SK280463B6 - Aerosol pharmaceutical composition for decreasing the blood pressure - Google Patents
Aerosol pharmaceutical composition for decreasing the blood pressure Download PDFInfo
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- SK280463B6 SK280463B6 SK922-95A SK92295A SK280463B6 SK 280463 B6 SK280463 B6 SK 280463B6 SK 92295 A SK92295 A SK 92295A SK 280463 B6 SK280463 B6 SK 280463B6
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- nifedipine
- weight
- solution
- blood pressure
- ethyl oleate
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- 230000036772 blood pressure Effects 0.000 title claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 239000000443 aerosol Substances 0.000 title abstract description 4
- 230000003247 decreasing effect Effects 0.000 title abstract description 3
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims abstract description 40
- 229960001597 nifedipine Drugs 0.000 claims abstract description 38
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims abstract description 24
- 229940093471 ethyl oleate Drugs 0.000 claims abstract description 24
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 9
- 239000000654 additive Substances 0.000 claims abstract description 4
- 239000007921 spray Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 abstract description 12
- 229960004063 propylene glycol Drugs 0.000 abstract 1
- 235000013772 propylene glycol Nutrition 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 31
- 235000019441 ethanol Nutrition 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000001077 hypotensive effect Effects 0.000 description 4
- 210000002200 mouth mucosa Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 206010002383 Angina Pectoris Diseases 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- OJYGBLRPYBAHRT-IPQSZEQASA-N chloralose Chemical compound O1[C@H](C(Cl)(Cl)Cl)O[C@@H]2[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]21 OJYGBLRPYBAHRT-IPQSZEQASA-N 0.000 description 1
- 229950009941 chloralose Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- MCTRZKAKODSRLQ-UHFFFAOYSA-N dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 MCTRZKAKODSRLQ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 230000009474 immediate action Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000012866 low blood pressure Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
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- 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
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- 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
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Abstract
Description
Oblasť technikyTechnical field
Vynález sa týka farmaceutického prípravku na znižovanie krvného tlaku. Konkrétne sa týka rozprašovateľného roztoku nifedipínu (t. j. 4-(2-nitrofenyl)-2,6-dimetyl-3,5-dimetoxykarbonyl-l,4-dihydropyridínu), ktorý’ obsahuje 1 až 5 % hmotnostných nifedipínu, 5 až 24 % hmotnostných polyetylénglykolu, 50 až 70 % hmotnostných etanolu, 10 až 30 % hmotnostných propylénglykolu a 0,1 až 0,5 % hmotnostných prísad.The invention relates to a pharmaceutical composition for lowering blood pressure. In particular, it relates to a sprayable solution of nifedipine (ie 4- (2-nitrophenyl) -2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydropyridine) containing 1 to 5% by weight nifedipine, 5 to 24% by weight polyethylene glycol, 50 to 70% ethanol, 10 to 30% propylene glycol, and 0.1 to 0.5% additives.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Je známe, že krvný obeh je účinne regulovaný 4-(2-nitrofenyl)-2,6-dimetyl-3,5-dimetoxykarbonyl-l,4-dihydropyridínom, známym pod medzinárodne používaným názvom nifedipín, ktorý je preto široko používaný v rôznych typoch farmaceutických prípravkov na liečbu chorobných stavov spojených s krvným obehom.It is known that blood circulation is efficiently regulated by 4- (2-nitrophenyl) -2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-dihydropyridine, known under the internationally used name of nifedipine, which is therefore widely used in various types pharmaceutical preparations for the treatment of circulatory conditions.
Nízka rozpustnosť nifedipínu je vážnym problémom pokiaľ ide o absorpciu z pevných farmaceutických prípravkov, rovnako ako v prípade udržania nifedipínu v rozpustenom stave v prípade kvapalných farmaceutických prípravkov. Uvedené ťažkosti sa často riešia prídavkom veľkých množstiev povrchovo aktívnych činidiel k farmaceutickým prípravkom.The low solubility of nifedipine is a serious problem in terms of absorption from solid pharmaceutical formulations, as well as in the case of keeping nifedipine in the dissolved state for liquid pharmaceutical formulations. These difficulties are often solved by adding large amounts of surfactants to the pharmaceutical compositions.
V poslednom čase sú k dispozícii pevné farmaceutické prípravky na báze nifedipínu, ktoré majú buď relatívne predĺžené pôsobenie alebo relatívne rýchle pôsobenie po podaní. Liečba anginóznych záchvatov alebo náhlych hypertonických stavov však vyžaduje jednoduchý postup podania a okamžité pôsobenie po ňom. V zásade sú tieto požiadavky splnené skôr pri kvapalných farmaceutických prípravkoch, predovšetkým pri rozprašovacích roztokoch.Recently, solid nifedipine-based pharmaceutical formulations have been available which have either a relatively prolonged action or a relatively rapid action after administration. However, the treatment of angina attacks or sudden hypertonic conditions requires simple administration and immediate action thereafter. In principle, these requirements are met earlier for liquid pharmaceutical preparations, in particular for spray solutions.
V spise DE-P 33 07 422 je opísaný roztok, ktorý môže byť podávaný buď perorálne vo forme kvapiek alebo ako intravenózna infúzia. Známy roztok obsahuje 0,5 až 10 % hmotnostných derivátu dihydropyridínu, napríklad nifedipínu, 20 až 60 hmotnostných prostriedku podporujúceho rozpustnosť, prednostne esteru glyceryl-poly(etylénglykolu) a 80 až 40 % hmotnostných riedidla tvoreného vodou, etanolom, propylénglykolom a/alebo polyetylénglykolom. Nevýhoda týchto známych prípravkov spočíva v trocha vysokom obsahu povrchovo aktívneho činidla, ktoré môže viesť k podráždeniu ústnej sliznice v prípade perorálneho podania.DE-P 33 07 422 discloses a solution which can be administered either orally in the form of drops or as an intravenous infusion. The known solution contains 0.5 to 10% by weight of a dihydropyridine derivative, for example nifedipine, 20 to 60% by weight solubility aid, preferably glyceryl-poly (ethylene glycol) ester, and 80 to 40% by weight of a diluent consisting of water, ethanol, propylene glycol and / or polyethylene glycol. A disadvantage of these known formulations lies in the slightly high surfactant content which may lead to oral mucosal irritation.
Rozprašovací roztok je známy zo spisu DE-P 35 44 692, kde je derivát dihydropyridínu, ako je nifedipín, rozpustený v polyetylénglykole a etanole, prípadne v prítomnosti vody a glycerolu, a roztok obsahuje 3 až 15 % hmotnostných polyvinylpyrolidónu. Podľa opisu má účinná zložka farmaceutického prípravku rýchle pôsobenie, ale nevýhodou tohto známeho prípravku je, že polyvinylpyrolidón ľahko tvorí pevný film a rozprašovacia dýza sa preto často upcháva v dôsledku vysychania polyvinylpyrolidónu. Aj keď dýza nie je upchaná úplne, stáva sa množstvo dávkovaného rozprašovaného nifedipínu v prítomnosti polyvinylpyrolidónu neistým, pretože rozprašovaná dávka je nižšia než požadované množstvo do času, než sa polyvinylpyrolidón, odlúčený v dýze, vymyje rozpúšťadlom. Ak sa teda tento známy farmaceutický prípravok používa zriedka, je rozprášené množstvo vždy nižšie než predpísaná dávka.The spray solution is known from DE-P 35 44 692, wherein a dihydropyridine derivative such as nifedipine is dissolved in polyethylene glycol and ethanol, optionally in the presence of water and glycerol, and the solution contains 3 to 15% by weight of polyvinylpyrrolidone. According to the disclosure, the active ingredient of the pharmaceutical composition has a rapid action, but the disadvantage of this known composition is that polyvinylpyrrolidone easily forms a solid film and the spray nozzle is therefore often clogged due to the drying of the polyvinylpyrrolidone. Although the nozzle is not completely clogged, the amount of sprayed nifedipine dosed in the presence of polyvinylpyrrolidone becomes uncertain, since the spray rate is lower than the required amount until the polyvinylpyrrolidone separated in the nozzle is washed out with the solvent. Thus, when this known pharmaceutical preparation is rarely used, the spray amount is always lower than the prescribed dose.
Zo spisu EP 190 292 je známy farmaceutický prípravok, ktorý môže byť prevedený do aerosólu. Prípravok pozostáva z nifedipínu rozpusteného v rozpúšťadle, obsahujúcom polyetylénglykol a/alebo glyceryl-poly(etylénglykol)EP 190 292 discloses a pharmaceutical preparation which can be converted into an aerosol. The formulation consists of nifedipine dissolved in a solvent containing polyethylene glycol and / or glyceryl poly (ethylene glycol)
-oxystearát a roztok sa rozprašuje pomocou propelantu alebo pumpy do prúdu nosného plynu. Podľa príkladov v opise je rozpúšťadlo tvorené etanolom, ktorý môže obsahovať taktiež vodu a glycerol. V niektorých príkladoch je uvedený taktiež prípravok vhodný na sublingválnu aplikáciu.the oxystearate and the solution is sprayed with a propellant or pump into the carrier gas stream. According to the examples, the solvent is ethanol, which may also contain water and glycerol. In some examples, a formulation suitable for sublingual administration is also disclosed.
Podľa našich výskumov nie je hypotenzívny účinok známych farmaceutických prípravkov dostatočný na účinnú liečbu anginóznych záchvatov alebo náhlych hypertonických stavov.According to our research, the hypotensive effect of known pharmaceutical preparations is not sufficient to effectively treat angina attacks or sudden hypertonic conditions.
Cieľom vynálezu je nájsť roztok, ktorý môže byť rozprašovaný pomocou pumpy a je vhodný na sublingválnu aplikáciu a aj v nízkej dávke znižuje v krátkom čase krvný tlak.It is an object of the present invention to find a solution which can be sprayed by a pump and is suitable for sublingual administration and also low blood pressure in a short time.
Podstata vynálezuSUMMARY OF THE INVENTION
Bolo zistené, že uvedený cieľ spĺňa roztok nifedipínu, vo forme spreja, obsahujúci okrem bežných zložiek nifedipínových roztokov 2 až 4 % hmotnostných etyloleátu.It has been found that a spray solution containing nifedipine containing 2-4% w / w ethyl oleate in addition to the conventional components of the nifedipine solutions has met this objective.
Je prekvapujúce, že hypotenzívny účinok nifedipínu sa významne zvyšuje v prítomnosti 2 až 4 % hmotnostných etyloleátu, t. j. medzi nifedipínom a 2 až 4 % hmotnostnými etyloleátu (percentuálny podiel etyloleátu je vztiahnutý na celkovú hmotnosť prípravku) je pozorovaná synergia. Táto synergia bola preukázaná nasledujúcim testom:It is surprising that the hypotensive effect of nifedipine is significantly increased in the presence of 2-4% by weight of ethyl oleate, i. j. between nifedipine and 2-4% by weight of ethyl oleate (the percentage of ethyl oleate based on the total weight of the formulation), synergy is observed. This synergy was demonstrated by the following test:
Pri pokusoch boli použité samce krýs LATI a Charles River, ktoré boli spontánne hypertonické. Na každú dávku bolo použitých 8 zvierat s hmotnosťou 250 až 300 g. Zvieratá boli anestetizované i. p. podaním 90 mg/kg chloralózy a 600 mg/kg uretánu, potom boli tracheotomizované a do ľavej femorálnej artérie každej krysy bol zavedený katéter. Krvný tlak bol zisťovaný a kontinuálne zaznamenávaný tlakomerom typu Statham P 23Gb. 30 minút po chirurgickom zákroku bol ponechaný kontrolný čas 10 min. a potom bola na ústnu sliznicu zvierat prenesená skúmaná vzorka a počas ďalších 60 min. bol zaznamenávaný krvný tlak.Male LATI and Charles River rats, which were spontaneously hypertonic, were used in the experiments. For each dose, 8 animals weighing 250-300 g were used. Animals were anesthetized i. p. by administration of 90 mg / kg chloralose and 600 mg / kg urethane, then they were tracheotomized and a catheter was inserted into the left femoral artery of each rat. Blood pressure was measured and continuously recorded with a Statham P 23Gb manometer. A control time of 10 min was left 30 minutes after surgery. and then the test sample was transferred to the oral mucosa of the animals and for a further 60 min. blood pressure was recorded.
Skúmané boli tieto vzorky:The following samples were examined:
- roztok podľa príkladu 1, dávka prenesená na ústnu sliznicu obsahovala 3 mg nifedipínu a 3 % hmotnostné etyloleátu (posledné uvedené číslo je vztiahnuté na hmotnosť aplikovaného roztoku),- the solution according to Example 1, the dose transferred to the oral mucosa contained 3 mg nifedipine and 3% ethyl oleate (the latter figure being based on the weight of the applied solution),
- roztok podobný ako v príklade 1, ale obsahujúci 2,5 % hmotnostného etyloleátu, dávka prenesená na ústnu sliznicu obsahovala 3 mg nifedipínu a 2,5 % hmotnostného etyloleátu (naposledy uvedené číslo je vztiahnuté na hmotnosť aplikovaného roztoku),- a solution similar to that of Example 1 but containing 2,5% ethyl oleate, the oral dose contained 3 mg nifedipine and 2,5% ethyl oleate (the latter figure being based on the weight of the applied solution),
- roztok podobný ako v príklade 1, ale obsahujúci 3,5 % hmotnostného etyloleátu, dávka prenesená na ústnu sliznicu obsahovala 3 mg nifedipínu a 3,5 % hmotnostného etyloleátu (naposledy uvedené číslo je vztiahnuté na hmotnosť aplikovaného roztoku),- a solution similar to Example 1 but containing 3,5% ethyl oleate, the oral dose contained 3 mg nifedipine and 3,5% ethyl oleate (the latter figure being based on the weight of the applied solution),
- roztok podobný ako v príklade 1, ale neobsahujúci etyloleát, dávka prenesená na ústnu sliznicu obsahovala 3 mg nifedipínu,- a solution similar to that in Example 1 but not containing ethyl oleate, the dose transferred to the oral mucosa contained 3 mg nifedipine,
- roztok podobný ako v príklade 1, ale neobsahujúci nifedipín, dávka prenesená na ústnu sliznicu obsahovala 3 % hmotnostné etyloleátu (posledné uvedené číslo je vztiahnuté na hmotnosť aplikovaného roztoku).a solution similar to that of Example 1 but not containing nifedipine, the dose transferred to the oral mucosa contained 3% by weight of ethyl oleate (the latter figure being based on the weight of the applied solution).
V prípade odchýlky od zloženia podľa príkladu 1 bolo zvyšované alebo znižované množstvo rozpúšťadiel v závislosti od zmeny množstva etyloleátu, resp. vynechania nifedipínu. V každom prípade bol zvieratám podaný roztok v množstve obsahujúcom 3 mg nifedipínu. (Bolo podané rovnaké množstvo - 0,103 g roztoku - i v prípade roztoku bez nifedipínu).In the case of deviation from the composition of Example 1, the amount of solvents was increased or decreased depending on the change in the amount of ethyl oleate and the amount of ethyl oleate respectively. omission of nifedipine. In each case, the animals were given a solution containing 3 mg nifedipine. (An equal amount of 0.103 g of solution was administered - even for a solution without nifedipine).
Zníženie krvného tlaku, docielené skúmanými roztokmi, je uvedené v nasledujúcej tabuľke. Zníženie, uvedené v tabuľke, bolo zistené porovnaním krvného tlaku, zaznamenaného po 10, 20, 30, 40, 50 a 60 min. po aplikácii skúmaného roztoku, s hodnotami krvného tlaku nameranými pred podaním roztoku.The blood pressure reduction obtained with the investigated solutions is shown in the following table. The decrease shown in the table was determined by comparing the blood pressure recorded after 10, 20, 30, 40, 50 and 60 min. after application of the test solution, with blood pressure values measured before administration of the solution.
Tabuľka zníženie krvného tlaku v mm Hg skilnaná vzorka 10 20 30 40 50 60 min.po aplikáciiTable of blood pressure reduction in mm Hg squared sample 10 20 30 40 50 60 min.After application
Z uvedených údajov je zrejmé, že hypotenzívny účinok prípravku podľa vynálezu je významne vyšší než súčet hypotenzívnych účinkov jeho zložiek stanovených samostatne. Medzi nifedipínom a etyloleátom teda existuje synergia.From the above data, it is clear that the hypotensive effect of the composition of the invention is significantly higher than the sum of the hypotensive effects of its components determined separately. Thus, there is a synergy between nifedipine and ethyl oleate.
Rozprašovací roztok nifedipinu podľa vynálezu sa pripravuje vytvorením roztoku z 1 až 5 % hmotnostných nifedipínu, 5 až 24 % hmotnostných polyetylénglykolu, 50 až 70 % hmotnostných etanolu, 10 až 30 % hmotnostných propylénglykolu a 0,1 až 0,5 % hmotnostných samých o sebe známych prísad a primiešaním 2 až 4 % hmotnostných etyloleátu do roztoku nifedipinu počas jeho prípravy.The nifedipine spray solution according to the invention is prepared by forming a solution of 1 to 5% by weight nifedipine, 5 to 24% by weight polyethylene glycol, 50 to 70% by weight ethanol, 10 to 30% by weight propylene glycol and 0.1 to 0.5% by weight per se of known ingredients and admixing 2 to 4% by weight of ethyl oleate in the nifedipine solution during its preparation.
Obvykle sa nifedipín rozpustí v zmesi organických rozpúšťadiel alebo v ich časti a k získanému roztoku nifedipínu sa pridajú zostávajúce zložky. Etyloleát sa pridáva k zmesi organických rozpúšťadiel, obsahujúcej nifedipín, buď pred pridaním ostatných zložiek alebo potom.Usually, nifedipine is dissolved in a mixture of organic solvents or a portion thereof, and the remaining components are added to the obtained nifedipine solution. Ethyl oleate is added to the nifedipine-containing organic solvent mixture either before or after the addition of the other ingredients.
Jednu alebo viac prísad môže tvoriť ochuťovacia prísada, farbiaca prísada a pod.The one or more ingredients may be a flavoring agent, a coloring agent and the like.
Získaný roztok sa prednostne prefíltruje a plní do aerosólových nádobiek. Do každej nádobky sa umiestni vhodná pumpa, nádobka sa zataví a vybaví rozprašovacou dýzou. Keďže nifedipín je dosť citlivý proti svetlu, je treba ho podľa týchto operácií pred svetlom chrániť.The solution obtained is preferably filtered and filled into aerosol containers. A suitable pump is placed in each container, the container is sealed and equipped with a spray nozzle. Since nifedipine is fairly sensitive to light, it should be protected from light according to these operations.
Farmaceutický prípravok podľa vynálezu je dobre sublingválne absorbovaný a má značný účinok po veľmi krátkom čase, tzn. je vhodný na účinné ošetrenie anginóznych záchvatov alebo náhlych hypertonických stavov. Rozprašovanie sa uskutočňuje mechanicky pomocou pumpy, takže životne prostredie nie je zaťažované propelentom.The pharmaceutical composition of the invention is well sublingually absorbed and has a considerable effect after a very short time, i. it is suitable for the effective treatment of angina attacks or sudden hypertonic conditions. The spraying is carried out mechanically by means of a pump so that the environment is not burdened with the propellant.
Príklad 2 hmotnostných dielov nifedipinu sa za miešania pri 55 až 60 °C rozpustí v zmesi 10 hmotnostných dielov polyetylénglykolu (molekulová hmotnosť 400) a 64,5 hmotnostných dielov etylalkoholu. K získanému roztoku sa primieša 16,9 hmotnostného dielu propylénglykolu a 3,5 hmotnostného dielu etyloleátu, zmes sa ochladí na 35 °C a za miešania sa pridá 0,1 hmotnostného dielu ochuťovacej prísady. Potom sa postupuje rovnako ako v príklade 1.Example 2 parts by weight of nifedipine are dissolved with stirring at 55 to 60 ° C in a mixture of 10 parts by weight of polyethylene glycol (molecular weight 400) and 64.5 parts by weight of ethyl alcohol. 16.9 parts by weight of propylene glycol and 3.5 parts by weight of ethyl oleate are added to the obtained solution, the mixture is cooled to 35 ° C and 0.1 part by weight of flavoring is added under stirring. The procedure is as in Example 1.
Príklad 3 hmotnostný diel nifedipinu sa za miešania pri 55 až 60 °C rozpusti v 65,4 hmotnostného dielu etylalkoholu, potom sa za stáleho miešania za rovnakej teploty pridá 12 hmotnostných dielov polyetylénglykolu a 19 hmotnostných dielov propylénglykolu. K získanému roztoku sa primiešaExample 3 parts by weight of nifedipine are dissolved in 65.4 parts by weight of ethanol under stirring at 55 to 60 ° C, then 12 parts by weight of polyethylene glycol and 19 parts by weight of propylene glycol are added while stirring at the same temperature. The solution obtained is admixed
2,5 hmotnostného dielu etyloleátu, zmes sa ochladí na 35 °C a pridá sa 0,1 hmotnostného dielu ochuťovacej prísady. Potom sa postupuje rovnako ako v príklade 1.2.5 parts by weight of ethyl oleate, the mixture was cooled to 35 ° C and 0.1 part by weight of flavoring agent was added. The procedure is as in Example 1.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9402193A HU214582B (en) | 1994-07-26 | 1994-07-26 | Spayable antihypertensive composition and process for it`s production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SK92295A3 SK92295A3 (en) | 1996-05-08 |
| SK280463B6 true SK280463B6 (en) | 2000-02-14 |
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ID=10985460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK922-95A SK280463B6 (en) | 1994-07-26 | 1995-07-20 | Aerosol pharmaceutical composition for decreasing the blood pressure |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPH08169829A (en) |
| AT (1) | AT402690B (en) |
| AU (1) | AU699386B2 (en) |
| BE (1) | BE1011413A4 (en) |
| CZ (1) | CZ286399B6 (en) |
| DE (1) | DE19527140A1 (en) |
| EE (1) | EE9500029A (en) |
| FR (1) | FR2722988B1 (en) |
| GB (1) | GB2291593B (en) |
| HR (1) | HRP950374A2 (en) |
| HU (1) | HU214582B (en) |
| IT (1) | IT1277348B1 (en) |
| LT (1) | LT4042B (en) |
| LV (1) | LV11026B (en) |
| PL (1) | PL181069B1 (en) |
| SK (1) | SK280463B6 (en) |
| UA (1) | UA39880C2 (en) |
| YU (1) | YU50795A (en) |
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|---|---|---|---|---|
| US20030095925A1 (en) * | 1997-10-01 | 2003-05-22 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating metabolic disorders |
| US7632517B2 (en) | 1997-10-01 | 2009-12-15 | Novadel Pharma Inc. | Buccal, polar and non-polar spray containing zolpidem |
| JP2001517689A (en) * | 1997-10-01 | 2001-10-09 | フレミントン ファーマシューティカル コーポレイション | Polar or non-polar buccal spray or capsule |
| EP2767163A1 (en) * | 2005-02-17 | 2014-08-20 | Abbott Laboratories | Transmucosal administration of drug compositions for treating and preventing disorders in animals |
| DE102006027794A1 (en) * | 2006-06-16 | 2007-12-20 | Lts Lohmann Therapie-Systeme Ag | Antihypertensive combination wafer |
| FR2906140B1 (en) * | 2006-09-22 | 2008-12-05 | Philippe Perovitch | GALENIC FORM FOR TRANSMUCOSUS ADMINISTRATION OF ACTIVE INGREDIENTS |
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|---|---|---|---|---|
| DE3307422A1 (en) * | 1983-03-03 | 1984-09-06 | Bayer Ag, 5090 Leverkusen | LIQUID PREPARATIONS OF DIHYDROPYRIDINES, A METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN THE FIGHT AGAINST DISEASES |
| EP0175671A1 (en) | 1984-08-23 | 1986-03-26 | Kuhlemann & Co. | Pharmaceutical preparation and method for the administration of this pharmaceutical preparation |
| DE3544692A1 (en) * | 1985-12-18 | 1987-06-19 | Bayer Ag | DIHYDROPYRIDINE SPRAY, METHOD FOR THE PRODUCTION THEREOF AND ITS PHARMACEUTICAL USE |
| EP0240484B1 (en) * | 1986-03-10 | 1992-01-15 | Kurt Dr. Burghart | Pharmaceutical composition and its preparation |
| ES2042527T3 (en) * | 1986-11-14 | 1993-12-16 | Theratech Inc | A METHOD FOR PREPARING A PENETRATION-INCREASING PHARMACEUTICAL COMPOSITION FOR TOPIC APPLICATION. |
| US4863970A (en) * | 1986-11-14 | 1989-09-05 | Theratech, Inc. | Penetration enhancement with binary system of oleic acid, oleins, and oleyl alcohol with lower alcohols |
| JPS63170316A (en) * | 1986-12-30 | 1988-07-14 | Fujimoto Seiyaku Kk | Percutaneously absorbable pharmaceutical of nifedipine for external use |
| DE3714402A1 (en) * | 1987-04-30 | 1988-11-10 | Kali Chemie Pharma Gmbh | DRUG FORMULATION |
| GB8828477D0 (en) * | 1988-12-06 | 1989-01-05 | Riker Laboratories Inc | Medical aerosol formulations |
| AT391269B (en) * | 1988-12-30 | 1990-09-10 | Burghart Kurt | PHARMACEUTICAL PREPARATION |
| US5298258A (en) * | 1989-12-28 | 1994-03-29 | Nitto Denko Corporation | Acrylic oily gel bioadhesive material and acrylic oily gel preparation |
| HU205249B (en) * | 1990-11-09 | 1992-04-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing suspensive aerosole composition |
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1994
- 1994-07-26 HU HU9402193A patent/HU214582B/en unknown
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1995
- 1995-06-27 AU AU23269/95A patent/AU699386B2/en not_active Ceased
- 1995-06-30 HR HRP9402193A patent/HRP950374A2/en not_active Application Discontinuation
- 1995-07-13 CZ CZ19951811A patent/CZ286399B6/en not_active IP Right Cessation
- 1995-07-17 FR FR9508598A patent/FR2722988B1/en not_active Expired - Fee Related
- 1995-07-17 AT AT0121495A patent/AT402690B/en not_active IP Right Cessation
- 1995-07-20 LT LT95-084A patent/LT4042B/en not_active IP Right Cessation
- 1995-07-20 SK SK922-95A patent/SK280463B6/en unknown
- 1995-07-21 JP JP7185275A patent/JPH08169829A/en active Pending
- 1995-07-24 BE BE9500646A patent/BE1011413A4/en not_active IP Right Cessation
- 1995-07-24 PL PL95309757A patent/PL181069B1/en not_active IP Right Cessation
- 1995-07-25 UA UA95073513A patent/UA39880C2/en unknown
- 1995-07-25 GB GB9515205A patent/GB2291593B/en not_active Expired - Fee Related
- 1995-07-25 EE EE9500029A patent/EE9500029A/en unknown
- 1995-07-25 LV LVP-95-225A patent/LV11026B/en unknown
- 1995-07-25 DE DE19527140A patent/DE19527140A1/en not_active Withdrawn
- 1995-07-26 IT IT95MI001621A patent/IT1277348B1/en active IP Right Grant
- 1995-07-26 YU YU50795A patent/YU50795A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CZ181195A3 (en) | 1996-02-14 |
| JPH08169829A (en) | 1996-07-02 |
| EE9500029A (en) | 1996-02-15 |
| PL181069B1 (en) | 2001-05-31 |
| HU9402193D0 (en) | 1994-09-28 |
| ITMI951621A1 (en) | 1997-01-26 |
| CZ286399B6 (en) | 2000-04-12 |
| PL309757A1 (en) | 1996-02-05 |
| UA39880C2 (en) | 2001-07-16 |
| HUT75457A (en) | 1997-05-28 |
| AU699386B2 (en) | 1998-12-03 |
| LV11026B (en) | 1996-04-20 |
| SK92295A3 (en) | 1996-05-08 |
| LT4042B (en) | 1996-09-25 |
| FR2722988B1 (en) | 1999-10-08 |
| ATA121495A (en) | 1996-12-15 |
| GB2291593B (en) | 1998-03-11 |
| HRP950374A2 (en) | 1997-10-31 |
| DE19527140A1 (en) | 1996-02-01 |
| LT95084A (en) | 1996-06-25 |
| ITMI951621A0 (en) | 1995-07-26 |
| HU214582B (en) | 1998-04-28 |
| GB9515205D0 (en) | 1995-09-20 |
| FR2722988A1 (en) | 1996-02-02 |
| LV11026A (en) | 1996-02-20 |
| IT1277348B1 (en) | 1997-11-10 |
| AU2326995A (en) | 1996-02-08 |
| AT402690B (en) | 1997-07-25 |
| GB2291593A (en) | 1996-01-31 |
| BE1011413A4 (en) | 1999-09-07 |
| YU50795A (en) | 1998-05-15 |
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