CS261526B1 - Method for pentakaine hydrochloride incorporating into antacide suspension - Google Patents
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- CS261526B1 CS261526B1 CS867813A CS781386A CS261526B1 CS 261526 B1 CS261526 B1 CS 261526B1 CS 867813 A CS867813 A CS 867813A CS 781386 A CS781386 A CS 781386A CS 261526 B1 CS261526 B1 CS 261526B1
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- 239000000725 suspension Substances 0.000 title claims abstract description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims abstract description 13
- 229940069428 antacid Drugs 0.000 claims abstract description 21
- 239000003159 antacid agent Substances 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 17
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 16
- BSMUOLWVMZUZON-MUCZFFFMSA-N [(1r,2r)-2-pyrrolidin-1-ium-1-ylcyclohexyl] n-(3-pentoxyphenyl)carbamate;chloride Chemical compound [Cl-].CCCCCOC1=CC=CC(NC(=O)O[C@H]2[C@@H](CCCC2)[NH+]2CCCC2)=C1 BSMUOLWVMZUZON-MUCZFFFMSA-N 0.000 claims abstract description 16
- 230000001458 anti-acid effect Effects 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims abstract description 14
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 9
- 229940088679 drug related substance Drugs 0.000 claims abstract description 9
- 239000004094 surface-active agent Substances 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 6
- 239000011541 reaction mixture Substances 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 239000000843 powder Substances 0.000 claims abstract description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 4
- 239000011777 magnesium Substances 0.000 claims abstract description 4
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 4
- 239000007864 aqueous solution Substances 0.000 claims abstract description 3
- 230000000694 effects Effects 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 claims description 4
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000292 calcium oxide Substances 0.000 claims description 4
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 4
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims description 4
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 claims description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- 229940068968 polysorbate 80 Drugs 0.000 claims description 4
- 229960001462 sodium cyclamate Drugs 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 claims description 3
- 229940043430 calcium compound Drugs 0.000 claims description 3
- 150000001674 calcium compounds Chemical class 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 2
- 238000001935 peptisation Methods 0.000 claims description 2
- 230000002035 prolonged effect Effects 0.000 claims description 2
- 239000002002 slurry Substances 0.000 claims description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 230000003247 decreasing effect Effects 0.000 claims 1
- 239000003599 detergent Substances 0.000 claims 1
- BUACSMWVFUNQET-UHFFFAOYSA-H dialuminum;trisulfate;hydrate Chemical compound O.[Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O BUACSMWVFUNQET-UHFFFAOYSA-H 0.000 claims 1
- 230000027119 gastric acid secretion Effects 0.000 claims 1
- 238000006386 neutralization reaction Methods 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000012545 processing Methods 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract 1
- HVYGHQWGUABUST-NHCUHLMSSA-N [(1r,2r)-2-pyrrolidin-1-ylcyclohexyl] n-(3-pentoxyphenyl)carbamate Chemical compound CCCCCOC1=CC=CC(NC(=O)O[C@H]2[C@@H](CCCC2)N2CCCC2)=C1 HVYGHQWGUABUST-NHCUHLMSSA-N 0.000 abstract 1
- 229910052791 calcium Inorganic materials 0.000 abstract 1
- 239000011575 calcium Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 239000003589 local anesthetic agent Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229960005015 local anesthetics Drugs 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 206010022998 Irritability Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000001156 gastric mucosa Anatomy 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- QTQPVLDZQVPLGV-UHFFFAOYSA-N oxomemazine Chemical compound C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3S(=O)(=O)C2=C1 QTQPVLDZQVPLGV-UHFFFAOYSA-N 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 230000009858 acid secretion Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 231100000029 gastro-duodenal ulcer Toxicity 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000004682 mucosal barrier function Effects 0.000 description 1
- 229960003045 oxomemazine Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 230000009979 protective mechanism Effects 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- -1 trans-2- (1-pyrrolidinyl) cyclohexyl 3-pentyloxyphenylcarbamic acid ester Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Riešenie sa týká technologického spůsobu spracovania hydrochloridu pentakainu do antacidnej suspenzie. Liečivoi sa rozpustí v etanole o koncentrácii 50 až 70 % hmot. a tento roztok sa přidává do suspenzie vo fáze reakcie hlinitých, horečnatých a vápenatých zlúčenín, kedy s-a pH reakčnej zmesi pohybuje v rozmedzí 9,0 až 13,0. Výhodou tohto spůsobu spracovania je skutočnosť, že liečivá látka sa -nachádza v systéme vo formě soli aj bázy, čo kladné ovplyvňuje jej biologickú dostupnost Preto hydrochlorid pentakainu spracováný týmto sposobom vykazuje lepšie charakteristiky liberácie, dokonalejšie sa disperguje a antacidná suspenzia má výhodnejšie reologi-cké vlastnosti v porovnaní so suspenziou, do ktorej bolo liečivo přidávané vo formě prášku, resp. vodného roztoku obsahujúceho tenzid, připadne so suspenziou, do ktorej bolo liečivo přidávané až nakoniec. Sposob je možné využit vo farmácii pri príprave antacidnej suspenzie s obsahom hydrochloridu pentakainu.The solution is technological treating the pentacaine hydrochloride to antacid suspension. The drug is dissolved in ethanol of 50 to 70 wt. and this solution is added to the suspension in phase aluminum, magnesium and calcium reactions of the compounds wherein the pH of the reaction mixture is .alpha ranges from 9.0 to 13.0. The advantage This way of processing is the fact that the drug substance is present in the system in the mold salts and bases, which affects it bioavailability Therefore hydrochloride pentacaine treated by this process better characteristics of liberation, more perfect and dispersing the antacid suspension it has more advantageous rheological properties compared to the suspension to which it was a drug added in the form of a powder, respectively an aqueous solution containing a surfactant, optionally with the drug suspension added in the end. The method can be used in pharmacy to prepare an antacid suspension containing pentacaine hydrochloride.
Description
Riešenie sa týká technologického spůsobu spracovania hydrochloridu pentakainu do antacidnej suspenzie. Liečivoi sa rozpustí v etanole o koncentrácii 50 až 70 % hmot. a tento roztok sa přidává do suspenzie vo fáze reakcie hlinitých, horečnatých a vápenatých zlúčenín, kedy s-a pH reakčnej zmesi pohybuje v rozmedzí 9,0 až 13,0. Výhodou tohto spůsobu spracovania je skutočnosť, že liečivá látka sa -nachádza v systéme vo formě soli aj bázy, čo kladné ovplyvňuje jej biologickú dostupnost Preto hydrochlorid pentakainu spracováný týmto sposobom vykazuje lepšie charakteristiky liberácie, dokonalejšie sa disperguje a antacidná suspenzia má výhodnejšie reologi-cké vlastnosti v porovnaní so suspenziou, do ktorej bolo liečivo přidávané vo formě prášku, resp. vodného roztoku obsahujúceho tenzid, připadne so suspenziou, do ktorej bolo liečivo přidávané až nakoniec. Sposob je možné využit vo farmácii pri príprave antacidnej suspenzie s obsahom hydrochloridu pentakainu.The present invention relates to a process for the processing of pentacaine hydrochloride into an antacid suspension. Drugs are dissolved in ethanol at a concentration of 50-70% by weight. and this solution is added to the suspension in the reaction phase of the aluminum, magnesium and calcium compounds, wherein the pH of the reaction mixture is between 9.0 and 13.0. The advantage of this treatment method is that the drug substance is present in the system in both salt and base form, which positively affects its bioavailability. as compared to the suspension to which the drug was added in the form of a powder and a powder, respectively. an aqueous solution containing the surfactant, optionally with a suspension to which the drug has been added until finally. The method can be used in pharmacy to prepare an antacid suspension containing pentacaine hydrochloride.
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Vynález sa týká spsobu inkorporovania lokálneho anestetika hydrochloridu pentakainu do antacidnej suspenzie so zřetelům na rýchlosť jeho liberácie z přípravku.The invention relates to a method of incorporating a local anesthetic pentacaine hydrochloride into an antacid suspension with respect to its rate of liberation from the formulation.
Antacida zaujímajú důležité miesto v terapii tých chorobných stavov, kde je přítomnost kyslého žalúdočného sekrétu důležitou zložkou pri patogenéze ochorenia. Preto úlohou terapie je potlačit agresivně faktory, alebo zvýšit protektívnu schopnost slizničnej bariéry tráviaceho traktu. Pretože podstata ochranných mechanizmov nie je ešte celkom známa, ťažiskom liečby vredovej choroby je potlačenie kyslosti žalúdočného obsahu a zníženie žalúdočnej sekrécie (Horňáková E.: Farm. obzor 52, 275 /1983/). Na zníženie pH žalúdočného obsahu sa používajú antacida (Kišoň Š., Hal'ko J., Lehký M.: Nežiadúce účinky liekov. Bratislava 1977, str. 568), výhodné sú najma přípravky adsorpčného typu (Gómez Puch L. M., Ríos Solans G., Muňoz Fernandez J. R.: Arzneim. Forsch 34 /11/, 1 378 /1984/).Antacids occupy an important place in the treatment of those disease states where the presence of acidic stomach secretion is an important component in the pathogenesis of the disease. Therefore, the role of therapy is to suppress the aggressive factors or increase the protective ability of the mucosal barrier of the digestive tract. Since the nature of the protective mechanisms is not yet fully understood, the main focus of the treatment of ulcer is to suppress the acidity of the stomach contents and to reduce the gastric secretion (Horňáková E .: Farm. Horizon 52, 275 (1983)). Antacids are used to lower the pH of gastric contents (Chison S., Hal'ko J., Lehký M .: Adverse drug effects. Bratislava 1977, p. 568), adsorption-type preparations (Gómez Puch LM, Ríos Solans G are preferred). , Munoz Fernandez JR: Arzneim, Forsch 34 (11), 1378 (1984)).
V terapii vredovej choroby sa uplatňujú aj lokálně anestetiká podávané súčasne s antacidami. Podta Babulůvej a spol. (Babulůvá A. a spol.: Ceskoslov. fysio.1. 31, 123 /1982/) důvodom pre ich používanie je potlačenie bolesti anestezujúcim účinkom na sliznicu gastrointestinálneho traktu a naviac sa možu uplatnit aj ich účinky spasmolytické a antihistamínové. Tento eíekt sa předpokládá aj u hydrochloridu pentakainu, původně syntetizovaného Benešom a spol. JBeneš L,. Borovanský A., Kopáčové L.: Arzneim. Forsch. 19, 1902 /1969/) ako lokál'ne anestetikum, ktorý však má aj mukosoprotektívny účinok. Vyplývá to z výsledku pokusov Babulůvej a spol. (Babulůvá A. a spol.: Ceskoslov. fysici. 31, 123 /1982/] a Tomčíkovej a spol. (Tomčíková O. a spol.: Pharmazie 40, 48 /1985/), pri ktorých sa zistil jeho významný protektívny účinok na žalúdočnú sliznicu pokusných zvierat.Local anesthetics administered concomitantly with antacids are also useful in the treatment of ulcer disease. Podta Babulova et al. (Babulůvá A. et al .: Ceskoslov. Fysio.1. 31, 123 (1982)) the reason for their use is the suppression of pain by anesthetic effect on the mucosa of the gastrointestinal tract, and their spasmolytic and antihistamine effects may also be applied. This effect is also contemplated for pentacaine hydrochloride originally synthesized by Benes et al. JBeneš L ,. Borovansky A., Kopacova L .: Arzneim. Forsch. 19, 1902 (1969)) as a local anesthetic which, however, also has a mucosoprotective effect. It results from the results of experiments Babulůvej et al. (Babulůvá A. et al .: Ceskoslov. Fysici. 31, 123 (1982)) and Tomčíková et al (Tomčíková O. et al .: Pharmazie 40, 48 (1985)), which were found to have a significant protective effect on gastric mucosa of test animals.
Hydrochlorid pentakainu je trans-2-(l-pyrolidinyl) cyklohexylester kyseliny 3-pentyloxyfenylkarbámovej, sumárneho vzorca C22H34N2O3. Je stabilný v kyslom prostředí, kde nedochádza k jeho deštrukcii, ale dokonca sa jeho lokálně anestetická účinnost zvyšuje. Keďže ide o novosyntetizovanú látku, jej použitie do antacidnej suspenzie nie je popísané a teda neriešili sa dosial' ani technologické otázky jej spracovania do tejto liekovej formy.Pentacaine hydrochloride is the trans-2- (1-pyrrolidinyl) cyclohexyl 3-pentyloxyphenylcarbamic acid ester of the general formula C22H34N2O3. It is stable in an acidic environment where it is not destroyed but even increases its local anesthetic effectiveness. Since it is a newly synthesized substance, its use in an antacid suspension is not described and hence the technological issues of its formulation into this dosage form have not been addressed.
Tekuté, resp. gél ovité přípravky sú velmi výhodné z hladiska aplikácie a účinku antacíd. Celkový povrch suspendovaných častíc v suspenzií je váčší, ako v tuhých prípravkoch, například v tabletách, preto ako sa uvádza (Brouwers J. R. B. J., Tijtgat G. N.: 'Pharm. Weekbl. 111, 1 244 /1976/), sú tekuté antacida účinnejšie. Tekuté antacidné přípravky majú naviac okrem vlastného účinku i protektívny účinok na sliznicu žalúdka, pretože vytvárajú na jeho povrchu mechanicko ochrannú vrstvu. Tým nepriamo podiporujú antacidný účinok (Mertl L., Technik P.: Prakt. lékař 60, 521 /1980/).Liquid, respectively. gel formulations are very advantageous in terms of application and effect of antacids. The overall surface area of the suspended particles in the suspension is heavier than in solid formulations, for example in tablets, therefore, as reported (Brouwers, J. R. B. J., Tijtgat G. N., Pharm. Weekbl. 111, 1244 (1976)), liquid antacids are more effective. In addition to their own effect, liquid antacid preparations also have a protective effect on the gastric mucosa, since they form a mechanical protective layer on its surface. They indirectly support the antacid effect (Mertl L., Technik P .: Prakt. Lékař 60, 521 (1980)).
1 Antacidným prípravkom na liečenie gastroduodenálnych vredov a iných ochorení gastrointestinálneho traktu sa zaoberá švajČiarsky patent (Switz. Pat. CH 643 144, 30. 5. 1984). Prípravok v tuhej alebo gélovite) formě obsahuje okrem látok s antacidným účinkom aj lokálně anestetiká lignokain a oxomemazin. Patejnt sa prevažne zaoberá farmakologickým a klinickým hodnotením přípravku so zaméraním na antiulceróznu účinnost lokálnycji anestetik. Nerieši však problém technológie přípravy a nezaoberá sa ,ani spůsobom spracovania liečiva do přípravku. Přitom technologický postup inkorporovania lokálneho anestetika může do značnej miery ovplyvniť jeho liberáciu z přípravku a tým i rýchlosť nástupu účinku, připadne dižku jeho· trvania. 1 An antacid preparation for the treatment of gastroduodenal ulcers and other diseases of the gastrointestinal tract is the subject of a Swiss patent (Switz. Pat. CH 643 144, May 30, 1984). The preparation in solid or gel form contains, in addition to antacid substances, also local anesthetics lignocaine and oxomemazine. The patient is mainly concerned with the pharmacological and clinical evaluation of the product with a focus on the anti-ulcer efficacy of local anesthetics. However, it does not solve the problem of the technology of preparation and does not deal with the way of processing the drug into a preparation. The technological process of incorporating a local anesthetic may have a significant effect on its liberation from the formulation and hence on the rate of onset of action, or its duration.
Predmetom tohto vynálezu je spůsob inkorporovania hydrochloridu pentakainu do antacidnej suspenzie. Podstata riešenia spočívá v tom, že sa 1,0 až 10,0 g 5,0 až 20 %-ného hmot. roztoku hydrochloridu pentakainu v 50 až 70 °/o-nom hmot. etanolu přidá do 50,0 až 90,0 g pripravovanej suspenzie vo fáze reakcie hlinitých, horečnatých a vápenatých zlúčenín, kedy sa pH reakčnej zmesi pohybuje v rozmedzí 9,0 až 13,0.It is an object of the present invention to provide a process for incorporating pentacaine hydrochloride into an antacid suspension. The essence of the solution is that from 1.0 to 10.0 g of 5.0 to 20% by weight. % of a solution of pentacaine hydrochloride in 50 to 70% by weight. ethanol is added to 50.0 to 90.0 g of the prepared suspension in the reaction phase of aluminum, magnesium and calcium compounds, the pH of the reaction mixture being in the range of 9.0 to 13.0.
Výhodou tohto spůsobu spracovania je skutočnosť, že liečivá látka sa nachádza v systéme vo· formě soli aj bázy. Táto skutočnosť kladné ovplyvňuje biologickú dostupnost, nakolko cez biologické membrány liečivá látka prechádza v neionizované] formě. Liečivá látka vo formě bázy působí po aplikácii ako lnici álna dávka, ktorá začne ihned' účinkovat. Přítomnost liečiva vo formě bázy tak urýchli nástup jeho· účinku.An advantage of this processing method is that the drug substance is present in the system in both salt and base form. This fact positively affects the bioavailability since the drug substance passes through the non-ionized form. The active substance in the form of a base acts upon administration as a linear dose which immediately becomes effective. Thus, the presence of a drug in the form of a base will accelerate the onset of its effect.
Vhodnost technologického· sposobu spracovania hydrochloridu pentakainu sa posudzovala na základe rýchlosti liberácie liečiva zo suspenzi! pri pH 2,0, ktoré zodpovedá patologickej aciditě a zo suspenzií is pH 4,5 zodpovedajúceho fyzio.logi.ckej aciditě v pokuse in vitro· za použitia semipermeabilnej membrány (používanej ako umělá oblička).The suitability of the technological process for the treatment of pentacaine hydrochloride was assessed on the basis of the rate of drug liberation from the suspension! at pH 2.0, which corresponds to pathological acidity, and from suspensions, is pH 4.5, corresponding to physiological acidity in an in vitro experiment using a semipermeable membrane (used as an artificial kidney).
Zistilo sa, že na 180 minút sa z takto· pripravenej suspenzie uvolní pri pH 2,0 = 7,2 porccnta a pri pH 4,5 = 14,25 !% hydrochloridu pentakainu pri rýchlosti uvofňovania· vyjádřeného· rýchlostnou konštantou k (h_1) = 0,025, resp. 0,055. Výsledky liberácie sa vyhodnotili matematicko-štatistickou metodou, ktorá potvrdila aj rovnoměrnost rozptýlenia inkorporovanej liečlvej látky.It was found that for 180 minutes, the suspension thus prepared was released at pH 2.0 = 7.2 porcine and at pH 4.5 = 14.25% pentacain hydrochloride at the release rate · expressed by the rate constant k (h -1). ) = 0.025, respectively. 0.055. The results of the liberation were evaluated by a mathematical-statistical method which also confirmed the uniformity of dispersion of the incorporated drug substance.
U suspenzií připravených podfa tohto· vynálezu sa ďalej hodnotili antacidná účinnost, neutralizačná mohutnost' a reologické charakteristiky.The suspensions prepared according to the invention were further evaluated for antacid activity, neutralizing power and rheological characteristics.
1 Pri sledovaní antacidnej účinnosti dynamickou metódou in vitro, ktorej podstatou !je sledovanie pH zmesi antacidnej suspenzie s umelou žalúdočnou šťávou po přidaní ky6 1 In monitoring antacid efficacy by the dynamic in vitro method based on ! is the monitoring of the pH of the mixture of antacid suspension with artificial gastric juice after addition of ky6
251326 seliny chlorovodíkové) (koncentrácia 0,2 mólu.l1) sa hranica pH pri dávke 10 ml suspenzie dosiahla za 37 až 91 sekúnd. Za 120 minút hodnota pH nepřekročila hranicu fyziologického optima (>pH = 5,0), maximálně dosiahnuté pH bolo 3,90.251326 hydrochloric selins) (concentration 0.2 mol.l L ), the pH limit at a dose of 10 ml of suspension was reached in 37-91 seconds. After 120 minutes the pH did not exceed the physiological optimum (> pH = 5.0), the maximum pH being 3.90.
Neutralizačná mohutnosť vyjádřená ipootom mililitrov 0,1 mólu. i“1 kyseliny chlorovodíkové) potrebnej k neutralizácii 1 g suspenzie bola 12,19 ml.Neutralizing power expressed by ipoot of milliliters of 0.1 mole. and "1 hydrochloric) needed to neutralize 1 g of the suspension was 12.19 ml.
Tieto výsledky poukazujú na sku-točnosť, že nástup účinku suspenzie je dostatočne rýchly (menej ako 2 minúty), jej účinok je protrahovaný (trvá viac ako 60 minút] a pH reakčnej zmesi sa nezvýši do alkalickej oblasti, čo by mohlo mať za .následok ref'lektorické spatné zvýšenie sekrécie kyseliny v žaludku.These results indicate that the onset of action of the suspension is fast enough (less than 2 minutes), its effect is prolonged (lasts more than 60 minutes), and the pH of the reaction mixture does not increase to the alkaline range, which could result reflective inverse increase in acid secretion in the stomach.
Změnou navrhovaného technologického postupu inkorporovania hydrochloridu pen'takainu sa dosiahli horšie charakteristiky liberácie a změnili sa aj reologické vlastnosti suspenzii.By changing the proposed technology for incorporating pen'tacaine hydrochloride, poorer liberation characteristics were achieved and the rheological properties of the suspensions were also altered.
Ak sa namiesto běhového roztoku spracuje hydrochlorid pentakainu vo formě prášku v prvej fáze přípravy suspenzie, uvoínené množstvo liečiva za 180 minút pri pH 4,5 poklesne na 11,1 % a pri pH 2,0 na '5,8 O/o.If, instead of the running solution, the pentacaine hydrochloride is treated as powder in the first stage of slurry preparation, the released amount of drug in 180 minutes at pH 4.5 drops to 11.1% and at pH 2.0 to 5.8 O / o.
Nevýhodné k spracovaniu hydrochloridu pentakainu do suspenzie je aj použitie tenzidu, například polysorbátu 80 (TweenR80). Tenzid sa použil preto, aby vzniknutá lipofilnú bázu liečivej látky rovnoměrně dispergoval v hydrofilnom heterogénnom systéme. Ukázalo sa, že pri použití 0,5 %-ného f hmot. vodného roztoku polysorbátu 80 uvolněné množstvo liečiva za 180 minút pokleshe pri pH 4,5 na 9,2 % a pri pH 2,0 n.a 4,4 percenta, čo možno zdůvodnit tvorbou zmiešaných micíel. Přísada tenzidu vyvolala aj čiastočnú deflokuláciu systému a zníženie kinetickej stability.The use of a surfactant, for example polysorbate 80 (Tween R 80), is also disadvantageous for suspending pentacaine hydrochloride. The surfactant was used to uniformly disperse the resulting lipophilic base of the drug substance in a hydrophilic heterogeneous system. It was found that using 0.5 wt. of the aqueous polysorbate 80 solution dropped the amount of drug released in 180 minutes at pH 4.5 to 9.2% and at pH 2.0 to 4.4 percent, which can be justified by the formation of mixed micelles. The surfactant additive also caused partial deflocculation of the system and reduced kinetic stability.
Liberácia hydrochloridu pentakainu sa zníži aj v tom případe, ak sa liečivo přidává nakoniec až do hotovej suspenzie. Výsledky ukázali, že ak sa takto inkorporuje hydrochlorid pentakainu ako běhový roztok, uvolní sa zai 180 minút 9,8 % liečiva pri pH 4,5 a 5,0 % pri ipH 2,0.The liberation of pentacaine hydrochloride will also decrease if the drug is finally added to the finished suspension. The results showed that if pentacain hydrochloride was incorporated as a running solution, 9.8% drug was released in 180 minutes at pH 4.5 and 5.0% at ipH 2.0.
Příklad 1Example 1
Do zmesi vzniknutej reakciou medzi 13,1 gramu síranu hlinitého, 4,2 g síranu horečnatého, 4,3 g oxidu vápenatého a 53,5 g vody sa pri pH 9,0 až 13,0 přidá roztok hydrochloridu pentakainu připravený tak, že 0,2 g liečivej látky sa rozpustí v 2,0 g 60! %-ného hmot. etanolu. Potom sa přidá 7,5 g sorbitolu, 7,5 g glycerínu a nakoniec 0,1 g xanthenovej gumy a 0,1 g cyklamátu sodného.To a mixture formed between 13.1 grams of aluminum sulfate, 4.2 grams of magnesium sulfate, 4.3 grams of calcium oxide and 53.5 grams of water, at pH 9.0-13.0, a solution of pentacaine hydrochloride prepared so that 0 Dissolve 2 g of the active substance in 2.0 g of 60 . % wt. ethanol. Then 7.5 g of sorbitol, 7.5 g of glycerin and finally 0.1 g of xanthene gum and 0.1 g of sodium cyclamate are added.
Příklad 2Example 2
5,1 g oxidu vápenatého, 13,3 g síranu hlinitého a 1,6 g oxidu horečnatého sa zmieša s 50 g vody. Keď má táto zmes pH 9,0 až 13,0, inkorporuje sa roztok hydrochloridu pentakainu připravený tak, že 0,2 g liečivej látky sa rozpustí v 2,0 g 60 %-ného hmot. etanolu. Potom sa přidá 7,5 g propylénglykolu, 7,5 g sorbitolu, 0,1 g xanthenovej gumy a 0,1 g cyklamátu sodného.5.1 g of calcium oxide, 13.3 g of aluminum sulfate and 1.6 g of magnesium oxide are mixed with 50 g of water. When this mixture has a pH of 9.0 to 13.0, a pentacaine hydrochloride solution prepared by dissolving 0.2 g of the drug substance in 2.0 g of 60% by weight is incorporated. ethanol. Then 7.5 g propylene glycol, 7.5 g sorbitol, 0.1 g xanthene gum and 0.1 g sodium cyclamate are added.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS867813A CS261526B1 (en) | 1986-10-29 | 1986-10-29 | Method for pentakaine hydrochloride incorporating into antacide suspension |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS867813A CS261526B1 (en) | 1986-10-29 | 1986-10-29 | Method for pentakaine hydrochloride incorporating into antacide suspension |
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| Publication Number | Publication Date |
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| CS781386A1 CS781386A1 (en) | 1988-07-15 |
| CS261526B1 true CS261526B1 (en) | 1989-02-10 |
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| CS867813A CS261526B1 (en) | 1986-10-29 | 1986-10-29 | Method for pentakaine hydrochloride incorporating into antacide suspension |
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| CS781386A1 (en) | 1988-07-15 |
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