Nanoformulation and methods of use of thyroid receptor beta1 agonists for liver targeting

• US 9,956,291 B2
• Filed: 07/10/2013
• Issued: 05/01/2018
• Est. Priority Date: 07/10/2012
• Status: Active Grant

• Current Assignee: Shaker A. Mousa
• Original Assignee: Shaker A. Mousa
• Inventors: Mousa, Shaker A.
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): AL-AWADI, DANAH J
• Application Number:
  US13/938,308
• Publication Number:
  US 20140017329A1
• Time in Patent Office: 1,756 Days
• Field of Search: None
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/7032 attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 47/6939 the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
• CPC Class Codes: A61K 49/0093 Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle

Abstract

A composition and an associated method for hepatic targeted delivery of thyroid receptor beta1 (TRβ1) agonist to a liver of a subject. The composition includes hydrophobic nanoparticles, a liver targeting moiety exterior to each nanoparticle and covalently bonded to each nanoparticle, and at least one TRβ1 agonist encapsulated within each nanoparticle. The nanoparticles include chitosan hybrid nanoparticles, amine-modified PLGA nanoparticles, solid lipid nanoparticles, and combinations thereof. The liver targeting moiety includes Glycyrrhetinic acid (GA), Lactobionic acid (LA), or combinations thereof.

Claims

1. A composition for hepatic targeted delivery of thyroid receptor beta1 (TRβ

1) agonist to a liver of a subject, said composition comprising;

hydrophobic nanoparticles, wherein the nanoparticles are selected from the group consisting of chitosan hybrid nanoparticles, amine-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles, solid lipid nanoparticles, and combinations thereof;

a liver targeting moiety exterior to each nanoparticle and covalently bonded to each nanoparticle, said liver targeting moiety selected from the group consisting of Glycyrrhetinic acid (GA), Lactobionic acid (LA), and combinations thereof; and

at least one TRβ

1 agonist encapsulated within each nanoparticle, wherein a second dosage, reduced about ten fold from a first dosage, of the TRβ

1 agonist in the composition exhibits about a two fold or more total cholesterol lowering in the subject as is exhibited by the first dosage of un-encapsulated TRβ

1 agonist.

2. The composition of claim 1, wherein the nanoparticles comprise the solid lipid nanoparticles and the amine-modified PLGA nanoparticles.

3. The composition of claim 1, wherein the nanoparticles comprise the chitosan hybrid nanoparticles, and wherein the chitosan hybrid nanoparticles are selected from the group consisting of chitosan cross linked to fatty acids, chitosan cross linked to amino acids, chitosan cross linked to hyaluronic acid, chitosan cross linked to deoxycholic acid, chitosan cross linked to aliginic acids, chitosan cross linked to PLGA, and chitosan cross linked to collagen-hydroxyapatite.

4. The composition of claim 3, wherein the nanoparticles comprise the chitosan cross linked to fatty acids, and wherein the fatty acids are selected from the group consisting of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), DHA and EPA, and linoleic acid, and combinations thereof.

5. The composition of claim 3, wherein the nanoparticles comprise the chitosan cross linked to collagen-hydroxyapatite.

6. The composition of claim 1, further comprising at least one other substance encapsulated within each nanoparticle, and wherein the least one other substance is selected from the group consisting of statins, PCSK9 inhibitor, niacin, Peroxisome Proliferator-Activated Receptor Agonists (PPAR), and combinations thereof.

7. The composition of claim 1, wherein the at least one TRβ

1 agonist consists of Sobertirome (GC-1) and Eprotirome (KB2115).

8. A method for targeted delivery of thyroid receptor beta1 (TRβ

1) agonist to a liver of a subject, said method comprising administering the composition of claim 1 to the subject.

9. The method of claim 8, wherein said administrating comprises administrating the composition to the subject in an amount in a range of 0.001 to 1.0 mg per kilogram of body weight of the subject.

10. The method of claim 8, wherein the subject is a human subject having a disorder, wherein said administrating comprises administrating the composition to the subject in a therapeutically effective amount to treat the disorder, and wherein the disorder is selected from the group consisting of dyslipidemia, familial hypercholesterolemia, obesity, metabolic syndrome, type 2 diabetes, and combinations thereof.

11. The method of claim 10, wherein the therapeutically effective amount of the composition is in a range of 0.001 to 1.0 mg per kilogram of body weight of the subject.

12. The method of claim 10, wherein the disorder comprises dyslipidemia and/or familial hypercholesterolemia, and wherein said administrating comprises administrating the composition to the subject in the therapeutically effective amount to lower serum cholesterol and/or triglyceride in the subject in order to reduce the subject'"'"'s cardiovascular risk.

13. The method of claim 10, wherein the subject is obese, and wherein said administrating comprises administrating the composition to the subject in the therapeutically effective amount in order to reduce the body weight of the subject.

14. The composition of claim 1, wherein the nanoparticles comprise the chitosan hybrid nanoparticles and the solid lipid nanoparticles.

15. The composition of claim 14, wherein the solid lipid nanoparticles comprise high density lipoprotein (HDL).

16. The composition of claim 1, wherein the nanoparticles comprise the chitosan hybrid nanoparticles and the amine-modified PLGA.

17. The composition of claim 1, wherein the targeting moiety consists of (i) the Glycyrrhetinic acid (GA) exterior to each nanoparticle and covalently bonded to each nanoparticle and (ii) the Lactobionic acid (LA) exterior to each nanoparticle and covalently bonded to each nanoparticle.

18. The composition of claim 6, wherein the at least one other substance encapsulated within each nanoparticle comprises the PCSK9 inhibitor and the PPAR, and wherein the PPAR is selected from the group consisting of fibrates, Nicotinic acid, and combinations thereof.

19. The composition of claim 6, wherein the at least one other substance encapsulated within each nanoparticle comprises the PCSK9 inhibitor, the statins, and the niacin.

20. The composition of claim 3, wherein the nanoparticles comprise the chitosan cross linked to PLGA.