selected from the group consisting of breast cancer, glioma, lymphoma, leukemia, prostate cancer, pancreatic cancer, carcinoma, sarcoma, mesothelioma, glioma, germinoma, and choriocarcinoma.

### Claim 38 (depends on 33)

The method of claim 33, wherein the imaging agent is suitable for detecting a malignant cancer in a patient.

### Claim 39 (depends on 1)

A capsule including at least one encapsulated agent produced by the method of claim 1.

### Claim 40 (depends on 39)

The capsule of claim 39, wherein the encapsulate agent is at least one of a therapeutic agent and an imaging agent.

### Claim 41 (depends on 39)

The capsule of claim 39, wherein the capsule comprises a shell region and a core region.

### Claim 42 (depends on 41)

The capsule of claim 41, wherein magnetic nanoparticles are dispersed in the shell region.

### Claim 43 (depends on 41)

The capsule of claim 41, wherein functional groups are dispersed on an outer surface of the shell region.

### Claim 44 (depends on 43)

The capsule of claim 43, wherein the functional group have an affinity to attach chemically or physically to a target cell.

### Claim 45 (depends on 44)

The capsule of claim 44, wherein the target cell is a malignant cancer cell selected from the group consisting of breast cancer, glioma, lymphoma, leukemia, prostate cancer, pancreatic cancer, carcinoma, sarcoma, mesothelioma, glioma, germinoma, and choriocarcinoma.

### Claim 46 (depends on 41)

The capsule of claim 41, wherein the shell region includes pores.

### Claim 47 (depends on 46)

The capsule of claim 46, wherein the pores have a size in the range of about 0.5 nm to about 2.0 μm.

### Claim 48 (depends on 39)

The capsule of claim 39, wherein the therapeutic agent is at least one of a chemotherapeutic agent, radioactive isotope, and a chemotherapeutic enhancing drug.

### Claim 49 (depends on 39)

The capsule of claim 39, wherein the therapeutic agent is a compound selected from the group consisting of anti-inflammatory compounds, anti-allergics, glucocorticoids, anti-infective agents, antibiotics, antifungals, antivirals, mucolytics, antiseptics, vasoconstrictors, wound healing agents, local anaesthetics, peptides, and proteins.

### Claim 50 (depends on 17)

The capsule of claim 17, wherein the functional group is capable of targeting a subcellular target.

### Claim 51 (depends on 50)

The capsule of claim 50, wherein the subcellular target is one or more components selected from the group consisting of endoplasmic reticulum, mitochondria, golgi apparatus, vacuole, nucleus, aerosome, centriole, cilium, glyoxysome, lysosome, melanosome, myofibril, nucleolus, peroxisome, actin, tubulin, plasma membrane, and ribosome, vesicles.

### Claim 52

A capsule, comprising:
a core region;
a shell region such that the shell region includes pores having a size in the range of about 0.5 nm to about 2.0 nm;
at least one entrapped an/or encapsulated agent; and
a functional group dispersed on a surface of the shell region.

### Claim 53 (depends on 52)

The capsule of claim 52, wherein the encapsulated and/or entrapped agent is at least one of a therapeutic agent and an imaging agent.

### Claim 54 (depends on 52)

The capsule of claim 52, wherein magnetic nanoparticles are dispersed in the shell region.

### Claim 55 (depends on 52)

The capsule of claim 52, wherein the functional group has an affinity to attach chemically or physically to a target cell.

### Claim 56 (depends on 55)

The capsule of claim 55, wherein the target cell is a malignant cancer cell selected from the group consisting of breast cancer, glioma, lymphoma, leukemia, prostate cancer, pancreatic cancer, carcinoma, sarcoma, mesothelioma, glioma, germinoma, and choriocarcinoma.

### Claim 57 (depends on 53)

The capsule of claim 53, wherein the therapeutic agent is at least one of a chemotherapeutic agent, radioactive isotope, and a chemotherapeutic enhancing drug.

### Claim 58 (depends on 57)

The capsule of claim 57, wherein the therapeutic agent is a compound selected from the group consisting of anti-inflammatory compounds, anti-allergics, glucocorticoids, and anti-infective agent, antibiotics, antifungals, antivirals, mucolytics, antiseptics, vasoconstrictors, wound healing agents, local anaethetics, peptides, and proteins.

### Claim 59 (depends on 52)

The capsule of claim 52, wherein the functional group is capable of targeting a subcellular target.

### Claim 60 (depends on 52)

The capsule of claim 52, wherein the subcellular target is one or more components selected from the group consisting of endoplasmic reticulum, mitochondria, golgi apparatus, vacuole, nucleus, aerosome, centriole, cilium, glyoxysome, lysosome, melanosome, myofibril, nucleolus, peroxisome, actin, tubulin, plasma membrane, and ribosome, vesicles.