Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/10—Peptides having 12 to 20 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
  • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/52—Cytokines; Lymphokines; Interferons
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu

Definitions

• NorV refers to norvaline
• the peptide consists of ammo acids having the sequence of X 1 X 2 X 3 X 4 -Nle-PX 5 X 6 X 7 X 8 -Tic-X 9 (SEQ ID NO: 1).
• the peptide comprises AAFY-Nle-PSQYA-Tic-dA (SEQ ID NO: 1]
• a lipid entity can comprise an entity capable of insertion into a lipid bilayer (e.g., a cell membrane).
• a lipid entity is capable of incorporating into a lipid raft in a lipid bilayer (e.g., a cell membrane)
• the saturated or unsaturated fatty acid can include about 4-24 carbons in the fatty acid chain.
• the number of double bonds in the fatty' acid chain can be in the range of 0-10, e.g., 0-8, 0-6, 1-8, 1-6.
• the lipid entity can be C22;0, C22: 1 , C22:2, C22:3, C22:4, C22:5, C22:6, C20:0,
• the lipid entity can be selected from the group consisting of a-lmolemc acid, g-hnolenic acid, steandonie acid, eicosapentaenoic acid, docosahexaenoic acid, Imoleic acid, dihomo-y-fmolenic acid, arachidonic acid, docosatetraenoic acid, palmitoleic acid, vaccemc acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, erucic acid, nervonic acid, mead acid, myristic acid, palmitic acid, stearic acid, l ,2-dipalmitoyl-sn-glyceio-3-phosphoethanolamine (DPPE), GM1 ganglioside, GM2 ganglioside, GM3 ganglioside, l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE
• the lipid entity can be a-linolenic acid. In some embodiments, the lipid entity can be g-linolenic acid. In some embodiments, the lipid entity can be palmitic acid. In some embodiments, the lipid entity can be vaccenic acid. In some embodiments, the lipid entity can be oleic acid. In some embodiments, the lipid entity can be elaidic acid. In some embodiments, the lipid entity can be myristic acid. In some embodiments, the lipid entity can be 17-carboxy-I-oxo-heptadecyl.
• lipidation may include fluorination.
• Fluorination can include the addition of one or more CeFo chains. Without wishing to be bound by theory, it is thought that the presence of one or more CeFis chains may allow a lipid entity to segregate from hydrocarbon Upid membrane components (see ./. Am. Chem. Soc. 2007, 129, 9037-9043; J. Phsy. Chem. B, 2008, 1 12, 8250-8256; J. Am. Chem. Soc., 2009, 131, 12091 -12093).
• the linker entity can have a length of between about 2 A and 300 A, inclusive. In some embodiments, the linker entity is between 30 A and 150 A, inclusive.
• the plurality of a-hehces is consecutive. In some embodiments, a plurality of a- helices is 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more a-helices.
• a peptide linker can comprise repeating units, for example a plurality of repeating gfycme-asparagme (GN) units.
• a peptide linker can comprise an epitope tag (e.g., a c-Myc tag) or other markers to allow for identification and/or characterization of provided agents and their fate in vitro and/or in vivo.
• a linker entity can comprise a polyethylene glycol (PEG).
• PEG polyethylene glycol
• the average number of ethylene glycol units in the PEG is 2-20, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
• the linker entity can comprise PEGS, which means that the average number of ethylene glycol units is 8.
• n represents an integer greater than or equal to 1. In some embodiments, n is an integer between 2 and 50, 4 and 24, and/or 8 and 24, inclusive. [0083]
• the linker entity can have any one of the following structures:
• a linker entity can comprise a monosaccharide, an
• oligosaccharide or a polysaccharide, e.g., glucose, fructose, galactose, inulin, or a trisaccharide.
• the combination of the lipid entity and linker entity can be
• palmitic acid- lysine palmitic aeid-y-glutamic acid-lysine, myristic acid-lysine, or 17-carboxy-1- oxo-heptadecyl-y-glutamic acid-(AEEA)2-iysme can be attached to the C-terminus of the peptide.
• a therapeutically effective amount of a composition is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer.
• the lipidated peptides described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
• suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
• the lipidated peptides will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
• the pharmaceutical composition can be formulated for oral administration.
• Oral formulations containing the pharmaceutical composition described herein can be formulated into any conventionally used oral forms, including: tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups, buccal forms, and oral liquids.
• Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g.
• surface modifying agents which include nonionic and anionic surface modifying agents.
• surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
• Oral formulations herein may utilize standard delay or time release
• the oral formulation may also consist of administering the active ingredient in water or a fruit juice, containing appropriate solubilizers or emulsifiers as needed.
• NSAIDS non-steroidal anti-inflammatory' drugs
• antidepressants e.g., antidepressants
• anticonvulsants e.g., baclofen
• neuromodulation modalities e.g., opiates
• compositions of the present disclosure can be administered in combination with the current therapy for treating neuropathic pain.
• the compositions of the present disclosure can be administered in combination with an NS AID, an antidepressant, an anticonvulsant, baclofen, a neuromodulation modality', or an opiate for treating neuropathic pain.
• the present disclosure provides a method of treating pain resulting from nerve injury or nerve degeneration with the compositions described herein.
• the present disclosure provides a method of treating pain resulting from an inflammatory condition, dysesthesia, or allodynia with the compositions described herein.
• compositions described herein can be administered in combination with an analgesic agent to treat pain.
• analgesic agents include, but are not limited to, paracetamol, an NS AID, a COX-2 inhibitor, an opioid, and medical cannabis.
• the present discl osure provides a method of treating ocular inflammation or retinal inflammation with the compositions described herein.
• Ocular inflammation can be caused by a microbial infection of the eye. Such infection may be fungal, viral or bacterial.
• Current therapies for treating ocular inflammation include locally administered anti-cytokine or anti-inflammatory agents.
• the compositions of the present disclosure can be administered in combination with an anti-cytokine or anti
• compositions of the present disclosure can be administered in combination with an anti-cytokine or anti-inflammatory agent for treating dry eye.
• a therapeutically effective amount for treating ocular inflammation is an amount that reduces the extent of inflammation in the subject by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to a placebo.
• compositions described herein can be used to prevent any one of the diseases, disorders, or conditions described herein.
• the compositions described herein can be used to prevent neuropathic pain, ocular pain, ocular inflammation, dry eye, uveitis, or allergic conjunctivitis.
• a reference to“A and/or B”, when used in conjunction with open-ended language such as“comprising” may refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
• the terms“peptide,”“polypeptide,” and“protein” are used interchangeably herein and typically refer to a molecule comprising a chain of two or more amino acids (e.g., most typically L-amino acids, but also including, e.g., D-amino acids, modified ammo acids, amino acid analogs, and ammo acid mimetic).
• Peptides may be naturally occurring, synthetically produced, or recombinantly expressed. Peptides may also comprise additional groups modifying the amino acid chain, for example, functional groups added via post-translational modification.
• post-translation modifications include, but are not limited to, acetylation, alkylation (including methylation), biotinylation, glutamylation, glyeylation, glycosylation, isoprenylation, lipoylation, phosphopantetheinylation, phosphorylation, selenation, and C-terminal amidation.
• the term peptide also includes peptides comprising modifications of the amino terminus and/or the carboxyl terminus. Modifications of the terminal amino group include, but are not limited to, des-amino, N-lower alkyl, N-di-lower alkyl, and N-acy1 modifications.
• amino acid residue refers to an amino acid that is incorporated into a peptide by an amide bond or an amide bond mimetic.
• the ammo acid can either be natural or synthetic.
• analog refers to a variant or mutant polypeptide having one or more amino acid modifications compared to the wild type.
• “Pharmaceutically acceptable carrier” means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. Useful pharmaceutical carriers for the preparation of the
• Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
• the compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.
• Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E. W Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.
• Cleavage time is typically between 60 min and
• the crude peptide is isolated by filtration to remove the spent resin beads and subsequently precipitated in ice cold methyl t-butyl ether.
• the precipitated peptide is collected using a sintered glass funnel and dried in drying oven until a constant weight is obtained.
• PathHunter® b-Arrestin GPCR cell lines co-expressing the ProLinkTM (PK) tagged GPCR (human Chemokine-like receptor 1 , CMKLR1 ) and the Enzyme Acceptor (EA) tagged b-Arrestin were used.
• PK ProLinkTM
• EA Enzyme Acceptor
• Activation of the GPCR-PK induces b-Arrestin-EA recruitment, forcing complementation of the two b-galactosidase enzyme fragments (EA and PK).
• the resulting functional enzyme hydrolyzes substrate to generate a chemiluminescent signal.
• the PathHunter® b-Arrestin assay monitors the activation of a GPCR in a homogenous, non-imaging assay format using a technology developed by DiscoverX called Enzyme Fragment
• (a) Cell Handling 1. PathHunter cell lines co-expressing the ProLinkTM (PK) tagged GPCR (human Chemokine-like receptor 1, CMKLR1) and the Enzyme Acceptor (EA) tagged b-Arrestin were expanded from freezer stocks according to standard procedures. 2. Cells were seeded in a total volume of 20 mL into white walled, 384- well microplates and incubated at 37 °C for the appropriate time prior to testing.
• PK ProLinkTM
• CMKLR1 human Chemokine-like receptor 1
• EA Enzyme Acceptor
• (b) Agonist Format 1. For agonist determination, cells were incubated with peptide to induce response. 2. Intermediate dilution of peptide stocks was performed to generate 5X sample in assay buffer. 3. 5 mL of 5X peptide was added to cells and incubated at 37°C or room temperature for 90 to 1 80 minutes. Vehicle concentration was 1 %.
• FIGS. 1 and 2 assessment of corneal barrier function is performed as follows. Corneal staining was measured by penetration of Oregon Green Dextran (OGD) For baseline assessment, 0.5 mL of OGD was instilled on the cornea of both eyes, and the mice were housed in the dark for 1 minute before washing with balanced saline solution (BSS) and imaging. For corneal permeability assessment at Day 5, 0.5 mL of OGD was instilled on the cornea of both eyes, and the mice were immediately housed in the dark for one minute, followed by
• Enucleated mouse eyes with intact conjunctiva were suspended in optimal cutting temperature (OCT) compound and flash frozen m liquid nitrogen. Immunohistochemistry was performed on six micrometer frozen sections to detect and count the number of cells in conjunctival epithelium that stained positively for CD4, a biotinylated secondary antibody and NovaRED peroxidase. Positively stained cells were counted in the conjunctiva using Nikon imaging software.
• OCT optimal cutting temperature
• GC conjunctival goblet ceils

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• 2020
  • 2020-07-29 US US17/631,032 patent/US12559523B2/en active Active
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