# US 9,433,685 B2 · Co-administration of an agent linked to an internalization peptide with an anti-inflammatory

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- Number: US 9,433,685 B2
- Document ID: US9433685B2
- Status: Granted
- Kind: B2
- Application number: 14/585,028
- Filed: 2014-12-29
- Published: 2015-05-07
- Granted: 2016-09-06
- Earliest claimed: 2009-06-10
- Assignees: NoNO Inc.
- Applicants: NoNO Inc.
- Inventors: Michael Tymianski; Jonathan David Garman; Hong Cui
- Web page: https://patentgrep.com/patent/US9433685B2

## CPC

- A61K 31/275: Nitriles; Isonitriles
- A61K 31/277: having a ring, e.g. verapamil
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/1147: {Regulatory proteins, e.g. trans-activator of transcription [TAT], rev or vacuolar protein targeting [VPT]}
- C07K 2319/10: containing a tag for extracellular membrane crossing, e.g. TAT or VP22
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The invention provides methods of delivering pharmacologic agents linked to an internalization peptide, in which an inflammatory response inducible by the internalization peptide is inhibited by co-administration of an anti-inflammatory or by linking the internalization peptide to biotin or similar molecule. Such methods are premised in part on the results described in the examples whereby administration of a pharmacological agent linked to tat at high dosages is closely followed by an inflammatory response, which includes mast cell degranulation, histamine release and the typical sequelae of histamine release, such as redness, heat, swelling, and hypotension.

## Claims

### Claim 1

A co-formulation comprising lodoxamide and a peptide having an amino acid sequence of SEQ ID NO:6 (YGRKKRRQRRRKLSSIESDV) and water.

### Claim 2 (depends on 1)

The co-formulation of claim 1 in which less than 5% by weight of the lodoxamide and less than 5% by weight of the peptide is in particulate form.

### Claim 3 (depends on 1)

The co-formulation composition of claim 1 further comprising sodium chloride at a concentration of 50-200 mM.

### Claim 4 (depends on 1)

The co-formulation of claim 1, wherein the concentration of lodoxamide is 0.5-1 mg/ml and the concentration of the peptide is 5-20 mg/ml.