EP2691087A2 - Pharmazeutische zusammensetzung mit no, verfahren zu ihrer herstellung und verwendung - Google Patents
Pharmazeutische zusammensetzung mit no, verfahren zu ihrer herstellung und verwendungInfo
- 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- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 230000008569 process Effects 0.000 title claims abstract description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 7
- 229910021653 sulphate ion Inorganic materials 0.000 claims abstract description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 134
- 229960003753 nitric oxide Drugs 0.000 claims description 65
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000006071 cream Substances 0.000 claims description 8
- 238000002560 therapeutic procedure Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 5
- 239000012153 distilled water Substances 0.000 claims description 5
- 239000011790 ferrous sulphate Substances 0.000 claims description 5
- 208000028867 ischemia Diseases 0.000 claims description 5
- 229940057995 liquid paraffin Drugs 0.000 claims description 5
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 claims description 5
- 239000003871 white petrolatum Substances 0.000 claims description 5
- 239000000839 emulsion Substances 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 3
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 claims description 3
- 208000007101 Muscle Cramp Diseases 0.000 claims description 3
- 208000000112 Myalgia Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000005392 Spasm Diseases 0.000 claims description 3
- 206010000496 acne Diseases 0.000 claims description 3
- 230000001580 bacterial effect Effects 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- 201000005851 intracranial arteriosclerosis Diseases 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 208000013465 muscle pain Diseases 0.000 claims description 3
- 208000031225 myocardial ischemia Diseases 0.000 claims description 3
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- 230000003612 virological effect Effects 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- 239000002250 absorbent Substances 0.000 claims description 2
- 230000002745 absorbent Effects 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 150000002191 fatty alcohols Chemical class 0.000 claims description 2
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 230000001575 pathological effect Effects 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 150000003377 silicon compounds Chemical class 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 238000003860 storage Methods 0.000 claims description 2
- 230000007704 transition Effects 0.000 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims 2
- 229940113124 polysorbate 60 Drugs 0.000 claims 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 9
- 229910052723 transition metal Inorganic materials 0.000 abstract description 9
- 150000003624 transition metals Chemical class 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 4
- 239000007789 gas Substances 0.000 description 21
- 230000001225 therapeutic effect Effects 0.000 description 16
- 230000000694 effects Effects 0.000 description 13
- 239000000825 pharmaceutical preparation Substances 0.000 description 9
- 229940127557 pharmaceutical product Drugs 0.000 description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 239000010457 zeolite Substances 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 238000012353 t test Methods 0.000 description 4
- 229940124549 vasodilator Drugs 0.000 description 4
- 239000003071 vasodilator agent Substances 0.000 description 4
- 238000000692 Student's t-test Methods 0.000 description 3
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910021536 Zeolite Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 230000004089 microcirculation Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 239000002840 nitric oxide donor Substances 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 208000000575 Arteriosclerosis Obliterans Diseases 0.000 description 1
- 241000819038 Chichester Species 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- -1 Fe2+ cations Chemical class 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000004298 cerebral vein Anatomy 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000002734 clay mineral Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011982 device technology Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000012067 mathematical method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000002120 nanofilm Substances 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- VQTGUFBGYOIUFS-UHFFFAOYSA-N nitrosylsulfuric acid Chemical compound OS(=O)(=O)ON=O VQTGUFBGYOIUFS-UHFFFAOYSA-N 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
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.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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HUP1100176 | 2011-03-31 | ||
PCT/HU2012/000023 WO2012131412A2 (en) | 2011-03-31 | 2012-03-30 | Pharmaceutical composition containing no, process for the preparation and use thereof |
Publications (1)
Publication Number | Publication Date |
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EP2691087A2 true EP2691087A2 (de) | 2014-02-05 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP12725876.2A Withdrawn EP2691087A2 (de) | 2011-03-31 | 2012-03-30 | Pharmazeutische zusammensetzung mit no, verfahren zu ihrer herstellung und verwendung |
Country Status (2)
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EP (1) | EP2691087A2 (de) |
WO (1) | WO2012131412A2 (de) |
Families Citing this family (1)
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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)
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 (de) | 2005-08-23 | 2007-02-28 | NOLabs AB | Vorrichtung, System und Methode enthaltend eine verkapselte Flüssigkeit zur Stickstoffmonoxyd-Freisetzung von einem Polymer |
EP1707224A1 (de) | 2005-02-11 | 2006-10-04 | NOLabs AB | Pharmazeutische Mischung mit Stickstoffmonoxidverstärker, Vorrichtung zu deren Verabreichung und deren Herstellungsverfahren |
WO2006097352A1 (en) | 2005-03-15 | 2006-09-21 | L'oreal | Cosmetic composition containing nitrogen monoxide in a microporous crystalline solid material |
WO2006097349A1 (en) | 2005-03-15 | 2006-09-21 | L'oreal | Cosmetic use of a microporous solid crystalline material no for improving the natural colouring and/or appearance of the skin and/or lips |
WO2006097351A1 (en) | 2005-03-15 | 2006-09-21 | L'oreal | Anhydrous cosmetic composition comprising nitrogen monoxide in a microporous solid crystalline material |
GB0616350D0 (en) | 2006-08-17 | 2006-09-27 | Univ St Andrews | Adsorption and release of nitric oxide in metal organic frameworks |
-
2012
- 2012-03-30 WO PCT/HU2012/000023 patent/WO2012131412A2/en active Application Filing
- 2012-03-30 EP EP12725876.2A patent/EP2691087A2/de not_active Withdrawn
Non-Patent Citations (2)
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None * |
See also references of WO2012131412A2 * |
Also Published As
Publication number | Publication date |
---|---|
WO2012131412A3 (en) | 2012-12-13 |
WO2012131412A2 (en) | 2012-10-04 |
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