IT8922339A1 - COMPOUNDS WITH EXPECTORANT ACTIVITY OBTAINED BY COMPLEXING THE TRANS-4- (2-AMINO-3, 5-DIBROMO-BENZYLAMINO) CYCLOHEXANOL WITH A CYCLODEXTRINE, THEIR PREPARATION AND USE - Google Patents
COMPOUNDS WITH EXPECTORANT ACTIVITY OBTAINED BY COMPLEXING THE TRANS-4- (2-AMINO-3, 5-DIBROMO-BENZYLAMINO) CYCLOHEXANOL WITH A CYCLODEXTRINE, THEIR PREPARATION AND USE Download PDFInfo
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- IT8922339A1 IT8922339A1 IT1989A22339A IT2233989A IT8922339A1 IT 8922339 A1 IT8922339 A1 IT 8922339A1 IT 1989A22339 A IT1989A22339 A IT 1989A22339A IT 2233989 A IT2233989 A IT 2233989A IT 8922339 A1 IT8922339 A1 IT 8922339A1
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- Prior art keywords
- compound
- formula
- cyclodextrin
- complexes
- pharmaceutical compositions
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- 229920000858 Cyclodextrin Polymers 0.000 title claims description 28
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 title claims description 14
- 239000003172 expectorant agent Substances 0.000 title claims description 9
- 230000003419 expectorant effect Effects 0.000 title claims description 9
- 230000000694 effects Effects 0.000 title claims description 7
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 title description 26
- 238000002360 preparation method Methods 0.000 title description 4
- 230000000536 complexating effect Effects 0.000 title 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- -1 hydroxy-propyl - Chemical class 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 229940124584 antitussives Drugs 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 230000000954 anitussive effect Effects 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000000889 atomisation Methods 0.000 claims description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229960005174 ambroxol Drugs 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000003434 antitussive agent Substances 0.000 description 2
- 229940097362 cyclodextrins Drugs 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000220304 Prunus dulcis Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Polysaccharides And Polysaccharide Derivatives (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Description
Domanda di Brevetto per Invenzione Industriale dal titolo: "Composti ad attivit? espettorante ottenuti per complessazione del trans-4-(2-amniino-3 ,5~ dibromo-benzilammino)cicloesanolo con una ciclodestrina, loro preparazione e loro utilizzazione." Patent Application for Industrial Invention entitled: "Compounds with expectorant activity obtained by complexation of trans-4- (2-amniino-3, 5 ~ dibromo-benzylamino) cyclohexanol with a cyclodextrin, their preparation and their use."
Riassunto Summary
I complessi del trans-4-(2-ammino~3.5~ dibromobenzilammino)-cicloesanolo con una ciclodestrina scelta tra ?, ?, dimetil-?, idrossi-propil-p-ciclodestrine, sono solubili in acqua e sono utili come espettoranti, antitosse e fluidificanti bronchiali. The complexes of trans-4- (2-amino ~ 3.5 ~ dibromobenzylamino) -cyclohexanol with a cyclodextrin chosen from?,?, Dimethyl- ?, hydroxy-propyl-p-cyclodextrin, are soluble in water and are useful as expectorants, antitussives and bronchial thinners.
Descrizione dell'invenzione Description of the invention
La presente invenzione riguarda i complessi del trans-4-(2-ammino-3,5- dibromo-benzilammino)-cicloesanolo in forma libera o salificata, con una ciclodestrina scelta tra ?, ?, ?, dimetil-?, idrossi-propil--ciclodestrine, la loro preparazione, e relative composizioni farmaceutiche. The present invention relates to the complexes of trans-4- (2-amino-3,5-dibromo-benzylamino) -cyclohexanol in free or salified form, with a cyclodextrin selected from?,?,?, Dimethyl- ?, hydroxy-propyl - cyclodextrins, their preparation, and related pharmaceutical compositions.
II composto trans-4-(2-ammino-3,5- dibromo-benzilammino)-cicloesanolo, meglio noto con il nome Ambroxol e caratterizzato dalla formula (I): The compound trans-4- (2-amino-3,5- dibromo-benzylamino) -cyclohexanol, better known by the name Ambroxol and characterized by the formula (I):
.(i) .(the)
? un composto appartenente alla classe dei medicamenti ad azione espettorante, antitosse e fluidificante bronchiale, ? utilizzato in maniera efficace per le malattie dell'apparato respiratorio. L'Ambroxol tal quale, ? per? praticamente insolubile nell'acqua e ci? pu? rappresentare un fattore limitativo per una sua utilizzazione ottimale. ? a compound belonging to the class of drugs with expectorant, antitussive and bronchial fluidifying action,? used effectively for respiratory diseases. Ambroxol as it is,? for? practically insoluble in water and there? can represent a limiting factor for its optimal use.
Oggetto della presente invenzione sono i complessi dell'Ambroxol in forma libera o salificata con un anione farmaceuticamente accettabile, con una ciclodestrina scelta tra a, ?,?, dimetil-?, idrossi-propil--ciclodestrine. Object of the present invention are the Ambroxol complexes in free or salified form with a pharmaceutically acceptable anion, with a cyclodextrin selected from a,?,?, Dimethyl- ?, hydroxy-propyl - cyclodextrin.
E' stato infatti inaspettatamente trovato che i complessi secondo la presente invenzione sono solubili in acqua vengono rapidamente assorbiti sono ben tollerati dall'organismo ed inoltre presentano un'attivit? terapeutica maggiore del principio attivo tal quale. In fact, it has been unexpectedly found that the complexes according to the present invention are soluble in water, are rapidly absorbed, are well tolerated by the organism and also exhibit an activity. therapeutic greater than the active ingredient as it is.
L'Ambroxol e le ciclodestrine possono essere presenti nei complessi secondo la presente invenzione in rapporto molare compreso tra 1:1 ed 1:4. Ambroxol and cyclodextrins can be present in the complexes according to the present invention in a molar ratio between 1: 1 and 1: 4.
Nei complessi secondo la presente invenzione l'Ambroxol pu? essere presente in forma salificata, preferibilmente come cloridrato. In the complexes according to the present invention, Ambroxol can be present in salified form, preferably as hydrochloride.
Ulteriore oggetto della presente invenzione sono composizioni farmaceutiche preferibilmente per uso orale o rettale, ad attivit? espettorante, fluidificante bronchiale ed antitosse comprendente come principio attivo uno o pi? complessi secondo la presente invenzione, in combinazione con eventuali veicoli o diluenti farmaceuticamente accettabili. A further object of the present invention are pharmaceutical compositions preferably for oral or rectal use, with activity? expectorant, bronchial fluidifying and antitussive including as active ingredient one or more? complexes according to the present invention, in combination with any pharmaceutically acceptable carriers or diluents.
Le composizioni farmaceutiche secondo la presente invenzione per uso orale possono presentarsi in forma solida come capsule, compresse o confetti in bustine monodosi, in forma liquida come soluzioni pronte o estemporanee; mentre le composizioni farmaceutiche secondo la presente invenzione per uso rettale si presentano sottoforma di supposte. The pharmaceutical compositions according to the present invention for oral use can be in solid form as capsules, tablets or sugared almonds in single-dose sachets, in liquid form as ready or extemporaneous solutions; while the pharmaceutical compositions according to the present invention for rectal use are in the form of suppositories.
Nel trattamento delle affezioni bronchiali le composizioni farmaceutiche secondo la presente invenzione per uso orale o rettale vengono somministrate in unit? posologiche contenenti da 20 a 100 mg di principio attivo 2, 3.4 volte al giorno. In the treatment of bronchial affections, the pharmaceutical compositions according to the present invention for oral or rectal use are administered in unit? dosage containing from 20 to 100 mg of active ingredient 2, 3.4 times a day.
Ulteriore oggetto della presente invenzione consiste nella preparazione dei complessi secondo la presente invenzione che pu? essere ottenuto secondo due differenti processi: A further object of the present invention consists in the preparation of the complexes according to the present invention which can? be obtained according to two different processes:
Il primo processo per ottenere i complessi oggetto della presente invenzione contenenti il composto di formula (I) in forma libera prevede i seguenti passaggi: The first process for obtaining the complexes object of the present invention containing the compound of formula (I) in free form involves the following steps:
al) si scioglie l'Ambroxol nella soluzione acquosa della ciclodestrina scelta .preferibilmente a caldo a temperature comprese tra 50 e 60 ?C, si agita la miscela ottenuta; oppure: al) the Ambroxol is dissolved in the aqueous solution of the selected cyclodextrin, preferably hot at temperatures between 50 and 60 ° C, the mixture obtained is stirred; or:
a2) si scioglie l'Ambroxol in solvente organico immiscibile con acqua, preferibilmente un solvente clorurato, quale ad esempio cloroformio, si miscela la soluzione organica ottenuta con una soluzione acquosa della ciclodestrina scelta, si agita la miscela ottenuta preferibilmente a temperatura ambiente, a2) Ambroxol is dissolved in organic solvent immiscible with water, preferably a chlorinated solvent, such as chloroform, the organic solution obtained is mixed with an aqueous solution of the selected cyclodextrin, the mixture obtained is stirred preferably at room temperature,
b) si precipita il complesso a freddo preferibilmente a temperature comprese tra 0 e 5?C. b) the complex is precipitated when cold preferably at temperatures ranging from 0 to 5 ° C.
Il secondo processo, che viene utilizzato per ottenere i complessi contenenti il cloridrato di Ambroxol, prevede i seguenti passaggi: The second process, which is used to obtain the complexes containing Ambroxol hydrochloride, involves the following steps:
a) si scioglie l'Ambroxol e la ciclodestrina scelta in una soluzione di acido cloridrico; a) Ambroxol and the chosen cyclodextrin are dissolved in a hydrochloric acid solution;
b) si separa il complesso per essiccamento, o per atomizzazione con aria calda, oppure per liofilizzazione. b) the complex is separated by drying, or by atomization with hot air, or by lyophilization.
Vengono riportati i seguenti esempi a scopo illustrativo ,ma non limitativo della presente invenzione. The following examples are reported for illustrative but not limitative purposes of the present invention.
ESEMPIO 1 -Complesso Ambroxol-a-ciclodestrina in rapporto molare 1:1 EXAMPLE 1 - Ambroxol-a-cyclodextrin complex in molar ratio 1: 1
Si sciolgono 37.796 g di Ambroxol (0.1 moli) e 97.2 g (0.1 moli) di ?-ciclodestrina in 2 litri di acqua riscaldata a 60?C. Si agita per 3 ore la soluzione ottenuta e si raffredda a circa 3?C, si separa il complesso per cristallizzazione. 37,796 g of Ambroxol (0.1 moles) and 97.2 g (0.1 moles) of? -Cyclodextrin are dissolved in 2 liters of water heated to 60 ° C. The obtained solution is stirred for 3 hours and cooled to about 3 ° C, the complex is separated by crystallization.
Si ottengono circa 135 g di prodotto con un titolo di circa il 28% in peso di Ambroxol. About 135 g of product are obtained with a title of about 28% by weight of Ambroxol.
ESEMPIO 2 - Complesso Ambroxol--ciclodestrina in rapporto molare 1:2 EXAMPLE 2 - Ambroxol complex - cyclodextrin in molar ratio 1: 2
Si sciolgono 37-796 g di Ambroxol (0.1 moli) e 227 8 (0.2 moli) di (S-ciclodestrina in 2.5 litri di acqua riscaldata a 60?C. Si agita per 3 ore la soluzione ottenuta e si raffredda a circa 3*C, si separa il complesso per cristallizzazione. ;Si ottengono circa 264 g di prodotto con un titolo di circa il 14.27% in peso di Ambroxol. ;ESEMPIO 3 -Complesso Ambroxol- ?-ciclodestrina in rapporto molecolare 1:3 ;Si sciolgono 3898 di -ciclodestrina (0.3 moli) in 3 litri di acqua a 40-45 ? C, si aggiungono alla soluzione risultante 37-796 g (0.1 moli) di Ambroxol sciolti in 200 mi di cloroformio. ;Si agita per 12 ore a temperatura ambiente , si precipita il complesso ottenuto per raffreddamento della miscela di reazione a 3 ?c. ;Si ottengono 400 g di prodotto con un titolo del 9-45 % in peso di Ambroxol. ;;ESEMPIO 4 - Complesso Ambroxol-dimetil-f?-ciclodestrina in rapporto molare 1:4 ;Si sospendono 532 g (0.4 moli) di dimetil--ciclodestrina in 2 litri di acqua, alla sospensione riscaldata a 60 ?C, si aggiungono 37.796 g (0.1 moli) di Ambroxol sciolti in 50 ml di acido cloridrico N e si agita fino a completa soluzione. ;La soluzione si porta a secco con l'aiuto del vuoto o per liofilizzazione o per atomizzazione con aria calda e si ottengono 500 g di prodotto con un titolo di circa il 7*5 % In peso di Ambroxol. 37-796 g of Ambroxol (0.1 moles) and 227 8 (0.2 moles) of (S-cyclodextrin are dissolved in 2.5 liters of water heated to 60 ° C. The resulting solution is stirred for 3 hours and cooled to about 3 °. C, the complex is separated by crystallization.; About 264 g of product are obtained with a title of about 14.27% by weight of Ambroxol.; EXAMPLE 3 -Ambroxol-? -Cyclodextrin complex in molecular ratio 1: 3; 3898 are dissolved of -cyclodextrin (0.3 moles) in 3 liters of water at 40-45 ° C, 37-796 g (0.1 moles) of Ambroxol dissolved in 200 ml of chloroform are added to the resulting solution.; The mixture is stirred for 12 hours at room temperature , the complex obtained by cooling the reaction mixture to 3 ° C is precipitated.; 400 g of product with a title of 9-45% by weight of Ambroxol are obtained. ;; EXAMPLE 4 - Ambroxol-dimethyl-f? - complex cyclodextrin in molar ratio 1: 4; 532 g (0.4 moles) of dimethyl - cyclodextrin are suspended in 2 liters of water, in the suspension heated to 60 ? C, 37,796 g (0.1 moles) of Ambroxol dissolved in 50 ml of hydrochloric acid N are added and stirred until completely dissolved. The solution is dried with the help of vacuum or by freeze-drying or by atomization with hot air and 500 g of product are obtained with a title of about 7 * 5% by weight of Ambroxol.
ESEMPIO 5 -Complesso Ambroxol -idrossipropil-?- ciclodestrina in rapporto molare 1:4 EXAMPLE 5 - Ambroxol -hydroxypropyl -? - cyclodextrin complex in molar ratio 1: 4
Si sciolgono 37-796 g di Ambroxol e 571-2 g di idrossi-propil-?ciclodestrina in 3 litri di acqua riscaldata a 60?C. 37-796 g of Ambroxol and 571-2 g of hydroxy-propyl-? Cyclodextrin are dissolved in 3 liters of water heated to 60 ° C.
Si agita per 3 ore e si raffredda a circa 3 ?C e si separa il complesso per cristallizzazione e si ottengono circa 510 g di prodotto con un titolo di circa il 7-3 % in peso di Ambroxol. Vengono brevemente riportate le caratteristiche tossicologiche e farmacologiche dei complessi dell'invenzione. The mixture is stirred for 3 hours and cooled to about 3 ° C and the complex is separated by crystallization and about 510 g of product with a title of about 7-3% by weight of Ambroxol are obtained. The toxicological and pharmacological characteristics of the complexes of the invention are briefly reported.
TOSSICIT?'ACUTA ACUTE TOXICITY
La tossicit? acuta dei complessi secondo la presente invenzione ? stata studiata nel ratto e nel topo per via orale e per via intraperitoneale. The toxicity acute of the complexes according to the present invention? has been studied in rats and mice by the oral and intraperitoneal routes.
Il valore della DL50 ? risultato (riferito al principio attivo presente nel complesso) superiore a 3000 mg /kg analogamente all'Ambroxol somministrato tal quale. The value of the LD50? result (referred to the active ingredient present in the complex) higher than 3000 mg / kg similarly to Ambroxol administered as it is.
AZIONE ESPETTORANTE EXPECTORATIVE ACTION
L'attivit? espettorante dei nuovi complessi ? stata studiata in riferimento a quantit? equivalenti di Ambroxol sui conigli adulti di sesso maschile ,del peso corporeo compreso tra 2.8 -3-00 kg. Si ? proceduto ad anestesia generale con uretano etilico , gli animali sono stati quindi legati su un lettuccio di contenzione e la testa ? stata mantenuta rivolta verso il basso in modo da poter incanalare il secreto bronchiale mediante una cannula tracheale. The activity? expectorant of the new complexes? been studied in reference to quantity? equivalent of Ambroxol on adult male rabbits, weighing between 2.8-3-00 kg. Yup ? under general anesthesia with ethyl urethane, the animals were then tied on a restraint mat and the head? was kept pointing downwards so that the bronchial secretion could be channeled through a tracheal cannula.
Tale secreto viene raccolto in un cilindro graduato ad intervalli regolari sia prima che dopo il trattamento con i complessi secondo la presente invenzione (10 e 20 DTS/kg) somministrati per via gastrica. This secretion is collected in a graduated cylinder at regular intervals both before and after the treatment with the complexes according to the present invention (10 and 20 DTS / kg) administered via the gastric route.
I nuovi prodotti hanno dimostrato di possedere attivit? espettorante superiore di circa il 25% rispetto a quelli dell'Ambroxol somministrato tal quale ; l'intensit? dell'azione espettorante ? apparsa dose-dipendente. Have the new products been shown to have assets? approximately 25% higher expectorant than those of Ambroxol administered as it is; the intensity? of the expectorant action? appeared dose-dependent.
ATTIVIT?'ANTITOSSE ACTIVITIES ANTITOSSE
1 nuovi composti hanno dimostrato di essere come agenti antitosse,pi? attivi dell'Ambroxol somministrato tal quale . La prova viene effettuata con i nuovi complessi ad una dose per via intraperitoneale di 20 mg /kg (metodo di Charber; Prost e coll. Arch. Int. Pharm., 1961,vol 134 pag 305) in seguito ad inalazione di acido citrico per via aerosol nei porcellini d'india. The new compounds have been shown to be antitussive agents, plus active ingredients of Ambroxol administered as it is. The test is carried out with the new complexes at an intraperitoneal dose of 20 mg / kg (Charber's method; Prost and coll. Arch. Int. Pharm., 1961, vol 134 pag 305) following inhalation of citric acid for via aerosol in guinea pigs.
La risposta ? uguale a quella dell'Ambroxol somministrato tal quale alla dose di 30 mg /kg. The answer ? equal to that of Ambroxol administered as it is at a dose of 30 mg / kg.
Claims (12)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02233989A IT1237128B (en) | 1989-11-10 | 1989-11-10 | Compound with expectorated additives obtained by trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol complexes with a cyclodextrin, their preparation and usage. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02233989A IT1237128B (en) | 1989-11-10 | 1989-11-10 | Compound with expectorated additives obtained by trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol complexes with a cyclodextrin, their preparation and usage. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IT8922339A0 IT8922339A0 (en) | 1989-11-10 |
| IT8922339A1 true IT8922339A1 (en) | 1991-05-10 |
| IT1237128B IT1237128B (en) | 1993-05-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT02233989A IT1237128B (en) | 1989-11-10 | 1989-11-10 | Compound with expectorated additives obtained by trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol complexes with a cyclodextrin, their preparation and usage. |
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| Country | Link |
|---|---|
| IT (1) | IT1237128B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201006463A (en) * | 2008-06-26 | 2010-02-16 | Merz Pharma Gmbh & Co Kgaa | Pharmaceutical compositions comprising aminocyclohexane derivatives |
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1989
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| Publication number | Publication date |
|---|---|
| IT1237128B (en) | 1993-05-18 |
| IT8922339A0 (en) | 1989-11-10 |
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