EP2691087A2 - Composition pharmaceutique contenant du no, procédé de préparation et utilisation de celui-ci - Google Patents

Composition pharmaceutique contenant du no, procédé de préparation et utilisation de celui-ci

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Publication number
EP2691087A2
EP2691087A2 EP12725876.2A EP12725876A EP2691087A2 EP 2691087 A2 EP2691087 A2 EP 2691087A2 EP 12725876 A EP12725876 A EP 12725876A EP 2691087 A2 EP2691087 A2 EP 2691087A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
ferrous
nitroso
following
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.)
Withdrawn
Application number
EP12725876.2A
Other languages
German (de)
English (en)
Inventor
László Gábor Szabó
István Piller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP2691087A2 publication Critical patent/EP2691087A2/fr
Withdrawn legal-status Critical Current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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K31/04—Nitro compounds
    • 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
    • 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
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • composition comprising nitrogen monoxide, process for its production and its use
  • the present invention relates to a composition comprising nitrogen-monoxide, wherein the nitrogen-monoxide is present as a complex of transition metals, primarily iron, wherein the said metal complexes, mixed with the suitable pharmaceutical excipient can be applied on the skin and thus the nitrogen-monoxide can be administered to a human or mammal body by the diffusion through the skin and thus can exert its therapeutic effect.
  • the invention also relates to the process of the production of the composition according to the invention and its use. Brief description of the state of the art
  • NO Nitrogen-monoxide
  • NO gas is produced on the surface of the skin with a chemical reaction by proportioning of nitrite salts in a reducing environment by mixing two components.
  • Such solutions are disclosed in EP 1328252 and WO 00/53196. However, all these solutions are very far from the solution according to the present invention.
  • WO/2008/020218 discloses organic polymers, where the chelate complexes of different metals are built into. This framework is then used to store the NO molecules. However, the description explicitly refers to organic ligands and chelating agents with 2 or more valences (2-9 valences) that can be used to formulate metal complexes.
  • the metal chelates are embedded in polymers.
  • EP 1707224 discloses an equipment that releases NO from polymers.
  • Polymer compounds are also used in EP 1757278. These compounds comprise specifically crosslinked zeolite, which is capable of storing NO gas. The silicate also contains microcapsulated water and by breaking these capsules, a relatively regulated NO gas release can be ensured.
  • WO/2006/097349, WO/2006/097351 and WO/2006/097352 disclose cosmetic products containing NO and their uses.
  • a common feature of these inventions is that NO complexes of transition metals present in zeolites are disclosed as the source of NO. These documents do not mention any solutions without zeolites.
  • JP 04818108 also relates to NO absorbed in zeolite and its therapeutic use.
  • the main problem of nitrogen-monoxide therapy is the administration of the therapeutic gas to the appropriate place for therapy and there are a great number of attempts to solve this problem.
  • NO it is essential to ensure an advantageous drug-release profile, which has not been present in the state of the art so far.
  • our objective was to provide a pharmaceutical product that would enable to administer NO to the desired place within the body with a better efficiency than the solutions of the state of the art.
  • the invention solves the above disclosed problem by admin istering NO gas transdermally, that is through the skin. Principal discovery of the invention
  • the basic discovery of the invention comes from the former knowledge on skin respiration, to which there are several examples in other fields of medical therapy.
  • Our invention is also based on such pharmaceutical therapy process, a transdermal therapy system (TTS).
  • TTS transdermal therapy system
  • NO gas can be administered to the body through the skin with the necessary efficiency, despite the fact that the state of the art could not present an adequate solution in this respect.
  • Our systematic research we found out the potentials and possible side effects of NO therapy.
  • Our discovery is that although complex NO is undoubtedly a promising candidate for the therapeutic use of NO, an efficient NO release profile also has to be ensured for the desired effect. As a result of this discovery we completed our invention.
  • transdermal method we administer the therapeutic gas to the body through the skin.
  • This is carried out by complexes of transition metals, primarily ferrous complexes, from which transdermally absorbable NO gas is released when said complex is applied on the skin in the form of a spreadable lipophilic substance.
  • a carrier substance is needed that dissolves NO gas in a concentration of at least mmol, which is about a thousand times of the concentration measured in the human tissues.
  • This carrier can primarily be a hydrophobic (lipophilic) formula, especially (but not limited to) a gel, ointment or cream.
  • NO gas can also be administered to the body with a solution of dissolving it in lipophilic substances and then applying on the skin.
  • Said compound when contacting air at the temperature of the skin acts as a loose complex, releases NO ligands in the form of free gas, it is not toxic and does not irritate the skin.
  • the complex in a lipophilic carrier is suitable for the transdermal use of NO molecules, which is also proved by therapeutic results.
  • the present invention relates to a pharmaceutical product comprising nitrogen-monoxide that as NO source comprises a zeolite-free transition metal NO complex, preferably a ferrous-nitroso complex, and also comprises one or more lipophilic carriers and optionally one or more further excipients.
  • the pharmaceutical product according to the present invention preferably contains NO sources selected from the following: ferrous- nitroso complexes, preferably nitroso-ferrous salts, preferably ferrous-nitroso-sulphate.
  • the pharmaceutical product comprises 0.1 - 10 w%, preferably 1 - 10 w%, more preferably 2-4 w% NO source and as lipophilic carrier an oil-in-water type emulsion.
  • the lipophilic carrier in the product is one or more substances selected from the following: white vaseline, liquid paraffin, Polisorbate 60.
  • the pharmaceutical product according to the invention optionally contains one or more of the following excipients: silicon compounds, preferably silicon dioxide, more preferably colloidal silicon dioxide, fatty alcohols with medium carbon number, preferably cetyl-stearyl-alcohol, antioxidants, preferably ascorbic acid, most preferably dithionite, dimethyl-sulphoxyde, cyclodextrines, absorbents and distilled water.
  • the antioxidant can also be ferrous-sulphate when applied in excess.
  • a most preferable form of the pharmaceutical product comprises the following:
  • the dosage forms of the pharmaceutical product according to the invention are not limited, as long as they are capable of ensuring the desired release profile of NO.
  • the especially preferable formula is chosen from (but not limited to) the following: ointment, cream, liquid, spray or patch.
  • the invention also relates to the process of producing any of the pharmaceutical products according to the invention, wherein the above disclosed ingredients are mixed into a homogeneous emulsion with the conventional pharmaceutial methods, . and stored in a special container, if needed. Preferably it is stored at low temperature, away from oxygen.
  • the invention also relates to the therapeutic use of the product according to the invention.
  • the invention relates to the use of the pharmaceutical product according to the invention for the prevention or treatment of pathological conditions selected from the following: limb ischaemia, preferably arteriosclerotic limb ischaemia; ischaemic heart diseases; cerebral arteriosclerosis; mycotic, bacterial and viral inflammations; skin conditions, especially inflammation, acne, psoriasis; muscle pains and spasms; depression; pulmonary hypertension.
  • pathological conditions selected from the following: limb ischaemia, preferably arteriosclerotic limb ischaemia; ischaemic heart diseases; cerebral arteriosclerosis; mycotic, bacterial and viral inflammations; skin conditions, especially inflammation, acne, psoriasis; muscle pains and spasms; depression; pulmonary hypertension.
  • Our invention contains transition metal, primarily iron molecules that by disengaging the complex bonds, release NO gas into a carrier, which can be applied to the skin and from where the NO can be absorbed.
  • the metal complexes are temperature-sensitive and this provides the theoretical background of the problem in the state of the art.
  • An advantage of the product according to our invention as opposed to e.g. the zeolites according to the state of the art - is that the NO content can be varied in a very broad therapeutic scope.
  • the products according to the invention have to be stored below 5°C (at least before use) and kept away from oxygen at all times.
  • the formulation of the product is a special container or tube with flexible walls, because if we store the receptacle (be it a container or a tube) at higher temperature, the pressure can increase. As we noted above, the storage is by all means preferable at low temperature. The lower temperature we store the product at, the longer it retains its vasodilator effect. For example, when the product is chilled the vasodilator effect is retained for months, although the efficiency will slightly decrease.
  • the standard dosage regime of the composition is determined by the solubility parameter of the gas in the carrier based on a given surface.
  • the thickness of the layer does not influence the NO concentration of the molecular film directly contacting the skin, as it depends only on the solubility of the gas.
  • TTS is based on the specific features of the skin, mainly on its barrier function.
  • the composition may comprise a non-absorbing component, which constitutes a film layer on the skin that helps keep the gas close to the surface of the skin.
  • silicon dioxide may be used in a concentration of 0.5 to 5 % of the composition. Finishing the therapy, this layer can easily be removed together with the metal salts, which are also unable to be absorbed.
  • Liquid paraffin 5 g The cream is applied on the skin, primarily on the leg, upper arms, tights, breast or back on a surface of 10x 10 cm evenly, in a relatively thin layer and rather quickly in a quantity of 2-3 g (2-3 ml). The surface is immediately covered with a foil, winding 3-4 layers of it. The foil is removed after about 2 hours. (It does not have to be used in all the cases during the therapy).
  • Table 1 The increase in the length of walk as a result of the treatment at the end of the 3rd month
  • Nr. 3 was very different from the others, according to the usual practice, such data are left out from the database. Usually the data is left out from the evaluation if it is outside +/- 2 S.D. This applied to Nr. 3 so it was left out of Table 2.
  • NO can diffuse into the skin in 1 -3 mm depth. It can be bound intracellularly to the haemoglobin-iron and then activates the guanyl-cyclase. Then cyclic guanyl-monophosphate (cGMP) is produced that relaxes the smooth muscles when getting into the circulation system.
  • cGMP cyclic guanyl-monophosphate
  • NO can be bound to the SH-groups of proteins (nitrosation).
  • An other option is when it creates the vasodilation as a neurotransmitter through the nerve fibers of the skin.
  • the extra-synaptic transmittal is also possible (See E. Sylvester Vizi: John Wiley and Sons, Chichester, New York, 1984).
  • limb ischaemia (Tucker et al.: Lancet, 354: 1670-0675, 1999), primarily arteriosclerotic; ischaemic heart disease; cerebral arteriosclerosis; inflammations (mycotic, bacterial, viral) (Fang: J.Clin.Invest, 99:2818-2825, 1997; Suga et al.: Infect Immun., 61 : 1980- 1989, 1993); skin conditions (inflammation, acne, psoriasis etc.); muscle pains and spasms (skeletal muscle and smooth muscle) (Desai et al.: Nature, 351 : 477-479, 1991 ); depression; pulmonary hypertension.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Inorganic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Urology & Nephrology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)
  • Vascular Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant du NO. Ladite composition comprend, en tant que source de NO, un complexe de métal de transition exempt de zéolite, de préférence un sulfate nitrosé ferreux, et un ou plusieurs vecteurs lipophiles, et éventuellement un ou plusieurs excipients pharmaceutiquement acceptables. L'invention porte en outre sur le procédé de préparation de la composition susmentionnée, et sur son utilisation en tant que médicament.˙
EP12725876.2A 2011-03-31 2012-03-30 Composition pharmaceutique contenant du no, procédé de préparation et utilisation de celui-ci Withdrawn EP2691087A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP1100176 2011-03-31
PCT/HU2012/000023 WO2012131412A2 (fr) 2011-03-31 2012-03-30 Composition pharmaceutique contenant du no, procédé de préparation et utilisation de celui-ci

Publications (1)

Publication Number Publication Date
EP2691087A2 true EP2691087A2 (fr) 2014-02-05

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ID=89621381

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12725876.2A Withdrawn EP2691087A2 (fr) 2011-03-31 2012-03-30 Composition pharmaceutique contenant du no, procédé de préparation et utilisation de celui-ci

Country Status (2)

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EP (1) EP2691087A2 (fr)
WO (1) WO2012131412A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022504310A (ja) * 2018-10-05 2022-01-13 アンパサンド バイオファーマシューティカルズ インコーポレイテッド 局所投与のための鉄製剤および鉄欠乏症の処置の方法

Family Cites Families (13)

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Publication number Priority date Publication date Assignee Title
DE4305881C1 (de) * 1993-02-26 1994-03-03 Lohmann Therapie Syst Lts Transdermales therapeutisches System mit Wirkstoffen, welche Stichoxid-Quellen darstellen, Verfahren zu seiner Herstellung sowie seine Verwendung
US6103275A (en) 1998-06-10 2000-08-15 Nitric Oxide Solutions Systems and methods for topical treatment with nitric oxide
ATE258801T1 (de) 1999-03-10 2004-02-15 Biora Bioex Ab Matrixprotein zusammensetzungen um apoptose zu induzieren
US6601580B1 (en) 2000-06-28 2003-08-05 The General Hospital Corporation Enhancing therapeutic effectiveness of nitric oxide inhalation
GB0021317D0 (en) 2000-08-30 2000-10-18 Queen Mary & Westfield College Transdermal pharmaceutical delivery composition
GB0119011D0 (en) 2001-08-03 2001-09-26 Univ Aberdeen Treatment of nail infections
MXPA05014212A (es) 2003-07-03 2006-08-11 Univ St Andrews Zeolitas para suministro de oxido nitrico.
EP1757278A1 (fr) 2005-08-23 2007-02-28 NOLabs AB Dispositif, système ou méthode contenant un liquide microencapsulé pour la libération d'oxyde nitrique à partir d'un polymère
EP1707224A1 (fr) 2005-02-11 2006-10-04 NOLabs AB Mélange pharmaceutique comprenant du monoxyde d'azote comme amplificateur, dispositif pour appliquer le mélange et son procédé de fabrication
WO2006097352A1 (fr) 2005-03-15 2006-09-21 L'oreal Composition cosmetique contenant du monoxyde d’azote dans un materiau microporeux solide cristallin
WO2006097349A1 (fr) 2005-03-15 2006-09-21 L'oreal Usage cosmetique d’un materiau microporeux solide cristallin (monoxyde d’azote) pour ameliorer la coloration et/ou l’apparence naturelle de la peau et/ou des levres
WO2006097351A1 (fr) 2005-03-15 2006-09-21 L'oreal Composition cosmetique anhydre comprenant du monoxyde d’azote dans un materiau microporeux solide cristallin
GB0616350D0 (en) 2006-08-17 2006-09-27 Univ St Andrews Adsorption and release of nitric oxide in metal organic frameworks

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2012131412A2 *

Also Published As

Publication number Publication date
WO2012131412A3 (fr) 2012-12-13
WO2012131412A2 (fr) 2012-10-04

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