Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms

Definitions

• thyroid hormone causes a reciprocal shift in cardiac myosin heavy chain (MHC) isoform expression, increasing the expression of the high activity Vj isoform and decreasing the low activity V 3 form.
• MHC myosin heavy chain
• Thyroid hormones include the L-forms of thyroxine (3,5,3'5'-L-thyronine; hereinafter thyroxine or T 4 ) and triiodothyronine (3',3,5-L-triiodothyrone; hereinafter triiodothyronine or T 3 ).
• Reverse T 3 or r T 3 is a normal metabolite of T 4 .
• T 4 is synthesized in the thyroid gland and is the circulating form of hormone found in plasma. Although small amounts of T 3 are synthesized by the thyroid gland, the majority is formed from the metabolism of thyroxine in peripheral tissues by the enzyme 5'-monodeiodinase. The molecular basis for the actions of thyroid hormones is though to be mediated through the binding of T 3 to chromatin-bound nuclear receptors. There are two major subtypes of the thyroid hormone receptor, TRtz and TR ?, which are the products of two different genes.
• T 3 has a relatively short half-life of two days or less.
• DITPA acts similarly to thyroid hormone, affecting both the heart and the peripheral circulation. Loss of the normal increase in contractility with heart rate, referred to as the positive force-frequency relationship, has been reported both in failing human myocardium and in animal models of heart failure.
• DITPA administration prevents the flattened contraction-frequency relationship in single myocytes from infarcted rabbit hearts. DITPA improves myocyte function, enhances calcium transport in the sarcoplasmic reticulum (SR) and prevents the down regulation of SR proteins associated with post-infarction heart failure in rabbits. In normal primates, DITPA enhances the in vivo force-frequency and relaxation- frequency relationships in a manner similar to thyroid hormone.
• SR sarcoplasmic reticulum
• DITPA is able to bring about these hemodynamic changes without increasing cardiac mass appreciably or adversely affecting ventricular dimensions.
• a morphometric analysis indicates that in post-infarction rats treated with DITPA there is an increase in capillary growth in the border zone around the infarct.
• the TRIPROP or TETRAPROP Prior to administration to either human patients, or to animals, the TRIPROP or TETRAPROP, as the case may be, is then dispersed or dissolved in a pharmaceutically acceptable carrier and, if desired, further compounded with one or more ingredients selected from a stabilizer, an excipient, a solubilizer, an antioxidant, a pain-alleviating agent, an isotonic agent, and combinations thereof.
• the TRIPROP and the TETRAPROP of the present invention may be formulated as a liquid preparation, e.g., for parenteral administration intravenously, subcutaneously or intramuscularly, or intranasally or orally, as a solid preparation for oral administration, e.g., pills, tablets, powders, or capsules, as an implant preparation, or as a suppository for rectal administration.
• the formulation for parenteral administration for injection may be prepared by conventional methods known to a person skilled in the art, such as by dissolving the TRIPROP or TETRAPROP in an appropriate solvent or carrier such as sterilized water, buffered solution, isotonic sodium chloride solution and the like, and may be formulated as solutions, emulsions or suspensions.
• a unit dose of TRIPROP or TETRAPROP may be formulated with cocoa butter or a glyceride.
• TRIPROP or TETRAPROP also may be administered in the form of inhalation or insufflation.
• a solution of TRIPROP or TETRAPROP is conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizer, with the use of suitable propellants such as carbon dioxide or other suitable gasses.
• TRIPROP or TETRAPROP may be administered using other conventional drug delivery systems well known to a person skilled in the art. Examples of the preparations for drug delivery system are microspheres (nanoparticle, microparticle, microcapsule, bead, liposome, multiple emulsion, etc.) and the like.
• a stabilizer may be added to the formulation, and the examples of a stabilizer include albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol and the like.
• the formulation of the present invention may include a necessary additive such as an excipient, a solubilizer, an antioxidant agent, a pain-alleviating agent, an isotonic agent and the like.
• the liquid formulation may be stored in frozen condition, or after removal of water by a process such as freeze-drying. The freeze-dried preparations are used by dissolving in pure water for injection and the like before use.
• TRIPROP or TETRAPROP also may be formulated for transdermal or implant administration. Such long acting implantation administrations include subcutaneous or intramuscular implantation.
• TRIPROP or TETRAPROP may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins or as sparing soluble derivatives, for example as a sparingly soluble salt.
• a TRIPROP or TETRAPROP-in-adhesive device can be prepared by preparing a coating formulation by mixing a solution of the adhesive in a solvent system containing TRIPROP or TETRAPROP, and any other desired components, to form a homogeneous solution or suspension; applying the formulation to a substrate such as a backing or a release liner; using well known knife or bar or extrusion die coating methods; drying the coated substrate to remove the solvent; and laminating the exposed surface to a release liner or backing.
• a coating formulation by mixing a solution of the adhesive in a solvent system containing TRIPROP or TETRAPROP, and any other desired components, to form a homogeneous solution or suspension; applying the formulation to a substrate such as a backing or a release liner; using well known knife or bar or extrusion die coating methods; drying the coated substrate to remove the solvent; and laminating the exposed surface to a release liner or backing.
• a solution of TRIPROP is prepared following the procedure described by Tomita and Lardy as above reported by iodination of DITPA as follows.
• a solution of 150 mg of DITPA in 150 ml of methanol and 70 ml of concentrated aqueous ammonium hydroxide was iodinated with 4.3 ml of 1 N iodine while being stirred in an ice bath (0-2° C).
• the color of iodine disappeared in about 15 minutes.
• TRIPROP was mixed with lactose and packed into gelatin capsules containing 1-2 mgs of the active ingredient per capsule.
• TRIPROP was prepared as in Example 1. However, the resulting solution was lyophilized and packaged in individual ampules containing 1-2 mgs of the active ingredient per capsule.
• Examples 1-4 were repeated, using TETRAPROP prepared either by the method of Tomita and Lardy 3 or Matsuura 5 .

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Cardiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Heart & Thoracic Surgery (AREA)
• Hospice & Palliative Care (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)

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• 2003
  • 2003-02-18 US US10/368,755 patent/US6716877B2/en not_active Expired - Fee Related
  • 2003-10-20 AU AU2003286546A patent/AU2003286546B2/en not_active Ceased
  • 2003-10-20 JP JP2004568567A patent/JP2006514665A/ja active Pending
  • 2003-10-20 CA CA002516450A patent/CA2516450A1/en not_active Abandoned
  • 2003-10-20 WO PCT/US2003/033333 patent/WO2004073694A1/en not_active Ceased
  • 2003-10-20 MX MXPA05008596A patent/MXPA05008596A/es active IP Right Grant
  • 2003-10-20 EP EP03777748A patent/EP1594480A4/en not_active Withdrawn

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