WO2012131412A2 - Pharmaceutical composition containing no, process for the preparation and use thereof - Google Patents
Pharmaceutical composition containing no, process for the preparation and use thereof Download PDFInfo
- Publication number
- WO2012131412A2 WO2012131412A2 PCT/HU2012/000023 HU2012000023W WO2012131412A2 WO 2012131412 A2 WO2012131412 A2 WO 2012131412A2 HU 2012000023 W HU2012000023 W HU 2012000023W WO 2012131412 A2 WO2012131412 A2 WO 2012131412A2
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- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- composition according
- ferrous
- nitroso
- following
- Prior art date
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)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
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- Animal Behavior & Ethology (AREA)
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Abstract
The invention relates to a pharmaceutical composition comprising NO, wherein the composition comprises as NO-source a zeolite-free transition metal complex, preferably a ferrous-nitroso-sulphate, furthermore one or more lipophil carrier(s) and optionally one or more pharmaceutically acceptable excipient(s). The invention further relates to the process for the preparation of the above-mentioned pharmaceutical composition, and the use thereof as a medicine.˙
Description
Pharmaceutical composition comprising nitrogen monoxide, process for its production and its use
Brief description of the invention
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
Nitrogen-monoxide (NO) has become more and more important in biological-medical research in the last few decades. NO has a highly versatile and extremely important effect in human and other mammal bodies (from now on: mammals). (Although most experiments, experiences and pharmacological results in the literature refer to humans, there is no theoretical and practical obstacle for applying these results on mammals, too. The same applies to our results). There are a vast number of fields where the use of NO proved to be effective. These include (but are not limited to) the following:
- increasing of microcirculation due to its vasodilator effect and thrombocyte-aggregation inhibition in several parts of the body (coronaries, cerebral veins, veins in the limbs);
- influencing of metabolysm, partly in the mythocondria;
- anticarcinogen effect;
- neurotransmitter effect;
- immunoregulatory effect;
- anti-inflammatory effect;
- antifungal, antibacterial and antiviral effect.
The therapeutical and cosmetic use of nitrogen-monoxide has an enormous literature, which discloses various ways of administering this therapeutic compound to the appropriate place. The detailed presentation of these would exceed the knowledge necessary for the state of the art, so we only present one example each to demonstrate the differences from the solution according to the present invention.
One solution is represented by the NO-donor compounds, from which nitrogen-monoxide is released by an enzymatic effect. This solution is summarized by Lehman [Expert Opinion Therapeutic Patents 10,559-574 (2000)].
According to an other solution, the advanced medical device technology provides help in administering the NO- gas to the appropriate place, primarily to the lungs. These devices, such as the so-called Plason device producing NO from the nitrogen in the air can only be used in high quality medical institutions, with medical supervision. Such medical devices are disclosed in EP 141 1908, EP 1301076 and WO 01 /89572, among others.
According to a further solution, 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.
The closest solutions to our invention are the ones using NO that is reversibly attached to various carriers. 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.
It can be seen from the above that clay minerals are widely used as the source of releasable NO. However, these have some disadvantageous features that limit their therapeutic use. By increasing the temperature, NO is released from the zeolites„explosively", which impedes the efficiency of targeted administration in the body. The fast intake can cause numerous complications.
Relating the state of the art we also mention the use of C02 dry baths or sulphurous (hydrogen-sulphide) baths, where the therapeutic gases are not absorbed through the lungs but through the skin (transdermally) to the body.
The problem according to the invention
As it can be seen from the state of the art, 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. For the therapeutic use of NO it is essential to ensure an advantageous drug-release profile, which has not been present in the state of the art so far. Thus, 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). Our presumption, which we also proved was that 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. During 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.
Detailed description of the invention
To solve the above disclosed problem we chose the transdermal method, thus 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. For the realization of the invention 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. However, this process in itself proved insufficient, because when the composition is applied on the skin and contacts air, it becomes ineffective in a few seconds. Thus we searched for and found NO donor molecules that contacting the air at the temperature of the skin can continuosly release the said gas in a standard amount and protect it from the oxigen in the air. The complex compounds of transition metals and the NO molecule proved to be the most suitable for this task. From the complexes formulated by transition metals, the complex of Fe2+-cation, nitroso-ferrous-sulphate was the most efficient. This complex is mixed with lipophils and other necessary excipients and thus a product is formulated that is suitable for the transdermal administration of NO gas in standard conditions.
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. Thus the complex in a lipophilic carrier is suitable for the transdermal use of NO molecules, which is also proved by therapeutic results.
Accordingly, 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:
1-5 w% colloidal silicon dioxide;
10-20 w% cetyl stearyl alcohol;
1- 10 w% nitroso-ferrous-sulphate (ferrous nitroso sulphate);
20-30 w% white vaseline;
2- 15 w% Polisorbate 60;
30-60 w% distilled water;
2- 15 w% liquid paraffin.
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. However, 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. Lastly, 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.
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. We prevent the„explosive" NO release resulting from thermal decomposition and the resulting non- desired drug release profile with a lipophilic carrier, among others. 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. However, 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. A special container can be used to ensure all these conditions. Although we do not want to limit our solution to only one theoretical explanation, we think that
beside the above, the oxidation of Fe2+ cations can protect the NO molecule from the oxygen in the air when applied on the skin, so the molecule can be released from the complex bond intact. The chemical reaction of NO and oxygen consists of complicated redox reactions comprising several steps, wherein the NO and the oxygen with the oxidation of the transition metal finally transforms into a stable, inactive N03 " anion. The redox process is pH-dependent and in an acidic environment it is shifted towards N03 production, but nitrogen oxides of different gas states can also be produced, which can leave the system unchanged. The chemical reactions mentioned so far happen only on the surface of the product that contacts the air, producing pharmacologically indifferent compounds. These processes are undesirable, mainly because they weaken the therapeutic effect. These processes can be prevented by the addition of antioxidants. Out of the several antioxidants tested, dithionite proved to be the most efficient. During our research we found that the use of antioxidants is not necessary, though it is not contraindicated. The spontaneous dissolution of oxygen in a lipophilic medium is so low that the above reactions happen only slowly, in about 30-60 minutes. During this time the product usually exerts its therapeutic effect. It is visible when the product finishes its activity, namely the release of NO gas, because the change of the oxidation rate (from Fe2+ to Fe3+, in case of iron) involves a characteristic colour change. Although we have already demonstrated the novelty of our invention, we would like to underline that the transition of Fe2+ into Fe3+ , which has a key importance in the release of NO in our solution, is not disclosed in any other known patent applications. During the application of the cream the layer contacting the air is transformed into a film-type ferri-compound, which slows down oxidation in the layer below.
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. Thus, 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. For this purpose 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.
Examples
Various compositions were prepared according to the above discussed considerations, and the following proved to be the most advantageous of them
Colloidal silicon dioxide 1 g Cetyl-stearyl alcohol
Nitroso-ferrous-sulphate White vaseline 5 g
Polisorbate 60 5 g Distilled water 47 g
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).
The efficiency of the invention is demonstrated below
We analyzed the efficiency of the invention mainly in chronic ischaemic conditions (arteriosclerosis obliterans). We examined how the length of walk changed before and after the use of the cream. It was surprising that the length of walk increased from 5- 10 m to 7-200 m in some cases, in other cases from 20-50- 100 m to 500-800 m and in a few cases to 1000-4000 m. (t-test: P<0,02; Wilcoxon test: P<0,001 ). The skin temperature of the limbs increased due to the improvement of microcirculation. The above described parameters improved in 1 -3 weeks from the start of the treatment and then they stabilized permanently. We provide the research data in Table 1. As it can be seen, we supply the initial data on the length of walk before treatment, then the length of walk after 3 months, after the continuous treatment with the cream. It took 1 -3 weks for the patients to have their pains alleviated and to increase their length of walk, which was constant from week 3 till the end of the third month. The research was done on males with the average age of 67.
Table 1 : The increase in the length of walk as a result of the treatment at the end of the 3rd month
5.20
3.00
65.00
3.33 6.00
25.71 3.43 6.67 4.57 2.50 2.00 3.08
Median: 75 600
We proved by mathematical methods that there is a significant difference between the walks of length before and after the treatment. This is shown by the t-test (PO.002) and the Wilcoxon test (PO.0001 ). (In case of the t test the difference was less significant because of the relatively broad scope, while the Wilcoxon test was strongly significant due to the big differences in the length of walk) As 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. With the so amended data the 2-tailed t-test shows a difference in a significance level of p<0,001 , so the level of significance is higher, despite the fact that the difference of both the means and the medians decreased.
Table 1 : The increase in the length of walk as a result of the treatment at the end of the 3rd month, omitting Nr 3.
What is the effect of mechanism of transdermally administered NO? 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. Besides, there can be other enzyme effects, for example the 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. Here the extra-synaptic transmittal is also possible (See E. Sylvester Vizi: John Wiley and Sons, Chichester, New York, 1984).
Industrial applicability of the invention
Based on our own evidences and the literature, it was obvious and convincing that the locally used NO (in the form of a liquid, ointment, gel or cream) has a general effect and can be used very effectively in various disorders. These include the following: 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. It is known that the NO content of the body
decreases in elders (Komori et al.: J. Vase. Surg., 26: 657-662, 1997; Wang et al.: Zhongg uo Zhong Xi Ji He Za Zhi, 20/ 1 1 /: 828-830, 2000/ abstract). In case of patients suffering from vasoconstriction in the legs the transdermal administration of NO results in an increase in the length of walk that can be 5, 10 or 20 times as compared to the effect of vasodilator medicines used in medical practice.
Claims
1. A pharmaceutical composition comprising nitrogen-monoxide (NO) that as NO source contains a zeolite-free transition metal-NO complex, preferably a ferrous-nitroso-complex; one or more lipohilic carriers and optionally one or more further excipients.
2. The pharmaceutical composition according to Claim 1 wherein the NO source comprises one or more substances selected from the following: ferrous-nitroso-complexes, preferably nitroso-ferrous salts, preferably ferrous-nitroso-sulphate.
3. The pharmaceutical composition according to any of Claims 1 -2 that comprises 0.1 - 10 w%, preferably 1 - 10 w%, more preferably 2-4 w% NO source.
4. The pharmaceutical composition according to any of Claims 1 -3 wherein the lipophilic carrier is an oil-in- water type emulsion.
5. The pharmaceutical composition according to any of Claims 1 -3 wherein the lipophilic carrier is one or more substances selected from the following: white vaseline, liquid paraffin and Polysorbate 60.
6. The pharmaceutical composition according to any of Claims 1 -5 wherein one or more excipients are selected from the following: silicon compounds, preferably silicon dioxide, more preferably colloidal silicon dioxide, fatty alcohols with medium carbon number, preferably cetyl-stearyl-alcohol, antioxidants, preferably dithionite, dimethyl-sulphoxyde, cyclodextrines, absorbents and distilled water.
7. The pharmaceutical composition according to any of Claims 1 -5 that comprises the following:
1-5 w% colloidal silicon dioxide;
10-20 w% cetyl stearyl alcohol;
1- 10 w% nitroso ferrous-sulphate (ferrous-nitroso-sulphate);
20-30 w% white vaseline;
2- 15 wg% Polysorbate 60;
30-60 w% distilled water;
2- 15 w% liquid paraffin.
8. The pharmaceutical composition according to any of Claims 1 -7, wherein the dosage form is selected from the following: ointment, cream, gel, liquid, spray or patch.
9. Process for the preparation of the pharmaceutical composition according to any of Claims 1 -7, wherein the ingredients of any of Claim 1 -7 are mixed into a homogeneous emulsion by the conventional pharmaceutial methods, and stored in a special container, if desired.
10. The process according to Claim 8, wherein the storage is at low temperature, keeping away from oxygen.
1 1. The pharmaceutical composition according to any of Claims 1 -8 for use in therapy.
12. The pharmaceutical composition according to any of Claims 1 -8 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
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EP12725876.2A EP2691087A2 (en) | 2011-03-31 | 2012-03-30 | Pharmaceutical composition containing no, process for the preparation and use thereof |
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HUP1100176 | 2011-03-31 | ||
HUP1100176 | 2011-03-31 |
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Cited By (1)
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EP3860621A4 (en) * | 2018-10-05 | 2022-07-06 | Ampersand Biopharmaceuticals, Inc. | Iron formulations for topical administration and methods of treatment of iron deficiency |
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