Abstract: The present invention relates to insulin degludec for use in medicine.

Abstract: The invention relates to a novel reconstitution composition, a pharmaceutical composition and kit of parts comprising said reconstitution composition. The invention further relates to a method of treatment using said pharmaceutical composition and/or the pharmaceutical composition for use as a medicament. Also provided is a method for reconstituting dried peptides and a method for preparing a pharmaceutical composition using the reconstitution composition of the invention.

Abstract: The present invention relates to insulin degludec for use in medicine.

Abstract: The invention is related to insulin compositions with a high content of zinc atoms per six molecules of acylated insulin. The insulin is an acylated insulin and may be mixed with a further insulin analogue such as the rapid acting insulin Asp B28 human insulin.

Abstract: Isolated non-naturally occurring, mutant-human islet amyloid polypeptides (IAPP) polypeptides, which are more soluble at neutral pH than the wild-type human islet amyloid polypeptide (hIAPP) protein are disclosed. These polypeptides can be formulated or co-formulated at physiological pH, which enable the polypeptides to be delivered to a subject in a single injection with an insulin agent. Methods and pharmacological compositions for treating an abnormal condition, such as an amyloid-based disease or type-1 diabetes in a subject are also disclosed.

Abstract: Provided is an acylated derivative of human insulin or an analogue thereof. Specifically disclosed is an acylated derivative of a human insulin analogue, or zinc complex thereof; the human insulin analogue being derivatized is preferably Des(B30) human insulin; the acylated derivative is longer-lasting than existing insulin analogues and acylated derivatives thereof, its blood glucose reduction is more steady, and it is more stable in storage.

Abstract: Disclosed herein are improved methods of treating hyperglycemia with a combination of an ultrarapid acting insulin and insulin glargine comprising prandial administration of the ultrarapid insulin, and administration of a first dose of insulin glargine within 6 hours of waking for a day.

Abstract: A two-chain insulin analogue contains Aspartic Acid at position B10 and penta-fluoro-Phenylalanine at position B24, optionally Histidine or Glutamic Acid at position A8, optionally additional substitutions or modifications at positions A13 and/or A14 and/or B28 and/or B29. The analogue may be an analogue of a mammalian insulin, such as human insulin, may optionally include (i) N-terminal deletion of one, two or three residues from the B chain, (ii) a mono-peptide or dipeptide C-terminal extension of the B-chain containing at least one acidic residue, and (iii) other modifications known in the art to enhance the stability of insulin. Formulations of the above analogues at successive strengths U-100 to U-1000 in soluble solutions at at least pH value in the range 7.0-8.0 in the absence or presence of zinc ions at a molar ratio of 0.00-0.10 zinc ions per insulin analogue monomer.

Abstract: Isolated non-naturally occurring, mutant-human islet amyloid polypeptides (hIAPP) are disclosed. These polypeptides can be formulated or co-formulated at physiological pH, which enable the polypeptides of the instant disclosure to be delivered to a subject having an amyloid-based disease in a single injection with an insulin agent. Methods and compositions for treating amyloid-based disease in a subject in need thereof, by administering an effective amount of an isolated, mutant-hIAPP polypeptide, including formulations or co-formulations thereof are also disclosed.

Abstract: A composition in aqueous solution includes insulin and at least one substituted anionic compound chosen from substituted anionic compounds consisting of a backbone formed from a discrete number u of between 1 and 8 (1?u?8) of identical or different saccharide units, linked via identical or different glycoside bonds, the saccharide units being chosen from the group consisting of hexoses, in cyclic form or in open reduced form, said compound comprising partially substituted carboxyl functional groups, the unsubstituted carboxyl functional groups being salifiable. A pharmaceutical formulation including the composition is also set forth.

Abstract: Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives are disclosed.

Abstract: A two-chain insulin analog contains Aspartic Acid at position B10 and penta-fluoro-Phenylalanine at position B24, optionally Histidine or Glutamic Acid at position A8, optionally additional substitutions or modifications at positions A13 and/or A14 and/or B28 and/or B29. The analog may be an analog of a mammalian insulin, such as human insulin, may optionally include (i) N-terminal deletion of one, two or three residues from the B chain, (ii) a mono-peptide or dipeptide C-terminal extension of the B-chain containing at least one acidic residue, and (iii) other modifications known in the art to enhance the stability of insulin. Formulations of the above analogs at successive strengths U-100 to U-1000 in soluble solutions at least pH value in the range 7.0-8.0 in the absence or presence of zinc ions at a molar ratio of 0.00-0.10 zinc ions per insulin analog monomer.

Abstract: The invention is a pharmaceutical composition of human insulin or insulin analog that includes citrate, treprostinil and stabilizing agents, that has faster pharmacokinetic and/or pharmacodynamic action than commercial formulations of existing insulin analog products and that is stable for commercial use.

Abstract: Stabilized pharmaceutical formulations of insulin analogs and/or insulin derivatives are disclosed.

Abstract: Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives are disclosed.

Abstract: A single-chain insulin analog containing a basic side chain at position A8 (Arginine, Histidine, Lysine, or Ornithine), a basic side chain at position B29 (Arginine, Histidine, Lysine, or Ornithine), and a foreshortened C-domain of length 6-11 residues is provided. Residues C1 and C2 of the C-domain have a net negative charge of ?1 or ?2; C3 is chosen from a group consisting of Gly, Ala, Pro, or Ser; and the remaining C-domain segment is successively derived from the C-domain of IGF-II (RRSR (SEQ ID NO: 18), SRRSR (SEQ ID NO: 17), VSRRSR (SEQ ID NO: 16), RVSRRSR (SEQ ID NO: 15), or SRVSRRSR SEQ ID NO: 13). A method of treating a patient with diabetes mellitus or obesity comprises administering a physiologically effective amount of the insulin analog or a physiologically acceptable salt thereof to a patient.

Abstract: A combination comprising at least a first insulin-like compound and a second insulin-like compound for treating a condition or a disease in a subject in need thereof where administration of insulin would be of benefit to said subject is described.

Abstract: An aqueous pharmaceutical formulation comprising 200-1000 U/mL of insulin glulisine.

Abstract: The present invention relates to novel insulin analogues exhibiting resistance towards protease, wherein at least two amino acids are substituted and/or deleted relative to the parent insulin molecule. A method for the preparation of such insulin analogues, insulin preparations containing the insulin analogues of the invention and a method of treating diabetes mellitus using these insulin analogues is also provided.

Abstract: The present invention relates to an improved method for treating diabetes wherein the improvement comprises administering a PEGylated insulin compound to a patient having moderate to severe chronic kidney disease using an effective amount of the compound.

Abstract: This invention relates to insulin derivatives having long duration of action. The insulin derivatives have been found to be useful for the treatment of diabetes, and in particular for less frequent administration to the diabetic patients, in particular as seldom as about once weekly.

Abstract: A method treating a patient includes administering a physiologically effective amount of a fibrillation-resistant insulin analogue or a physiologically acceptable salt thereof to the patient. The fibrillation-resistant insulin analogue or a physiologically acceptable salt thereof, contains an insulin A-chain sequence modified at position A8 and an insulin B-chain sequence or an analogue thereof. The fibrillation-resistant insulin analogue may exhibit thermodynamic stability similar to or exceeding that of wild-type human insulin and displays a susceptibility to fibrillation similar to or exceeding that of wild-type human insulin. An insulin analogue may display greater in vitro insulin receptor binding than normal insulin while displaying binding to IGFR less than twice that of normal insulin and less than that of fast-acting insulin analogs.

Abstract: Novel PEGylated insulin analogs exhibiting resistance towards proteases can, effectively, be administered pulmonary or orally. The insulin analogs contain B25H and A14E or A14H. The PEGylation is at B29K.

Abstract: A rapid acting injectable formulation is provided comprising a therapeutic peptide and a vasodilatory agent. The therapeutic peptide has a molecular weight of greater than about 500 Daltons, and the vasodilatory agent is present in an amount effective to increase the absorption of the therapeutic peptide. A method of increasing absorption of a therapeutic peptide by using such a formulation is also provided.

Abstract: Modified insulin polypeptides and their uses thereof are provided.

Abstract: Prodrug formulations of insulin and insulin analogs are provided wherein the insulin peptide has been modified by an amide bond linkage of a dipeptide prodrug element. The prodrugs disclosed herein have extended half lives of at least 10 hours, and more typically greater than 2 hours, 20 hours and less than 70 hours, and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Abstract: Single chain insulin analogs are provided having high potency and specificity for the insulin receptor. As disclosed herein optimally sized linking moieties can be used to link human insulin A and B chains, or analogs or derivatives thereof, wherein the carboxy terminus of the B25 amino acid of the B chain is linked to the amino terminus of the A1 amino acid of the A chain via the intervening linking moiety. In on embodiment the linking moiety comprises a polyethylene glycol of 6-16 monomer units and in an alternative embodiment the linking moiety comprises a non-native amino acid sequence derived form the IGF-1 C-peptide and comprising at least 8 amino acids and no more than 12 amino acid in length. Also disclosed are prodrug and conjugate derivatives of the single chain insulin analogs.

Abstract: An insulin analogue comprises a B-chain polypeptide incorporating a halogenated phenylalanine at position B24, B25 or B26. The halogenated phenylalanine may be ortho-monofluoro-phenylalanine, ortho-monobromo-phenylalanine, ortho-monochloro-phenylalanine, or para-monochloro-phenylalanine. The analogue may be of a mammalian insulin, such as human insulin. A nucleic acid encodes such an insulin analogue. The halogenated insulin analogues retain significant activity. A method of treating a patient comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient. Halogen substitution-based stabilization of insulin may enhance the treatment of diabetes mellitus in regions of the developing world lacking refrigeration.

Abstract: Provided are methods relating to the use of CDP-therapeutic agent conjugates for the treatment of a disease or disorder, e.g., autoimmune disease, inflammatory disease, central nervous system disorder, cardiovascular disease, or metabolic disorder. Also provided are CDP-therapeutic agent conjugates, particles comprising CDP-therapeutic agent conjugates, and compositions comprising CDP-therapeutic agent conjugates.

Abstract: An insulin analogue comprises a B-chain polypeptide incorporating a halogenated phenylalanine at position B24, B25 or B26. The halogenated phenylalanine may be ortho-monofluoro-phenylalanine, ortho-monobromo-phenylalanine, ortho-monochloro-phenylalanine, or para-monochloro-phenylalanine. The analogue may be of a mammalian insulin, such as human insulin. A nucleic acid encodes such an insulin analogue. The halogenated insulin analogues retain significant activity. A method of treating a patient comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient. Halogen substitution-based stabilization of insulin may enhance the treatment of diabetes mellitus in regions of the developing world lacking refrigeration.

Abstract: Disclosed is a formulation for parenteral administration comprising insulin that comprises a pH memory between 1 to 4 or between 6 to 8 and an aprotic polar solvent, wherein the insulin is solubilized in the aprotic polar solvent, wherein the solubilized insulin comprises stable monomeric or dimeric forms of insulin or mixtures thereof, and wherein the water content of the formulation is equal to or less than 15% w/v.

Abstract: The present invention is based, at least in part, on the identification of a pharmaceutical container formed, at least in part, of a glass composition which exhibits a reduced propensity to delaminate, i.e., a reduced propensity to shed glass particulates. As a result, the presently claimed containers are particularly suited for storage of pharmaceutical compositions and, specifically, a pharmaceutical solution comprising a pharmaceutically active ingredient, for example, FORTEO® (recombinant human teriparatide), DULAGLUTIDE® (LY2189265), recombinant insulin glargine, RAMUCIRUMAB® (IMC-1121B), SOLANEZUMAB® (LY2062430), IXEKIZUMAB® (LY2439821), TABALUMAB® (LY2127399), NECITUMUMAB® (IMC-11F8), or CIXUTUMUMAB® (IMC-A12).

Abstract: Compositions containing a therapeutic peptide covalently linked to Vitamin B12 at the 5?-hydroxyl group of the ribose moiety of ?-ligand are described. The length of the linkage is optimized so that the biological activity of both the Vitamin B12 and the therapeutic peptide is maintained. Therapeutic peptide includes insulin, PYY, NPY and GLP-1. Attachment to Vitamin B12 provides uptake of the therapeutic peptide from the digestive tract and longer residence time.

Abstract: A pharmaceutical formulation comprises insulin having a variant insulin B-chain polypeptide containing an ortho-monofluoro-Phenylalanine substitution at position B24 in combination with a substitution of an amino acid containing an acidic side chain at position B10, allowing the insulin to be present at a concentration of between 0.6 mM and 3.0 mM. The formulation may optionally be devoid of zinc. Amino-acid substitutions at one or more of positions B3, B28, and B29 may additionally be present. The variant B-chain polypeptide may be a portion of a proinsulin analogue or single-chain insulin analogue. The insulin analogue may be an analogue of a mammalian insulin, such as human insulin. A method of lowering the blood sugar of a patient comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to the patient.

Abstract: The subject matter of this invention is directed towards chemically and thermodynamically stable single-chain insulin (SCI) analogues that are resistant to deamidation and fibrillation. The invention further discloses improved methods for the recombinant expression, purification and refolding of SCI.

Abstract: The present invention is related to insulin derivatives having a side chain attached either to the ?-amino group of the N-terminal amino acid residue of B chain or to an ?-amino group of a Lys residue present in the B chain of the parent insulin molecule via an amide bond which side chain comprises one or more residues of ethyleneglycol, propyleneglycol and/or butyleneglycol containing independently at each termini a group selected from —NH2 and —COOH; a fatty diacid moiety with 4 to 22 carbon atoms, at least one free carboxylic acid group or a group which is negatively charged at neutral pH; and possible linkers which link the individual components in the side chain together via amide or ether bonds, said linkers optionally comprising a free carboxylic acid group.

Abstract: An insulin analogue comprises a B-chain polypeptide containing a cyclohexanylalanine substitution at position B24 and optionally containing additional amino-acid substitutions at positions A8, B28, and/or B29. A proinsulin analogue or single-chain insulin analogue containing a B domain containing a cyclohexanylalanine substitution at position B24 and optionally containing additional amino-acid substitutions at positions A8, B28, and/or B29. The analogue may be an analogue of a mammalian insulin, such as human insulin. A nucleic acid encoding such an insulin analogue is also provided. A method of lowering the blood sugar of a patient comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient. A method of semi-synthesis using an unprotected octapeptide by means of modification of an endogenous tryptic site by non-standard amino-acid substitutions.

Abstract: The present invention is related to insulin derivatives containing additional disulfide bonds and methods of making such.

Abstract: The invention relates to a pharmaceutical composition comprising 1.a and/or 1.b according to claim 1 in combination with at least one second therapeutic agent 2 which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia. In addition the present invention relates to methods for preventing or treating of metabolic disorders and related conditions.

Abstract: Conjugates which comprise a drug and a ligand which includes a first saccharide; wherein the conjugate is characterized in that, when the conjugate is administered to a mammal, at least one pharmacokinetic or pharmacodynamic property of the conjugate is sensitive to serum concentration of a second saccharide. Exemplary conjugates and sustained release formulations are provided in addition to methods of use and preparation.

Abstract: Compositions and formulations comprising N-glycosylated insulin analogues are described. In particular embodiments, the glycosylated insulin analogues are produced in vivo and comprise one or more the N-linked N-glycans selected from high mannose or fucosylated or non-fucosylated hybrid, paucimannose, or complex N-glycans. In other embodiments, the N-glycan comprising the high mannose or fucosylated or non-fucosylated hybrid, paucimannose, or complex N-glycan is attached to the insulin analogue in vitro. Examples of N-glycans include but are not limited to a molecule having a structure selected from N-glycans in the group consisting of Man(1—9)GlcNAc2; or selected from N-glycans in the group consisting of GlcNAc(1—4)Man3GlcNAc2; or selected from N-glycans in the group consisting of Gal(j.

Abstract: Prodrug formulations of bioactive polypeptides are provided wherein the bioactive polypeptide has been modified by the linkage of a dipeptide to the bioactive polypeptide through an ester linkage. The prodrugs disclosed herein in some embodiments have extended half lives of at least 1.5 hours (e.g., at least 10 hours), and more typically greater than 20 hours and less than 70 hours, and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Abstract: Insulin preparations comprising an insulin compound or a mixture of two or more insulin compounds, a nicotinic compound and an amino acid.

Abstract: The present invention is related to insulin derivatives having a side chain attached to an ?-amino group of a Lys residue present in the A-chain or to an ?-amino group of a Lys residue in the B-chain.

Abstract: An insulin analogue comprises a B-chain polypeptide incorporating a halogenated phenylalanine at position B24, B25 or B26. The halogenated phenylalanine may be ortho-monofluoro-phenylalanine, ortho-monobromo-phenylalanine, ortho-monochloro-phenylalanine, or para-monochloro-phenylalanine or penta-fluoro-Phenylalanine at position B24 alone or in combination with an acidic substitution (Aspartic Acid or Glutamic Acid) at position B10. The analogue may be of a mammalian insulin, such as human insulin. A nucleic acid encodes such an insulin analogue. The halogenated insulin analogues retain significant activity. A method of treating a patient comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient. Halogen substitution-based stabilization of insulin may enhance the treatment of diabetes mellitus in regions of the developing world lacking refrigeration.

Abstract: The present invention relates to a non-peptidyl polymer-insulin multimer comprising two or more of a non-peptidyl polymer-insulin conjugate prepared by linking a non-peptidyl polymer and insulin via a covalent bond, in which the conjugates are complexed with cobalt ion to form a multimer, a method and kit for the preparation of the multimer, a pharmaceutical composition for the prevention or treatment of diabetes comprising the multimer as an active ingredient, and a method for preventing or treating diabetes by administering the composition to a subject.

Abstract: A conjugate that includes a drug covalently linked to a polymer. Upon administration, the conjugate is digested by an enzyme that is present at the site of administration thereby releasing a therapeutic agent. The conjugate may demonstrate substantially the same pharmacokinetic and pharmacodynamic behavior as the drug itself. A material for controllably releasing a conjugate in response to the local concentration of a molecular indicator. The material includes a plurality of conjugates and a plurality of multivalent cross-linking agents. The polymers of the conjugates include an analog of the indicator within their covalent structure. The multivalent cross-linking agents include cross-link receptors that interact with the indicator analog and thereby cross-link the conjugates.

Abstract: Prodrug formulations of bioactive polypeptides are provided wherein the bioactive polypeptide has been modified by the linkage of a dipeptide to the bioactive polypeptide through an ester linkage. The prodrugs disclosed herein in some embodiments have extended half lives of at least 1.5 hours (e.g., at least 10 hours), and more typically greater than 20 hours and less than 70 hours, and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Abstract: Novel acylated insulin analogues exhibiting resistance towards proteases can, effectively, be administered pulmonary or orally. The insulin analogues contain B25H and A14E or A14H.

Abstract: The present invention relates to insulin derivatives having a side chain attached either to the ?-amino group of the N-terminal amino acid residue of the B chain or to the ?-amino group of a Lys residue present in the B chain of the parent insulin via an amide bond which side chain comprises at least one aromatic group; at least one free carboxylic acid group or a group which is negatively charged at neutral pH, a fatty acid moiety with 4 to 22 carbon atoms in the carbon chain; and possible linkers which link the individual components in the side chain together via amide bonds.