Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules

• US 5,840,701 A
• Filed: 02/22/1996
• Issued: 11/24/1998
• Est. Priority Date: 08/16/1993
• Status: Expired due to Fees

• Current Assignee: Synzyme Technologies Incorporated
• Original Assignee: Jen-Chang Hsia
• Inventors: Hsia, Jen-Chang
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): Delaney, Patrick R.
• Application Number:
  US08/605,531
• Time in Patent Office: 1,006 Days
• Field of Search: 514/6, 514/21, 424/1.69, 424/9.3
• US Class Current: 514/9.4
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/42 Haemoglobins; Myoglobins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/52 the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
• CPC Class Codes: A61K 47/6445 Haemoglobin
• CPC Class Codes: A61K 47/6895 Rescue therapy; Agonist-antagonist; Antidotes; Targeted rescue or protection, e.g. by folic acid-folinic acid or conjugated to antibodies
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61K 49/20 containing free radicals , e.g. trityl radical for overhauser
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 14/76 Albumins
• CPC Class Codes: C07K 14/805 Haemoglobins; Myoglobins
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002

Abstract

Compositions and processes to alleviate free radical toxicity are disclosed based on the use of nitroxides in association with physiologically compatible macromolecules. In particular, hemoglobin-based red cell substitutes are described featuring stable nitroxide free radicals for use in cell-free hemoglobin solutions, encapsulated hemoglobin solutions, stabilized hemoglobin solutions, polymerized hemoglobin solutions, conjugated hemoglobin solutions, nitroxide-labelled albumin, and nitroxide-labelled immunoglobulin. Formulations are described herein that interact with free radicals, acting as antioxidant enzyme-mimics, which preserve nitroxides in their active form in vivo. Applications are described including blood substitutes, radioprotective agents, imaging agents, agents to protect against ischemia and reperfusion injury, particularly in cerebral ischemia in stroke, and in vivo enzyme mimics among others.

Claims

1. A method to alleviate tissue damage from cerebral ischemia comprising intravenously administering a physiologically compatible dose of polynitroxylated albumin wherein the average molar ratio of nitroxide to albumin is between approximately 17 to 95.

2. The method of claim 1 wherein the average molar ratio of nitroxide to albumin is between approximately 30 and 95.

3. The method of claim 1 wherein the average molar ratio of nitroxide to albumin is between approximately 42 and 52.

4. The method of claim 1 wherein the average molar ratio of nitroxide to albumin is between approximately 52 and 95.

5. The method of claim 1, 2, or 3 wherein the nitroxide is selected from the group consisting of TEMPOL (2,2,6,6-Tetramethylpiperidine-N-oxyl), PROXYL (2,2,5,5-Tetramethypyrrolidine-N-oxyl), and DOXYL (4,4-Dimethyloxazolidine-N-oxyl).