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 . The pharmaceutical composition of  claim 1  or  2 , wherein the composition is an aqueous formulation. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the composition is formulated for subcutaneous or intra-dermal administration. 
     
     
         5 . The pharmaceutical composition of any one of  claims 1  to  4 , wherein the composition comprises less than 0.05 moles of zinc per mole of insulin. 
     
     
         6 . The pharmaceutical composition of any one of  claims 1  to  5 , 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 . The pharmaceutical composition of any one of  claims 1  to  5 , wherein the calcium ion-chelating or charge masking agent(s) comprise an anionic polysaccharide. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the calcium ion-chelating or charge-masking agent(s) comprise alginic acid. 
     
     
         10 . The pharmaceutical composition of any one of  claims 1  to  5 , wherein the calcium ion-chelating or charge-masking agent(s) comprise one or more organosulfur compounds. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the calcium ion-chelating agent or charge-masking agents comprises one or more of alpha lipoic acid, dimercaptosuccinic acid (DMSA), dimercaprol, and dimercaptopropane sulfonate (DMPS). 
     
     
         12 . The pharmaceutical composition of any one of  claims 1  to  5 , 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 . The pharmaceutical composition of any one of  claims 1  to  5 , wherein the calcium ion-chelating agent(s) comprise one or more of penicillamine, and extract or partial extract of chlorella and/or cilantro. 
     
     
         15 . The pharmaceutical composition of any one of  claims 1  to  5  wherein the charge-masking agent is a benzoate salt. 
     
     
         16 . The pharmaceutical composition of any one of  claims 1  to  15 , 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 . The pharmaceutical composition of  claim 18 , wherein the composition provides a duration of insulin activity of from 1 to 2 hours. 
     
     
         20 . The pharmaceutical composition of any one of  claims 1  to  19 , wherein the monomeric insulin analogue is formulated at about U10 to about U500. 
     
     
         21 . The pharmaceutical composition of any one of  claims 1  to  20 , wherein the composition is stable for at least about one month at 25° C. without substantial formation of insulin fibrils. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the composition maintains at least about 90% potency after six months at 25° C. 
     
     
         23 . The pharmaceutical composition of  claim 21 , wherein the monomeric insulin analogue has one or more mutations that reduce or eliminate fibril formation. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein said one or more mutations comprise a mutation at B24, B25, or B26. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the monomeric insulin analogue contains a halogenated phenylalanine at a position corresponding to B24, B25, or B26 of native human insulin, wherein the halogenated phenylalanine is optionally 2-fluoro, 4-chloro, 2-chloro, or 2-bromo. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein the monomeric insulin has 2-fluorophenylalanine at position B24. 
     
     
         27 . The pharmaceutical composition of  claim 24 , wherein the amino acid at position B24 of the monomeric insulin has a non-planar aliphatic ring as a side chain, and wherein the amino acid at position B24 is optionally cyclohexanylalanine (Cha). 
     
     
         28 . The pharmaceutical composition of  claim 23 , 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 . The pharmaceutical composition of  claim 28 , wherein the monomeric insulin analogue has a lysine at the position corresponding to Pro B28  and a proline at the amino acid corresponding to Lys B29 . 
     
     
         30 . The pharmaceutical composition of  claim 28 , wherein the monomeric insulin analogue has an aspartic acid at the position corresponding to Pro B28 . 
     
     
         31 . The pharmaceutical composition of  claim 28 , wherein the monomeric insulin analogue has a lysine at the position corresponding to Asn B3 , and glutamic acid at the position corresponding to Lys B29 . 
     
     
         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, Gin, 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 . The pharmaceutical composition of  claim 33 , wherein the monomeric insulin analogue has an ornithine or Glu at position B29. 
     
     
         35 . The pharmaceutical composition of  claim 21 , wherein the monomeric insulin analogue has a B chain with the amino acid sequence KPIEE, EPIEE, POTEE, or POTO at the C-terminal segment respectively comprising residues B28-B32, B28-32, B28-B32, and B28-B31, in which residues B31-B32 C-terminal extensions of the B chain. 
     
     
         36 . The pharmaceutical composition of any one of  claims 1  to  35 , wherein the monomeric insulin analogue is a single chain insulin having a peptide linker between the A and B chains. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the peptide linker is between 4 and 10 amino acids, optionally comprising the sequence GPRR. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the peptide linker has the sequence: GGGPRR, GGPRR, GSEQRR, RREQKR, RREALQKR, GAGPRR, or GGGPGKR, EEGSRRSR, EEGPRR, GEGPRR, AEGSRRSR, ASGSRRSR, EEGSRRD, or EEGSRRK. 
     
     
         39 . The pharmaceutical composition of any one of  claims 1  to  38 , 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 . The pharmaceutical composition of  claim 39 , wherein the composition comprises a peptide agent that opens tight junctions. 
     
     
         43 . The pharmaceutical composition of any one of  claims 1  to  42 , wherein the composition is provided within an insulin infusion set. 
     
     
         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 . The infusion set of  claim 44 , wherein the transducer, tactor, and/or electrophoresis electrode increases the rate at which a pharmaceutical formulation is absorbed into the circulation from a subcutaneous depot. 
     
     
         46 . The infusion set of  claim 45 , wherein the pharmaceutical formulation is an insulin formulation, and which is optionally a rapid-acting insulin formulation. 
     
     
         47 . The infusion set of  claim 46 , wherein the insulin formulation is a substantially zinc-free formulation of a stable monomeric insulin analogue or dimeric insulin analogue. 
     
     
         48 . The infusion set of  claim 46 , wherein the formulation is a pharmaceutical composition of any one of  claims 1  to  43 . 
     
     
         49 . The infusion set of  claim 48 , wherein the infusion catheter projects about 1 mm to about 10 mm into the subcutis, and optionally about 7 mm into the subcutis. 
     
     
         50 . The infusion set of  claim 49 , further comprising a supply tube or port to which a supply tube can be connected, where a pharmaceutical composition reservoir can be connected and disconnected to the supply tube. 
     
     
         51 . The infusion set of  claim 50 , further comprising a pump and controller operably connected to the reservoir delivering a pharmaceutical composition through the supply tube to the catheter. 
     
     
         52 . The infusion set of  claim 51 , wherein the controller comprises a microprocessor, a control algorithm, and an interface display, which are optionally contained in the first body. 
     
     
         53 . The infusion set of  claim 52 , further comprising one or more external user controls and/or a communication interface, which are optionally contained in the first body. 
     
     
         54 . The infusion set of  claim 51 , wherein the reservoir is comprised in a second body that can be detached from the first body. 
     
     
         55 . The infusion set of  claim 54 , wherein the adhesive surface is on the second body, and the second body comprises the infusion catheter. 
     
     
         56 . The infusion set of any one of  claims 44  to  55 , comprising a low intensity ultrasound (LITUS) transducer or low-frequency piezoelectric tactor. 
     
     
         57 . The infusion set of  claim 56 , wherein the LITUS transducer or tactor is contained within the first body, and is optionally positioned above the distal end of the infusion catheter. 
     
     
         58 . The infusion set of  claim 56 , wherein the ultrasound transducer or tactor is powered by a battery that powers a pump, and is optionally driven by a signal generator in the pump. 
     
     
         59 . The infusion set of  claim 56 , wherein the ultrasound transducer emits a signal within the range of about 0.2 MHz to about 3 MHz, and optionally in the range of about 0.5 MHz to 2.5 MHz, and optionally in the range of about 1 to 2 MHz, and optionally about 1.0, 1.5, or 2.0 MHz. 
     
     
         60 . The infusion set of  claim 56 , wherein the piezoelectric tactor has a frequency of less than about 1 kHz. 
     
     
         61 . The insulin infusion set of  claim 56 , wherein the signal is continuous or pulsed. 
     
     
         62 . The infusion set of  claim 59 , wherein the adhesive surface is ultrasonically transmissive. 
     
     
         63 . The infusion set of any one of  claims 44  to  55 , comprising a first electrophoresis electrode proximal to the distal end of the infusion catheter. 
     
     
         64 . The infusion set of  claim 63 , wherein the adhesive surface is electrically conductive. 
     
     
         65 . The infusion set of  claim 63 , further comprising a second electrophoresis electrode on the skin surface, which is optionally attached to the adhesive surface. 
     
     
         66 . The infusion set of  claim 65 , wherein the second electrode has a coating increasing electrical conductivity to the skin, and which is optionally an electrochemical gel or adhesive. 
     
     
         67 . The infusion set of  claim 65 , wherein the second electrode is positioned above the distal end of the infusion catheter. 
     
     
         68 . The infusion set of  claim 65 , wherein the first and second electrophoresis electrodes are connected to opposite ends of a voltage source. 
     
     
         69 . The infusion set of  claim 68 , wherein the voltage is a constant voltage, and the voltage is optionally in the range of 1 volt to about 15 volts, and is optionally in the range of 1 volt to about 10 volts. 
     
     
         70 . The infusion set of  claim 68 , wherein the first electrophoresis electrode is the cathode and the second electrophoresis electrode is the anode. 
     
     
         71 . The infusion set of  claim 70 , wherein the electrodes are connected by an electrical conductor to an interface plug, wherein the plug can be connected and disconnected to the voltage source. 
     
     
         72 . The infusion set of  claim 70 , wherein the electrophoresis electrodes comprise a conductive coating. 
     
     
         73 . The infusion set of  claim 72 , wherein the conductive coating comprises a material with anti-microbial characteristics. 
     
     
         74 . The infusion set of  claim 73 , wherein the anti-microbial material comprises a silver-containing compound. 
     
     
         75 . The infusion set of any one of  claims 44  to  74 , further comprising a reservoir of a pharmaceutical formulation. 
     
     
         76 . An infusion set system, comprising the insulin infusion set of any one of  claims 44  to  75 , and a catheter insertion device. 
     
     
         77 . A method for treating a subject with diabetes mellitus, comprising: administering the pharmaceutical composition of any one of  claims 1  to  43  to said subject. 
     
     
         78 . The method of  claim 77 , wherein the patient has type 1 diabetes or type 2 diabetes, and where the patient optionally suffers from obesity or metabolic disease. 
     
     
         79 . The method of  claim 77 , wherein the patient has prediabetes. 
     
     
         80 . The method of any one of  claims 77  to  79 , wherein the composition is administered less than about 20 minutes before a meal. 
     
     
         81 . The method of any one of  claims 77  to  79 , wherein the composition is administered within 10 to 20 minutes of commencing a meal. 
     
     
         82 . The method of  claim 80  or  81 , wherein the composition is administered three times daily in connection with meals. 
     
     
         83 . The method of any one of  claims 77  to  79 , wherein the composition is administered upon symptoms of hyperglycemia. 
     
     
         84 . The method of any one of  claims 77  to  83 , wherein the patient is undergoing a regimen of basal insulin formulation or basal insulin analogue formulation. 
     
     
         85 . The method of any one of  claims 77  to  84 , wherein the composition is administered as a single-bolus subcutaneous injection or infusion. 
     
     
         86 . The method of  claim 85 , wherein the composition is administered by an infusion set of any one of  claims 43  to  76 . 
     
     
         87 . The method of  claim 86 , wherein the composition is automatically administered upon a detection of low blood glucose by the insulin infusion system. 
     
     
         88 . The method of  claim 86 , wherein the composition is administered in an injectate volume of less than about 0.1 ml. 
     
     
         89 . The method of  claim 86 , wherein one or more of low intensity ultrasound (LITUS), mechanical massage, and electrophoresis is initiated at the injection site, to thereby increase the speed of insulin uptake into the circulation. 
     
     
         90 . The method of  claim 89 , wherein the ultrasound, mechanical massage, and/or electrophoresis operates for at least 10 minutes before and/or after the injection. 
     
     
         91 . The method of  claim 89 , wherein the ultrasound, mechanical massage, and/or electrophoresis operates for at least 30 minutes before and/or after the injection, or at least one hour before and/or after the injection. 
     
     
         92 . The method of  claim 86 , wherein the ultrasound, mechanical massage, and/or electrophoresis is turned off manually by the subject, or operates for a predetermined amount of time, or operates for an amount of time determined by an algorithm. 
     
     
         93 . The method of  claim 87 , wherein the patient receives the composition as controlled by an artificial pancreas system. 
     
     
         94 . A method for treating a subject with diabetes, comprising: administering a rapid acting insulin formulation to said subject, using the insulin infusion set of any one of  claims 44  to  76 . 
     
     
         95 . The method of  claim 94 , wherein the patient has type 1 diabetes mellitus or type 2 diabetes mellitus, and where the patient optionally suffers from obesity or metabolic disease. 
     
     
         96 . The method of  claim 94 , wherein the patient has prediabetes. 
     
     
         97 . The method of any one of  claims 94  to  96 , wherein the rapid acting insulin is administered less than about 20 minutes before a meal. 
     
     
         98 . The method of any one of  claims 94  to  96 , wherein the rapid acting insulin composition is administered within 10 to 20 minutes of commencing a meal. 
     
     
         99 . The method of  claim 97  to  98 , wherein the rapid-acting insulin composition or rapid-acting insulin analogue composition is administered three times daily in connection with meals. 
     
     
         100 . The method of any one of  claims 94  to  96 , wherein the rapid-acting insulin composition or rapid-acting insulin analogue composition is administered upon symptoms of hyperglycemia. 
     
     
         101 . The method of any one of  claims 94  to  100 , wherein the patient is undergoing a regimen of basal insulin formulation or basal insulin analogue formulation. 
     
     
         102 . The method of  claim 101 , wherein the basal insulin formulation or basal insulin analogue formulation is administered from one to three times daily, or is administered by continuous infusion. 
     
     
         103 . The method of any one of  claims 94  to  102 , wherein the rapid-acting insulin composition or rapid-acting insulin analogue formulation is administered as a single bolus subcutaneous injection. 
     
     
         104 . The method of  claim 102 , wherein the rapid-acting insulin formulation or rapid-acting insulin analogue formulation is automatically administered upon a detection of low blood glucose by the insulin infusion system. 
     
     
         105 . The method of any one of  claims 94  to  104 , wherein ultrasound, mechanical massage, and/or electrophoresis operates for at least about 10 minutes before and/or after injection of the rapid-acting insulin formulation or rapid-acting insulin analogue formulation. 
     
     
         106 . The method of  claim 105 , wherein ultrasound, mechanical massage, and/or electrophoresis operates for at least about 30 minutes before and/or after injection of the rapid-acting insulin formulation or rapid-acting insulin analogue formulation, or at least one hour before and/or after the injection of the rapid acting insulin or analogue. 
     
     
         107 . The method of  claim 105  or  106 , wherein the ultrasound, mechanical massage, and/or electrophoresis is turned off manually by the subject, or operates for a predetermined amount of time, or operates for an amount of time determined by an algorithm. 
     
     
         109 . The method of any one of  claims 94  to  107 , wherein the patient receives the rapid acting insulin composition and a basal insulin composition, as controlled by an artificial pancreas system.