Stable peptide compositions

Abstract

This application generally relates to stable peptide compositions and kits comprising low levels of buffering and chelating agents, and methods of using the same.

What is claimed is: 
     
         1 . A liquid composition comprising:
 0.00001-0.1%, or 0.001-0.05% of a polypeptide, or a pharmaceutically acceptable salt thereof;   0.01-0.6% of a buffer;   no, or 0.0005-0.01% disodium EDTA;   no, or 0.01-0.1% tyloxapol,   and sodium chloride;   wherein the pH of the composition is between 6.2 to about 6.8 and the osmolality of the composition is between about 250 to 350 mOsm/kg.   
     
     
         2 . The composition of  claim 1 ,
 wherein the polypeptide is 0.01% or 0.005%, or a pharmaceutically acceptable salt thereof;   wherein the buffer is 0.25-0.31, or 0.2888%;   wherein the disodium EDTA is 0.001%;   wherein the tyloxapol is 0.05%,   wherein the pH of the composition is between 6.2 to about 6.8 and the osmolality of the composition is between about 250 to 350 mOsm/kg.   wherein the polypeptide is Lacripep having SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof.   
     
     
         3 . The composition of any of  claims 1 - 2 , wherein the buffer is a citrate buffer. 
     
     
         4 . The composition of  claim 3 , wherein the citrate buffer comprises 0.0098% anhydrous citric acid and 0.279% sodium citrate dihydrate. 
     
     
         5 . The composition of any of  claims 1 - 4 , wherein the pH of the composition is about 6.5. 
     
     
         6 . The composition of any of  claims 1 - 5 , wherein the osmolality of the composition is between 280 to 320 mOsm/kg. 
     
     
         7 . The composition of any of  claims 1 - 6 , wherein the osmolality of the composition is 300 mOsm/kg. 
     
     
         8 . The composition of any of  claims 1 - 7 , wherein the amount of NaCl is between 0.4% and 0.6%. 
     
     
         9 . The composition of any of  claims 1 - 8 , wherein the amount of NaCl is 0.5%. 
     
     
         10 . The composition of any of  claims 1 - 9 , wherein the composition further comprises 0.04% methylparaben. 
     
     
         11 . The composition of any of  claims 1 - 10 , wherein the composition is sterile. 
     
     
         12 . A kit, comprising a plurality of single-use containers, wherein each container comprises a vessel for holding the composition of any of  claims 1 - 11 . 
     
     
         13 . The kit of  claim 12 , wherein the container comprises between about 0.05 mL to about 1 mL of the composition. 
     
     
         14 . The kit of any of  claims 12 - 13 , wherein the container comprises a removable seal top for sealing the vessel, and a neck portion interconnecting the vessel and the seal top. 
     
     
         15 . The kit of  claim 14 , wherein the removable seal top cannot reseal the vessel once removed. 
     
     
         16 . The kit of any of  claims 12 - 15 , wherein the container comprises polyvinyl chloride, polypropylene, polyethylene terephthalate, polyethylene terephthalate, polyethylene terephthalate G, high-density polyethylene, low-density polyethylene, polybutylene terephthalate, polyurethane, polyethylene vinyl acetate, silicone, acrylonitrile butadiene styrene, polytetrafluoroethylene, polycarbonate, polystyrene, polymethylmethacrylate, polysulfone, polyvinylidene chloride, or combinations thereof. 
     
     
         17 . A method of administration comprising topically applying one or more drops of the composition of any of  claims 1 - 11  to the eye. 
     
     
         18 . The method of  claim 17 , wherein the administration further comprises topically applying a drop of the composition to the eye from the single-use container of any of  claims 12 - 16 . 
     
     
         19 . A use of the composition of any of  claims 1 - 11  for the treatment of dry eye. 
     
     
         20 . A use of the composition of any of  claims 1 - 11  for the treatment of one or more symptoms of Sjögren's Syndrome. 
     
     
         21 . A topical composition comprising:
 0.005-0.05% of a polypeptide, and one or more of the following:
 0.1-0.6% of a buffer; 
 0.0005-0.01% disodium EDTA; 
 0.01-0.1% tyloxapol, 
 and sodium chloride, 
   wherein the composition is a solution, gel or ointment.   
     
     
         22 . The composition of  claim 21 , wherein the polypeptide is provided in amount between 0.001 and 0.01%. 
     
     
         23 . The composition of  claim 21  or  22 , wherein the polypeptide is a tear glycoprotein or a fragment thereof. 
     
     
         24 . The composition of  claims 21 - 23 , wherein the polypeptide is any one of SEQ ID NOs 1-9. 
     
     
         25 . The composition of  claims 21 - 24 , wherein the polypeptide is Lacripep. 
     
     
         26 . The composition of  claims 21 - 25  for use in treating one or more symptoms of dry eye or Sjögren's Syndrome. 
     
     
         27 . A method of treating Dry Eye and/or Primary Sjögren's Syndrome comprising administering the composition of any of the preceding claims to the eye of a subject having Dry Eye and/or Primary Sjögren's Syndrome,
 wherein the polypeptide or pharmaceutically acceptable salt thereof is in an amount of 0.005%, or 0.01% 
 wherein the polypeptide has a sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH 2 , where “Ac” represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1) 
 and wherein one drop is administered to the eye of the subject up to three times daily. 
 
     
     
         28 . The method of  claim 27 , wherein the administration improves the FCS total score (NEI/Industry Workshop 0-15 scale) in the subject's eye after at least two weeks of treatment, or after at least four weeks of treatment, or after at least six weeks from the start of four weeks of treatment, compared to a baseline measure prior to starting treatment. 
     
     
         29 . The method of  claims 27 - 28  wherein the administration improves one or more of:
 eye dryness after at least two weeks of treatment, or after at least four weeks of treatment, compared to baseline on a visual analog scale; 
 SANDE (global scores SANDE 1) after at least two weeks of treatment compared to a baseline measure prior to starting treatment; 
 Mean Scores for SANDE (global scores SANDE-1) after at least two weeks of treatment compared to a baseline measure prior to starting treatment; 
 Individual Symptom Assessments (Instantaneous) after at least two weeks of treatment compared to a baseline measure prior to starting treatment; 
 Mean Scores for Individual Symptom Assessments (Reflective) after at least two weeks of treatment compared to a baseline measure prior to starting treatment; 
 LGCS in the subject's eye after at least two weeks of treatment compared to a baseline measure prior to starting treatment; 
 Anesthetized Schirmer test in the subject's eye after at least two weeks of treatment compared to a baseline measure prior to starting treatment; 
 TFBUT in the subject's eye after at least two weeks of treatment compared to a baseline measure prior to starting treatment; 
 FCS in the subject's eye after at least two weeks of treatment compared to a baseline measure prior to starting treatment; 
 SANDE (global scores for SANDE 1) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks treatment compared to a baseline measure prior to starting treatment; 
 Individual Symptoms (Instantaneous) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks treatment compared to a baseline measure prior to starting treatment; 
 Mean Scores for (global scores SANDE-2) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks treatment compared to a baseline measure prior to starting treatment; 
 Mean Scores for Individual Symptom Assessments (Reflective) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks treatment compared to a baseline measure prior to starting treatment; 
 FCS and SANDE 1 and Individual Symptom Assessments (Instantaneous) after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to a baseline measure prior to starting treatment; 
 LGCS after at least 2 weeks of treatment, or after at least 4 weeks of treatment compared to a baseline measure prior to starting treatment; 
 Anesthetized Schirmer test results after at least 2 weeks of treatment, or after at least 4 weeks of treatment, compared to a baseline measure prior to starting treatment; 
 TFBUT after at least 2 weeks of treatment, or after at least 4 weeks of treatment, or 1 week after 4 weeks treatment compared to a baseline measure prior to starting treatment. 
 
     
     
         30 . The method of any of  claims 27 - 29 , wherein administration of the composition to a group of subjects does not result in a rate of adverse events that is significantly higher compared to a rate of adverse events for administration of placebo to a similar group of subjects. 
     
     
         31 . The method of any of  claims 27 - 29 , wherein administration of the composition to a group of subjects does not result in a rate of adverse events that is statistically higher compared to a rate of adverse events for administration of placebo to a similar group of subjects. 
     
     
         32 . The method of any of any of  claims 27 - 29 , wherein administration of the composition to a group of subjects does not result in a rate of severe adverse events that is statistically higher compared to a rate of severe adverse events for administration of placebo to a similar group of subjects. 
     
     
         33 . The method of any of the preceding claims wherein the concentration of polypeptide or pharmaceutically acceptable salt thereof is about 0.005%. 
     
     
         34 . The method of any of the preceding claims wherein the concentration of polypeptide or pharmaceutically acceptable salt thereof is about 0.01%. 
     
     
         35 . The method of any of the preceding claims wherein the subject meets all the following criteria:
 age 18 years of age or older;   a documented prior history or current diagnosis of Primary Sjögren's Syndrome per the American-European Consensus Group Sjögren's Syndrome Criteria, having either 4 out of 6 total criteria or 3 out of 4 signs;   if the subject is on systemic (oral) therapy for the treatment of Sjögren's Syndrome, the subject must be on stable systemic treatment defined as the same treatment for the immediately prior 90 days;   a history of dry eye-related ocular symptoms, and who has self-reported use of over the counter ocular wetting agents within the last 120 days; and   meet all the following criteria at prior to beginning treatment:   a) Fluorescein corneal staining (FCS) total score ≥4 and <15 in the National Eye Institute (NEI)/Industry Workshop scale (where 0=no staining);   b) Symptom score of ≥40 using the SANDE questionnaire;   c) Anesthetized Schirmer test score ≤5 mm wetting/5 min;   d) Lissamine green conjunctival staining (LGCS) total score ≥5 using the NEI/Industry Workshop scale, (where 0=no staining);   wherein the Subject must meet all 4 criteria in at least one and the same eye at the time of the visit.   
     
     
         36 . The method of any of the preceding claims wherein the subject does not meet one or more of the following criteria:
 any active infectious ocular condition;   monocular or have a Best Corrected Visual Acuity (BCVA), using corrective lenses if necessary, of +1.0 logMAR or worse as assessed by Early Treatment Diabetic Retinopathy Study (ETDRS);   ocular inflammatory conditions (e.g., conjunctivitis, keratitis, anterior blepharitis, etc.) not related to dry eye syndrome;   clinical evidence of cicatricial ocular surface disease, such as cicatricial ocular pemphigoid or Stevens Johnson syndrome;   cannot suspend the use of any topical eye medications (including topical cyclosporine) during treatment with the composition;   has used Restasis® (topical ophthalmic cyclosporine) within 60 days prior to beginning treatment with the composition;   has used Xiidra® (topical ophthalmic lifitegrast) within 60 days prior to beginning treatment with the composition;   the subject's eye has fluorescein corneal staining (FCS) total score=15 or a score=3 in the superior region NEI/Industry Workshop scale or the subject's eye has FCS with diffuse confluent staining, filaments or frank epithelial defects;   has active or have had an outbreak of herpetic keratitis within 365 days of Beginning treatment or subjects who are on chronic oral antivirals for herpetic disease;   cannot suspend the use of and abstain from contact lens use during treatment;   has a history of collagen vascular disease, auto immune disease or rheumatic disease other than Primary Sjögren's Syndrome (e.g., Lupus, Rheumatoid Arthritis, etc.);   has a history of or current Anterior Membrane Dystrophy;   has had a corneal transplant or similar corneal surgery (DALK, DSEK, DMEK, etc.);   has used or anticipate use of amiodarone;   within 30 days prior to beginning treatment alter the dose or anticipate alterations to the dose of the following: tetracyclines, Omega 3 or Omega 6;   who within 60 days prior to beginning treatment and/or for the duration of treatment, altered the dose or anticipate alterations to the dose of the following:   anticholinergics, antidepressants, oral contraceptives, isotretinoin, oral systemic corticosteroids, oral systemic immunosuppressive agents,   within 30 days prior to beginning treatment and/or for the duration of the study have used topical ocular antihistamines, ocular, inhaled or intranasal corticosteroids, topical or oral mast cell stabilizers, oral antihistamines, topical or nasal vasoconstrictors, topical ocular NSAIDs, topical ocular antibiotics;   in the subject's eye and within the past 90 days have had cauterization of the punctum or alterations to (insertion or removal) punctal plug(s) before beginning treatment;   in the subject's eye, have had corneal refractive surgery (LASIK, PRK, RK);   a history of any operative procedure on the ocular surface or eyelids within 365 days prior to beginning treatment with a history of intraocular surgery within 90 days prior to beginning treatment;   is pregnant or suspected to be pregnant;   is breastfeeding or intend to breastfeed; and   has participated in a device or investigational drug study or clinical trial within 30 days of beginning treatment.   
     
     
         37 . The composition, kit or method of any of the preceding claims, wherein the polypeptide has a sequence consisting of Ac-Lys-Gln-Phe-Ile-Glu-Asn-Gly-Ser-Glu-Phe-Ala-Gln-Lys-Leu-Leu-Lys-Lys-Phe-Ser-NH 2 , where “Ac” represents an acetyl group and the C-terminus is amidated (SEQ ID NO: 1). 
     
     
         38 . The composition, kit or method of any of the preceding claims, wherein the amount of polypeptide of pharmaceutically acceptable salt thereof is 0.01% or 0.005%. 
     
     
         39 . The composition, kit or method of any of the preceding claims, wherein the comparison to a baseline measure prior to starting treatment instead or further comprises a comparison of treatment with said polypeptide relative a vehicle control. 
     
     
         40 . The composition, kit or method of any of the preceding claims, wherein the composition comprises:
 0.001-0.05% of a polypeptide, or a pharmaceutically acceptable salt thereof;   0.01-0.6% of a buffer;   0.0005-0.01% disodium EDTA;   0.01-0.1% tyloxapol,   and sodium chloride;   wherein the pH of the composition is between 6.2 to about 6.8 and the osmolality of the composition is between about 250 to 350 mOsm/kg.   
     
     
         41 . The composition, kit or method of  claim 40 ,
 wherein the polypeptide is 0.01%, or a pharmaceutically acceptable salt thereof;   wherein the buffer is 0.2888%;   wherein the disodium EDTA is 0.001%;   wherein the tyloxapol is 0.05%,   wherein the pH of the composition is between 6.2 to about 6.8 and the osmolality of the composition is between about 250 to 350 mOsm/kg.   wherein the polypeptide is Lacripep having SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof.   
     
     
         42 . The composition, kit or method of any of the preceding claims, wherein the composition contains no tyloxapol. 
     
     
         43 . The composition, kit or method of any of the preceding claims, wherein the composition contains no EDTA. 
     
     
         44 . The composition, kit or method of any of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in undegraded form in said composition after storage of said composition for 1 week at 5±3° C. or 25±2° C. and 25±5% relative humidity. 
     
     
         45 . The composition, kit or method of any of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in undegraded form in said composition after storage of said composition for 2 weeks at 25±2° C. and 25±5% relative humidity. 
     
     
         46 . The composition, kit or method of any of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in undegraded form in said composition after storage of said composition for 1 month at 5±3° C. or 25±2° C. and 25±5% relative humidity. 
     
     
         47 . The composition, kit or method of any of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in undegraded form in said composition after storage of said composition for 2 months at 5±3° C. 
     
     
         48 . The composition, kit or method of any of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in undegraded form in said composition after storage of said composition for 3 months at 5±3° C. or −20±5° C. 
     
     
         49 . The composition, kit or method of any of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in undegraded form in said composition after storage of said composition for 4 months at 5±3° C. 
     
     
         50 . The composition, kit or method of any of the preceding claims, wherein the composition maintains at least about 99.0% of the polypeptide in undegraded form in said composition after storage of said composition for 5 months at 5±3° C. 
     
     
         51 . The composition, kit or method of any of  claims 44 - 50 , wherein the composition maintains at least about 99.5% of the polypeptide in undegraded form in said composition. 
     
     
         52 . The composition, kit or method of any of  claims 44 - 50 , wherein the composition maintains at least about 99.9% of the polypeptide in undegraded form in said composition. 
     
     
         53 . The composition, kit or method of any of  claims 44 - 50 , wherein the composition maintains at least about 99.95% of the polypeptide in undegraded form in said composition. 
     
     
         54 . The composition, kit or method of any of the preceding claims, wherein the composition maintains at least about 80% of the polypeptide in undegraded form in said composition after storage of said composition for 12 months at 5±3° C. 
     
     
         55 . The composition, kit or method of  claim 54 , wherein the composition maintains at least about 90% of the polypeptide in undegraded form in said composition