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WO2016210409A1 - Formulations de l-carnosine et de zinc et méthodes d'utilisation - Google Patents

Formulations de l-carnosine et de zinc et méthodes d'utilisation Download PDF

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Publication number
WO2016210409A1
WO2016210409A1 PCT/US2016/039542 US2016039542W WO2016210409A1 WO 2016210409 A1 WO2016210409 A1 WO 2016210409A1 US 2016039542 W US2016039542 W US 2016039542W WO 2016210409 A1 WO2016210409 A1 WO 2016210409A1
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WIPO (PCT)
Prior art keywords
zinc
solvated
carnosine
composition
camosine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2016/039542
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English (en)
Inventor
Richard J. Di Rocco
Dale M. LOMBARDI
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Publication date
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Publication of WO2016210409A1 publication Critical patent/WO2016210409A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • L-camosine zinc L-C AZ
  • methods of using and administering such formulations to patients suffering from various diseases, disorders, or conditions.
  • L-carnosine zinc is a polymeric compound that has been shown to reduce inflammation and promote healing of ulcers of the gastrointestinal (GI) tract.
  • L-carnosine zinc is registered and approved as an orally administered tablet and powder in a sachet for the treatment of peptic ulcers in Japan. It is manufactured by Hamari Chemicals, Ltd. and sold by Zeria Pharmaceuticals, Ltd.
  • L-carnosine zinc is a true chelate comprising L-camosine, a naturally occurring dipeptide, and zinc that is manufactured in polymeric form of Formula I:
  • L-carnosine zinc dissociates slowly in the acidic environment of the stomach into L-camosine and zinc.
  • the parent chelate molecule is therefore not absorbed into the systemic circulation.
  • More and better formulations for the delivery of L-carnosine zinc beyond the gastrointestinal mucosal tissues are desirable to improve its effectiveness, applicability, to expand its usefulness, and for other reasons.
  • Some embodiments provide a pharmaceutical composition comprising solvated L- camosine zinc in one or more pharmaceutically acceptable solvents.
  • the solvation is accomplished in a lipid based cream or ointment that is suitable for topical application to the body surface, as well as ano-rectal, nasal, or vaginal tissues.
  • the solvation is accomplished in a suitable lipid or group of lipids, and other agents such as emulsifiers, to form a lipid emulsion when mixed with an aqueous medium suitable for injection into the body.
  • the solvation is accomplished in a liposomal composition suitable for injection into the body, inhalation for delivery to the lungs, or intranasal spraying to reach nasal mucosal tissue, or the brain via the olfactory nerves and bulb.
  • Some embodiments provide a capsule for swallowing to reach the GI mucosa.
  • Some embodiments provide a method of treating or protecting vascular endothelium including administering a composition described herein to a patient in need thereof.
  • Some embodiments provide a method of treating or protecting the vascular endothelium, comprising administering a composition comprising L-camosine zinc solvated in a lipid emulsion or a preparation of liposomes, or another suitable solvent system, into the circulatory system.
  • the administration includes injecting or infusing the composition into a vein or an artery.
  • Some embodiments provide a method to treat lung inflammatory disorders via inhalation of solvated L-carnosine zinc.
  • Some embodiments provide a method of treating inflammatory and degenerative disorders of the brain by spraying solvated L-carnosine zinc using a special device to direct the spray to reach the upper third of the sinus cavities for direct administration to brain via the olfactory nerve endings in the cribiform plate and the olfactory bulb.
  • Some embodiments provide a method of treating or protecting the vascular endothelium comprising administering a composition comprising L-camosine zinc solvated in a lipid emulsion, or in liposomes, by injection or infusion into the circulatory system via a vein or artery.
  • the arterial or venous injection will be accomplished with the aid of a catheter to reach a distal site within the circulatory system.
  • intra-arterial or intravenous administration via a catheter comprises a method to deliver solvated L-carnosine zinc into a part of the circulatory system in which the endothelium is at risk of damage from reperfusion injury during and after an ischemic episode.
  • the method of intra-arterial or intravenous administration of solvated L-camosine zinc via a catheter will be administered, before, during, or after thrombolytic therapy has been applied to establish reperfusion of a tissue affected by an ischemic event.
  • solvated L-camosine zinc is administered intravenously to provide therapy to endothelial tissues throughout the vasculature of the entire body.
  • Some embodiments involve administration of solvated L-carnosine zinc into a vein to reach vascular endothelial tissues at risk of reperfusion injury before the
  • the intravenous administration comprises an injection or infusion.
  • the intravenous systemic injection or infusion comprises a method to treat vascular endothelium throughout the body in individuals suffering from a viral-induced hemorrhagic disease such as that caused by but not limited to Ebola virus, Marburg virus, Dengue virus serotypes, DEN 1, DEN 2, DEN 3, and DEN 4, as well as other viruses of the arenaviruses, filoviruses, bunyaviruses, and flaviviruse families.
  • the intravenous systemic injection or infusion comprises a method to protect or treat the vascular endothelium throughout the body in individuals suffering from a bacterial blood infection such as sepsis. In some embodiments, the intravenous systemic injection or infusion comprises a method to prevent or treat disruption of the vascular endothelium that results from severe blood loss or hemorrhage and the resulting hemorrhagic shock. In some embodiments, the intravenous injection or infusion comprises a method to prevent or treat organ failure and sepsis that results from vascular endothelial damage during hemorrhagic shock.
  • Some embodiments comprise a method of injecting solvated L-carnosine zinc intravenously to protect gastrointestinal epithelium damaged by radiation injury, and to prevent disruption of gastrointestinal epithelial integrity to avoid sepsis and organ failure following such injury. Some embodiments comprise a method of administering solvated L- camosine zinc by inhalation to treat inflammatory disorders of lung tissues, such as asthma and other manifestations of chronic obstructive pulmonary disease or inflammation that results from inhalation of toxic substances, Some embodiments comprise inhalation of L- camosine zinc solvated in a stable liposomal composition. Some embodiments comprise spraying L-carnosine zinc solvated in a stable liposomal preparation into the upper third of the nasal cavity to reach the brain to treat inflammatory and degenerative disorders of the brain.
  • L-carnosine zinc is attributed to its ability to inhibit inflammation signaling pathways (for example, suppression of IL-8 secretion induced by TNF-a or IL- ⁇ ⁇ in a dose-dependent manner; to down-regulate NF- ⁇ and IL-8 expression); to promote mucosal wound healing; to protect tight junctions between intestinal epithelial cells by inhibiting apoptosis in these cells after a variety of insults related to chemotoxicity and radiation exposure, to inhibit increased gut permeability and/or gastropathies caused by exposure to high-dose non-steroidal anti-inflammatory drugs (NSAIDs); to stimulate production of HSP72 a Heat-Shock Protein that has been shown to protect mucosal cell types.
  • inflammation signaling pathways for example, suppression of IL-8 secretion induced by TNF-a or IL- ⁇ ⁇ in a dose-dependent manner; to down-regulate NF- ⁇ and IL-8 expression
  • to promote mucosal wound healing to protect tight junctions between intestinal epithelial cells
  • L-carnosine zinc a unique constellation of cellular- protective and healing properties. These properties allow L-carnosine zinc to be an effective treatment and prevention for inflammatory disorders and other pathogenic processes that result in injuries to epithelial tissues.
  • Intravenous administration of the new compositions described herein will also provide a method of delivering solvated L-camosine zinc to the tissues of the gastrointestinal tract via the systemic circulation for the first time instead of the oral route of administration. This will be of particular importance in treating instances of damage to the gastrointestinal epithelial mucosal tissues that result from acute life-threatening radiation poisoning.
  • L-carnosine zinc's unique structure provides a mechanism for the simultaneous delivery of a carbonyl trapping moiety, L- camosine, and an anti-oxidant moiety, zinc, in mutual Angstrom scale proximity.
  • the mutual Angstrom scale proximity of the two moieties of L-camosine zinc is destroyed by
  • compositions and uses described herein preserve the Angstrom scale proximity of the L-carnosine and zinc moieties in L-carnosine zinc, and permit intravascular administration to reach endothelial and other tissue targets in patients in need of the therapeutic benefits of L-camosine zinc, as well as inhalational administration to reach lung, intranasal spraying to reach nasal mucosa and the brain, and also topical application to contact the body surface and ano-rectal and vaginal tissues.
  • L-carnosine zinc to provide a system for the delivery of the L-carnosine moiety to trap toxic aldehydes and the zinc moiety to trap ROS in tandem and at mutual atomic scale proximity stoichiometrically eliminates both toxic aldehydes and ROS.
  • the simultaneous temporal, and Angstrom scale proximity, of these actions may interfere with the synergistic aspects of toxic aldehydes and ROS in a manner that is not duplicated by administration of a mixture of a zinc salt together with L-carnosine.
  • the particulate polymeric L-camosine zinc is reduced to a monomeric form.
  • the solvation compositions disclosed herein increase exposure of L-camosine zinc and its zinc and L-camosine moieties, in Angstrom scale proximity, to a therapeutic site of action.
  • compositions in which L-camosine zinc is solvated in an appropriate solvent system for administration by injection, topical application, infusion, spraying, or inhalation onto or into the body of a human or animal, permit greater contact between L-carnosine zinc and a therapeutic site of action than the particulate polymeric formulations of L-carnosine zinc comprised of a plurality of particle sizes that have been used previously for oral administration in clinical practice directed toward the treatment of inflammatory and ulcerative disorders of the gastrointestinal tract.
  • L-camosine zinc when delivered orally, it slowly dissociates in the stomach to its two constituent moieties, L-carnosine and zinc, as described by Matsukura and Tanaka in Applicability of Zinc Complex of L-Carnosine [Biochemistry (Moscow) 65: 817-823, 2000] . Therefore, none, or very little, of the chelate parent molecule is absorbed into the circulation. This has been demonstrated in double radiolabel experiments to show that the zinc is absorbed through normal intestinal absorption mechanisms for metals and that the dipeptide, L-camosine is broken down to its constituent amino acids that are either absorbed or excreted (S. Furuta et al, JPBA 1999 19 453-461).
  • compositions of L-camosine zinc in which the chelate is solvated in appropriate solvent systems and administered in a manner that by -passes the gastrointestinal system, would provide greater distribution volume in the body to reach target tissues that cannot be reached via the oral route of administration.
  • contact of solvated L-carnosine zinc with a target tissue is enhanced because the molecule is present in monomeric form owing to the solvation process.
  • the use of the compositions described herein provides, among other things, methods for enhanced exposure of tissues previously inaccessible by L-carnosine zinc.
  • compositions and methods disclosed herein for intravascular or inhalational administration of solvated monomeric L- camosine zinc will therefore enable the therapeutic targeting of vascular endothelium and lung tissues, respectively, as well as other tissues in the body such as, but not limited to, brain, nasal mucosa, pancreas, kidneys, lower urogenital tissues, bladder, urethra, heart, retina, thyroid, bone, bone marrow, cartilage, the skin as well as vaginal and ano-rectal tissues.
  • Some embodiments comprise compositions of L-camosine zinc in which the L- camosine zinc is solvated in a biocompatible solvent for administration to the body.
  • L- camosine zinc is insoluble in water. Therefore solvation requires the use of an effective organic solvent.
  • An appropriate lipid based solvent system is required to achieve a composition that is compatible with administration to an animal or human in need thereof.
  • the composition is comprised of L-carnosine zinc solvated in a lipid-based cream, ointment, or emulsion using various lipids and emulsifiers, methods of preparation, characterization, and manufacturing, such as those described by, but not limited to, K. Hippalgaonkar, et al. [APS ParmSciTec, Vol. 1 1, No.4: 1526-1540, December, 2010].
  • the composition is comprised of L-carnosine zinc solvated in a preparation of stable liposomes using various lipids and methods of preparation, characterization, and manufacturing as described by, but not limited to, A. Samad et al.
  • excipients such as fillers, buffers, solubilizers, stabilizers, preservatives, and the like may be employed in various amounts and combinations to achieve the desired effect.
  • the L-carnosine zinc formulation can be adjusted with the addition of buffers, sugars, and the like to prepare an isotonic or isosmolar composition compared to body fluids, such as but not limited to blood, lymph, or interstitial fluid.
  • liposomes that contain L-carnosine zinc can have surface molecules that will selectively target the liposomes to inflamed tissues or tissues affected by related pathogenic processes.
  • L-carnosine zinc is present and administered in a pharmaceutically effective amount.
  • L-carnosine may be administered at a single dose, or daily dose, of 10-500mg.
  • a daily dosage of 10-100 mg, or 50-150 mg may be used.
  • the daily dosage may be 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg or any number or range of numbers between any of those values.
  • vascular endothelial disorders include, but are not limited to, pathogenic processes that damage or disrupt the integrity of the endothelium as a result of any of the following: tissue inflammation; severe loss of blood that may cause hemorrhagic shock; sepsis and organ failure; a cerebrovascular or cardiovascular ischemic episode; reperfusion injury in the brain or heart that results from thrombolytic therapy to re-establish circulation to previously ischemic tissue; concussive or contusive injury of the brain or other internal organ;
  • intracranial bleeding viral injury such as that produced by, but not limited to, Ebola virus and other viruses such as those mentioned above that induce hemorrhagic fever and/or intra- parenchymal bleeding; bacterial blood infections such as sepsis and organ failure that frequently results from it.
  • Some embodiments are particularly well-suited for the prevention and healing of disorders of the vascular endothelium throughout the body in a patient in need thereof.
  • Ebola virus has been shown to cause production of TNF-alpha in infected cells and increased blood levels of this key inflammatory cytokine which in turn cause increased permeability of the vascular endothelium and extravasation of blood elements and fluids into the tissue spaces. This loss of blood from the intravascular space into the tissue compartment results in severe hemorrhagic shock which would then be expected to intensify the disruption of the vascular endothelium.
  • Inflammation of alveolar and other lung tissues associated with disorders related to various forms of chronic obstructive pulmonary disease including but not limited to, asthma, chronic bronchitis, emphysema, as well as lung inflammation that derives from various insults such as smoke inhalation and other noxious or injurious agents are well documented in the field of pulmonary medicine.
  • the mechanisms of inflammation in alveolar and other lung tissues involve inflammation signaling such as described above in the pathogenic mechanisms of inflammation in other tissues.
  • Inhalation of L-carnosine zinc solvated in a suitable stable preparation of liposomes will deliver L-carnosine zinc directly to the affected tissues.
  • the use of L-carnosine zinc that is enabled by the liposomal composition described herein will provide a nonsteroidal anti-inflammatory therapeutic mechanism of action.
  • this method and route of administration comprises a method to deliver solvated L-camosine zinc directly to forebrain tissues that are affected by inflammatory states related to multiple sclerosis trauma, neurodegeneration such as but not limited to Alzheimer's Disease, or inflammation of other etiologies such as but not limited to viral or bacterial encephalopathies. Skin Vaginal and Ano-Rectal Inflammatory Disorders and Wounds
  • Topical application of L-camosine zinc to areas on the body surface, vagina and ano-rectal tissues that are affected by inflammatory disorders, and wounds of various etiologies would bring the therapeutic benefits described above directly to affected tissues in a patient in need thereof.
  • Pathologies of relevance for the skin are contact dermatitis, eczema, bed sores and diabetic wounds, as well as other inflammatory, infectious, or traumatic syndromes that affect the skin.
  • Pathologies of relevance to ano-rectal tissues are pruritis ani, anal fissures, radiation proctitis, ano-rectal hemorrhoids, as well as other inflammatory, infectious, or traumatic syndromes that affect the ano-rectal tissues.
  • Pathologies of relevance to vaginal tissues include cuts, tears and wounds related to sexual activity or the birth of an infant, as well as episiotomies involving both vaginal and perineal tissues during delivery of a fetus through the vagina.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions comprenant du zinc et de la L-carnosine solvatés ainsi que des méthodes de traitement de divers troubles par l'administration de zinc et de L-carnosine solvatés à un patient ayant besoin d'un tel traitement. Le zinc et la L-carnosine peuvent être solvatés dans une émulsion lipidique, une préparation liposomale, ou un autre milieu non aqueux. Le zinc et la L-carnosine solvatés sont particulièrement bien appropriés pour une application par voie topique ou intraveineuse ou intraartérielle. La composition peut être utilisée pour traiter des troubles de la peau et de tissus ano-rectaux, des troubles de l'endothélium vasculaire, et d'autres troubles.
PCT/US2016/039542 2015-06-26 2016-06-27 Formulations de l-carnosine et de zinc et méthodes d'utilisation Ceased WO2016210409A1 (fr)

Applications Claiming Priority (2)

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US201562185284P 2015-06-26 2015-06-26
US62/185,284 2015-06-26

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WO2016210409A1 true WO2016210409A1 (fr) 2016-12-29

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0466029A2 (fr) * 1990-07-06 1992-01-15 Zeria Pharmaceutical Co., Ltd. Agents préventifs et curatifs pour les inflammations intestinales contenant comme ingrédient actif un sel ou un complexe de zinc-L-carnosine
EP0914826A1 (fr) * 1996-07-17 1999-05-12 Zeria Pharmaceutical Co., Ltd. Accelerateurs de cicatrisation
CA2259997C (fr) * 1996-07-03 2006-02-21 Zeria Pharmaceutical Co., Ltd. Medicaments pour la prevention/le traitement de la stomatite
JP2009019017A (ja) * 2007-07-13 2009-01-29 Hamari Chemicals Ltd 皮膚用剤
US20130142869A1 (en) * 2011-12-05 2013-06-06 Phillip Alex Compositions Comprising Non Steroidal Anti-inflammatory Drugs and Methods for Use Thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0466029A2 (fr) * 1990-07-06 1992-01-15 Zeria Pharmaceutical Co., Ltd. Agents préventifs et curatifs pour les inflammations intestinales contenant comme ingrédient actif un sel ou un complexe de zinc-L-carnosine
CA2259997C (fr) * 1996-07-03 2006-02-21 Zeria Pharmaceutical Co., Ltd. Medicaments pour la prevention/le traitement de la stomatite
EP0914826A1 (fr) * 1996-07-17 1999-05-12 Zeria Pharmaceutical Co., Ltd. Accelerateurs de cicatrisation
JP2009019017A (ja) * 2007-07-13 2009-01-29 Hamari Chemicals Ltd 皮膚用剤
US20130142869A1 (en) * 2011-12-05 2013-06-06 Phillip Alex Compositions Comprising Non Steroidal Anti-inflammatory Drugs and Methods for Use Thereof

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
A. SAMAD ET AL., CURRENT DRUG DELIVERY, vol. 4, 2007, pages 297 - 305
A.R. HIPKISS ET AL., ANN. N.Y. ACAD. SCI., vol. 959, 2002, pages 285 - 294
ANN. N.Y. ACAD. SCI., vol. 959, pages 285 - 294
C. ZHANG ET AL., ARTERIOSCLER THROMB VASC BIOL., vol. 34, 2014, pages 2473 - 2477
CHAUDRY, I.H. ET AL.: "Shock, Sepsis and Organ Failure", 1993, SPRINGER-VERLAG, pages: 73 - 127
K. HIPPALGAONKAR ET AL., APS PARMSCITEC, vol. 11, no. 4, December 2010 (2010-12-01), pages 1526 - 1540
MATSUKURA; TANAKA: "Applicability of Zinc Complex of L-Carnosine", BIOCHEMISTRY (MOSCOW, vol. 65, 2000, pages 817 - 823
S. FURUTA ET AL., JPBA, vol. 19, 1999, pages 453 - 461
S. KANG ET AL., CLIN INVESTMED, vol. 30, no. 3, 2007, pages E133 - E145
SZABO, C.; C. THIERMERMANN, SHOCK, vol. 2, no. 2, 1994, pages 145 - 155
WAHL-JENSEN ET AL., J. VIROL., vol. 79, 2005, pages 10442 - 10450
Y. GURSOY-OZDEMIR ET AL., STROKE, vol. 35, 2004, pages 1449 - 1453

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