Metal Complexes, E.g., Zn-insulin, Etc. Patents (Class 530/304)
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Patent number: 5534488Abstract: The present invention is directed to an insulin formulation comprising a suspension of Ultralente crystals and a total formulation zinc concentration of between about 0.5 milligrams to about 20 milligrams per 100 units of insulin. Greater than fifty percent of the total zinc in the formulation resides in the soluble fraction, rather than in complex with the insulin. This insulin formulation generally has a pH from between about 6.0 to about 7.4. In addition, the insulin formulation of the present invention does not contain other proteins like protamine. This zinc-modified formulation displays characteristics of a very long lasting human insulin product.Type: GrantFiled: August 13, 1993Date of Patent: July 9, 1996Assignee: Eli Lilly and CompanyInventor: James A. Hoffmann
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Patent number: 5508260Abstract: Methods for treatment of diabetes and other insulin-requiring conditions by administering insulin and a calcitonin with or without amylin, and methods for treatment of hypoglycemic conditions by administering a calcitonin alone or in combination with glucagon and/or an amylin, and related compositions.Type: GrantFiled: June 10, 1994Date of Patent: April 16, 1996Assignee: Amylin Pharmaceuticals, Inc.Inventors: Kevin Beaumont, Andrew A. Young
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Patent number: 5504188Abstract: The present invention discloses a process of preparing a crystalline insulin analog. The process is useful in the purification and manufacture of Lys.sup.B28 Pro.sup.B29 -human insulin. Lys.sup.B28 Pro.sup.B29 -human insulin is useful in the treatment of diabetes.Type: GrantFiled: June 16, 1994Date of Patent: April 2, 1996Assignee: Eli Lilly and CompanyInventors: Jeffrey C. Baker, Nancy D. Carter, Bruce H. Frank
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Patent number: 5474978Abstract: The present invention discloses a human insulin analog hexamer complex and formulations. More specifically, the present invention relates to various parenteral formulations, which comprise: human insulin analogs in a hexamer conformation, zinc ions, and at least three molecules of a phenolic derivative selected from the group consisting of m-cresol, phenol, or a mixture of m-cresol and phenol. The formulation provides a rapid onset of action.Type: GrantFiled: June 16, 1994Date of Patent: December 12, 1995Assignee: Eli Lilly and CompanyInventors: Diane L. Bakaysa, David N. Brems, Bruce H. Frank, Henry A. Havel, Allen H. Pekar
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Patent number: 5461031Abstract: The present invention discloses various parenteral pharmaceutical formulations, which comprise: a monomeric insulin analog, zinc, protamine, and phenolic derivative. The analog formulations provide a prolonged duration of action. A process for preparing insulin analog-protamine formulations is also described.Type: GrantFiled: June 16, 1994Date of Patent: October 24, 1995Assignee: Eli Lilly and CompanyInventor: Michael R. De Felippis
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Patent number: 5457066Abstract: This specification describes a process for converting a human insulin precursor to human insulin, which comprises treating such human insulin precursor with trypsin and carboxypeptidase B in an aqueous medium containing per mole of human insulin precursor from about 0.1 to about 10 moles of one or more metal ions of those metals having Atomic Numbers 21 to 34, 39 to 52, 57 to 84, and 89 to 92.Type: GrantFiled: May 11, 1992Date of Patent: October 10, 1995Assignee: Eli Lilly and CompanyInventors: Bruce H. Frank, Walker E. Prouty, Richard E. Heiney, Mark R. Walden
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Patent number: 5442043Abstract: The present invention provides a conjugate capable of passing the blood-brain barrier comprising a bioactive peptide or protein incapable of passing the blood-brain barrier and a carrier peptide which exhibits substantially no bioactivity and which is capable of passing the blood-brain barrier. The conjugate makes it possible to allow a bioactive peptide or protein incapable of passing the blood-brain barrier to easily pass the blood-brain barrier for uniform transport to the brain without any side effect of the carrier peptide.Type: GrantFiled: November 29, 1993Date of Patent: August 15, 1995Assignee: Takeda Chemical Industries, Ltd.Inventors: Makoto Fukuta, Satoshi Iinuma, Hiroaki Okada
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Patent number: 5410020Abstract: The invention contemplates a metallopeptide and a method for producing the metallopeptide. The metallopeptide comprises a polypeptide bonded to a metal cation at two coordinating amino acid residues that are aqueous solvent-accessible, said metallopeptide having a secondary structure stabilized by said bonded metal cation.Type: GrantFiled: January 19, 1993Date of Patent: April 25, 1995Assignee: The Scripps Research InstituteInventor: M. Reza Ghadiri
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Patent number: 5408036Abstract: This invention contemplates an isolated metallopolypeptide comprising a polyvalent metal ion coordinately linked to 2 to about 8 polypeptide binding ligands, wherein at least 2 of said polypeptide binding ligands are covalently bonded to a linear amphiphilic peptide. The linear amphiphilic peptide has an alpha-helix, beta-sheet or beta-turn conformation. This invention further contemplates a metal ion-assisted, self-assembly method for producing a metallopolypeptide.Type: GrantFiled: December 9, 1993Date of Patent: April 18, 1995Assignee: The Scripps Research InstituteInventor: M. Reza Ghadiri
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Patent number: 5342921Abstract: Novel methods and compositions are provided for enhanced yield of heterologous proteins in fungi. The method and compositions involve employing fusion sequences involving a sequence encoding a heterologous product produced in relatively large amount as a stable polypeptide in the host fused to a second sequence in open reading frame with the prior sequence coding for a different heterologous polypeptide, where the two polypeptides are joined by a selectively cleavable linkage. In particular, a sequence coding for superoxide dismutase is joined to another polypeptide of interest at either terminus of the superoxide dismutase in a yeast expression vector under transcriptional control of an active promoter and the vector introduced into a yeast host and the host grown. High yields of the fusion product are obtained in this manner, where the fusion product can be selectively cleaved so as to produce both the superoxide dismutase and the other polypeptide in high yield.The S.Type: GrantFiled: March 29, 1991Date of Patent: August 30, 1994Assignee: Chiron CorporationInventors: Lawrence S. Cousens, Patricia A. Tekamp-Olson, Jeffrey R. Shuster, James P. Merryweather
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Patent number: 5219555Abstract: The invention relates to a method for labeling substances with--in particular radioactive--technetium or rhenium isotopes with the aid of N-substituted or C-substituted macrocyclic amine derivatives of the formula I and/or II ##STR1## in which R.sup.1 -R.sup.7, Y, m, n, o, p, f, g, h, i and j have the stated meanings, and to the use of these labeled substances, especially in medical diagnosis.Type: GrantFiled: August 25, 1988Date of Patent: June 15, 1993Assignee: Hoechst AktiengesellschaftInventors: Karl-Heinz Bremer, Ludwig Kuhlmann, Michael Magerstadt, Alexander Schwarz, Axel Steinstrasser
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Patent number: 5200504Abstract: The invention contemplates a metallopeptide and a method for producing the metallopeptide. The metallopeptide comprises a polypeptide bonded to a metal cation at two coordinating amino acid residues that are aqueous solvent-accessible, said metallopeptide having a secondary structure stabilized by said bonded metal cation.Type: GrantFiled: October 2, 1990Date of Patent: April 6, 1993Assignee: The Scripps Research InstituteInventor: Reza M. Ghadiri
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Patent number: 5192741Abstract: There is disclosed a pharaceutical composition for sustained and controlled release of drug over an extended period of time comprising a polylactide, a copolymer of lactic and glycolic acid, a mixture of such polymers and a water-insoluble peptide which, when placed in an aqueous physiologically-type environment releases the peptide in continuous manner for a period of at least one week, and with an initial release for the first twenty-four hours of not more than 30% of the total amount released. There is thus provided the control of the release pattern and in general a decrease of the initial burst effect.Type: GrantFiled: September 20, 1988Date of Patent: March 9, 1993Assignee: Debiopharm S.A.Inventors: Piero Orsolini, Rolland-Yves Mauvernay, Romano Deghenghi
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Patent number: 5177058Abstract: Pharmaceutical formulations for the treatment of diabetes mellitus are disclosed, wherein the pharmaceutical formulations contain at least one insulin derivative modified with a base in position B31 of the insulin B chain and having an isoelectric point between 5.8 and 8.5 and/or at least one of its physiologically tolerated salts in a pharmaceutically acceptable excipient and a relatively high zinc ion content in the range from above 1 .mu.g to about 200 .mu.g of zinc/IU. The preferred insulin derivative modified with a base for this pharmaceutical formulation is human insulin-B31-Arg-OH and human insulin-B31-Arg-B32-Arg-OH. The formulation is used for the treatment of diabetes mellitus; it has a particularly favorable action profile.Type: GrantFiled: August 11, 1989Date of Patent: January 5, 1993Assignee: Hoechst AktiengesellschaftInventor: Michael Dorschug
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Patent number: 5108610Abstract: A process for obtaining a material possessing glucose tolerance factor activity and capable of binding with insulin including the steps of (i) contacting a eukaryotic cell mass with a mixture of water and alcohol to form a water phase and an alcohol phase; (ii) separating the alcohol phase from the water phase and isolating a water phase extract; and (iii) subjecting the water phase extract to gel exclusion chromatography, eluting all material having a molecular weight of approximately 720 to 1120 to obtain a material possessing glucose tolerance factor activity and capable of binding with insulin.Type: GrantFiled: June 11, 1991Date of Patent: April 28, 1992Assignee: Thymax CorporationInventor: Scott King
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Patent number: 5094950Abstract: A compound of the formula II: ##STR1## wherein n is an integer of 2 to 10, A' is a bivalent linking group formed by reacting both the reactive groups of a cross linking reagent, andB is a residue of a polypeptide compound, and physiologically acceptable salts thereof are disclosed. Such compound is useful as a non-radioactive carrier for radioactive metal elements.Type: GrantFiled: June 5, 1989Date of Patent: March 10, 1992Assignee: Nihon Medi-Physics Co., Ltd.Inventors: Susumu Kondo, Miki Kurami, Makoto Azuma
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Patent number: 5070186Abstract: Insulin preparations with improved properties for parenteral administration can be prepared at pH values of about 3 to 8.5 by presence of magnesium ions in concentration of about 0.005 to 0.5M, a preferred range is 0.02M to 0.5M.Type: GrantFiled: April 19, 1989Date of Patent: December 3, 1991Assignee: Novo Industri A/SInventor: Klaus Joergensen
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Patent number: 5070074Abstract: This application discloses an invention comprising a polypeptide fraction isolated from commercial bacitracin and which contains most if not all of the anti-insulinase activity of bacitracin while exhibiting few if any of the antibacterial properties. The invention herein described also involves the use of this polypeptide fraction given orally or if given parenterally either together (as composite) or in sequence as a means of treating diabetics. For such purposes, the insulin and anti-insulinase polypeptide fraction may be used as separate substances or chemically linked by a wide variety of chemical linking agents well known in the art. In addition to clinical uses, the application describes a method of using the polypeptide fraction as a growth promoter substance to be added to animal feed and also a composition useful for this purpose.Type: GrantFiled: July 23, 1990Date of Patent: December 3, 1991Assignee: Protor Co.Inventors: Victor Medina, Alfred Stracher, Leo Kesner
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Patent number: 5059329Abstract: A process for purifying dithiochrome from a natural source is disclosed. The process comprises: (i) contacting a eukaryotic cell mass with a mixture of water and an alcohol; (ii) separating the alcohol phase from the water phase and obtaining a water phase extract; (iii) subjecting the water phase extract to a sulfhydryl exchange chromatography matrix; (iv) washing said chromatography matrix; and (v) treating said chromatrography matrix with an active thiol to obtain dithiochromate; a material capable of binding with insulin. Dithiochromate may be used to treat patients suffering from elevated blood glucose or suboptimal glucose kinetics. An adduct of this compound with insulin may be used to treat patients for type I diabetes.Type: GrantFiled: September 19, 1989Date of Patent: October 22, 1991Assignee: Thymax CorporationInventor: Scott King
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Patent number: 5008241Abstract: Insulin analogs characterized by amino acid residue at A21 other than Asn, with a resulting improvement in stability of insulin solutions at acid pH levels. Some insulin analogs may also have amino acid residue changes elsewhere so that these insulin analogs exhibit at least about one charge more than human insulin at a pH value of 7, with preferred substitutions being made for the glutamic acid residues at A4, A17, B13, B21 and/or a basic amino acid residue being substituted at B27. Also contemplated is optional blocking the C-terminal carboxyl group of the B-chain with an amido or ester residue.Type: GrantFiled: October 20, 1989Date of Patent: April 16, 1991Assignee: Novo Nordisk A/SInventors: Jan Markussen, Kjeld Norris, Liselotte Langkjaer
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Patent number: 4801684Abstract: A process for the preparation of insulin precursors of the formula (I) ##STR1## in which R is hydrogen or the presequence P.sub.m --Q.sub.n --, in which P is a sequence of naturally occurring amino acids with m being from 0 to 50, Q are basic natural amino acids, and n is an integer from 1 to 4, Y represents --Lys.sup.B29 --Z.sup.B30 --, in which Z denotes Ala, Thr or Ser, and the bridge extending from A-1 to A-21 is an insulin A-chain, the bridge extending from B-1 to B-30 represents an insulin B-chain, and X is a bridge which is bonded to the insulin A-chain at the amino group of A-1 and is bonded to the insulin B-chain at the .epsilon.-amino group of B-29-- in which case it is bonded to the free bond of Z.sup.Type: GrantFiled: September 2, 1986Date of Patent: January 31, 1989Assignee: Hoechst AktiengesellschaftInventor: Ulrich Grau
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Patent number: 4789660Abstract: A therapeutic composition for trans-mucosal administration in the treatment of diabetes including insulin, as an adjuvant a water-soluble fusidic acid salt and as a co-adjuvant methylparaben and/or propylparaben.Type: GrantFiled: September 10, 1987Date of Patent: December 6, 1988Assignee: American Home Products CorporationInventors: Robin P. Enever, Thomas W. Leonard, Karol K. Mikula
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Patent number: 4764592Abstract: This disclosure provides a crystalline human proinsulin, the preparation of which comprises(a) preparing an aqueous mixture containing from about 5 to about 50 mg/ml human proinsulin, from about 0.1 to about 5 mg/ml of a phenolic substance, from about 0.03 to about 0.6 milliequivalents/ml of a salt of a cation selected from the group consisting of lithium, calcium, sodium, potassium, ammonium, magnesium, and barium, and from about 0.2 to about 5 milliequivalents of Zn.sup.+2 cation;(b) adjusting the aqueous mixture to a pH in the range of from about 5.4 to about 6.5;(c) allowing crystal formation to occur; and(d) recovering crystalline human proinsulin from the aqueous mixture.Type: GrantFiled: April 23, 1987Date of Patent: August 16, 1988Assignee: Eli Lilly and CompanyInventors: Eddie H. Massey, Richard L. Jackson
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Patent number: 4743583Abstract: Lewis acid-Lewis base high molecular weight salt microparticulate material of the type referred to in U.S. Pat. No. 3,959,457, which include biologically active peptides and proteins solubilized in a non-aqueous, non-denaturing manufacturing solvent.Type: GrantFiled: July 20, 1987Date of Patent: May 10, 1988Assignee: Temple UniversityInventors: Tully J. Speaker, Tycho J. Speaker
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Patent number: 4705845Abstract: A process for sulphation and phosphorylation of a protein or peptide comprising contacting said protein or peptide with sulphuric or phosphoric acid in the presence of a non-aqeuous apolar organic solvent and contacting the resultant solution with a dehydrating agent is disclosed. Non-aggregating insulin products with bioactivity may be prepared by this process.Type: GrantFiled: September 5, 1986Date of Patent: November 10, 1987Assignee: Rockefeller UniversityInventors: Anthony Cerami, Sandor Pongor, Michael Brownlee