Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
  • A61K38/1729—Cationic antimicrobial peptides, e.g. defensins
• • 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
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
  • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
  • A61L15/42—Use of materials characterised by their function or physical properties
  • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
  • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
  • A61L29/16—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/16—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

• compositions comprising: a peptide or pharmaceutically acceptable salt thereof comprising at least about 70% sequence identity to a polypeptide sequence of Arg-Arg-Trp-Val-Arg-Arg-Val-Arg-Arg-Val-Trp-Arg-Arg-Val-Val- Arg-Val-Val-Arg-Arg-Trp-Val-Arg-Arg (SEQ ID NO: 1); Arg- Vai - Vai -Arg- Vai -Vai- Arg- Arg- Val -Vai -Arg- Arg (SEQ ID NO: 15); Arg-Val-Val-Arg-Val-Val-Arg-Arg-Trp-Val-Arg-Arg (SEQ ID NO: 16); Arg-Trp-Trp-Arg-Trp-Trp-Arg-Arg-Arg (SEQ ID NO: 17); Trp-Arg-Arg-Trp-Trp-Arg-Arg-Trp-Trp-Trp-Trp-Arg-Arg (SEQ ID NO:
• the pharmaceutical formulation comprises at most 5% by weight of at least one impurity as measured by high-performance liquid chromatography (HPLC) when stored for at least 3 months at -20 °C.
• HPLC high-performance liquid chromatography
• the pharmaceutical formulation is stable for at least 6 months at -20 °C.
• the pharmaceutical formulation is stable for at least 9 months at -20 °C.
• the pharmaceutical formulation is stable for at least 12 months at -20 °C.
• the pharmaceutical formulation is stable for at least 2 years at -20 °C.
• the pharmaceutical formulation is stable for at least 3 years at -20 °C.
• the pharmaceutical formulation comprises at most 5% by weight of at least one impurity as measured by HPLC when stored for at least 3 months at -5 °C. In some embodiments, the pharmaceutical formulation is stable for at least 6 months at -5 °C. In some embodiments, the pharmaceutical formulation is stable for at least 9 months at -5 °C. In some embodiments, the pharmaceutical formulation is stable for at least 12 months at -5 °C. In some embodiments, the pharmaceutical formulation is stable for at least 2 years at -5 °C. In some embodiments, the pharmaceutical formulation is stable for at least 3 years at -5 °C. In some embodiments, the pharmaceutical formulation comprises at most 5% by weight of at least one impurity as measured by HPLC when stored for at least 3 months at room temperature.
• the pharmaceutical formulation is stable for at least 6 months at room temperature. In some embodiments, the pharmaceutical formulation is stable for at least 9 months at room temperature. In some embodiments, the pharmaceutical formulation is stable for at least 12 months at room temperature. In some embodiments, the pharmaceutical formulation is stable for at least 2 years at room temperature. In some embodiments, the pharmaceutical formulation is stable for at least 3 years at room temperature. In some embodiments, the pharmaceutical formulation comprises at most 5% by weight of at least one impurity as measured by HPLC when stored for at least 1 month at 40 °C. In some embodiments, the pharmaceutical formulation comprises at most 5% by weight of at least one impurity as measured by HPLC when stored for at least 50 days at 40 °C.
• compositions comprising: a peptide or pharmaceutically acceptable salt thereof comprising at least about 70% sequence identity to a polypeptide sequence of: Arg-Arg-Trp-Val-Arg-Arg-Val-Arg-Arg-Val-Trp-Arg-Arg-Val-Val- Arg-Val-Val-Arg-Arg-Trp-Val-Arg-Arg (SEQ ID NO: 1); Arg- Vai - Vai -Arg- Vai -Vai- Arg- Arg- Val -Vai -Arg- Arg (SEQ ID NO: 15); Arg-Val-Val-Arg-Val-Val-Arg-Arg-Trp-Val-Arg-Arg (SEQ ID NO: 16); Arg-Trp-Trp-Arg-Trp-Trp-Arg-Arg-Arg (SEQ ID NO: 17); Trp-Arg-Arg-Trp-Trp-Arg-Arg-Trp-Arg-Arg-Trp-
• compositions comprising: a peptide or pharmaceutically acceptable salt thereof comprising at least about 70% sequence identity to a polypeptide sequence of: Arg-Arg-Trp-Val-Arg-Arg-Val-Arg-Arg-Val-Trp-Arg-Arg-Val-Val- Arg-Val-Val-Arg-Arg-Trp-Val-Arg-Arg (SEQ ID NO: 1); Arg- Vai - Vai -Arg- Vai -Vai- Arg- Arg- Val -Vai -Arg- Arg (SEQ ID NO: 15); Arg-Val-Val-Arg-Val-Val-Arg-Arg-Trp-Val-Arg-Arg (SEQ ID NO: 16); Arg-Trp-Trp-Arg-Trp-Trp-Arg-Arg-Arg (SEQ ID NO: 17); Trp-Arg-Arg-Trp-Trp-Arg-Arg-Trp-Arg-Arg-Trp-
• the pharmaceutical formulation can be stable for at least about 3 months at a temperature of about 40 °C. In some embodiments, the pharmaceutical formulation can be stable for at least about 6 months at a temperature of about 40 °C. In some embodiments, the pharmaceutical formulation can be stable for at least about 9 months at a temperature of about 40 °C. In some embodiments, the pharmaceutical formulation can be stable for at least about 12 months at a temperature of about 40 °C. In some embodiments, the pharmaceutical formulation can comprise a pH of about 5.0. In some embodiments, the pharmaceutical formulation can comprise a pH of about 4.5. In some embodiments, the pharmaceutical formulation can comprise a pH of about 4.9. In some embodiments, the pharmaceutical formulation comprises a pH of about 4.0.
• the pharmaceutical formulation can comprise at most 3.5% by weight of said at least one impurity as measured by HPLC. In some embodiments, the pharmaceutical formulation can comprise at most 2% by weight of said at least one impurity as measured by HPLC. In some embodiments, the pharmaceutical formulation can comprise at most 1.5% by weight of said at least one impurity measured by HPLC. In some embodiments, the pharmaceutical formulation can comprise at most 3% by weight of said at least one impurity as measured by UV-Vis spectroscopy. In some embodiments, the peptide is present at a concentration of about 10 mg/mL to about 100 mg/mL.
• the peptide is present at a concentration at about 15 mg/mL, about 30 mg/mL, about 40 mg/mL, about 70 mg/mL, or about 80 mg/mL.
• the peptide comprises at least about 90% sequence identity to a polypeptide sequence of: Arg-Arg- Trp- Vai - Arg- Arg- V al - Arg- Arg- V al -Trp - Arg- Arg- V al - Vai - Arg- V al - Vai - Arg- Arg-T rp- V al - Arg- Arg (SEQ ID NO: 1).
• the excipient comprises an isotonicity agent.
• the isotonicity agent is sodium chloride.
• the pharmaceutical formulation can further comprise a pH adjustment agent.
• the pH adjustment agent comprises hydrochloric acid, sodium hydroxide, or any combination thereof.
• the pharmaceutical formulation can comprise further comprising a pH buffering agent.
• the pH buffering agent is selected from the group consisting of sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, glycine, tri s(hydroxymethyl)aminom ethane, and any combination thereof.
• the formulation is free of a buffering agent.
• the pharmaceutical formulation can comprise an osmolality of at least about 30 milliosmoles per kilogram (mOsm/kg) to at least about 800 mOsm/kg.
• the pharmaceutical formulation can comprise an osmolality of about 100 mOsm/kg to about 500 mOsm/kg.
• the pharmaceutical formulation can have an increase in solubility.
• the increase in solubility is a function of the pH.
• the pharmaceutical formulation can be in the form of a tablet, a liquid, a syrup, an oral formulation, an intravenous formulation, an intranasal formulation, an ocular formulation, an otic formulation, a subcutaneous formulation, a suppository, and any combination thereof.
• kits comprising (i) the pharmaceutical formulation disclosed herein; (ii) an aqueous carrier, wherein the aqueous carrier is sterile water for injection; (iii) a mixing container; and (iv) instructions for use.
• the kit further can comprise (v) a second aqueous carrier, wherein the second aqueous carrier is aqueous sodium bicarbonate.
• the pharmaceutical formulation, (ii) the aqueous carrier, (v) the second aqueous carrier is combined in (iii) the mixing container prior to use.
• the infection is periprosthetic joint infection.
• the infection is a bacterial infection
• the bacterial species is selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdenensis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Staphylococcus warnerii, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus pettenkoferi, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Group C streptococci, Streptococcus constellatus, Enterococcus faecalis, Enterococcus faecium, Corynebacterium jeikeium, Lactobacillus acidophilus, Listeria monocytogenes, Escher
• the infection further comprises a biofilm.
• the administration of the pharmaceutical formulation results in at least partially penetrating, inhibiting formation of, or destroys the biofilm.
• the method comprising locally administering the kit described herein to a site of infection, wherein administration comprises washing, irrigating, debridement, or a combination thereof of the site of infection, thereby preventing or treating the infection.
• FIG. 1 illustrates an exemplary HPLC chromatograph of SEQ ID NO: 1 prior to storage in solid form.
• FIG. 2 illustrates an exemplary HPLC chromatograph of SEQ ID NO: 1 after 3 years of storage at -20 °C.
• FIG. 3 illustrates an exemplary HPLC chromatograph of solid SEQ ID NO: 1.
• FIG. 4 illustrates an exemplary HPLC chromatograph of SEQ ID NO: 1 after 7 days at 40 °C and after 54 days at 40 °C.
• FIG. 5 illustrates an exemplary overlaid HPLC chromatograph of SEQ ID NO: 1 and impurities at 0 day (bottom) and after 3 months (top) stored in PBS buffer at pH of 7.4. Impurity peaks are circled on the 3 months graph.
• FIG. 6 illustrates an exemplary overlaid HPLC chromatograph of SEQ ID NO: 1 and impurities at 0 day (bottom) and after 3 months (top) stored in saline at pH of 5.0. Impurity peaks are circled on the 3 months graph.
• FIG. 7 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at 5 °C in saline at pH of 5.0.
• FIG. 8 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in saline at pH of 5.0.
• FIG. 9 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at -20 °C in saline at pH of 5.0.
• FIG. 10 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at 5 °C in PBS solution at pH of 7.4.
• FIG. 11 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in PBS solution at pH of 7.4.
• FIG. 12 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at -20 °C in PBS solution at pH of 7.4.
• FIG. 13 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at 5 °C in tromethamine buffer at pH of 7.4.
• FIG. 14 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in tromethamine buffer at pH of 7.4.
• FIG. 15 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at -20 °C in tromethamine buffer at pH of 7.4.
• FIG. 16 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at 5 °C in glycine buffer at pH of 7.4.
• FIG. 17 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in glycine buffer at pH of 7.4.
• FIG. 18 illustrates an exemplary HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at -20 °C in glycine buffer at pH of 7.4.
• FIG. 19 plots % area of exemplary SEQ ID NO: 1 solutions at different pH and stored at 40 °C over period of time.
• peptides that comprise antimicrobial, antiviral, antifungal or antitumor activity when administered to a subject.
• a peptide described herein can be used to disrupt the integrity of a membrane by (a) binding to a negatively charged surface on a membrane; and/or (b) integrating into a membrane.
• the ability of a peptide disclosed herein to bind to a negatively charged surface on a membrane and/or integrate into a membrane can allow a peptide to act as a toxic agent to cells with a negatively charged surface by disrupting membrane integrity.
• a peptide disclosed herein can have anti-bacterial, anti-fungal, anti-mycotic, anti-parasitic, anti -protozoal, anti-viral, anti-infectious, anti-infective and/or germicidal, algicidal, amoebicidal, microbicidal, bactericidal, fungicidal, parasiticidal, protozoacidal, and/or protozoicidal properties.
• the methods of treating a disease or condition described herein can be by administering to a subject a peptide or formulation containing a peptide as disclosed therein.
• a peptide or formulation comprising a peptide described herein can be administered as an antimicrobial agent in order to at least partially inhibit the growth of a pathogen, such as bacteria, through disruption of the structural integrity of the bacterial cell membrane.
• a peptide described herein can be screened for broad spectrum activity against a variety of pathogens for broad utility when administered to a subject.
• an antimicrobial peptide described herein can also be used as a means to produce an antimicrobial film for coating a device.
• the peptides disclosed herein can be used to coat the interior and/or exterior of a medical device, for example, an implantable medical device.
• the coating of a device with a peptide disclosed herein can reduce the growth and proliferation of cells, bacteria, fungi or virus on a surface coated with a peptide.
• coating an implantable medical device with a peptide disclosed herein can reduce the risk of an infection to a subject upon implanting the medical device in a subject.
• kits can be utilized, for example, by a subject or healthcare professional to coat a device or to treat a condition or disease described herein.
• the antimicrobial peptides may be derived from, and are analogs of, the LLP-1 peptide parent sequence corresponding to amino acids 828- 856 of the HIV-1 viral isolate HXB2R Env, (see Table 1 below).
• the antimicrobial activity of other LLP-1 peptide analogues has been previously described (see, Tencza et al., 1999, Journal of Antimicrobial Chemotherapy 44:33-41, U.S. Patent No. 5,714,577 of Montelaro et al. and U.S. Patent No. 5,945,507 of Montelaro et al., the disclosures of which are incorporated herein by reference).
• the antimicrobial peptides may be LLP-1 analogs having modifications based on the following principles: (i) optimizing amphipathicity, (ii) substituting arginine (Arg) on the charged face and/or valine (Vai) or tryptophan (Trp) on the hydrophobic face with another amino acid, and (iii) increasing peptide length; see Table 1). Amino acid sequences are provided, left-to-right, from their N-terminus to their C-terminus in 1 letter designations and 3 letter designations.
• the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 1. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 2. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 3. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 4. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 5. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 6. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 7.
• the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 8. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 9. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 10. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 11. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 12. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 13. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 14.
• the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 15. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 16. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 17. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 18. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 19. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 20. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 21.
• the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 22. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 23. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 24. In some embodiments, the peptide or pharmaceutically acceptable salt thereof as described herein comprises SEQ ID NO: 25.
• the peptide or pharmaceutically acceptable salt thereof has at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 1, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 2, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 3, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 4, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 5, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 6, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 7, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 8, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 9, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 10, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 11, at least 70% sequence identify to a polypeptide sequence of SEQ ID NO: 12, at least 70% sequence identify to
• the pharmaceutical formulation comprises at least one peptide described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises one or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises two or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises three or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises four or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises five or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises six or more peptides described herein as listed in Table 1.
• the pharmaceutical formulation comprises seven or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises eight or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises nine or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises ten or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises eleven or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises twelve or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises thirteen or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises fourteen or more peptides described herein as listed in Table 1. In some embodiments, the pharmaceutical formulation comprises fifteen or more peptides described herein as listed in Table 1.
• a peptide disclosed herein can be a salt thereof.
• recitation of the phrases “peptide” or “polypeptide” should be construed to include a salt thereof even if not explicitly recited.
• a salt can include a carboxylate salt (e.g.
• a sulfonate salt e.g. benzene sulfonate, methyl-, bromo- or chloro- benzenesulfonate, xylenesulfonate, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, propanesulfonate, hydroxy ethanesulfonate, 1- or 2- naphthal ene-sulfonate or 1,5- naphthalenedisulfonate salts); a sulfate salt; a pyrosulfate salt; a bisulfate salt; a sulfite salt; a bisulfite salt; a phosphate salt; a monohydrogenphosphate salt; a dihydrogenphosphate salt; a metaphosphate salt; a pyrophosphate salt; a nitrate salt; a chromium salt
• a sulfonate salt e.
• amino acids of the peptides described herein can be L-amino acids. In some embodiments, amino acids of the peptides described herein can be D-amino acids. In some embodiments, the peptides can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 D-amino acids and the rest are L-amino acids within the peptide sequence.
• the peptides can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 L-amino acids and the rest are D- amino acids within the peptide sequence.
• a peptide can be formulated with one or more pharmaceutically acceptable salts.
• a pharmaceutically acceptable salt can be a salt described in Berge et al, J. Pharm. Set, 1977.
• a pharmaceutically acceptable salts can include those salts prepared by reaction of a peptide with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bitartrate, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6
• a peptide can be formulated as a cleavable prodrug.
• prodrug can refer to a drug precursor that, following administration to a subject and subsequent absorption, can be converted to an active, or a more active species via some process, such as conversion by a metabolic pathway.
• the term can encompass a derivative, which, upon administration to a recipient, can be capable of providing, either directly or indirectly, a peptide, pharmaceutically acceptable salt or a metabolite or residue thereof.
• Some prodrugs can have a chemical group present on a prodrug that renders it less active and/or confers solubility or some other property to the drug.
• a prodrugs can be a prodrug that can increase the bioavailability of a peptide when administered to a subject (e.g., by allowing an administered peptide to be more readily absorbed) or which enhance delivery of the peptide to a biological compartment (e.g. the brain or lymphatic system).
• the pharmaceutical formulation described herein may further comprise a pH value of about 3.5 to about 5.5.
• the pharmaceutical formulation may comprise a pH value from 3.5 to 5.5, including increments therebetween, such as 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5, including increments therebetween.
• the pharmaceutical formulation has a pH of about 3.5.
• the pharmaceutical formulation has a pH of about 3.6.
• the pharmaceutical formulation has a pH of about 3.7.
• the pharmaceutical formulation has a pH of about 3.8. In some embodiments, the pharmaceutical formulation has a pH of about 3.9. In some embodiments, the pharmaceutical formulation has a pH of about 4.0. In some embodiments, the pharmaceutical formulation has a pH of about 4.1. In some embodiments, the pharmaceutical formulation has a pH of about 4.2. In some embodiments, the pharmaceutical formulation has a pH of about 4.3. In some embodiments, the pharmaceutical formulation has a pH of about 4.4. In some embodiments, the pharmaceutical formulation has a pH of about 4.5. In some embodiments, the pharmaceutical formulation has a pH of about 4.6. In some embodiments, the pharmaceutical formulation has a pH of about 4.7. In some embodiments, the pharmaceutical formulation has a pH of about 4.8.
• the pharmaceutical formulation has a pH of about 4.9. In some embodiments, the pharmaceutical formulation has a pH of about 5.0. In some embodiments, the pharmaceutical formulation has a pH of about 5.1. In some embodiments, the pharmaceutical formulation has a pH of about 5.2. In some embodiments, the pharmaceutical formulation has a pH of about 5.3. In some embodiments, the pharmaceutical formulation has a pH of about 5.4. In some embodiments, the pharmaceutical formulation has a pH of about 5.5.
• the pharmaceutical formulation comprising a peptide or pharmaceutically acceptable salt is at a pH value of at least 3.5 to at least 5.5, at least 3.6 to at least 5.5, at least 3.7 to at least 5.5, at least 3.8 to at least 5.5, at least 3.9 to at least 5.5, at least 4.0 to at least 5.5, at least 4.1 to at least 5.5, at least 4.2 to at least 5.5, at least 4.3 to at least 5.5, at least 4.4 to at least 5.5, at least 4.5 to at least 5.5, at least 4.6 to at least 5.5, at least 4.7 to at least 5.5, at least 4.8 to at least 5.5, at least 4.9 to at least 5.5, at least 5.0 to at least 5.5, at least 5.1 to at least 5.5, at least 5.2 to at least 5.5, at least 5.3 to at least 5.5, or at least 5.4 to at least 5.5.
• the pharmaceutical formulation comprising a peptide or pharmaceutically acceptable salt is at a pH value of at least 3.5 to at least 5.5, at least 3.5 to at least 5.4, at least 3.5 to at least 5.3, at least 3.5 to at least 5.2, at least 3.5 to at least 5.1, at least 3.5 to at least 5.0, at least 3.5 to at least 4.9, at least 3.5 to at least 4.8, at least 3.5 to at least 4.7, at least 3.5 to at least 4.6, at least 3.5 to at least 4.5, at least 3.5 to at least 4.4, at least 3.5 to at least 4.3, at least 3.5 to at least 4.2, at least 3.5 to at least 4.1, at least 3.5 to at least 4.0, at least 3.5 to at least 3.9, at least 3.5 to at least 3.8, at least 3.5 to at least 3.7, or at least 3.5 to at least 3.6.
• the pharmaceutical formulation comprising a peptide or pharmaceutically acceptable salt is at a pH value of at least 3.5 to at least 5.5, at least 3.6 to at least 5.4, at least 3.7 to at least 5.3, at least 3.8 to at least 5.2, at least 3.9 to at least 5.1, at least 4.0 to at least 5.0, at least 4.1 to at least 4.9, at least 4.2 to at least 4.8, at least 4.3 to at least 4.7, at least 4.4 to at least 4.6, at least 4.0 to about 5.5, at least 4.5 to about 5.5, at least 5.0.
• the pharmaceutical formulation comprising a peptide or pharmaceutically acceptable salt is at a pH value of at most 3.5 to at most 5.5, at most 3.6 to at most 5.5, at most 3.7 to at most 5.5, at most 3.8 to at most 5.5, at most 3.9 to at most 5.5, at most 4.0 to at most 5.5, at most 4.1 to at most 5.5, at most 4.2 to at most 5.5, at most 4.3 to at most 5.5, at most 4.4 to at most 5.5, at most 4.5 to at most 5.5, at most 4.6 to at most 5.5, at most 4.7 to at most 5.5, at most 4.8 to at most 5.5, at most 4.9 to at most 5.5, at most 5.0 to at most 5.5, at most 5.1 to at most 5.5, at most 5.2 to at most 5.5, at most 5.3 to at most 5.5, or at most 5.4 to at most 5.5.
• the pharmaceutical formulation comprising a peptide or pharmaceutically acceptable salt is at a pH value of at most 3.5 to at most 5.5, at most 3.5 to at most 5.4, at most 3.5 to at most 5.3, at most 3.5 to at most 5.2, at most 3.5 to at most 5.1, at most 3.5 to at most 5.0, at most 3.5 to at most 4.9, at most 3.5 to at most 4.8, at most 3.5 to at most
• the pharmaceutical formulation comprising a peptide or pharmaceutically acceptable salt is at a pH value of at most 3.5 to at most 5.5, at most 3.6 to at most 5.4, at most 3.7 to at most 5.3, at most 3.8 to at most 5.2, at most 3.9 to at most 5.1, at most 4.0 to at most 5.0, at most 4.1 to at most 4.9, at most 4.2 to at most 4.8, at most 4.3 to at most
• the pharmaceutical formulation may further comprise a pH adjusting agent, such as hydrochloric acid, sodium hydroxide, ammonium hydroxide, acetic acid, citric acid, or other pH adjusting agents known to those skilled in the art, or combinations thereof to the aqueous carrier.
• the pH adjusting agent is hydrochloric acid.
• the pH adjusting agent is sodium hydroxide.
• the pH adjusting agent is ammonium hydroxide.
• the pH adjusting agent is acetic acid.
• the pH adjusting agent is citric acid.
• the pH adjusting agent is hydrochloric acid, sodium hydroxide, or any combination thereof.
• the pharmaceutical formulation further comprises a pH buffer or pH buffering agent.
• suitable pH buffers or pH buffering agents includes sodium citrate, citric acid, sodium acetate, acetic acid, phosphoric acid, trisodium phosphate, lactic acid, sodium lactate, tartaric acid, monosodium tartrate, sodium tartrate dibasic, 4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid (HEPES), piperazine-N,N'-bis(2- ethanesulfonic acid) (PIPES), 2-(N-morpholino)ethanesulfonic acid (MES), other pH buffers known to those skilled in the art, or combinations thereof.
• HEPES 4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid
• PPES piperazine-N,N'-bis(2- ethanesulfonic acid)
• MES 2-(N-morpholino)ethanesulfonic acid
• the pH buffer or pH buffering agent comprises sodium citrate. In some embodiments, the pH buffer or pH buffering agent comprises citric acid, some embodiments, the pH buffer or pH buffering agent comprises sodium acetate. In some embodiments, the pH buffer or pH buffering agent comprises acetic acid. In some embodiments, the pH buffer or pH buffering agent comprises phosphoric acid. In some embodiments, the pH buffer or pH buffering agent comprises trisodium phosphate. In some embodiments, the pH buffer or pH buffering agent comprises lactic acid. In some embodiments, the pH buffer or pH buffering agent comprises sodium lactate. In some embodiments, the pH buffer or pH buffering agent comprises tartaric acid. In some embodiments, the pH buffer or pH buffering agent comprises monosodium tartrate.
• the pH buffer or pH buffering agent comprises sodium tartrate dibasic.
• the pH buffer or pH buffering agent comprises 4-(2 -hydroxy ethyl)- 1- piperazineethanesulfonic acid (HEPES).
• the pH buffer or pH buffering agent comprises piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES).
• the pH buffer or pH buffering agent comprises 2-(N-morpholino)ethanesulfonic acid (MES).
• the pH buffer or pH buffering agent comprises sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, glycine, tris(hydroxymethyl)aminomethane, and any combination thereof.
• the pH buffer or pH buffering agent comprises sodium hydrogen phosphate.
• the pH buffer or pH buffering agent comprises sodium dihydrogen phosphate.
• the pH buffer or pH buffering agent comprises potassium dihydrogen phosphate.
• the pH buffer or pH buffering agent comprises potassium hydrogen phosphate.
• the pH buffer or pH buffering agent comprises glycine.
• the pH buffer or pH buffering agent comprises tris(hydroxymethyl)aminomethane.
• the pH buffer comprises a phosphate buffer.
• the phosphate buffer comprises Dulbecco’s phosphate buffered saline (dPBS).
• the pharmaceutical formulation can be free of a pH buffering agent or pH buffer.
• the peptide or pharmaceutically acceptable salt thereof can have an increase in solubility.
• the solubility of the peptide or pharmaceutically acceptable salt thereof is a function of the pH of the pharmaceutical formulation.
• the solubility of the peptide or pharmaceutically acceptable salt thereof increases as the pH value of a pharmaceutical formulation is lowered.
• the solubility of the peptide or pharmaceutically acceptable salt thereof in a pharmaceutical formulation increases where the pH of the pharmaceutical formulation is below about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, or about 8.5.
• the solubility of the peptide or pharmaceutically acceptable salt thereof in a pharmaceutical formulation increases where the pH of the pharmaceutical formulation is about 3.5 to about 6.9, about 3.5 to about 5.5, about 3.5 to about 5.0, about 3.5 to about 6.0, about 3.5 to about 6.5.
• the solubility of the peptide or pharmaceutically acceptable salt thereof in a pharmaceutical formulation increases with a pH of about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9 about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7 about 6.8, or about 6.9 in the pharmaceutical formulation.
• the solubility of the peptide or pharmaceutically acceptable salt thereof in a pharmaceutical formulation increases with a pH of the pharmaceutical formulation of about 5. In some embodiments, the solubility of the peptide or pharmaceutically acceptable salt thereof in a pharmaceutical formulation increases with a pH of about 5 compared to a pH above 5 in a pharmaceutical formulation as disclosed herein.
• stability can refer to an amount impurities (such as degradation products) in a pharmaceutical formulation after a certain amount of time.
• a pharmaceutical formulation can be stable for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or 5 years when stored in a closed container at 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% relative humidity at a temperature of from about -80 °C to about 70 °C, from about -80 °C to about 60 °C, from about -70 °C to about 60 °C, from about -50 °C to about 60 °C, from about - 40 °C to about 60 °C, from about -30 °C to about 60 °
• a pharmaceutical formulation is stable when stored at - 20° C for about 1 month, about 50 days, about 2 months, about 3 months, about 6 months, about 9 months, about 12 months, about 2 years, about 3 years, about 5 years, or about 10 years. In some embodiments, a pharmaceutical formulation is stable when stored at - 5° C for about 1 month, about 50 days, about 2 months, about 3 months, about 6 months, about 9 months, about 12 months, about 2 years, about 3 years, about 5 years, or about 10 years.
• a pharmaceutical formulation is stable when stored at room temperature for about 1 month, about 50 days, about 2 months, about 3 months, about 6 months, about 9 months, about 12 months, about 2 years, about 3 years, about 5 years, or about 10 years. In some embodiments, a pharmaceutical formulation is stable when stored at 40 ° C for about 1 month, about 50 days, about 2 months, about 3 months, about 6 months, about 9 months, about 12 months, about 2 years, about 3 years, about 5 years, or about 10 years.
• Stability can be determined by measuring an amount of peptide remaining after a period of time. In some embodiments, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 95.1%, 95.2%, 95.3%, 95.4%, 95.5%, 95.6%, 95.7%, 95.8%, 95.9%, 96%, 96.1%, 96.2%, 96.3%, 96.4%, 96.5%, 96.6%, 96.7%, 96.8%, 96.9%, 97%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99, 99.
• Stability can further be determined by measuring an amount of peptide and certain impurities (such as degradation products) after a period of time.
• the amount of impurities after a period of time may be at most 6%, at most 5.9%, at most 5.8%, at most 5.7%, at most 5.6%, at most 5.5%, at most 5.4%, at most 5.3%, at most 5.2%, at most 5.1%, at most 5%, at most 4.9%, at most 4.8%, at most 4.7%, at most 4.6%, at most 4.5%, at most 4.4%, at most 4.3%, at most 4.2%, at most 4.1%, at most 4.0%, at most 3.9%, at most 3.8%, at most 3.7%, at most 3.6%, at most 3.6%, at most 3.5%, at most 3.4%, at most 3.3%, at most 3.2%, at most 3.1%, at most 3%, at most 2.9%, at most 2.8%, at most 2.7%, at most 2.6%, at most 2.5%, at most 2.4%, at most 2.3%, at most 2.2%,
• the amount of impurities (such as degradation products) after period of time may be about 6%, about 5.9%, about 5.8%, about 5.7%, about 5.6%, about 5.5%, about 5.4%, about 5.3%, about 5.2%, about 5.1%, about 5%, about 4.9%, about 4.8%, about 4.7%, about 4.6%, about 4.5%, about 4.4%, about 4.3%, about 4.2%, about 4.1%, about 4.0%, about 3.9%, about 3.8%, about 3.7%, about 3.6%, about 3.6%, about 3.5%, about 3.4%, about 3.3%, about 3.2%, about 3.1%, about 3%, about 2.9%, about 2.8%, about 2.7%, about 2.6%, about 2.5%, about 2.4%, about 2.3%, about 2.2%, about 2.1%, about 2%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, most 0.7%, about 0.6%, about 0.5%,
• the amount of peptide and/or impurities are measured after storage of a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 3 weeks, 1 month, 54 days, 2 months, 3 months, 4, months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years or 5 years.
• the amount of peptide and/or impurities are measured after storage of a period of 7 days.
• the amount of peptide and/or impurities are measured after storage of a period of 14 days.
• the amount of peptide and/or impurities are measured after storage of a period of 1 month. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 2 months. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 54 days. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 3 months. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 4 months. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 5 months.
• the amount of peptide and/or impurities are measured after storage of a period of 6 months. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 7 months. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 8 months. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 9 months. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 10 months. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 11 months.
• the amount of peptide and/or impurities are measured after storage of a period of 1 year. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 2 years. In some embodiments, the amount of peptide and/or impurities are measured after storage of a period of 3 years.
• the amount of peptide and/or impurities (such as degradation products) remaining after a period of time can be determined by performing an area under the curve analysis of a mass spectra. In some embodiments, the amount of peptide and/or impurities remaining after a period of time can be determined by performing an area under the curve analysis of a mass spectra from tandem mass spectrometry (MS/MS). In some embodiments, the amount of peptide and/or impurities remaining after a period of time can be determined by using a UV-Vis Assay.
• the amount of peptide and/or impurities remaining after a period of time can be determined by performing an area under the curve analysis of a High- performance liquid chromatography (HPLC). In some embodiments, the amount of peptide and/or impurities remaining after a period of time can be determined by performing an area under the curve analysis of an Ultra-performance liquid chromatography (UPLC). In some embodiments, the amount of peptide remaining after a period of time can be measured as purity by % or purity by % area under the curve. In some embodiments, the amount of impurities remaining after a period of time can measured as % total impurities or % total impurities area under the curve.
• HPLC High- performance liquid chromatography
• UPLC Ultra-performance liquid chromatography
• the pharmaceutical formulation comprises impurities (such as degradation products) at a measured weight % of the formulation after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 5% by weight of a plurality of impurities after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 4.5% by weight of a plurality of impurities as measured by HPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 4% by weight of a plurality of impurities as measured by HPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 3.5% by weight of a plurality of impurities as measured by HPLC after a period of time.
• the pharmaceutical formulation comprises at most 3% by weight of a plurality of impurities as measured by HPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 2.5% by weight of a plurality of impurities as measured by HPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 2% by weight of a plurality of impurities as measured by HPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 1.5% by weight of a plurality of impurities as measured by HPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 1% by weight of a plurality of impurities as measured by HPLC after a period of time.
• the pharmaceutical formulation comprises at most 0.5% by weight of a plurality of impurities as measured by HPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 0.1% by weight of a plurality of impurities as measured by HPLC after a period of time.
• the pharmaceutical formulation comprises impurities (such as degradation products) at a measured weight % of the formulation after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 5% by weight of a plurality of impurities after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 4.5% by weight of a plurality of impurities as measured by UPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 4% by weight of a plurality of impurities as measured by UPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 3.5% by weight of a plurality of impurities as measured by UPLC after a period of time.
• impurities such as degradation products
• the pharmaceutical formulation comprises at most 3% by weight of a plurality of impurities as measured by UPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 2.5% by weight of a plurality of impurities as measured by UPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 2% by weight of a plurality of impurities as measured by UPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 1.5% by weight of a plurality of impurities as measured by UPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 1% by weight of a plurality of impurities as measured by UPLC after a period of time.
• the pharmaceutical formulation comprises at most 0.5% by weight of a plurality of impurities as measured by UPLC after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 0.1% by weight of a plurality of impurities as measured by UPLC after a period of time. [0058] In some embodiments, the pharmaceutical formulation comprises at most 5% by weight of a plurality of impurities (such as degradation products) as measured by UV-Vis spectroscopy after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 4.5% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time.
• the pharmaceutical formulation comprises at most 4% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 3.5% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 3% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 2.5% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time.
• the pharmaceutical formulation comprises at most 2% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 1.5% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 1% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 0.5% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time. In some embodiments, the pharmaceutical formulation comprises at most 0.1% by weight of a plurality of impurities as measured by UV-Vis spectroscopy after a period of time.
• the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at from about 0.001 pg/mL to about 10 g/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 0.001 pg/mL, about 0.01 pg/mL, about 0.1 pg/mL, about 1 pg/mL, about 10 pg/mL, about 100 pg/mL, about 1 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90
• the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 15 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, or about 40 mg/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 40 mg/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 80 mg/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 90 mg/mL.
• the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 100 mg/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 200 mg/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 300 mg/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 400 mg/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 500 mg/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 1 g/mL. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored at about 10 g/mL.
• the pharmaceutical formulation may be hypertonic, isotonic, or hypotonic. In some embodiments, the pharmaceutical formulation may be hypertonic. In some embodiments, the pharmaceutical formulation may be isotonic. In some embodiments, the pharmaceutical formulation may be hypotonic.
• the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored as a liquid or solid. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored as a liquid. In some embodiments, the pharmaceutical formulation, peptide, or pharmaceutically acceptable salt thereof can be stored as a solid.
• an impurity or a plurality of impurities may arise from acid-catalyzed C-terminal deamidation that converts the C-terminal -CONH2 (amide) to -CO2H (carboxylic acid).
• high basicity of a peptide sequence or amino acid may contribute to long-term stability.
• high level of acid present in a peptide formulation may contribute to long-term stability.
• an acidic peptide formulation may lead to long-term stability.
• a peptide formulation with a pH of at least less than 7 may lead to long-term stability.
• a peptide formulation with a pH of about 5 may lead to long-term stability.
• an impurity or a plurality of impurities may arise from deamination of at least one Arg, at least one Arg converts into citrulline, loss of at least one amino acid, loss of at least one side chain, or loss or cleavage of at least one Arg side chain.
• At least one peptide disclosed herein can be formulated as a pharmaceutical formulation.
• a pharmaceutical formulation can comprise a peptide described herein and at least one excipient.
• pharmaceutically acceptable it is meant that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• compatible means that the components of the formulation are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction that would substantially reduce the pharmaceutical efficacy of the formulation under ordinary use situations.
• a pharmaceutical formulation can comprise an excipient.
• An excipient can be an excipient described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).
• Non-limiting examples of suitable excipients can include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a chelator, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, and/or a coloring agent.
• the pharmaceutical formulation further comprises one or more additional pharmaceutically acceptable excipients. See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005) for a list of pharmaceutically acceptable excipients.
• the pharmaceutically acceptable excipient is of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably a mammal, being treated.
• an excipient can comprise a preservative.
• suitable preservatives can include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol.
• Antioxidants can further include but not limited to EDTA, citric acid, ascorbic acid, butylated hyd oxytoluene (BI -IT), butylated hydroxy anisole (BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl gallate, cysteine, methionine, ethanol and N- acetyl cysteine.
• a preservatives can include validamycin A, TL-3, sodium ortho vanadate, sodium fluoride, N-a-tosyl-Phe- chloromethylketone, N-a-tosyl-Lys-chloromethylketone, aprotinin, phenylmethylsulfonyl fluoride, diisopropylfluorophosphate, kinase inhibitor, phosphatase inhibitor, caspase inhibitor, granzyme inhibitor, cell adhesion inhibitor, cell division inhibitor, cell cycle inhibitor, lipid signaling inhibitor, protease inhibitor, reducing agent, alkylating agent, antimicrobial agent, oxidase inhibitor, or other inhibitor.
• an excipient can comprise a binder.
• suitable binders can include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C 12 -C 18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof.
• the binders that can be used in a pharmaceutical formulation can be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.
• an excipient can comprise a lubricant.
• suitable lubricants can include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.
• the lubricants that can be used in a pharmaceutical formulation can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc or a combination thereof.
• metallic stearates such as magnesium stearate, calcium stearate, aluminium stearate
• fatty acid esters such as sodium stearyl fumarate
• fatty acids such as stearic acid
• fatty alcohols glyceryl behenate
• mineral oil such as paraffins, hydrogenated vegetable oils
• an excipient can comprise a dispersion enhancer.
• suitable dispersants can include starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.
• an excipient can comprise a disintegrant.
• a disintegrant can be a non-effervescent disintegrant.
• suitable non- effervescent disintegrants can include starches such as com starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth.
• a disintegrant can be an effervescent disintegrant.
• suitable effervescent disintegrants can include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.
• an excipient can comprise a flavoring agent.
• Flavoring agents incorporated into an outer layer can be chosen from synthetic flavor oils and flavoring aromatics; natural oils; extracts from plants, leaves, flowers, and fruits; and combinations thereof.
• a flavoring agent can be selected from the group consisting of cinnamon oils; oil of wintergreen; peppermint oils; clover oil; hay oil; anise oil; eucalyptus; vanilla; citrus oil such as lemon oil, orange oil, grape and grapefruit oil; and fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.
• an excipient can comprise a sweetener.
• suitable sweeteners can include glucose (com syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as a sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; and sugar alcohols such as sorbitol, mannitol, sylitol, and the like.
• the excipient may be a sugar.
• suitable sugars can include glucose, sucrose, dextrose, lactose, maltodextrin, fructose, and mixtures thereof.
• an excipient can comprise a coloring agent.
• suitable color agents can include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), and external drug and cosmetic colors (Ext. D&C).
• a coloring agent can be used as dyes.
• an excipient can comprise an isotonicity agent.
• examples can include, but are not limited to: sodium chloride, calcium chloride, potassium chloride, sodium lactate, copper chloride, copper sulfate, monopotassium phosphate, sucrose, dextrose, or glucose.
• the isotonicity agent is sodium chloride.
• an excipient can comprise a chelator.
• a chelator can be a fungicidal chelator. Examples can include, but are not limited to: ethylenediamine-N,N,N',N' -tetraacetic acid (EDTA); a disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salt of EDTA; a barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, or zinc chelate of EDTA; trans-l,2-diaminocyclohexane-N,N,N',N'- tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; l,3-diamino-2-hydroxypropane
• EDTA ethylenediamine-
• an excipient can comprise a diluent.
• diluents can include water, glycerol, methanol, ethanol, and other similar biocompatible diluents.
• a diluent can be an aqueous acid such as acetic acid, citric acid, maleic acid, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or similar.
• a diluent can be selected from a group comprising alkaline metal carbonates such as calcium carbonate; alkaline metal phosphates such as calcium phosphate; alkaline metal sulphates such as calcium sulphate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, caoline, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or pharm ceutically acceptable derivatives thereof or combinations thereof.
• alkaline metal carbonates such as calcium carbonate
• alkaline metal phosphates such as calcium phosphate
• alkaline metal sulphates such as calcium sulphate
• cellulose derivatives such as cellulose, microcrystalline
• an excipient can comprise a surfactant.
• Surfactants can be selected from, but not limited to, polyoxyethylene sorbitan fatty acid esters (polysorbates), sodium lauryl sulphate, sodium stearyl fumarate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols (PEG), polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, amino acids such as L- leucine, sugar esters of fatty acids, glycerides of fatty acids or a combination thereof.
• an excipient can comprise an aqueous carrier.
• the aqueous carrier is lactated Ringer’s solution, normal saline (0.9% w/v), sterile water for injection, or aqueous sodium carbonate.
• the aqueous carrier is lactated Ringer’s solution.
• the aqueous carrier is normal saline (0.9% w/v).
• the aqueous carrier is sterile water for injection.
• the aqueous carrier is aqueous sodium bicarbonate.
• the aqueous sodium bicarbonate is 8.4% sodium bicarbonate.
• the aqueous carrier is physiologically isotonic, physiologically hypotonic, or physiologically hypertonic. In some embodiments, the aqueous carrier is physiologically isotonic. In some embodiments, the aqueous carrier is physiologically hypotonic. In some embodiments, the aqueous carrier is physiologically hypotonic (sub-physiologic osmolarity or osmolality), for example, modified versions of lactated Ringer’s solution, normal saline (0.9% w/v), or aqueous sodium bicarbonate diluted with water. In some embodiments, the aqueous carrier is physiologically hypertonic.
• the aqueous carrier has a total osmolarity ranging from about 1 milliosmoles per one liter (mOsm/L) to about 5,000 mOsm/L. In some embodiments, the aqueous carrier has a total osmolarity of about 1 mOsm/L, about 50 mOsm/L, about 100 mOsm/L, about 150 mOsm/L, about 200 mOsm/L, about 250 mOsm/L, about 300 mOsm/L, about 350 mOsm/L, about 400 mOsm/L, about 450 mOsm/L, about 500 mOsm/L, about 1000 mOsm/L, about 1500 mOsm/L, about 2000 mOsm/L, about 2500 mOsm/L, about 3000 mOsm/L, about 3500 mOsm/L, about 4
• the aqueous carrier has a total osmolality ranging from about 1 milliosmole per kilogram (mOsm/kg) from 5000 mOsm/kg. In some embodiments, the aqueous carrier has a total osmolarity of about 1 mOsm/kg, about 50 mOsm/kg, about 100 mOsm/kg, about 150 mOsm/kg, about 200 mOsm/kg, about 250 mOsm/kg, about 300 mOsm/kg, about 350 mOsm/kg, about 400 mOsm/kg, about 450 mOsm/kg, about 500 mOsm/kg, about 1000 mOsm/kg, about 1500 mOsm/kg, about 2000 mOsm/kg, about 2500 mOsm/kg, about 3000 mOsm/kg, about 3500 mOsm/kg, about 4000 mOsm
• the aqueous carrier may have a total ionic strength ranging from about 0.001 molar (M) and 1.0 M. In some embodiments, the aqueous carrier may have a total ionic strength of about 0.001 M, about 0.01 M, about 0.015 M, about 0.02 M, about 0.025 M, about 0.03 M, about 0.035 M, about 0.04 M, about 0.05 M, about 0.055 M, about 0.06 M, about 0.065 M, about 0.07 M, about 0.075 M, about 0.08 M, about 0.085 M, about 0.09 M, about 0.1 M, about 0.12 M, about 0.14 M, about 0.15 M, about 0.16 M, about 0.18 M, about 0.2 M, about 0.22 M, about 0.24 M, about 0.25 M, about 0.26 M, about 0.28 M, about 0.03 M, about 0.35 M, about 0.4 M, about 0.45 M, about 0.5 M, about 0.55 M, about 0.6 M, about 0.65 M, about 0.7
• the aqueous carrier may have an electrolyte concentration ranging from about 0.1 milliequivalent per mL (mEq/mL) to about 1000 mEq/mL. In some embodiments, the aqueous carrier may have an electrolyte concentration of about 0.1 mEq/mL, about 1 mEq/mL, about 25 mEq/mL, about 50 mEq/mL, about 100 mEq/mL, about 150 mEq/mL, about 200 mEq/mL, about 250 mEq/mL, about 300 mEq/mL, about 350 mEq/mL, about 400 mEq/mL, about 450 mEq/mL, about 500 mEq/mL, about 550 mEq/mL, about 600 mEq/mL, about 650 mEq/mL, about 700 mEq/mL, about 750 mEq/
• the aqueous carrier may have an electrolyte concentration of about 1 mEq/mL to about 500 mEq/mL, about 50 mEq/mL to about 500 mEq/mL, about 100 mEq/mL to about 300 mEq/mL, about 125 mEq/mL to about 250 mEq/mL, about 100 mEq/mL to about 500 mEq/mL, or about 100 mEq/mL to about 1000 mEq/mL.
• the pharmaceutical formulation is in the form of a tablet, a liquid, a syrup, an oral formulation, an intravenous formulation, an intranasal formulation, an ocular formulation, an otic formulation, a subcutaneous formulation, an inhalable respiratory formulation, a suppository, and any combination thereof.
• a weight fraction of an excipient or combination of excipients in a pharmaceutical formulation can be less than about 80%, 70%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, or 1% as compared to a total weight of a pharmaceutical formulation. See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005).
• a pharmaceutical formulation disclosed herein can be formulated into a variety of forms and administered by a number of different means.
• a pharmaceutical formulation can be administered orally, rectally, or parenterally, in formulations containing conventionally acceptable carriers, adjuvants, and vehicles as desired.
• parenteral as used herein can include subcutaneous, intravenous, intramuscular, or intrasternal injection and infusion techniques.
• Administration can include injection or infusion, including intra-arterial, intracardiac, intracerebroventricular, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration.
• a route of administration can be via an injection such as an intramuscular, intravenous, subcutaneous, or intraperitoneal injection.
• the method of administration can be local administration of the peptide or formulation.
• local administration comprises washing, irrigating, debridement, or a combination thereof of a site of infection.
• a site of infection is an open wound, an implant (in vivo or ex vivo), a joint, or topical.
• a site of infection is an implant or a joint.
• washing or irrigation of a site of infection may occur over a time period of from at about 0.5 minute (min) to at about 600 min. In some embodiments, washing or irrigation of a site of infection may occur over a time period of at least about 1 min, 2 min, 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, and any increments there between. In some embodiment, washing or irrigation of a site of infection may occur over 15 min. In some embodiment, washing or irrigation of a site of infection may occur over 30 min.
• the administration of a formulation described herein can be after a surgical procedure or before, during, or after a care regiment of a surgical procedure (e.g., debridement, antibiotics, and imponent retention (DAIR)).
• a surgical procedure e.g., debridement, antibiotics, and imponent retention (DAIR)
• DAIR imponent retention
• Solid dosage forms for oral administration can include capsules, tablets, caplets, pills, troches, lozenges, powders, and granules.
• a capsule can comprise a core material comprising a nutritive protein or formulation and a shell wall that encapsulates a core material.
• a core material can comprise at least one of a solid, a liquid, and an emulsion.
• a shell wall material can comprise at least one of a soft gelatin, a hard gelatin, and a polymer.
• Suitable polymers can include but not limited to: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate (e.g., those copolymers sold under the trade name "Eudragit"); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinylacetate crotonic acid copolymer
• At least one polymer can function as taste-masking agents. Tablets, pills, and the like can be compressed, multiply compressed, multiply layered, and/or coated.
• a coating can be single or multiple.
• a coating material can comprise at least one of a saccharide, a polysaccharide, and glycoproteins extracted from at least one of a plant, a fungus, and a microbe.
• Non-limiting examples can include com starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextrans, maltodextrin, cyclodextrins, inulins, pectin, mannans, gum arabic, locust bean gum, mesquite gum, guar gum, gum karaya, gum ghatti, tragacanth gum, funori, carrageenans, agar, alginates, chitosans, or gellan gum.
• a coating material can comprise a protein.
• a coating material can comprise at least one of a fat and/or an oil.
• the at least one of a fat and/or an oil can be high temperature melting. In some embodiments the at least one of a fat and/or an oil can be hydrogenated or partially hydrogenated. In some embodiments the at least one of a fat and/or an oil can be derived from a plant. In some embodiments the at least one of a fat and/or an oil can comprise at least one of glycerides, free fatty acids, and fatty acid esters. In some embodiments a coating material can comprise at least one edible wax. An edible wax can be derived from animals, insects, or plants. Non-limiting examples can include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets and pills can additionally be prepared with enteric coatings. In some embodiments, a tablet, pill, and the like can be formulated for an extended release profile.
• a peptide described herein or pharmaceutically acceptable salt thereof can be administered in a formulation for topical administration.
• an active agent may be formulated as is known in the art for direct application to a target area.
• Forms chiefly conditioned for topical application can take the form, for example, of creams, milks, gels, powders, dispersion or microemulsions, lotions thickened to a greater or lesser extent, impregnated pads, ointments or sticks, soaps, detergents, lotions or cakes of soap.
• Other conventional forms for this purpose include wound dressings, coated bandages or other polymer coverings, ointments, creams, lotions, pastes, jellies.
• a therapeutic peptide disclosed herein can be delivered via patches or bandages for dermal administration.
• a peptide can be formulated to be part of an adhesive polymer, such as polyacrylate or acrylate/vinyl acetate copolymer.
• an adhesive polymer such as polyacrylate or acrylate/vinyl acetate copolymer.
• a backing layer can be any appropriate thickness that will provide a desired protective and support functions.
• a suitable thickness will generally be from about 1 to about 1000 microns. For example, from about 10 to about 300 microns.
• Topical administration may be in the form of a nail coating or lacquer.
• an antifungal peptide can be formulated in a solution for topical administration that contains ethyl acetate (NF), isopropyl alcohol (USP), and butyl monoester of polyfmethylvinyl ether/maleic acid] in isopropyl alcohol.
• Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
• Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
• Liquid formulations can include a syrup (for example, an oral formulation), an intravenous formulation, an intranasal formulation, an ocular formulation (e.g., for treating an eye infection), an otic formulation (e.g., for treating an ear infection), an ointment, a cream, an aerosol, and the like.
• a combination of various formulations can be administered.
• Drops such as eye drops or nose drops, may be formulated with one or more peptide(s) in an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspending agents. Drops can be delivered via a simple eye dropper-capped bottle, via a plastic bottle adapted to deliver liquid contents drop-wise, or via a specially shaped closure.
• the method of administration may last over a course of at least about 1 hour, 5 hours, 12 hours, 24 hours, 48 hours, 72 hours, 4 days, 5 days, 1 week, 2 weeks, 3 week, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 20 years, 25 years, 30 years, 35 years, 40 years, 45 years, 50 years, 55 years, 60 years, 65 years, 70 years, 75 years, or 80 years.
• Administration of a peptide, pharmaceutically acceptable salt thereof, or a formulation comprising a peptide or salt thereof to a subject can be used to at least partially ameliorate a bacterial infection in a subject.
• Administration of a peptide, pharmaceutically acceptable, or formulation can be performed for a treatment duration of at least about at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,
• a treatment duration can be from about 1 to about
• 30 days from about 2 to about 30 days, from about 3 to about 30 days, from about 4 to about 30 days, from about 5 to about 30 days, from about 6 to about 30 days, from about 7 to about 30 days, from about 8 to about 30 days, from about 9 to about 30 days, from about 10 to about 30 days, from about 11 to about 30 days, from about 12 to about 30 days, from about 13 to about 30 days, from about 14 to about 30 days, from about 15 to about 30 days, from about 16 to about 30 days, from about 17 to about 30 days, from about 18 to about 30 days, from about 19 to about 30 days, from about 20 to about 30 days, from about 21 to about 30 days, from about 22 to about 30 days, from about 23 to about 30 days, from about 24 to about 30 days, from about 25 to about 30 days, from about 26 to about 30 days, from about 27 to about 30 days, from about 28 to about 30 days, or from about 29 to about 30 days.
• Administration of a peptide, pharmaceutically acceptable, or formulation can be performed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times a day. In some embodiments, administration of a peptide, pharmaceutically acceptable, or formulation can be performed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times a week. In some embodiments, administration of a peptide, pharmaceutically acceptable, or formulation can be performed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
• administration of the pharmaceutical formulation comprising a peptide or pharmaceutically acceptable salt occurs over a time period of from at least about 0.5 min to at least about 1 min, from at least about 1 min to at least about 2 min, from at least about 2 min to at least about 3 min, from at least about 3 min to at least about 4 min, from at least about 4 min to at least about 5 min, from at least about 5 min to at least about 6 min, from at least about 6 min to at least about 7 min, from at least about 7 min to at least about 8 min, from at least about 8 min to at least about 9 min, from at least about 9 min to at least about 10 min, from at least about 10 min to at least about 11 min, from at least about 11 min to at least about 12 min, from at least about 12 min to at least about 13 min, from at least about 13 min to at least about 14 min, from at least about 14 min to at least about 15 min, from at least about 15 min to at least about 16 min, from at least about 16 min to at least about 17 min,
• a peptide disclosed herein, salt thereof, or a formulation containing a peptide or salt thereof can be administered to a subject in order to at least partially ameliorate a disease or condition.
• a subject can be in need of a treatment of a disease or condition.
• a subject may have been previously diagnosed with a disease or condition described herein, and/or may be at risk of developing a disease or condition as described herein.
• a coating comprising a peptide disclosed herein, salt thereof, or a formulation containing a peptide or salt thereof.
• a coating can be an antimicrobial coating that can be applied to a surface to remove contaminants from a surface, or to prevent contamination in the first instance.
• a coating can comprise an antimicrobial peptide disclosed herein.
• a coating can generally be prepared by contacting a coating material with a peptide disclosed herein, salt thereof, or a formulation containing a peptide or salt thereof.
• a coating can be in the form of a film, sheet, or liquid used to coat a biological or non-biological surface.
• a film can be prepared by coating material capable of producing a film with a peptide disclosed herein, salt thereof, or a formulation containing a peptide or salt thereof.
• a coating material capable of producing a film can be an adhesive compound, such as a mucoadhesive, used to bind a compound to a biological surface.
• An exemplary mucoadhesive can be a highly negatively charged polymer such as polycarbophil.
• a coating material capable of producing a film can be adhered to a biological surface to treat or prevent an infection on a biological surface.
• a peptide described herein can be formulated as a coating for adherence onto an open wound, thereby eliminating a need for a bandage by directly adhering an antimicrobial compound to a site of action.
• Further applications can include adhering a coating onto a transplanted organ to prevent infection by a pathogen during a transplant process.
• a coating can comprise a peptide disclosed herein, salt thereof, or a formulation containing a peptide or salt thereof can be used to sterilize a surface.
• a coating can be applied to surgical equipment, and any surface in contact with surgical equipment, prior to an operation. Such practice can mitigate a risk contamination of the surgical equipment during transport. Scientific equipment can also be coated with such a coating to prevent cross contamination of certain microbes that could interfere with a measurement to be taken with the equipment.
• a coating containing a peptide described herein can include coating an article such as a medical device.
• the medical device can be an implantable medical device.
• a medical device such as a catheter or prosthetic limb can be coated with a coating as described above to prevent contamination during packaging, storage, or during a transplant operation.
• a peptide can be the sole antimicrobial compound in a coating.
• a coating can comprise other antimicrobial compounds such as those described herein.
• Metallic antimicrobial compounds such as silver nitrate can also be used in combination with a peptide scribed herein.
• An article for implant in contact with a coating containing a peptide, pharmaceutically acceptable salt thereof, or pharmaceutical formulation can be assembled as a formulation containing an article and coating.
• the pharmaceutical formulations described herein is in the form of a unit dose.
• a pharmaceutical formulation can be formulated to optimize pharmacokinetics/pharmacodynamics of a peptide or salt thereof contained therein.
• a peptide, pharmaceutically acceptable salt thereof, or pharmaceutical formulation comprising a peptide or salt thereof described herein can be administered at a dose of from about 1 mg to about 1000 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 15 mg to about 1000 mg, from about 20 mg to about 1000 mg, from about 25 mg to about 1000 mg, from about 30 mg to about 1000 mg, from about 35 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 45 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 55 mg to about 1000 mg, from about 60 mg to about 1000 mg, from about 65 mg to about 1000 mg, from about 70 mg to about 1000 mg, from about 75 mg to about 1000 mg, from about 80 mg to about 1000 mg, from about 85 mg to about 1000 mg, from about 90 mg to about 1000 mg, from about 95 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 250
• a peptide, pharmaceutically acceptable salt thereof, or pharmaceutical formulation comprising a peptide or salt thereof described herein can be administered at a dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
• the pharmaceutical formulation comprising a peptide or pharmaceutically acceptable salt is present at a concentration from at least about 0.01 pg/mL to at least about 100 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration from at least about at least about 0.1 mg/mL to at least about 5 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration from at least about at least about 0.5 mg/mL to at least about 1 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 1 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 2 mg/mL.
• the peptide or pharmaceutically acceptable salt is present at a concentration about 3 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 4 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 5 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 6 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 7 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 8 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 9 mg/mL.
• the peptide or pharmaceutically acceptable salt is present at a concentration about 10 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 20 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 30 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 40 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 40.7 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 50 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 60 mg/mL.
• the peptide or pharmaceutically acceptable salt is present at a concentration about 70 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 80 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 81.4 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 90 mg/mL. In some embodiments, the peptide or pharmaceutically acceptable salt is present at a concentration about 100 mg/mL.
• the pharmaceutical formulation comprising a peptide or pharmaceutically acceptable salt can exhibit antimicrobial activity against an infection at a concentration from at least about 0.01 pg/mL to at least about 0.02 pg/mL, from at least about 0.02 pg/mL to at least about 0.03 pg/mL, from at least about 0.03 pg/mL to at least about 0.04 pg/mL, from at least about 0.04 pg/mL to at least about 0.05 pg/mL, from at least about 0.05 pg/mL to at least about 0.06 pg/mL, from at least about 0.06 pg/mL to at least about 0.07 pg/mL, from at least about 0.07 pg/mL to at least about 0.08 pg/mL, from at least about 0.08 pg/mL to at least about 0.09 pg/mL, from at least about 0.09 pg/mL to at least about 0.1
• effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection can be a concentration from at least about 0.01 pg/mL to at least about 100 mg/mL. In some embodiments, effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration from at least about at least about 0.1 mg/mL to at least about 5 mg/mL. In some embodiments, effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration from at least about at least about 0.5 mg/mL to at least about 1 mg/mL.
• effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration from at least about at least about 1 mg/mL to at least about 10 mg/mL. In some embodiments, effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration from at least about at least about 3 mg/mL to at least about 10 mg/mL. In some embodiments, effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration from at least about at least about 1 mg/mL to at least about 100 mg/mL.
• effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 1 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 2 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 3 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 4 mg/mL.
• the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 5 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 6 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 7 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 8 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 9 mg/mL.
• the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 10 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 20 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 50 mg/mL. In some embodiments, the effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection is at a concentration about 100 mg/mL.
• effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection may be a concentration from at least about 0.01 pg/mL to at least about 0.02 pg/mL, from at least about 0.02 pg/mL to at least about 0.03 pg/mL, from at least about 0.03 pg/mL to at least about 0.04 pg/mL, from at least about 0.04 pg/mL to at least about 0.05 pg/mL, from at least about 0.05 pg/mL to at least about 0.06 pg/mL, from at least about 0.06 pg/mL to at least about 0.07 pg/mL, from at least about 0.07 pg/mL to at least about 0.08 pg/mL, from at least about 0.08 pg/mL to at least about 0.09 pg/mL, from at least about 0.09 pg/mL to at least about 0.1 pg
• effective amounts of a peptide or pharmaceutically acceptable salt for treating or preventing an infection may be from at least about 1 pL to at least about 2 pL, from at least about 2 pL to at least about 3 pL, from at least about 3 pL to at least about 4 pL, from at least about 4 pL to at least about 5 pL, from at least about 5 pL to at least about 6 pL, from at least about 6 pL to at least about 7 pL, from at least about 7 pL to at least about 8 pL, from at least about 8 pL to at least about 9 pL, from at least about 9 pL to at least about 10 pL, from at least about 10 pL to at least about 20 pL, from at least about 20 pL to at least about 30 pL, from at least about 30 pL to at least about 40 pL, from at least about 40 pL to at least about 50 pL, from at least about
• the pharmaceutical formulation is physiologically isotonic, physiologically hypotonic, or physiologically hypertonic. In some embodiments, the pharmaceutical formulation is physiologically isotonic. In some embodiments, the pharmaceutical formulation is physiologically hypotonic. In some embodiments, the pharmaceutical formulation is physiologically hypertonic.
• the pharmaceutical formulation may have an osmolarity of from at least 1 milliosmoles per kilogram (mOsm/kg) to at least 10 osmoles per kilogram (Osm/kg), at least 1 mOsm/kg to at least 5 Osm/kg, at least 1 mOsm/kg to at least 4 Osm/kg, at least 1 mOsm/kg to at least 3 Osm/kg, at least 1 mOsm/kg to at least 2 Osm/kg, at least 1 mOsm/kg to at least 1 Osm/kg, at least 1 mOsm/kg to at least 900 mOsm/kg, at least 1 mOsm/kg to at least 800 mOsm/kg, at least 1 mOsm/kg to at least 700 mOsm/kg, at least 1 mOsm/kg to at least 600 mOsm/kg, at least 1 mOsm
• the pharmaceutical formulation may have an osmolarity of from at least 30 mOsm/kg to at least 400 mOsm/kg. In some embodiments, the pharmaceutical formulation may have an osmolarity of from at least 275 mOsm/kg to at least 295 mOsm/kg. In some embodiments, the pharmaceutical formulation has a total osmolarity ranging from about 1 mOsm/L to about 5,000 mOsm/L.
• the pharmaceutical formulation has a total osmolarity of about 1 mOsm/L, about 50 mOsm/L, about 100 mOsm/L, about 150 mOsm/L, about 200 mOsm/L, about 250 mOsm/L, about 300 mOsm/L, about 350 mOsm/L, about 400 mOsm/L, about 450 mOsm/L, about 500 mOsm/L, about 1000 mOsm/L, about 1500 mOsm/L, about 2000 mOsm/L, about 2500 mOsm/L, about 3000 mOsm/L, about 3500 mOsm/L, about 4000 mOsm/L, about 4500 mOsm/L, or about 5000 mOsm/L.
• the pharmaceutical formulation has a total osmolality ranging from about 1 milliosmole per kilogram (mOsm/kg) from 5000 mOsm/kg. In some embodiments, the pharmaceutical formulation has a total osmolarity of about 1 mOsm/kg, about 50 mOsm/kg, about 100 mOsm/kg, about 150 mOsm/kg, about 200 mOsm/kg, about 250 mOsm/kg, about 300 mOsm/kg, about 350 mOsm/kg, about 400 mOsm/kg, about 450 mOsm/kg, about 500 mOsm/kg, about 1000 mOsm/kg, about 1500 mOsm/kg, about 2000 mOsm/kg, about 2500 mOsm/kg, about 3000 mOsm/kg, about 3500 mOsm/kg, about 4000 mOsm/kg, about 4500
• the pharmaceutical formulation has a total ionic strength ranging from about 0.001 molar (M) and 1.0 M.
• the aqueous carrier may have a total ionic strength of about 0.001 M, about 0.01 M, about 0.015 M, about 0.02 M, about 0.025 M, about 0.03 M, about 0.035 M, about 0.04 M, about 0.05 M, about 0.055 M, about 0.06 M, about 0.065 M, about 0.07 M, about 0.075 M, about 0.08 M, about 0.085 M, about 0.09 M, about 0.1 M, about 0.12 M, about 0.14 M, about 0.15 M, about 0.16 M, about 0.18 M, about 0.2 M, about 0.22 M, about 0.24 M, about 0.25 M, about 0.26 M, about 0.28 M, about 0.03 M, about 0.35 M, about 0.4 M, about 0.45 M, about 0.5 M, about 0.55 M, about 0.6 M, about 0.65 M, about 0.7 M, about 0.75 M about 0.8
• combination products that include one or more peptides disclosed herein and one or more other antimicrobial or antifungal agents, for example, polyenes such as amphotericin B, amphotericin B lipid complex (ABCD), liposomal amphotericin B (L-AMB), and liposomal nystatin, azoles and triazoles such as voriconazole, fluconazole, ketoconazole, itraconazole, pozaconazole and the like; glucan synthase inhibitors such as caspofungin, micafungin (FK463), and V-echinocandin (LY303366); griseofulvin; allylamines such as terbinafine; flucytosine or other antifungal agents, including those described herein.
• polyenes such as amphotericin B, amphotericin B lipid complex (ABCD), liposomal amphotericin B (L-AMB), and liposomal nystatin
• a peptide can be combined with topical antifungal agents such as ciclopirox olamine, haloprogin, tolnaftate, undecylenate, topical nysatin, amorolfme, butenafine, naftifine, terbinafine, and other topical agents.
• a pharmaceutical formulation can comprise an additional agent.
• an additional agent can be present in a therapeutically effective amount in a pharmaceutical formulation.
• an additional pharmaceutical agent can be an antibiotic agent.
• An antibiotic agent can of the group consisting of aminoglycosides, ansamycins, carbacephem, carbapenems, cephalosporins (including first, second, third, fourth and fifth generation cephalosporins), lincosamides, macrolides, monobactams, nitrofurans, quinolones, penicillin, sulfonamides, polypeptides and tetracycline.
• an antibiotic agent may be effective against mycobacteria.
• an antibiotic agent may be an aminoglycoside such as Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin or Paromomycin.
• an antibiotic agent may be an Ansamycin such as Geldanamycin and Herbimycin.
• an antibiotic agent may be a carbacephem such as Loracarbef.
• an antibiotic agent can be a carbapenem such as Ertapenem, Doripenem, Imipenem/Cilastatin or Meropenem.
• an antibiotic agent may be a beta lactam antibiotic or pharmaceutically acceptable salt thereof may include but are not limited to Cephalexin, Cephradine, Cefadroxil, Cefazolin, B-lactam antibiotic C, Cephalothin, Cefapirin, Cefuroxime, Cefprozil, Loracarbef, Cefuroxime, Cefoxitin, Cefotetan, Cefaclor, Cefamandole, Ceftriaxone, Cefdinir, Cefixime, Cefpodoxime, Cefditoren, Ceftibuten, Ceftazidime, Cefotaxime, Cefoperazone, Ceftizoxime, Cefepime, Cefiderocol, Cefpirome, Ceftaroline, Benzathine, Benzylpenicillin, Phenoxymethylpenicillin, Procaine penicillin, Pheneticillin, Cioxacillin, Di cl o
• an antibiotic agent may be a cephalosporins (first generation) such as Cefadroxil, Cefazolin, Cefalexin, Cefalotin or Cefalothin, or alternatively a Cephalosporins (second generation) such as Cefaclor, Cefamandole, Cefoxitin, Cefprozil or Cefuroxime.
• first generation such as Cefadroxil, Cefazolin, Cefalexin, Cefalotin or Cefalothin
• Cephalosporins second generation
• Cefaclor, Cefamandole, Cefoxitin, Cefprozil or Cefuroxime such as Cefaclor, Cefamandole, Cefoxitin, Cefprozil or Cefuroxime.
• an antibiotic agent may be a Cephalosporins (third generation) such as Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftibuten, Ceftizoxime and Ceftriaxone or a Cephalosporins (fourth generation) such as Cefepime and Ceftobiprole.
• an antibiotic agent may be a lincosamide such as Clindamycin and Azithromycin, or a macrolide such as Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin and Spectinomycin.
• an antibiotic agent may be a monobactams such as Aztreonam, or a nitrofuran such as Furazolidone or Nitrofurantoin.
• an antibiotic agent may be a penicillin such as Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cioxacillin, Dicloxacillin, Flucioxacillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G or V, Piperacillin, Temocillin and Ticarcillin.
• an antibiotic agent may be a sulfonamide such as Mafenide, Sulfonamidochrysoidine, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim, and Trimethoprim-Sulfamethoxazole (Co-trimoxazole) (TMP-SMX).
• a sulfonamide such as Mafenide, Sulfonamidochrysoidine, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim, and Trimethoprim-Sulfameth
• an antibiotic agent may be a quinolone such as Ciprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfl oxacin and Temafloxacin.
• an antibiotic agent may be a polypeptide such as Bacitracin, Colistin and Polymyxin B.
• an antibiotic agent may be a tetracycline such as Demeclocy cline, Doxycycline, Minocycline and Oxytetracycline.
• an antibiotic agent may be effective against mycobacteria.
• An antibiotic agent may be Clofazimine, Lamprene, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine or Streptomycin.
• an antibiotic agent can include Ceftobiprole, Ceftaroline, Clindamycin, Dalbavancin, Daptomycin, Linezolid, Mupirocin, Oritavancin, Tedizolid, Telavancin, Tigecycline, Vancomycin, an Aminoglycoside, a Carbapenem, Ceftazidime, Cefepime, Ceftobiprole, a Fluoroquinolone, Piperacillin, Ticarcillin, Methicillin, Linezolid, a Streptogramin, Tigecycline, Daptomycin, a salt of any of these, or any combination thereof.
• an additional pharmaceutical agent can be an antimicrobial agent disclosed herein.
• an antimicrobial agent can be cysteamine or a salt thereof. While cysteamine can be typically used to treat conditions such as cystinosis that are not derived from an infection, the use of cysteamine as an antimicrobial compound has shown promise.
• WO2010112848 describes the use of formulations containing cysteamine for as antimicrobial agents capable of inhibiting the formation of a bacterial biofilm for a broad range of bacterial strains, including Pseudomonas spp., Staphylococcus spp., Haemophilus spp., Burkholderia spp., Streptococcus spp., Propionibacterium spp.
• an additional pharmaceutical agent can be an antiviral agent.
• an antiviral agent can be Acyclovir, Brivudine, Cidofovir, Docosanol, Famciclovir, Foscarnet, Fomivirsen, Ganciclovir, Idoxuridine, Penciclovir, Peramivir, Trifluridine, Valacyclovir, Vidarabine, Lamivudine, Ribavirin Amantadine, Rimantadine, a neuraminidase inhibitor, Oseltamivir, Zanamivir, a salt of any of these, or any combination thereof.
• an additional pharmaceutical agent can be an antineoplastic.
• an antineoplastic can be selected from the group consisting of cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, cisplatin, epirubicin, a salt of any of these, and any combination thereof.
• a peptide disclosed herein, salt thereof, or a formulation containing a peptide or salt thereof can be an antiviral agent.
• a peptide, pharmaceutically acceptable, or formulation can be administered in combination with an antibiotic or an additional antiviral agent disclosed herein.
• compositions comprising a peptide and method of treating or preventing a disease or condition comprising administering the pharmaceutical formulation.
• the condition or disease is an infection.
• the infection is a microbial infection.
• the infection is a bacterial infection, viral infection, fungal infection, or a combination thereof.
• bacterial infection may be derived from a bacterial species selected from the group, but not exclusive to the group, consisting of: Staphylococcus spp., e.g. Staphylococcus aureus (e.g. Staphylococcus aureus NCTC 10442 and Staphylococcus aureus ATCC25923), Staphylococcus epidermidis; Chlamydia spp., e.g. Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci; Enterococcus spp., e.g. Enterococcus faecalis;
• Staphylococcus aureus e.g. Staphylococcus aureus NCTC 10442 and Staphylococcus aureus ATCC25923
• Staphylococcus epidermidis e.g. Chlamydia trachomatis, Chlamy
• Streptococcus pyogenes Listeria spp.; Pseudomonas spp .; Mycobacterium spp., e.g. Mycobacterium tuberculosis complex; Enterobacter spp.; Campylobacter spp.; Salmonella spp.; Streptococcus spp., e.g. Streptococcus Group A or B, Streptoccocus pneumoniae; Helicobacter spp., e.g. Helicobacter pylori, Helicobacter felis,; Neisseria spp., e.g.
• Neisseria gonorrhoea Neisseria meningitidis; Borrelia burgdorferi; Shigella spp., e.g. Shigella jlexneri; Escherichia coli (E.coli 0157:H7 NCTC 12900); Haemophilus spp., e.g. Haemophilus influenzae;
• Francisella tularensis Bacillus spp., e.g. Bacillus anthraces; Clostridia spp., e.g. Clostridium botulinum, Clostridium difficile; Yersinia spp., e.g. Yersinia pestis; Treponema spp.;
• Burkholderia spp. e.g. Burkholderia cepacia complex, B. mallei, B pseudomallei; Propionibacterium spp., e.g. P. acnes, Acinetobacter species, an Actinomyces species, a Campylobacter species, a Candida species, Corynebacterium minutissium, Corynebacterium pseudodiphtheriae, Corynebacterium stratium, Corynebacterium group Gl, Corynebacterium group G2, Enter obacteriaceae, an Enterococcus species, Klebsiella pneumoniae, a.
• Moraxella species a non-tuberculous mycobacteria species, a Porphyromonas species, Prevotella melaninogenicus, Salmonella typhimurium, Serratia marcescens Streptococcus agalactiae, Staphylococcus salivarius, Streptococcus mitis, Streptococcus sanguis, Streptococcus pneumoniae, Vibrio cholerae, a Coccidioides species, or a Cryptococcus species.
• a peptide or pharmaceutically acceptable salt thereof described herein can reduce infection of bacteria against at least one of Staphylococcus aureus, methicillin resistant Staphylococcus aureus, Streptococcus pneumonia, carbapenem-resistant Enter oacteriaceae, Staphylococcus epidermidis, Staphylococcus salivarius, Corynebacterium minutissium, Corynebacterium pseudodiphtheriae, Corynebacterium stratium, Corynebacterium group Gl, Corynebacterium group G2, Streptococcus pneumonia, Streptococcus mitis, Streptococcus sanguis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Burkholderia cepacia, Serratia marcescens, Haemophilus influenzae, Moraxella sp., Neisseria meningitidis, Neisseria
• bacterial infection may be derived from a bacterial species selected from the group Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdenensis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Staphylococcus warnerii, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus pettenkoferi, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Group C streptococci, Streptococcus constellatus, Enterococcus faecalis, Enterococcus faecium, Corynebacterium jeikeium, Lactobacillus acidophilus, Listeria monocytogenes, Escherichia coli,
• the bacterial may be antibiotic-tolerant or antibiotics-resistant.
• a bacterial strain can also be an antibiotic-resistant variant or a bacterial strain described herein.
• a bacterial strain can be resistant to an antibiotic described herein.
• a bacterial strain can be resistant to an antibiotic such as a Ceftobiprole, Ceftaroline, Clindamycin, Dalbavancin, Daptomycin, Linezolid, Mupirocin, Oritavancin, Tedizolid, Telavancin, Tigecycline, Vancomycin, an Aminoglycoside, a Carbapenem, Ceftazidime, Cefepime, Ceftobiprole, a Fluoroquinolone, Piperacillin, Ticarcillin, Linezolid, a Streptogramin, Tigecycline, Daptomycin, or any combination thereof.
• a microbial biofilm also referred to as a biological biofilm, can be a community of microbial cells embedded in an extracellular matrix of polymeric substances and adherent to a biological or a non-biotic surface.
• a range of microorganisms bacteria, fungi, and/or protozoa, with associated bacteriophages and other viruses
• Biofilms are ubiquitous in nature, are commonly found in a wide range of environments. Biofilms are being increasingly recognized by the scientific and medical community as being implicated in many infections, and especially their contribution to the recalcitrance of infection treatment.
• Biofilms can be etiologic agents for a number of disease states in mammals and are involved in 80% of infections in humans.
• Examples can include skin and wound infections, middle-ear infections, gastrointestinal tract infections, peritoneal membrane infections, urogenital tract infections, oral soft tissue infections, formation of dental plaque, eye infections (including contact lens contamination), endocarditis, infections in cystic fibrosis, and infections of indwelling medical devices such as joint prostheses, dental implants, catheters and cardiac implants.
• Microbes in biofilms can be significantly more resistant to antimicrobial treatment than their planktonic counterparts. Biofilm formation is not limited solely to the ability of microbes to attach to a surface. Microbes growing in a biofilm can interact more between each other than with the actual physical substratum on which the biofilm initially developed.
• biofiIm-associated microorganisms elicit diseases in their host can include the following: (i) delayed penetration of the antimicrobial agent through the biofilm matrix, (ii) detachment of cells or cell aggregates from indwelling medical device biofilms, (iii) production of endotoxins, (iv) resistance to the host immune system, (v) provision of a niche for the generation of resistant organisms through horizontal gene transfer of antimicrobial resistance &/or virulence determinant genes, and (vi) altered growth rate (i.e. metabolic dormancy).
• the infection is periprosthetic joint infection.
• periprosthetic joint infection is caused by a bacterial infection.
• the periprosthetic joint infection further comprises a biofilm.
• the infection arises after a surgical procedure (e.g., implant of a prosthesis or surgical site infection). Exemplary surgical procedures can include, but not limited to, total knee arthroplasty, joint replacement surgery, and implant of a prosthesis.
• bacteria, fungi, and/or protozoa, with associated bacteriophages and other viruses described herein can secrete a biofilm.
• bacteria, fungi, and/or protozoa, with associated bacteriophages and other viruses described herein can form a biofilm.
• a peptide, pharmaceutically acceptable salt thereof described herein, or a formulation comprising a peptide or salt thereof described herein can be administered to at least partially penetrate, inhibit formation of, or destroy a biological biofilm.
• additional agents can be added to at least partially inhibit formation of, or destroy, a biological biofilm.
• the infection is a viral infection.
• a virus can be a DNA virus, a RNA virus, or a reverse transcriptase (retro) virus.
• a virus can be a dsDNA (double stranded DNA) virus, a ssDNA (single stranded DNA) virus, a dsRNA (double stranded RNA) virus, a +ssRNA (+ strand or sense single stranded RNA) virus, a -ssRNA (- strand or antisense RNA) virus, a ssRNA-RT (single stranded RNA reverse transcriptase) virus, or a dsDNA-RT (double stranded DNA reverse transcriptase) virus.
• a peptide described herein can be engineered to disrupt the integrity of a viral envelope of an enveloped virus. Such a disruption can at least partially reduce a viability of a virus, which can ameliorate an infection brought about by a virus.
• a virus may be derived from the group, but not exclusive to the group, of a herpesvirus, a poxvirus, a hepadnavirus, a flavivirus, a togavirus, a coronavirus, hepatitis C, hepatitis D, an orthomyxovirus, a papillomavirus, a polyomaviridae, a parvovirus, a cytomegalovirus, an Epstein-Barr virus, a small pox virus, a cow pox virus, a sheep pox virus, an orf virus, a monkey pox virus, a vaccinia virus, a paramyxovirus, a retrovirus, an adenovirus, a rhabdo
• the virus can be an enveloped virus.
• an enveloped viruses can include: a poxvirus, a hepadnavirus, a flavivirus, a togavirus, a coronavirus, hepatitis C, hepatitis D, an orthomyxovirus, a cytomegalovirus, an Epstein-Barr virus, a small pox virus, a cow pox virus, a sheep pox virus, an orf virus, a monkey pox virus, a vaccinia virus, a rhabdovirus, a bunyavirus, a filovirus, an alphavirus, an arenavirus, a lentivirus, and the like.
• a pathogen can be a drug-resistant fungal, protozoal, or other parasitic organism.
• a parasitic pathogen may be derived from a parasite selected from, but not limited to, the group consisting of Trypanosoma spp. (Trypanosoma cruzi, Trypansosoma brucei), Leishmania spp., Giardia spp., Trichomonas spp., Entamoeba spp., Naegleria spp., Acanthanioeba spp., Schistosoma spp., Plasmodium spp., Crytosporidium spp., Isospora spp., Balantidium spp., Loa Loa, Ascaris lumbricoides, Dirofdaria immitis, and Toxoplasma ssp., e.g. Toxoplasma gondii.
• a fungal pathogen may be derived from a fungus (including yeast) selected from, but not limited to, the genera Candida spp., (e.g. C. albicans'), Epidermophyton spp., Exophiala spp., Mier osporum spp., Trichophyton spp., (e.g. T. rubrum and T. interdigitale), Tinea spp., Aspergillus spp., Blastomyces spp., Blastoschizomyces spp., Coccidioides spp., Cryptococcus spp. (e.g.
• Cryptococcus neoformans Histoplasma spp., Paracoccidiomyces spp., Sporotrix spp., Absidia spp., Cladophialophora spp., Fonsecaea spp., Phialophora spp., Lacazia spp., Arthrographis spp., Acremoniwn spp., Actinomadura spp., Apophysomyces spp., Emmonsia spp., Basidiobolus spp., Beauveria spp., Chrysosporium spp., Conidiobolus spp., Cunninghamella spp., Fusarium spp., Geotrichum spp., Graphiwn spp., Leptosphaeria spp., Malassezia spp.
• a fungal pathogen may be Malassezia Furfur , Mucor spp., Neotestudina spp., Nocardia spp., Nocardiopsis spp., Paecilomyces spp., Phoma spp., Piedraia spp., Pneurrweystis spp., Pseudallescheria spp., Pyrenochaeta spp., Rhizoinucor spp., Rhizopus spp., Rhodotorula spp., Saccharomyces spp., Scedosporium spp., Scopulariopsis spp., Sporobolomyces spp., Syncephalastrum spp., Trichoderma spp., Trichosporon spp., Ulocladium spp., Ustilago spp., Verticillium spp., and Wangiella spp.
• a fungal, bacterial, or viral infection may be a systemic, topical, subcutaneous, cutaneous or mucosal infection.
• Topical fungal infections of nails and skin are generally caused by detinatophytes although some non-dermatophytes such as yeast can also cause skin infections.
• a dermatophyte infection may include a Tinea infection for example Tinea barbae (beard), Tinea capitis (head), Tinea corporis (body), Tinea cruris (groin), Tinea faciei (face), Tinea manuum (hand), Tinea pedis (foot) Tinea unguium (nail), Tinea (Pityriasis) versicolor, Tinea incognito or Tinea nigra.
• An infection may be derived from fungi of the genera Epidermophyton, Microsporum or Trichophyton spp. (e.g., T. rubrum and T interdigitale). Exemplary dermatophytes can include Epidermophyton floccosum.
• Microsporum canis. Microsporum audouinii. Microsporum gypseum, Microsporum nanum. Microsporum ferrugineum.
• a dermatophytic infection can be onychomycosis.
• onychomycosis can include, but is not limited to, distal lateral subungual, superficial white, proximal white subungual, secondary dystrophic, primary dystrophic, endonyx, candidal (e.g., onycholysis & chronic mucocutaneous disease) types of onychomycosis and Tinea ungium.
• Non-dermatophytic fungi associated with onychomycosis can include Aspergillus spp., Cephalosporum spp., Fusarium oxysporum, Scopularis brevicaulis, and Scytalidium spp.
• kits can comprise a peptide, pharmaceutically acceptable salt thereof, formulation, or formulation described herein.
• a peptide, formulation, or formulation can be packaged in a container.
• a kit can further comprise one or more aqueous carriers in a separate container from the peptide or formulation.
• a kit comprises one aqueous carrier.
• a kit comprises more than one aqueous carrier.
• a kit comprises two aqueous carrier.
• a kit can further comprise a separate container for mixing (e.g., an intravenous bag) an aqueous carrier or aqueous carriers and the peptide or formulation.
• the pharmaceutical composition is mixed with one or more aqueous carriers of a kit in a separate container for mixing prior to use.
• the aqueous carrier in the kit dilutes the concentration of the peptide or formulation to about 0.5 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL or about 50 mg/mL.
• a kit can further comprise instructions that direct administration of a unit dose of a peptide or formulation to a subject.
• a kit can comprise a peptide disclosed herein and instructions for the use thereof.
• Methods of making a kit can include placing a peptide, pharmaceutically acceptable salt thereof, formulation, or formulation described herein in a container for packaging.
• a method can further comprise an inclusion of instructions for use.
• instructions for use can direct administration of a unit dose of a peptide or formulation to a subject.
• biofilm As used herein, the terms “biofilm”, “microbial film”, “microbial biofilm”, “bacterial film”, refers to any film comprising microorganisms and their excretions.
• the term “object” refers to any object with a surface. Some embodiments in the present disclosure may be applied to the surface of an object to prevent or to treat microbial biofilm.
• the object can a solid object, a liquid object, a hard object, a soft object, a metallic object, a polymeric object, a ceramic object, a composite object, a biological object, members of the animal kingdom, a human being, a biological transplant object, a replaced joint, or any other object with a surface on which some of the disclosed methods and the formulations can be applied.
• the terms "patient” or “subject” generally refer to any individual that has, may have, or may be suspected of having a disease condition (e.g., a bacterial infection).
• the bacterial infection may be caused by surgeries, physical wounds, etc.
• the subject may be an animal.
• the animal can be a mammal, such as a human, non-human primate, a rodent such as a mouse or rat, a dog, a cat, pig, sheep, or rabbit. Animals can be fish, reptiles, or others. Animals can be neonatal, infant, adolescent, or adult animals.
• the subject may be a living organism.
• the subject may be a human.
• Humans can be greater than or equal to 1, 2, 5, 10, 20, 30, 40, 50, 60, 65, 70, 75, 80 or more years of age.
• a human may be from about 18 to about 90 years of age.
• a human may be from about 18 to about 30 years of age.
• a human may be from about 30 to about 50 years of age.
• a human may be from about 50 to about 90 years of age.
• the subject may have one or more risk factors of a condition and be asymptomatic.
• the subject may be asymptomatic of a condition.
• the subject may have one or more risk factors for a condition.
• the subject may be symptomatic for a condition.
• the subject may be symptomatic for a condition and have one or more risk factors of the condition.
• the subject may have or be suspected of having a disease, such as an infection.
• the subject may be a patient being treated for a disease, such as an infection.
• the subject may be predisposed to a risk of developing a disease such as a bacterial infection.
• the subject may be in remission from a disease, such as a bacterial infection.
• the subject may not have a bacterial infection.
• the subject may be healthy.
• a “pharmaceutically acceptable excipient”, “aqueous carrier” or “pharmaceutically acceptable aqueous carrier” refer to solvents or dispersion media, and the like, that are physiologically compatible and known to those skilled in the art.
• examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof.
• Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the active agent.
• an “effective amount” of an active agent can refer to an amount that is effective to achieve a desired result.
• An effective amount of a given active agent can vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the patient.
• the term “homology” can refer to a % identity of a polypeptide to a reference polypeptide. As a practical matter, whether any particular polypeptide can be at least 50%, 60%, 70%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to any reference amino acid sequence of any polypeptide described herein (which may correspond with a particular nucleic acid sequence described herein), such particular polypeptide sequence can be determined conventionally using known computer programs such the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wis. 53711).
• the parameters can be set such that the percentage of identity is calculated over the full length of the reference amino acid sequence and that gaps in homology of up to 5% of the total number of amino acid residues in the reference sequence are allowed.
• the identity between a reference sequence (query sequence, i.e., a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment may be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci. 6:237-245 (1990)).
• the percent identity can be corrected by calculating the number of residues of the query sequence that are lateral to the N- and C-terminal of the subject sequence, which are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence.
• a determination of whether a residue is matched/aligned can be determined by results of the FASTDB sequence alignment. This percentage can be then subtracted from the percent identity, calculated by the FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score can be used for the purposes of this embodiment. In some embodiments, only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the purposes of manually adjusting the percent identity score. That is, only query residue positions outside the farthest N- and C-terminal residues of the subject sequence are considered for this manual correction. For example, a 90 amino acid residue subject sequence can be aligned with a 100 residue query sequence to determine percent identity.
• the deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/alignment of the first 10 residues at the N-terminus.
• the 10 unpaired residues represent 10% of the sequence (number of residues at the N- and C-termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 residues were perfectly matched the final percent identity would be 90%.
• a 90 residue subject sequence is compared with a 100 residue query sequence. This time the deletions are internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query.
• co-administration can encompass administration of selected therapeutic agents to a subject, and can include treatment regimens in which agents are administered by the same or different route of administration or at the same or different times.
• a peptide disclosed herein can be co-administered with other agents.
• These terms can encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the subject at the same time. They can include simultaneous administration, administration at different times, and/or administration in a formulation in which both agents are present.
• a peptide and an additional agent(s) can be administered in a single formulation.
• a peptide and an additional agent(s) can be admixed in the formulation.
• a same peptide or agent can be administered via a combination of different routes of administration.
• each agent administered can be in a therapeutically effective amount.
• Peptide Formulation A 282.59 mg of SEQ ID NO: 1 was added to 200 mL of 0.9% saline solution. IN sodium hydroxide or IN hydrochloric acid was added into peptide formulation A to adjust the pH to 5.0 ⁇ 0.2. The concentration of the peptide was 1.0 mg/mL.
• Peptide Formulation B 282.44 mg of SEQ ID NO: 1 was added to 200 mL of glycine buffer (7.5 mg/mL, 0.1M). IN sodium hydroxide or IN hydrochloric acid was added into peptide formulation B to adjust the pH to 7.4 ⁇ 0.2. The concentration of the peptide was 1.0 mg/mL.
• Peptide Formulation C 282.53 mg of SEQ ID NO: 1 was added to 200 mL of tromethamine buffer (2.422 mg/mL, 20 mM). IN sodium hydroxide or IN hydrochloric acid was added into peptide formulation C to adjust the pH to 7.4 ⁇ 0.2. The concentration of the peptide was 1.0 mg/mL.
• Peptide Formulation D 282.5 mg of SEQ ID NO: 1 is added to 200 mL of 0.9% saline solution. Acetic acid is added into peptide formulation D to adjust the pH to 5.0 ⁇ 0.2. The concentration of the peptide is 1 mg/mL.
• Peptide Formulation E 847.5 mg of SEQ ID NO: 1 is added to 200 mL of 0.9% saline solution. Acetic acid is added into peptide formulation E to adjust the pH to 5.0 ⁇ 0.2. The concentration of the peptide is 3 mg/mL.
• Peptide Formulation F 2.825 g of SEQ ID NO: 1 is added to 200 mL of 0.9% saline solution. Acetic acid is added into peptide formulation F to adjust the pH to 5.0 ⁇ 0.2. The concentration of the peptide is 10 mg/mL.
• Peptide Formulation G 11.3 g of SEQ ID NO: 1 is added to 200 mL of 0.9% saline solution. Acetic acid is added into peptide formulation G to adjust the pH to 5.0 ⁇ 0.2. The concentration of the peptide is 40 mg/mL.
• Peptide Formulation H 18.363 g of SEQ ID NO: 1 is added to 200 mL of 0.9% saline solution. Acetic acid is added into peptide formulation H to adjust the pH to 5.0 ⁇ 0.2. The concentration of the peptide is 65 mg/mL.
• Peptide Formulation I 25.425 g of SEQ ID NO: 1 is added to 200 mL of 0.9% saline solution. Acetic acid is added into peptide formulation I to adjust the pH to 5.0 ⁇ 0.2. The concentration of the peptide is 90 mg/mL.
• FIG. 1 depicts the chromatograph of SEQ ID NO: 1 at 1.0 mg/mL.
• the retention time at 14.38 and relative retention time at 1.00 (RTT) corresponded to SEQ ID NO: 1.
• the area percent of the SEQ ID NO: 1 was 99.09.
• the retention time at 14.77 and RTT at 1.03 corresponded to an impurity.
• the area percent of the impurity was 0.91.
• SEQ ID NO: 1 is stable after 3 years of storage at -20 °C as a dry powder in a glass vial.
• FIG. 2 depicts the HPLC chromatograph after 3 years of storage SEQ ID NO: 1 in solid form at -20 °C (Batch 2K18005).
• the retention time at 18.03 and relative retention time at 1.00 (RTT) corresponded to SEQ ID NO: 1.
• the area percent of the SEQ ID NO: 1 was 97.87.
• the retention times at 18.83 (RTT at 0.99), 18.31 (RTT at 1.02), 18.54 (RTT at 1.03), 18.74 (RTT at 1.04), 18.95 (RTT at 1.05) corresponded to a plurality of impurities with area percentages of 0.09, 1.28, 0.41, 0.19, and 0.15, respectively.
• the retention time at 14.39 and relative retention time at 1.00 (RTT) corresponded to SEQ ID NO: 1.
• the area percent of the SEQ ID NO: 1 was 97.21.
• the retention times at 14.76 (RTT at 1.03), 15.84 (RTT at 1.10), and 16.41 (RTT at 1.14) corresponded to a plurality of impurities with area percentages of 1.73, 0.55, and 0.51, respectively.
• FIG. 4 depict the overlaid chromatograph of SEQ ID NO: 1 after 7 days at 40 °C (bottom graph) and after 54 days at 40 °C (top graph). An increase in the level of impurity at RRT 0.98 was shown, from 0.4% to 1.1%. Data compared to the frozen samples at -20 °C is shown in Table 2.
• SEQ ID NO: 1 in is solid form was white to off-white powder with a solubility of above 100 mg/mL in water at room temperature.
• SEQ ID NO: 1 was stable at frozen temperatures when protected in light.
• the pKa was approximately 12.48 for SEQ ID NO: 1 and was approximately 3.4 kDa (-3399.19 g/mol).
• the saline solution or buffer solutions were prepared in sterile water. The pH of the buffer was recorded. The pH of the buffer or solution was adjusted to the target pH with either 1 N HC1 or IN NaOH. The peptide was dissolved in the buffer or saline. The pH of the dissolved peptide in saline or buffer was adjusted to the target pH with either 1 N HC1 or IN NaOH. The volume was adjusted to 200 mL, additional buffer solution was added into the peptide/buffer formulation and additional saline solution was added into the peptide/saline solution. The solution was filtered through a 0.22 pm membrane filter.
• FIG. 5 depict an overlaid HPLC chromatograph of SEQ ID NO: 1 and impurities at an initial time point (0 day) (bottom graph) and after 3 months (top graph).
• the peptide formulation was stored in PBS buffer at pH of 7.4. Impurity peaks are circled on the 3 months graph.
• FIG. 6 depict an overlaid HPLC chromatograph of SEQ ID NO: 1 at an initial time point (0 day) (bottom) and after 3 months (top) stored in saline at pH of 5.0.
• the peptide formulation was stored in a saline solution at pH of 5.0.
• the single impurity peak was circled on the 3 months graph.
• FIG. 7 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at 5 °C in saline at pH of 5.0. The retention time at 15.639 minutes correspond to SEQ ID NO: 1.
• FIG. 8 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in saline at pH of 5.0. The retention time at 15.637 minutes correspond to SEQ ID NO: 1.
• FIG. 9 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at -20 °C in saline at pH of 5.0. The retention time at 15.611 minutes correspond to SEQ ID NO: 1.
• FIG. 8 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in saline at pH of 5.0. The retention time at 15.637 minutes correspond to SEQ ID NO: 1.
• FIG. 9 depicts
• FIG. 10 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at 5 °C in PBS solution at pH of 7.4. The retention time at 15.585 minutes correspond to SEQ ID NO: 1.
• FIG. 11 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in PBS solution at pH of 7.4. The retention time at 15.593 minutes correspond to SEQ ID NO: 1.
• FIG. 12 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at -20 °C in PBS solution at pH of 7.4. The retention time at 15.596 minutes correspond to SEQ ID NO: 1.
• FIG. 11 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in PBS solution at pH of 7.4. The retention time at 15.593 minutes correspond to SEQ ID NO: 1.
• FIG. 12 depicts the HPLC chromatograph of
• FIG. 13 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at 5 °C in tromethamine buffer at pH of 7.4. The retention time at 15.689 minutes correspond to SEQ ID NO: 1.
• FIG. 14 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in tromethamine buffer at pH of 7.4. The retention time at 15.529 minutes correspond to SEQ ID NO: 1.
• FIG. 15 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at -20 °C in tromethamine buffer at pH of 7.4. The retention time at 15.555 minutes correspond to SEQ ID NO: 1.
• FIG. 14 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in tromethamine buffer at pH of 7.4. The retention time at 15.529 minutes correspond to SEQ ID NO: 1.
• FIG. 16 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at 5 °C in glycine buffer at pH of 7.4. The retention time at 15.564 minutes correspond to SEQ ID NO: 1.
• FIG. 17 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at room temperature in glycine buffer at pH of 7.4. The retention time at 15.559 minutes correspond to SEQ ID NO: 1.
• FIG. 18 depicts the HPLC chromatograph of 1.0 mg/mL SEQ ID NO: 1 at after 3 months stored at -20 °C in glycine buffer at pH of 7.4. The retention time at 15.549 minutes correspond to SEQ ID NO: 1.
• the lower pH peptide formulations showed higher stability, therefore a saline solution at pH 5.0 was better in comparison to the pH of 7.4 of any of the tested buffered formulations.
• Impurity growth observed at the tail of the SEQ ID NO: 1 peak starting at 1 month time point, may be temperature dependent. Ambient room temperature had higher values of impurities compared to 5 °C and -20 °C.
• the saline based formulations had the least overall total impurities of about 1.4% at 3 month ambient temperature condition, due to the lower pH of the formulation.
• the impurities data at 3 month reveals that the total impurities recorded for SEQ ID NO: 1 formulated in Tromethamine at -20 °C and 5 °C was approximately half the number of observed in both PBS and Glycine formulations at the 3 month time point and match the impurity levels observed in the saline formulations. There was no significant difference in impurities values (approximately 3.5%) for PBS, Tromethamine, and Glycine based formulations at the 3 month ambient room temperature conditions.
• the pH results during stability did not change and remained within target pH.
• the SEQ ID NO: 1 formulated in Tromethamine and Glycine resulted in drug product with low osmolality values (36 mOsmo/kg and 105 mOsm/kg) as compared to 290 mOsm/kg and 287 mOsm/kg for the saline and PBS based formulations respectively. This may have been due to the lack of osmotic agent (sodium chloride) for glycine and tromethamine formulations. All SEQ ID NO: 1 solutions were at all storage conditions met the acceptance criteria for visual appearance and particulate matter testing.
• the peptide formulation of SEQ ID NO: 1 dissolved in a saline solution with a pH of 5.0 ⁇ 0.1 was tested for stability under either -20 °C or 40 °C with 75% relative humidity (RH).
• the peptide formulations varied in concentrations (15.3 mg/mL, 36.7 mg/mL, 72.4 mg/mL, 81.4 mg/mL) and stored inverted in 2 mL amber glass vial containing 2 mL. Additionally, peptide formulation of 40.7 mg/mL stored in an amber glass vial at -20 °C was tested for stability over several months.
• Tables 23-28 show 6 peptide formulations that were stored at a pH of 7.4 ⁇ 0.2 for 197 days.
• the impurity at RRT 1.02 was initially hypothesized as the loss or cleavage of the Arg functional group (Des- Arg). Additional impurity peaks may arise from Des-Arg, deamidation (conversion of the C-terminal -CONH2 to -CO2H), or deamination (conversion of at least one Arg group into citrulline), or a combination at two or more processes.
• SEQ ID NO: 1 was dissolved to near saturation of different pH values.
• the formulations had a pH value of 5.0 ⁇ 0.1, 7.4 ⁇ 0.1, or 8.0 ⁇ 0.1.
• Table 29 HPLC Method Information Table 30. Solubility of near saturation for SEQ ID NO: 1 at pH 5.0, 7.4, and 8.1
• SEQ ID NO: 1 was dissolved in sterile water for injection resulting solutions at a concentration of 1 mg/mL and pH adjusting agents were added to achieve a pH value in the range of 4-7.
• the pH adjusting chosen were acetate and sodium hydroxide and citric acid (for pH 4).

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