# US 2014/0154203 A1 · Hydrophobic Core Carrier Compositions for Delivery of Therapeutic Agents, Methods of Making and Using The Same

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- Number: US 2014/0154203 A1
- Document ID: US20140154203A1
- Status: Published application
- Kind: A1
- Application number: 14/087,523
- Filed: 2013-11-22
- Published: 2014-06-05
- Earliest claimed: 2005-12-19
- Assignees: PharmaIN Corporation
- Applicants: PharmaIN Corporation
- Inventors: Gerardo M. Castillo; Elijah M. Bolotin
- Web page: https://patentgrep.com/patent/US20140154203A1

## CPC

- A61K 47/6907: {the form being a microemulsion, nanoemulsion or micelle}
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 38/1808: {Epidermal growth factor [EGF] urogastrone}
- A61K 38/1841: {Transforming growth factor [TGF]}
- A61K 38/2207: {Gastrins; Cholecystokinins [CCK]}
- A61K 38/26: Glucagons
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/06: of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
- A61P 5/18: of the parathyroid hormones
- A61P 5/24: of the sex hormones
- A61P 5/30: Oestrogens
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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 relates, in part, to a biocompatible hydrophobic-core carrier comprising a carrier, and a plurality of hydrophobic groups covalently linked to the polymeric carrier. The hydrophobic groups are capable of dissociably linking load molecules such as therapeutic agents. The hydrophobic-core carrier may also comprise protective side chains, orienting molecules, and targeting molecules.

## Claims

### Claim at position 1

1-32. (canceled)

### Claim 33

A composition, comprising:
(i) a carrier; and
(ii) a plurality of first hydrophobic groups with a covalently linked protective side chain, wherein the first hydrophobic group has a first end that is covalently linked to the carrier and a second end that is covalently linked to the protective side chain; wherein the first hydrophobic group has a molecular weight between 150 to 1000 Daltons independent of the carrier and protective side chain weights; and wherein the protective side chain has a molecular weight between about 400 and 20,000 Daltons independent of the carrier and hydrophobic group weights.

### Claim 34 (depends on 33)

The composition of claim 33, wherein the protective side chain is polyethylene glycol, polypropylene glycol, a co-polymer of polyethylene glycol and polypropylene glycol, or alkoxy derivatives thereof.

### Claim 35 (depends on 34)

The composition of claim 34, wherein the alkoxy derivative is methoxypolyethylene glycol, methoxypolypropylene glycol, or a methoxylated co-polymer of polyethylene glycol and polypropyleneglycol.

### Claim 36

(canceled)

### Claim 37 (depends on 33)

The composition of claim 33, further comprising a load molecule dissociably linked to the hydrophobic groups.

### Claim 38 (depends on 37)

The composition of claim 37, wherein the load molecule is a therapeutic agent.

### Claim 39 (depends on 38)

The composition of claim 38, wherein the therapeutic agent is selected from the group consisting of glucagon-like-peptide, glucagon-like-peptide derivatives, exenatide, glucagon-like-peptide-1, glucagon-like-peptide-2, leptin fragment, Gastric inhibitory polypeptide (GIP), Epidermal Growth Factor (EGF) receptor ligand, EGF, Transforming Growth Factor alpha (TGF-alpha), Betacellulin, Gastrin/Cholecystokinin receptor ligand, Gastrin, Cholecystokinin, lysostaphin, interferon, interferon gamma, interferon beta, interferon alpha, interleukin-1, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-12, tumor necrosis factor, tumor necrosis factor alpha, tumor necrosis factor beta, auristatin, nisin, insulin, insulin-like growth factor, growth hormone, nerve growth factor, brain-derived neurotrophic factor, enzymes, endostatin, angiostatin, trombospondin, urokinase, streptokinase, blood clotting factor VII, blood clotting factor VIII, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), thrombopoietin, calcitonin, parathyroid hormone (PTH) and its fragments, erythropoietin, atrial natriuretic factor, monoclonal antibodies, monoclonal antibody fragments, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim, prostaglandins, epoprostenol, prostacyclin, cyclosporine, vasopressin, terlipressin, desmopressin, cromolyn sodium (sodium or disodium chromoglycate), vasoactive intestinal peptide (VIP), vancomycin, antimicrobials, polymyxin b, anti-fungal agents, anti-viral agents, enfuvirtide, doxorubicin, etoposide, fentanyl, ketamine, and vitamins.

### Claim 40 (depends on 38)

The composition of claim 38, wherein the therapeutic agent is glucagon-like-peptide, Epidermal Growth Factor (EGF) receptor ligand, EGF, Transforming Growth Factor alpha (TGF-alpha), Betacellulin, Gastrin/Cholecystokinin receptor ligand, Gastrin, Cholecystokinin, prostaglandin, interferon, factor VIII, terlipressin, Gastric inhibitory polypeptide (GIP), vasoactive intestinal peptide (VIP) or nisin.

### Claim at position 10

41-48. (canceled)

### Claim 49 (depends on 33)

The composition of claim 33, further comprising an orienting molecule covalently linked to the carrier, wherein the orienting molecule is selected from the group consisting of a peptide, sulfate, sulfonate, phosphate, phosphonate, bisphosphonate, carboxylate, metal chelating moiety, amino group, lysine, and arginine.

### Claim 50

(canceled)

### Claim 51 (depends on 49)

The composition of claim 49, further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.

### Claim 52 (depends on 33)

The composition of claim 33, further comprising a targeting molecule covalently linked to the protective side chains, wherein the targeting molecule is selected from the group consisting of an antibody, fragment of an antibody, chimeric antibody, enzymes, peptides, quasi substrates of enzymes, lectins, receptor, and saccharide ligands of lectins.

### Claim 53

(canceled)

### Claim 54 (depends on 52)

The composition of claim 52, further comprising a load molecule dissociably linked to the hydrophobic groups.

### Claim 55 (depends on 52)

The composition of claim 52, further comprising an orienting molecule covalently linked to the carrier.

### Claim 56 (depends on 55)

The composition of claim 55, further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.

### Claim 57 (depends on 33)

The composition of claim 33, further comprising a plurality of second hydrophobic group, wherein the second hydrophobic group is covalently linked to the carrier and has a molecular weight less than 1,000 Daltons independent of the carrier weight.

### Claim 58 (depends on 57)

The composition of claim 57, further comprising a load molecule dissociably linked to the hydrophobic groups.

### Claim 59 (depends on 57)

The composition of claim 57, further comprising an orienting molecule covalently linked to the carrier.

### Claim 60 (depends on 59)

The composition of claim 59, further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.

### Claim 61 (depends on 57)

The composition of claim 57, further comprising a targeting molecule covalently linked to the protective side chains.

### Claim 62 (depends on 61)

The composition of claim 61, further comprising a load molecule dissociably linked to the hydrophobic groups.

### Claim 63 (depends on 61)

The composition of claim 61, further comprising an orienting molecule covalently linked to the carrier.

### Claim 64 (depends on 63)

The composition of claim 63, further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.

### Claim at position 27

65-78. (canceled)

### Claim 79 (depends on 40)

A method of treating diabetes in mammals, comprising administering one or more of a composition selected from the group consisting of the compositions of claim 40.

### Claim at position 29

80-81. (canceled)

### Claim 82 (depends on 79)

The method of claim 79 further comprising administering a proton-pump inhibitor or a DPP4 inhibitor.

### Claim 83 (depends on 82)

The method of claim 82, wherein the proton-pump inhibitor is omeprazole.

### Claim at position 32

84-90. (canceled)

### Claim 91

A composition comprising
(i) a carrier;
(ii) a plurality of first hydrophobic groups, wherein the first hydrophobic group is covalently linked to the carrier, is capable of binding a load molecule, and has a molecular weight of less than about 1,000 Daltons independent of the carrier weight; and
(iii) a plurality of first protective side chains, wherein, each first protective side chain is covalently linked to the carrier and has a molecular weight between about 400 and 20,000 Daltons independent of the carrier weight, wherein the ratio of the hydrophilic protective side chains to the hydrophobic groups is more than 17:1, whereby the composition is soluble in aqueous buffer.

### Claim 92 (depends on 91)

The composition of claim 91, wherein the first protective side chain is polyethylene glycol, polypropylene glycol, a co-polymer of polyethylene glycol and polypropylene glycol, polysaccharide, or alkoxy derivatives thereof

### Claim 93 (depends on 91)

The composition of claim 91, further comprising a load molecule dissociably linked to the hydrophobic groups, wherein the load molecule is a therapeutic agent.

### Claim 94 (depends on 93)

The composition of claim 93, wherein the therapeutic agent is selected from the group consisting of glucagon-like-peptide, glucagon-like-peptide derivatives, exenatide, glucagon-like-peptide-1, glucagon-like-peptide-2, leptin fragment, Gastric inhibitory polypeptide (GIP), Epidermal Growth Factor (EGF) receptor ligand, EGF, Transforming Growth Factor alpha (TGF-alpha), Betacellulin, Gastrin/Cholecystokinin receptor ligand, Gastrin, Cholecystokinin, lysostaphin, interferon, interferon gamma, interferon beta, interferon alpha, interleukin-1, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-12, tumor necrosis factor, tumor necrosis factor alpha, tumor necrosis factor beta, auristatin, nisin, insulin, insulin-like growth factor, growth hormone, nerve growth factor, brain-derived neurotrophic factor, enzymes, endostatin, angiostatin, trombospondin, urokinase, streptokinase, blood clotting factor VII, blood clotting factor VIII, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), thrombopoietin, calcitonin, parathyroid hormone (PTH) and its fragments, erythropoietin, atrial natriuretic factor, monoclonal antibodies, monoclonal antibody fragments, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastin, prostaglandins, epoprostenol, prostacyclin, cyclosporine, vasopressin, terlipressin, desmopressin, cromolyn sodium (sodium or disodium chromoglycate), vasoactive intestinal peptide (VIP), vancomycin, antimicrobials, polymyxin b, anti-fungal agents, anti-viral agents, enfuvirtide, doxorubicin, etoposide, fentanyl, ketamine, and vitamins.

### Claim 95 (depends on 91)

The composition of claim 91, further comprising an orienting molecule covalently linked to the carrier, wherein the orienting molecule is selected from the group consisting of a peptide, sulfate, sulfonate, phosphate, phosphonate, bisphosphonate, carboxylate, metal binding moiety, amino group, lysine, and arginine.

### Claim 96 (depends on 95)

The composition of claim 95, further comprising a load molecule dissociably linked to the hydrophobic groups and/or the orienting molecule.

### Claim 97 (depends on 91)

The composition of claim 91, further comprising a targeting molecule covalently linked to the protective side chains, wherein the targeting molecule is selected from the group consisting of an antibody, fragment of an antibody, chimeric antibody, lectins, receptor ligands, proteins, enzymes, peptides, saccharides, quasi substrates of enzymes, cell-surface-binding compounds, and extracellular-matrix-binding compounds.

### Claim 98 (depends on 91)

The composition of claim 91, further comprising a second protective side chain and a plurality of second hydrophobic groups, wherein the second hydrophobic group has a first end that is covalently linked to the carrier and a second end that is covalently linked to the second protective side chain; wherein the second hydrophobic group has a molecular weight of less than 1,000 Daltons independent of the carrier and protective side chain weights; and wherein the second protective side chain covalently linked to the hydrophobic group has a molecular weight between 400 and 20,000 Daltons independent of the hydrophobic group weight.