Mar. 26, 2020  1  US 2020/0093894 Al  NOVEL FORMULATIONS  FIELD OF THE INVENTION  BACKGROUND OF THE INVENTION  [0012]  Further approaches to accelerating the absorption  and effect of insulin through the use of specific accelerating  additives have been described:  [0011]  WO2015/120457  (Wilson) describes  stabilized  ultra-rapid acting insulin formulations comprising insulin in  combination with a zinc chelator such as EDTA, a dissolu› tion/stabilization agent such as citric acid, a magnesium salt,  a zinc compound and optionally additional excipients.  [0010]  US2010/0227795 (Steiner) describes a composi› tion comprising insulin, a dissociating agent such as citric  acid or sodium citrate, and a zinc chelator such as EDTA  wherein the formulation has a physiological pH and is a  clear aqueous solution. The formulations are said to have  improved stability and rapid onset of action.  [0009]  WO2012/006283 (Pohl) describes formulations  containing insulin together with a zinc chelator such as  ethylenediaminetetraacetate (EDTA). Modulating the type  and quantity of EDTA is said to change the insulin absorp› tion profile. Calcium EDTA is the preferred form of EDTA  since it is said to be associated with reduced pain at the  injection site and is less likely to remove calcium from the  body. Preferred formulations also contain citrate which is  said to further enhance absorption and to improve the  chemical stability of the formulation.  [0004]  Insulin is a peptide hormone formed of two chains  (A chain and B chain, respectively 21 and 30 amino acids in  length) linked via disulfide bridges. Insulin normally exists  at neutral pH in the form of a hexamer, each hexamer  comprising three dimers bound together by zinc ions. His› tidine residues on the insulin are known to be involved in the  interaction with the zinc ions. Insulin is stored in the body  in the hexameric form but the monomer form is the active  form. Traditionally, therapeutic compositions of insulin have  also been formulated in hexameric form in the presence of  zinc ions. Typically, there are approximately three zinc  cations per one insulin hexamer.  It has been appreciated that  the hexameric form is absorbed from the injection site  considerably more slowly than the monomeric and dimeric  form. Therefore, a faster onset of insulin action can be  achieved if the hexameric form is destabilised allowing a  more rapid dissociation of the zinc-bound hexamer into  dimers and monomers in the subcutaneous space following  injection. Three insulin analogues have been genetically  engineered with this principle in mind. A first is insulin  lispro (Humalogfi) in which residues 28 and 29 of the B  chain (Pro and Lys respectively) are reversed, a second is  insulin aspart (NovoLogfi) in which residue 28 of the B  [0008]  US2008/0194461 (Maggio) describes formulations  of peptides and polypeptides including insulin which con› tain an alkylglycoside, which component is said to reduce  aggregation and immunogenicity.  [0003]  For patients requiring insulin replacement therapy,  a range of therapeutic options are possible. The use of  recombinant human insulin has in recent times been over› taken by use of insulin analogues which have modified  properties, for example, are longer acting or faster acting  than normal insulin. Thus, a common regimen for a patient  involves receiving a long acting basal insulin supplemented  by a rapid acting insulin around mealtimes.  [0007]  U.S. Pat. No. 7,205,276 (Boderke) addresses the  stability problems associated with preparing zinc free for› mulations of insulin and insulin derivatives and analogues  and describes an aqueous liquid formulation comprising at  least one insulin derivative, at least one surfactant, option› ally at least one preservative and optionally at least one of  an isotonicizing agent, a buffer and an excipient, wherein the  formulation is stable and free from or contains less than  0.4% (e.g. less than 0.2%) by weight of zinc based on the  insulin content of the formulation. The preferred surfactant  appears to be polysorbate 20 (polyoxyethylene (20) sorbitan  monolaurate ).  [0006]  U.S. Pat. No. 5,866,538 (Norup) describes insulin  preparations of superior chemical stability comprising  human insulin or an analogue or derivative thereof, glycerol  and/or mannitol and 5 to 100 mM of a halogenide (e.g.  NaCl).  [0002]  Diabetes mellitus ("diabetes") is a metabolic dis› order associated with poor control of blood sugar levels  leading to hypo or hyperglycemia. Untreated diabetes can  lead to serious microvascular and macrovascular complica› tions including coronary artery disease, peripheral artery  disease, stroke, diabetic nephropathy, neuropathy and retin› opathy. The two main types of diabetes are (i) Type 1  diabetes resulting from the pancreas not producing insulin  for which the usual treatment is insulin replacement therapy  and (ii) Type 2 diabetes where patients either produce  insufficient insulin or have insulin resistance and for which  treatments include insulin sensitising agents (such as met› formin or pioglitazone ), traditional insulin secretagogues  (such as sulfonylureas), SGLT2 inhibitors (such as dapagli› flozin, canagliflozin and empagliflozin) which reduce glu› cose absorption in the kidneys and so promote glucose  excretion, GLP-1 agonists (such as exenatide and dula› glutide) which stimulate insulin release from pancreatic beta  cells and DPPIV inhibitors (such as sitagliptin or vildaglip› tin) which inhibit breakdown ofGLP-1 leading to increased  insulin secretion. Patients with Type 2 diabetes may even› tually require insulin replacement therapy.  [0005]  Whilst the existing rapid acting insulin analogues  can achieve a more rapid onset of action, it has been  appreciated that an even more rapid acting ("ultra rapid  acting") insulins can be achieved by removing the zinc  cations from insulin altogether. Unfortunately, the conse› quence of the hexamer dissociation is typically a consider› able impairment in insulin stability both with respect to  physical stability ( e.g. stability to aggregation) and chemical  stability (e.g. stability to deamidation). For example, mono› meric insulin or insulin analogues having a rapid onset of  action are known to aggregate and become physically  unstable very rapidly because the formulation of insoluble  aggregates proceeds via monomers of insulin. Various  approaches to addressing this problem have been described  in the art:  chain, normally Pro, is replaced by Asp and a third is insulin  glulisine (Apidrafi) in which residue 3 of the B chain,  normally Asn, is replaced by Lys and residue 29 of the B  chain, normally Lys, is replaced by Glu.  [0001]  This invention relates inter alia to rapid acting  aqueous liquid formulations of insulin and insulin ana› logues. Such formulations are suitable for the treatment of  subjects suffering from diabetes mellitus, especially Type 1  diabetes mellitus. 