WO2013014476A1 - Ear drop compositions and process for producing the ear drop compositions - Google Patents
Ear drop compositions and process for producing the ear drop compositions Download PDFInfo
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- WO2013014476A1 WO2013014476A1 PCT/HU2012/000053 HU2012000053W WO2013014476A1 WO 2013014476 A1 WO2013014476 A1 WO 2013014476A1 HU 2012000053 W HU2012000053 W HU 2012000053W WO 2013014476 A1 WO2013014476 A1 WO 2013014476A1
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- WIPO (PCT)
- Prior art keywords
- adenosine
- mass parts
- compositions
- lecithin
- ear drop
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 46
- 239000003221 ear drop Substances 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 9
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims abstract description 109
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims abstract description 54
- 229960005305 adenosine Drugs 0.000 claims abstract description 54
- 230000004054 inflammatory process Effects 0.000 claims abstract description 26
- 206010061218 Inflammation Diseases 0.000 claims abstract description 24
- 239000000787 lecithin Substances 0.000 claims abstract description 21
- 229940067606 lecithin Drugs 0.000 claims abstract description 21
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 20
- 235000010445 lecithin Nutrition 0.000 claims abstract description 20
- 210000000959 ear middle Anatomy 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 239000013543 active substance Substances 0.000 claims abstract description 5
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 claims description 14
- 239000008347 soybean phospholipid Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000004615 ingredient Substances 0.000 claims description 8
- 235000013311 vegetables Nutrition 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 6
- 239000012266 salt solution Substances 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 4
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 3
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 17
- 239000000243 solution Substances 0.000 description 13
- 238000004020 luminiscence type Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000003714 granulocyte Anatomy 0.000 description 4
- 230000020411 cell activation Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 2
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- 206010011878 Deafness Diseases 0.000 description 2
- 229930010555 Inosine Natural products 0.000 description 2
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 2
- 206010033078 Otitis media Diseases 0.000 description 2
- 241001091465 Sempervivum Species 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000003835 adenosine derivatives Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 231100000895 deafness Toxicity 0.000 description 2
- 235000008995 european elder Nutrition 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 208000016354 hearing loss disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229960003786 inosine Drugs 0.000 description 2
- 210000001539 phagocyte Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 210000003454 tympanic membrane Anatomy 0.000 description 2
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 1
- 240000000073 Achillea millefolium Species 0.000 description 1
- 235000007754 Achillea millefolium Nutrition 0.000 description 1
- 102000009346 Adenosine receptors Human genes 0.000 description 1
- 108050000203 Adenosine receptors Proteins 0.000 description 1
- 240000000662 Anethum graveolens Species 0.000 description 1
- 101100001085 Dictyostelium discoideum ado-2 gene Proteins 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 240000000982 Malva neglecta Species 0.000 description 1
- 235000000060 Malva neglecta Nutrition 0.000 description 1
- 240000000366 Melilotus officinalis Species 0.000 description 1
- 235000017822 Melilotus officinalis Nutrition 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 208000003734 Supraventricular Tachycardia Diseases 0.000 description 1
- 244000178289 Verbascum thapsus Species 0.000 description 1
- 235000010599 Verbascum thapsus Nutrition 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- NFXWJYUDIOHFAW-UHFFFAOYSA-N acetic acid;tetradecanoic acid Chemical compound CC(O)=O.CCCCCCCCCCCCCC(O)=O NFXWJYUDIOHFAW-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000001994 activation Methods 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 150000003838 adenosines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ZMRUPTIKESYGQW-UHFFFAOYSA-N propranolol hydrochloride Chemical compound [H+].[Cl-].C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 ZMRUPTIKESYGQW-UHFFFAOYSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- -1 soy lecithin Chemical compound 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
- A61K9/0046—Ear
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
Definitions
- Ear drop compositions and process for producing the. ear drop compositions are provided.
- the invention relates to an ear drop compositions and a process for producing the ear drop compositions primarily for treating inflammation of the middle ear.
- an inflammatory process runs its course in the hollow system of the middle ear while the eardrum is closed, and the process can be acute or chronic.
- the early recognition of the serous inflammation and the treatment of the inflammation of the middle ear are very important from the viewpoint to avoid the later complications, particularly the later hardness of hearing or deafness.
- the characteristics of the serous inflammation of the middle ear are the abundant thick discharge, which is frequently pus, and the perforation of the eardrum in a great number of cases.
- the patent description HUP 198125 describes a compositions containing an amino acid including a sulfhydryl group, advantageously acetyl-cysteine, an aniiDiotic of amino-glycoside type and steroid inflammation inhibitor compounds for the treatment of the inflammation of the middle ear.
- HUP 196558 cold squeezed juice of elderflower, houseleek, melilot, dill and leaves of mullein is mixed with a mixture of oily yarrow extract, bee-glue extract, juices of elderflower, mallow and houseleek.
- the oily compositions gained in this way is used as ear-drop.
- adenosine compounds being present in the organism, among others the adenosine triphosphate (ATP) and the adenosine diphosphate (ADP) fulfill important biochemical role in the energy household of the organism.
- ATP adenosine triphosphate
- ADP adenosine diphosphate
- Adenosine being intermediate product of the above mentioned compounds, is a purine-nucleoside, which is present in the organism, occurs as four adenosine receptor subtypes : A 1 , A2 A, A2B and A3.
- the molecular mass of adenosine is 267.241 g/mol.
- the concentration of adenosine increases in the cells from the normal value of 300 nM and it can reach even 600 to 1200 nM.
- the increased adenosine concentration in the organism cannot, however, combat or heal the serous inflammation of the middle ear in most cases.
- adenosine derivatives as known inflammation inhibiting active agents, are used for treatment of wounds on the feet occurring in case of diabetes (USP 6020321).
- i n* uuiioiied European patent application EP 0297630 recommends one or more . nucleosides among others adenosine or inosine for the treatment of myasthenia.
- Adenosine is widely used in form of intravenous injection or in infusion in case of supraventricular tachycardia.
- the injection in solution under brand name Adenocor is a known compositions, which is administered intravenously or through a venous cannula for quick restoration of sinal rhythm of the heart.
- compositions in form injection containing adenosine have, however, a number of side effects this is the reason why only certain adenosine derivatives are recently used in cardiologic treatments.
- the adenosine containing compositions have extraordinarily short half-period i. e. they decompose quickly.
- 111V 111 v viniOn relates to compositions of ear drop containing adenosine or a mixture of adenosine and vegetable lecithin - as active agent and known, therapeutically acceptable ingredients.
- compositions of ear drop according to the invention contain advantageously 0.2 to 4.0 mass parts of adenosine, or 0.2 to 4.0 mass parts of adenosine and 0.01 to 1.0 mass parts of vegetable lecithin, particularly soy lecithin, in given case 0.001 to 1.0 mass parts of a therapeutically acceptable ingredient and purified water and/or physiological salt solution in the quantity necessary to the 100 mass parts.
- compositions contain advantageously a stabilizer for example benzoate salts, methyl-p-hydroxy-benzoate, propyl-p-hydroxy-benzoate and other ingredient for example propylene-glycol.
- a stabilizer for example benzoate salts, methyl-p-hydroxy-benzoate, propyl-p-hydroxy-benzoate and other ingredient for example propylene-glycol.
- the invention relates as well to the process for producing ear drop compositions applying adenosine or a mixture of adenosine and lecithin which are applicable for treatment of inflammation of the middle ear.
- the inventive compositions are produced in such a way that 0.2 to 4.0 mass parts of adenosine is mixed with purified water or physiological salt solution, in given case 0.01 to 1.0 mass parts of vegetable lecithin is added to the mixture which previously was solved in water, then in given case 0.001 to 1.0 mass parts of a therapeutically applicable ingredient, advantageously a stabilizer is added to it, then purified water and/or physiological salt solution of quantity necessary to the 100 mass parts is admixed, then the mixture is homogenized then packaged.
- compositions and the process are presented by means of the following examples.
- Example 2 The mixture is homogenized and packaged. Example 2
- soy lecithin 0.1 mass parts of soy lecithin is admixed to 1.34 mass parts (0.5x10 "2 moles) of adenosine in form of aqueous solution.
- Physiological NaCl solution is added to the mixture in the quantity necessary to the 100 mass parts.
- the mixture is homogenized and packaged.
- adenosine as active agent Three types of ear drop containing adenosine as active agent were examined and compared applying individually and in combination with varying concentration (0.5 to 5xl0 '2 moles) of adenosine and identical concentration (1 mg/ml) of soy lecithin found optimal in view of pharmaceutical technology in vitro.
- the inhibiting effects were measured in suspensions of human neutrophylic granulocytes (inflammatory phagocytes) activated with forbol myristate acetate (FMA), as well as in non-activated ones (10 6 cells/ml) in Hank's type culture solution in presence of 10 "7 moles of luminol for chemical luminescence originating from free radicals containing oxygen produced in the cells, using Berthold-type luminometer.
- FMA forbol myristate acetate
- the unit of measure of the chemical luminescence is " KLE", the numbers in the table indicate the KLE values.
- J.. 111 / IfUCU itity of adenosine is 0,5x 10 "2 mole (Adol)
- the soy lecithin produces a small increase of chemical luminescence in the 5 inert cells and it results in hindering of luminescence in the cells stimulated with FMA.
- the adenosine gets free from the lecithin coating and it can create its immediate hindering effect to the cell activation processes.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The subject of the invention is ear drop compositions, which contain adenosine or a mixture of adenosine and lecithin - as active agent. The invention is relating to the process for producing ear drop compositions applying adenosine or a mixture of adenosine and lecithin, which are applicable for treatment of inflammation of the middle ear. ˙
Description
Ear drop compositions and process for producing the. ear drop compositions
The invention relates to an ear drop compositions and a process for producing the ear drop compositions primarily for treating inflammation of the middle ear.
Hundreds of thousands of people, primarily in childhood, get sick each yea with serous inflammation of the middle ear (otitis media) resistant to antibiotics in the whole world.
In the first decade of their life 93% of children get over at least once while 74% of them get over inflammation of the middle ear three or more times. The treatment of inflammations of the middle ear requires also surgical intervention in numerous cases.
In the greater group of cases of inflammation of the middle ear an inflammatory process runs its course in the hollow system of the middle ear while the eardrum is closed, and the process can be acute or chronic.
There is a close relationship between the acute, mostly purulent inflammation of middle ear and the chronic serous one.
It is a widely accepted opinion, that they do not constitute two separate disease entities, but they represent two states of one disease and the chronic serous inflammation of the middle ear is a not healed state of an acute inflammation, which ran its course previously.
The early recognition of the serous inflammation and the treatment of the inflammation of the middle ear are very important from the viewpoint to avoid the later complications, particularly the later hardness of hearing or deafness. The characteristics of the serous inflammation of the middle ear are the abundant thick discharge, which is frequently pus, and the perforation of the eardrum in a great number of cases.
The later hardness of hearing and deafness can be traced back to a serous inflammation of the middle ear in the childhood.
The patent description HUP 198125 describes a compositions containing an amino acid including a sulfhydryl group, advantageously acetyl-cysteine, an
aniiDiotic of amino-glycoside type and steroid inflammation inhibitor compounds for the treatment of the inflammation of the middle ear.
According to the patent description HUP 196558 cold squeezed juice of elderflower, houseleek, melilot, dill and leaves of mullein is mixed with a mixture of oily yarrow extract, bee-glue extract, juices of elderflower, mallow and houseleek.
The oily compositions gained in this way is used as ear-drop.
We set the aim to develop a compositions of ear-drop, which is applicable particularly for the treatment of serous inflammation of the middle ear of childhood, resistant to antibiotic during several weeks or months and the development of serious complication can be prevented or inhibited using it. We established by means of our explorations that the concentration of several inflammatory cytoquinines increases in the ear secretion of children suffering inflammation of the middle ear (Rezes Sz. et al.: American Otologycal Society American Neurotology Society and European Academy of Otology and Neurology (2007), volume 28, issue 5, pp. 663-667).
It is known, that the adenosine compounds being present in the organism, among others the adenosine triphosphate (ATP) and the adenosine diphosphate (ADP) fulfill important biochemical role in the energy household of the organism.
Adenosine, being intermediate product of the above mentioned compounds, is a purine-nucleoside, which is present in the organism, occurs as four adenosine receptor subtypes : A 1 , A2 A, A2B and A3.
The molecular mass of adenosine is 267.241 g/mol.
In case of inflammatory processes the concentration of adenosine increases in the cells from the normal value of 300 nM and it can reach even 600 to 1200 nM.
The increased adenosine concentration in the organism cannot, however, combat or heal the serous inflammation of the middle ear in most cases.
The adenosine derivatives, as known inflammation inhibiting active agents, are used for treatment of wounds on the feet occurring in case of diabetes (USP 6020321).
i n*, uuiioiied European patent application EP 0297630 recommends one or more . nucleosides among others adenosine or inosine for the treatment of myasthenia.
Adenosine is widely used in form of intravenous injection or in infusion in case of supraventricular tachycardia.
The injection in solution under brand name Adenocor is a known compositions, which is administered intravenously or through a venous cannula for quick restoration of sinal rhythm of the heart.
The compositions in form injection containing adenosine have, however, a number of side effects this is the reason why only certain adenosine derivatives are recently used in cardiologic treatments.
It is another disadvantage, that the adenosine containing compositions have extraordinarily short half-period i. e. they decompose quickly.
The published international patent application WO 2007/112986 describes the usage of a mixture of adenosine and inosine as cardiologic compositions for infusion.
While we experimented seeking a compositions adequate for the treatment of inflammation of the middle ear, we found an astonishing result that a significant inflammation inhibiting effect can be reached using an adenosine containing solution introduced into the middle ear through a tube provided with a ventilator even in such cases where antibiotics proved to be useless. There is no compositions applicable for treating the diseases of inflammation of the ear described in the specialized literature, which contains adenosine. While experimenting, we reached an unexpected result that the phagocyte cell activation inhibiting, essentially inflammation inhibiting effect of adenosine can be multiplied in such a way that vegetable lecithin, advantageously soy lecithin is applied additionally to the adenosine.
This unexpected effect may be probably due to the fact that lecithin and adenosine are linked together by secondary bonds.
The adenosine is released in long acting way from the great molecule bound together by secondary bonds and so it can exert a longer inflammation inhibiting effect.
111V 111 v viniOn relates to compositions of ear drop containing adenosine or a mixture of adenosine and vegetable lecithin - as active agent and known, therapeutically acceptable ingredients.
The compositions of ear drop according to the invention contain advantageously 0.2 to 4.0 mass parts of adenosine, or 0.2 to 4.0 mass parts of adenosine and 0.01 to 1.0 mass parts of vegetable lecithin, particularly soy lecithin, in given case 0.001 to 1.0 mass parts of a therapeutically acceptable ingredient and purified water and/or physiological salt solution in the quantity necessary to the 100 mass parts.
The compositions contain advantageously a stabilizer for example benzoate salts, methyl-p-hydroxy-benzoate, propyl-p-hydroxy-benzoate and other ingredient for example propylene-glycol.
The invention relates as well to the process for producing ear drop compositions applying adenosine or a mixture of adenosine and lecithin which are applicable for treatment of inflammation of the middle ear.
According to the process the inventive compositions are produced in such a way that 0.2 to 4.0 mass parts of adenosine is mixed with purified water or physiological salt solution, in given case 0.01 to 1.0 mass parts of vegetable lecithin is added to the mixture which previously was solved in water, then in given case 0.001 to 1.0 mass parts of a therapeutically applicable ingredient, advantageously a stabilizer is added to it, then purified water and/or physiological salt solution of quantity necessary to the 100 mass parts is admixed, then the mixture is homogenized then packaged.
The compositions and the process are presented by means of the following examples.
Example 1
1.34 mass parts (0.5xl0"2 moles) of adenosine is mixed with physiological sodium chloride solution.
The mixture is homogenized and packaged.
Example 2
0.1 mass parts of soy lecithin is admixed to 1.34 mass parts (0.5x10"2 moles) of adenosine in form of aqueous solution. Physiological NaCl solution is added to the mixture in the quantity necessary to the 100 mass parts.
The mixture is homogenized and packaged.
Example 3
One proceeds in all according to the Example 2 but the quantity of adenosine is 2.67 mass parts (lxlO'2 moles) and the quantity of soy lecithin is 0.02 mass parts.
Example 4
One proceeds in all as in the Example 2 but in addition 0.001 mass parts of methyl-p-hydroxy-benzoate is added to the mixture.
Example 5
Pharmacological example
Three types of ear drop containing adenosine as active agent were examined and compared applying individually and in combination with varying concentration (0.5 to 5xl0'2 moles) of adenosine and identical concentration (1 mg/ml) of soy lecithin found optimal in view of pharmaceutical technology in vitro. The inhibiting effects were measured in suspensions of human neutrophylic granulocytes (inflammatory phagocytes) activated with forbol myristate acetate (FMA), as well as in non-activated ones (106 cells/ml) in Hank's type culture solution in presence of 10"7 moles of luminol for chemical luminescence originating from free radicals containing oxygen produced in the cells, using Berthold-type luminometer.
The unit of measure of the chemical luminescence is " KLE", the numbers in the table indicate the KLE values.
The result of the examinations are the following:
J.. 111 / IfUCU itity of adenosine is 0,5x 10"2 mole (Adol)
2. the quantity of adenosine is l,0x 10"2 mole (Ado2)
3. the quantity of adenosine is 5, Ox 10"2 mole (Ado3)
4. soy lecithin solved in water (lmg/ml) (solution 4)
5 5. 0,5x 10"2 mole of adenosine + soy-lecithin (Ado5)
6. l,0x 10"2 mole of adenosine + soy-lecithin (Ado6)
7. 5,0x 10"2 mole of adenosine + soy-lecithin (Ado7)
These solutions exerted their effects in the reaction mixture being diluted in 0 proportion of 1 :6.
The results of the examination are as follows.
Table 1
The influence of the solution of 0.5 x 10" mole of adenosine according to Example 2 (Adol) and 1 mg/ml of soy lecithin (solution 4) to the chemical luminescence (KLU) of human neutrophylic granulocytes induced with FMA during its individual application and in combination (Ado5).
Table 2
The influence of the solution of 1 x 10"2 mole of adenosine according to the Example 2 (Adol) and 1 mg/ml of soy lecithin (solution 4) to the chemical 5 luminescence (KLU) of human neutrophylic granulocytes induced with FMA during its individual application and in combination (Ado6).
Cells + Adol +
Cells Cells + Adol Cells + FMA FMA
589 131 1919 1374
Cells + Cells + lecithin + Cells + lecithin + Cells + Ado6 + lecithin Ado6 FMA FMA
876 415 935 163
Table 3
5 The influence of the solution of 5 x 10"2 moles of adenosine according to the Example 2 (Ado3) and 1 mg/ml of soy lecithin to the chemical luminescence (KLU) of human neutrophylic granulocytes induced with FMA during its individual application and in combination (Ado7).
1. The adenosine hindered chemical luminescence of non-stimulated human neutrophylic cells, as well as those stimulated with FMA in increasing degree depending on its concentration.
2. The soy lecithin produces a small increase of chemical luminescence in the 5 inert cells and it results in hindering of luminescence in the cells stimulated with FMA.
A possible explanation of this phenomenon is that the lecithin emulsion enters the cells and produces a slight activation of cells.
ine activating effect of FMA becomes effective in smaller extent at the same time in the activated cells.
3. The lecithin of lmg/ml applied in the same solutions in addition to the adenosine in increasing concentrations unexpectedly increased "made potentiation" the chemical luminescence inhibiting influence of adenosine mainly in the cells activated with FMA and at the concentration of 1.0 x 10" moles of adenosine in the sample Ado7.
This phenomenon can be explained in such a way that the optimal physic- chemical connection between the molecules of adenosine and lecithin can come into being at this concentration of adenosine and in the course of that adenosine-lecithin bound by secondary bonds enters the cells.
In the cytoplasm the adenosine gets free from the lecithin coating and it can create its immediate hindering effect to the cell activation processes.
Claims
1. Compositions of ear drop ch aract eri z e d b y that it contains adenosine - or a mixture of adenosine and lecithin as active agent. 2. The compositions of ear drop according to the Claim 1 ch ara cte riz ed by that it contains 0.2 to 4.0 mass parts of adenosine or 0.
2 to 4 mass parts of adenosine and 0.01 to 1.0 mass parts of vegetable lecithin, advantageously 0.001 to 1 mass parts of a therapeutically applicable ingredient, and purified water and/or physiological salt solution in a quantity necessary to 100 mass parts.
3. The compositions of ear drop according to any of the Claims 1 or 2 ch ar a ct erize d by th at it contains soy lecithin as vegetable lecithin.
4. The compositions of ear drop according to any of the Claims 1 to 3 ch ara ct e riz e d by th at the ingredient advantageously a stabilizer for example benzoate salts, methyl-p-hydroxy-benzoate or propyl-p- hydroxy-benzoate.
5. The compositions of ear drop according to any of the Claims 1 to 3 ch ara ct e ri z ed by th at it contains propylene glycol as ingredient.
6. Process for producing ear drop compositions applying adenosine or a mixture of adenosine and lecithin, which are applicable for treatment of inflammation of the middle ear ch aract er i z e d b y th at 0.2 to 4.0 mass parts of adenosine is mixed with purified water or physiological salt solution, in given case 0.01 to 1.0 mass parts of vegetable lecithin is added to the mixture, which previously was solved in water, then in given case a therapeutically applicable ingredient, advantageously a stabilizer is admixed to the mixture in a mass proportion of 0.001 to 1.0 mass parts, then purified water and/or physiological salt solution is added to it in a quantity necessary to 100 mass parts, then the mixture is homogenized and packaged.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP1100394 | 2011-07-22 | ||
| HU1100394A HU227743B1 (en) | 2011-07-22 | 2011-07-22 | Eardrop composition and process for producing this |
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| Publication Number | Publication Date |
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| WO2013014476A1 true WO2013014476A1 (en) | 2013-01-31 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2012/000053 WO2013014476A1 (en) | 2011-07-22 | 2012-06-21 | Ear drop compositions and process for producing the ear drop compositions |
Country Status (2)
| Country | Link |
|---|---|
| HU (1) | HU227743B1 (en) |
| WO (1) | WO2013014476A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0297630A1 (en) | 1987-01-20 | 1989-01-04 | Wolfgang Frankhof | Medicine containing local anesthetics and nucleosides |
| WO1997029756A1 (en) * | 1996-02-21 | 1997-08-21 | Inspire Pharmaceuticals, Inc. | Method of treating otitis media with uridine triphosphates and related compounds |
| US5965549A (en) * | 1995-06-06 | 1999-10-12 | Bayer Aktiengesellschaft | Ciprofloxacin-hydrocortisone suspension |
| US6020321A (en) | 1993-04-15 | 2000-02-01 | New York University | Adenosine receptor agonists for the promotion of wound healing |
| WO2007112986A1 (en) | 2006-03-31 | 2007-10-11 | Adenobio N.V. | Compositions, methods, and kits using adenosine and inosine in combination for diagnosis and treatment |
-
2011
- 2011-07-22 HU HU1100394A patent/HU227743B1/en not_active IP Right Cessation
-
2012
- 2012-06-21 WO PCT/HU2012/000053 patent/WO2013014476A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0297630A1 (en) | 1987-01-20 | 1989-01-04 | Wolfgang Frankhof | Medicine containing local anesthetics and nucleosides |
| US6020321A (en) | 1993-04-15 | 2000-02-01 | New York University | Adenosine receptor agonists for the promotion of wound healing |
| US5965549A (en) * | 1995-06-06 | 1999-10-12 | Bayer Aktiengesellschaft | Ciprofloxacin-hydrocortisone suspension |
| WO1997029756A1 (en) * | 1996-02-21 | 1997-08-21 | Inspire Pharmaceuticals, Inc. | Method of treating otitis media with uridine triphosphates and related compounds |
| WO2007112986A1 (en) | 2006-03-31 | 2007-10-11 | Adenobio N.V. | Compositions, methods, and kits using adenosine and inosine in combination for diagnosis and treatment |
Non-Patent Citations (3)
| Title |
|---|
| ANONYMOUS: "Adenocor(R)", 31 December 2008 (2008-12-31), pages 1 - 3, XP002683906, Retrieved from the Internet <URL:http://www.racgp.org.au/cmi/swcadeno.pdf> [retrieved on 20120918] * |
| CRONSTEIN B N: "ADENOSINE REGULATION OF NEUTROPHIL FUNCTION AND INHIBITION OF INFLAMMATION VIA ADENOSINE RECEPTORS", PURINERGIC APPROACHES IN EXPERIMENTAL THERAPEUTICS, WILEY-LISS INC, US, 1 January 1997 (1997-01-01), pages 285 - 299, XP009080711 * |
| REZES SZ. ET AL., AMERICAN OTOLOGYCAL SOCIETY AMERICAN NEUROTOLOGY SOCIETY AND EUROPEAN ACADEMY OF OTOLOGY AND NEUROLOGY, vol. 28, no. 5, 2007, pages 663 - 667 |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP1100394A2 (en) | 2011-12-28 |
| HU227743B1 (en) | 2012-02-28 |
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