# US 12,005,146 B2 · Methods of treatment using cholestosome vesicles for incorporation of molecules into chylomicrons

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- Number: US 12,005,146 B2
- Document ID: US12005146B2
- Status: Granted
- Kind: B2
- Application number: 18/126,251
- Filed: 2023-03-24
- Published: 2023-09-07
- Granted: 2024-06-11
- Earliest claimed: 2013-03-14
- Assignees: Therasyn Sensors, Inc.
- Applicants: Therasyn Sensors, Inc
- Inventors: Jerome J. Schentag; Mary P. McCourt; Lawrence Mielnicki; Julie Hughes
- Web page: https://patentgrep.com/patent/US12005146B2

## CPC

- A61K 9/51: Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)}
- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 9/1275: Lipoproteins or protein-free species thereof, e.g. chylomicrons; Artificial high-density lipoproteins [HDL], low-density lipoproteins [LDL] or very-low-density lipoproteins [VLDL]; Precursors thereof
- A61K 31/12: Ketones
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/546: containing further heterocyclic rings, e.g. cephalothin
- A61K 31/7034: attached to a carbocyclic compound, e.g. phloridzin
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/14: Peptides containing saccharide radicals; Derivatives thereof {, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin}
- A61K 38/28: Insulins
- A61K 39/29: Hepatitis virus
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/06: of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 9/12: Antihypertensives
- A61P 11/06: Antiasthmatics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 35/00: Antineoplastic agents
- 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

## Abstract

The present invention is directed to a cargo-loaded cholesteryl ester nanoparticle with a hollow compartment (“cholestosome”) consisting essentially of at least one non-ionic cholesteryl ester and one or more encapsulated active molecules which cannot appreciably pass through an enterocyte membrane in the absence of said molecule being loaded into said cholestosome, the cholestosome having a neutral surface and having the ability to pass into enterocytes in the manner of orally absorbed nutrient lipids using cell pathways to reach the golgi apparatus. Pursuant to the present invention, the novel cargo loaded cholestosomes according to the present invention are capable of depositing active molecules within cells of a patient or subject and effecting therapy or diagnosis of the patient or subject.

## Claims

### Claim 1

A method of treating a patient or subject in need of treatment of a disease state or condition comprising administering to said patient or subject a composition comprising one or more active molecules encapsulated in a liquid vesicle to provide an intact loaded vesicle wherein the outer surface coating of said loaded vesicle comprises at least one cholesteryl ester obtained from cholesterol and a C6-C26 fatty acid, said molecules obtaining in an effective amount an intracellular concentration in target cells of said patient or subject which is at least 2-fold greater than the concentration obtained by said molecules in the absence of said coating, wherein said molecules are selected from the group consisting of small molecules, proteins, monoclonal antibodies, peptides, polynucleotides, oligonucleotides, nucleic acids and mixtures thereof, wherein said administration includes at least one oral, parenteral or topical dosage form and said outer surface coating of said loaded vesicle remains intact during passage of said loaded vesicle across a membrane of a cell in said patient or subject and wherein said vesicle optionally releases said one or more molecules inside target cells by the action of cholesteryl ester hydrolases on said vesicle, and said disease state or condition is asthma, cancer, arthritis, Crohn's disease, multiple sclerosis, hyperlipidemia, obesity, type II diabetes, psoriasis, pulmonary arterial hypertension (PAH), inflammation, an intracellular viral, bacterial or fungal infection.

### Claim 2 (depends on 1)

The method according to claim 1 wherein said disease state or condition is inflammation and said molecule is a compound selected from the group consisting of tocilizumab, adalimumab, etanercept, infliximab or combinations of at least two of said molecules, wherein said administration is by oral or parenteral dosage form.

### Claim 3 (depends on 2)

The method according to claim 2, wherein said disease state or condition is a bacterial or viral infection and said molecule is tocilizumab, wherein said administration is by oral or parenteral dosage form.

### Claim 4 (depends on 1)

The method according to claim 1 wherein said disease state or condition is cancer and said molecule is bevacizumab, wherein said administration is by oral or parenteral dosage form.

### Claim 5 (depends on 1)

The method according to claim 1 wherein said disease state or condition is cancer and said molecule is a compound selected from the group consisting of nivolumab, ipilimumab, or a combination of nivolumab and ipilimumab, wherein said administration is by oral or parenteral dosage form.

### Claim 6 (depends on 1)

The method according to claim 1 wherein said disease state or condition is cancer and said molecule is a compound selected from the group consisting of pembrolizumab, ipilimumab, tremelimumab or a combination of pembrolizumab and either ipilimumab or tremelimumab, wherein said administration is by oral or parenteral dosage form.

### Claim 7 (depends on 1)

The method according to claim 1 wherein said disease state or condition is cancer and said molecule is pembrolizumab, wherein said administration is by oral or parenteral dosage form.

### Claim 8 (depends on 1)

The method according to claim 1 wherein said disease state or condition is cancer and said molecule is a compound selected from the group consisting of alemtuzumab, ipilimumab, or a combination of alemtuzumab and ipilimumab, wherein said administration is by oral or parenteral dosage form.

### Claim 9 (depends on 1)

The method according to claim 1 wherein said disease state or condition is cancer and said molecule is a compound selected from the group consisting of trastuzumab, or T-DM1, wherein said T-DM1 is trastuzumab linked to emtansine, wherein said administration is by oral or parenteral dosage form.

### Claim 10 (depends on 1)

The method according to claim 1 wherein said disease state or condition is Crohn's disease and said molecule is ustekinumab, wherein said dosing form is by oral capsule with coating to release ustekinumab in said patient's ileum.

### Claim 11 (depends on 1)

The method according to claim 1 wherein said disease state or condition is Crohn's disease and said molecule is adalimumab, wherein said dosing form is by oral capsule with coating to release adalimumab in said patient's ileum.

### Claim 12 (depends on 1)

The method according to claim 1 wherein said disease state or condition is Crohn's disease and said molecule is infliximab, wherein said dosing form is by oral capsule with coating to release infliximab in said patient's ileum.

### Claim 13 (depends on 1)

The method according to claim 1 wherein said disease state or condition is Crohn's disease and said molecule is etanercept, wherein said dosing form is by oral capsule with coating to release etanercept in said patient's ileum.

### Claim 14 (depends on 1)

The method according to claim 1 wherein said disease state or condition is multiple sclerosis and said molecule is natalizumab, wherein said administration is by oral or parenteral dosage form.

### Claim 15 (depends on 1)

The method according to claim 1 wherein said disease state or condition is multiple sclerosis and said molecule is alemtuzumab, wherein said administration is by oral or parenteral dosage form.

### Claim 16 (depends on 1)

The method according to claim 1 wherein said disease state or condition is psoriasis, psoriatic arthritis, or arthritis and said molecule is secukinumab, wherein said administration is by oral or parenteral dosage form.

### Claim 17 (depends on 1)

The method according to claim 1 wherein said disease state or condition is type 2 diabetes or obesity and said molecule is a GLP-1 hydrophilic peptide, wherein said administration is by oral or parenteral dosage form.

### Claim 18 (depends on 1)

The method according to claim 1 wherein said disease state or condition is allergic asthma and said molecule is omalizumab, wherein said administration is by oral or parenteral dosage form.

### Claim 19 (depends on 1)

The method according to claim 1 wherein said disease state or condition is allergic asthma and said molecule is dupilumab, wherein said administration is by oral or parenteral dosage form.

### Claim 20 (depends on 1)

The method according to claim 1 wherein said disease state or condition is allergic asthma and said molecule is benralizumab, wherein said administration is by oral or parenteral dosage form.