# US 10,478,501 B2 · Method of treating disorders using a pharmaceutical composition of oligopeptides

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- Number: US 10,478,501 B2
- Document ID: US10478501B2
- Status: Granted
- Kind: B2
- Application number: 14/122,956
- Filed: 2012-05-16
- Published: 2016-08-11
- Granted: 2019-11-19
- Earliest claimed: 2011-06-09
- Assignees: Merck Patent GmbH
- Applicants: Simon Goodman; Christiane Amendt; Marcus Eber
- Inventors: Simon Goodman; Christiane Amendt; Marcus Eber
- Web page: https://patentgrep.com/patent/US10478501B2

## CPC

- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/10: Dispersions; Emulsions
- A61K 9/1611: {Inorganic compounds}
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/1664: {Compounds of unknown constitution, e.g. material from plants or animals (oils, fats, waxes, shellac A61K9/1617)}
- A61K 9/1682: {Processes}
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 47/44: Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14)
- A61N 5/1077: {Beam delivery systems}
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a pharmaceutical composition of oligopeptides, preferably cyclic oligopeptides, said composition further comprising one or more lipophilic and/or amphiphilic compounds, in the presence or absence of water as the main ingredients, the use of the lipophilic and/or amphiphilic compounds for making pharmaceutical compositions of said oligopeptides, and methods of making said pharmaceutical composition.

## Claims

### Claim 1

A method for the treatment of cancer wherein said cancer expresses αvβ3 and/or αvβ5 integrins, comprising a step of subcutaneously and/or intramuscularly administering to a patient who has been identified as having a cancer which expresses αvβ3 and/or αvβ5 integrins an effective amount of a composition which is a suspension comprising:
a) 12 to 90% of the oligopeptide cyclo-(Arg-Gly-Asp-DPhe-NMeVal) having a solubility in water at 20° C. between 3 mg/ml and 10 mg/ml,
b) 0.01 to 60% of one or more lipophilic and/or amphiphilic compounds having a molar weight in the range of 200 g/mol to 2000 g/mol, and optionally
c) 0 to 87.99% of water, with the proviso that the sum of a), b) and c) sums up to 80 or more percent of the total composition with the proviso that said suspension composition contains 100 mg/ml or more of said oligopeptide, and with the further proviso that said suspension composition comprises 40% or more of said oligopeptide as solid particles.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said composition is a pharmaceutical composition.

### Claim 3 (depends on 1)

The method according to claim 1, wherein said patient is a human.

### Claim 4 (depends on 1)

The method as claimed in claim 1, wherein in said composition at least one of the one or more lipophilic and/or amphiphilic compounds according to b) comprises:
i) a glycerol moiety,
ii) one or more fatty acid moieties, and/or
iii) one or more fatty alcohol moieties.

### Claim 5 (depends on 1)

The method as claimed in claim 1, wherein in said composition at least one of the one or more amphiphilic compounds according to b) comprises a hydrophilic moiety.

### Claim 6 (depends on 5)

The method according to claim 5, wherein in said composition the hydrophilic moiety comprises an ethanolamine moiety, a choline moiety, a phosphatidyl moiety, a sulfatidyl moiety, and/or a salt thereof.

### Claim 7 (depends on 5)

The method as claimed in claim 5, wherein in said composition the hydrophilic moiety comprises an phosphoethanolamine moiety, a phosphatidylcholine moiety, a phosphatidylglycerol moiety, a sulfatidylglycerol moiety, and/or a salt thereof.

### Claim 8 (depends on 6)

The method as claimed in claim 6, wherein in said composition the hydrophilic moiety comprises an phosphoethanolamine moiety, a phosphatidylcholine moiety, a phosphatidylglycerol moiety, a sulfatidylglycerol moiety, and/or a salt thereof.

### Claim 9 (depends on 1)

The method according to claim 1, wherein in said composition the one or more lipophilic compounds according to b) comprise one or more compounds selected from natural oils and synthetic oils, and mixtures thereof, and/or wherein the one or more amphiphilic compounds according to b) comprise one or more compounds selected from amphiphilic lipids having phosphatidyl-polyol or sulfatidyl-polyol groups as the hydrophilic part, and derivatives, salts and/or alcoholates thereof.

### Claim 10 (depends on 9)

The method according to claim 9, wherein in said composition the phosphatidyl- or sulfatidyl-polyoles are selected from
a) polyphosphatidylglycerol, triphosphatidylglycerol, diphosphatidylglycerol, monophosphatidylglycerol, and/or
b) polysulfatidylglycerol, trisulfatidylglycerol, disulfatidylglycerol, and monosulfatidylglycerol.

### Claim 11 (depends on 1)

The method according to claim 1, wherein, in said composition the amphiphilic compounds are selected from the group consisting of dioleoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dimyristoylphosphatidylcholine, distearoylphosphatidylglycerol, dioleoylglycerophosphocholine, dipalmitoylglycerophosphoglycerol, distearoylglycerophosphoethanolamine, egg phosphatidylcholine, soy phosphatidylcholine, and pharmaceutically acceptable derivatives, salts and alcoholates thereof.

### Claim 12 (depends on 1)

The method according to claim 1, wherein, in said composition the amphiphilic compounds are selected from the group consisting of dioleoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, and pharmaceutically acceptable derivatives, salts and alcoholates thereof.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the oligopeptide in said composition comprises solid cyclo-(Arg-Gly-Asp-DPhe-NMeVal) in a polymorphic form having crystallographic unit cell with the lattice parameters: a=9.8±0.1 Å, b=19.5±0.5 Å, and c=15.4±0.1 Å.

### Claim 14 (depends on 1)

The method as claimed in claim 1, wherein, the ratio between the amphiphilic compounds and the oligopeptide is in the range between 0.01 and 0.5 or is in the range between 0.001 and 0.05.

### Claim 15 (depends on 1)

The method according to claim 1, wherein said cancer is metastatic.

### Claim 16 (depends on 15)

The method according to claim 15, wherein said metastases are selected from bone metastases, lung metastases, liver metastases and brain metastases.

### Claim 17 (depends on 1)

The method according to claim 1, wherein the cancer is selected from breast cancer, lung cancer, head and neck cancer, prostate cancer, brain cancer, colorectal cancer, liver cancer and malignant melanoma.

### Claim 18 (depends on 17)

The method according to claim 17, wherein, the lung cancer is selected from non-small cell carcinoma (NSCLC) and small cell carcinoma (SCLC), the head and neck cancer is squamous cell carcinoma of the head and neck (SCCHN), the liver cancer is hepatocellular carcinoma and/or the brain cancer is selected from astrocytoma, gliblastoma and glioblastoma multiforme.

### Claim 19 (depends on 1)

The method according to claim 1, wherein, said patient receives radiotherapy.

### Claim 20 (depends on 1)

The method according to claim 1, wherein, said method further comprises administering radiotherapy concurrently or consecutively to said patient.

### Claim 21 (depends on 20)

The method according to claim 20, wherein, the radiotherapy is selected from radioimmunotherapy and external beam radiation.

### Claim 22 (depends on 16)

The method according to claim 16, wherein, the treatment of the bone metastases comprises or induces:
a) reduced bone resorption,
b) new bone formation,
c) regulation or normalisation of the osteoclast activity,
d) resumption of bone formation and
e) regrowth of bone or partial re-growth of the bone,
in said subject.

### Claim 23 (depends on 1)

The method according to claim 1, wherein said suspension composition comprises 150 to 300 mg/ml of said oligopeptide.

### Claim 24 (depends on 1)

The method according to claim 1, wherein said suspension composition comprises 70% or more of said oligopeptide in the form of solid particles.

### Claim 25 (depends on 1)

The method according to claim 1, wherein said suspension composition comprises 150 to 300 mg/ml of said oligopeptide and wherein 70% or more of said oligopeptide is contained in the form of solid particles.