Rapid action insulin formulations and pharmaceutical delivery systems

Abstract

The present invention provides rapid-acting insulin and insulin analogue formulations. The invention further provides delivery devices, particularly infusion sets, which allow for the rapid absorption of insulin and insulin analogues, as well as other active agents. Methods of using the insulin and insulin analogue formulations as well as the insulin delivery devices for treating subjects with diabetes mellitus are also provided.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising an effective amount of a monomeric insulin analogue or dimeric insulin analogue and one or more calcium ion-chelating agents. 
     
     
         2 . A pharmaceutical composition comprising an effective amount of a monomeric insulin analogue or dimeric insulin analogue and an effective amount of one or more charge-masking agents sufficient to mask charges in subcutaneous tissue. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the composition comprises less than 0.05 moles of zinc per mole of insulin. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the calcium ion-chelating agent or charge-masking agent(s) comprise one or more amino polycarboxylic acid compounds. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the calcium ion-chelating or charge-masking agent(s) comprise one or more of ethylenediamine tetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), and cyclohexane diamino tetraacetic acid (CDTA), and wherein the agent is optionally a sodium or magnesium salt. 
     
     
         8 - 11 . (canceled) 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the calcium ion-chelating or charge-masking agent(s) comprise one or more di- or tri-carboxylic acids. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the calcium ion-chelating or charge-masking agent(s) comprise citric acid or oxalic acid. 
     
     
         14 . (canceled) 
     
     
         15 . The pharmaceutical composition of  claim 1  wherein the charge-masking agent is a benzoate salt. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the composition provides an onset of insulin activity of less than about 40 minutes after subcutaneous administration. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the composition reaches T max  at less than about 120 minutes after administration. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the composition provides a duration of insulin activity of about 5 hours or less. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the composition is stable for at least about one month at 25° C. without substantial formation of insulin fibrils. 
     
     
         22 - 27 . (canceled) 
     
     
         28 . The pharmaceutical composition of  claim 1 , wherein the monomeric insulin analogue comprises one or more mutations at positions corresponding to the following positions of native human insulin: B2, B3, B4, B10, B13, B17, B28, B29, A8, A10, A12, A13, A14, A17, and A21, and is optionally a single chain insulin. 
     
     
         29 - 31 . (canceled) 
     
     
         32 . The pharmaceutical composition of  claim 28 , wherein the monomeric insulin analogue contains one or more of:
 Leu at the position corresponding to A3;   Glu, His, Gln at the position corresponding to A8;   Cys at the position corresponding to A10;   Asp or Thr at the position corresponding to A12;   Trp, Tyr, His, Glu, Ala, or Phe at the position corresponding to A13;   His or Glu at the position corresponding to A14;   Trp, Tyr, Ala, His, Glu, Gln, Phe, or Apn, at the position corresponding to A17   Gly at the position corresponding to A21;   Cys at the position corresponding to B2;   Lys at the position corresponding to B3;   Cys at the position corresponding to B4;   Asp at the position corresponding to B10;   Trp, Tyr, Ala, His, Glu, Phe, Apn, or Gln at the position corresponding to B13;   Trp, Tyr, His, or Gln at the position corresponding to B17;   Trp, Tyr, His, Gln, Asp, Thr, Ala, Phe, or Cha at the position corresponding to B24; and   Glu at the position corresponding to B29.   
     
     
         33 . The Pharmaceutical composition of  claim 21 , wherein the monomeric insulin analogue has a deletion of amino acids B1-B3. 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . The pharmaceutical composition of  claim 1 , wherein the monomeric insulin analogue is a single chain insulin having a peptide linker between the A and B chains. 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . The pharmaceutical composition of  claim 1 , wherein the composition comprises one or more pharmaceutically acceptable excipients. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more of a pharmaceutically acceptable buffer, stabilizing agent(s), surfactant(s), solubilizing agent, anti-aggregation agent, diffusion-enhancing agent, absorption enhancing agent, and preservative(s). 
     
     
         41 . The pharmaceutical composition of  claim 39 , wherein the composition comprises one or more anti-inflammatory agents and/or one or more anti-fibrotic agents. 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . An infusion set comprising a first body, an adhesive surface, a subcutaneous infusion catheter, and one or more of an ultrasound transducer, a tactor, and an electrophoresis electrode. 
     
     
         45 - 76 . (canceled) 
     
     
         77 . A method for treating a subject with diabetes mellitus, comprising: administering the pharmaceutical composition of  claim 1  to said subject. 
     
     
         78 - 109 . (canceled)