ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING DEXTRORPHAN SALTS

Abstract: Dextrorphan salts with polycarboxylic organic acids are effectively absorbed by the oral route and can conveniently be formulated in pharmaceutical compositions suitable to the oral administration.

Description: The present invention relates to oral pharmaceutical compositions containing dextrorphan salts as the active ingredient. Dextrorphan is known to be the main metabolite of dextromethorphan, which is a drug widely used as an antitussive agent. The activity of dextromethorphan is due for the major part to the one of dextrorphan which displays a remarkable antitussive action as well as other desirable characteristics, such as lack of analgesic activity and of affinity to the opiaceous receptors. Moreover, dextrorphan has a very low toxicity, even lower than that of dextromethorphan. As a consequence, the therapeutical use of dextrorphan in substitution of or alternatively to dextromethorphan has already been proposed. Thus, for example, EP-A-219896 discloses pharmaceutical compositions containing dextrorphan for intranasal administration. EP-A-270290 mentions that dextrorphan has been approved for oral clinical use. Even though dextrorphan has previously been reported not to be conveniently used by the oral route (Schanker L.S., Shore Parkhurst P.A., Brodie B.B., Hoghen C.A.M., J. Pharmacol. Exp. Therap. 120, 528, 1957), it has been found, and it is the object of the invention, that dextrorphan salts with organic acids are efficiently absorbed by the oral route, attaining pharmacologically significant hematic levels of dextrorphan. According to the invention, therefore, oral pharmaceutical compositions are provided containing, as the active ingredient, dextrorphan citrate The compositions according to the invention contain 1 to 100 mg of dextrorphan citrate per unitary dose, more preferably 5 to 50 mg. Suited administration forms are tablets, controlled - release tablets, sublingual tablets, chewable tablets, sugar-drops, granulate sachets for extemporary dissolution, drops and syrups. Said compositions are prepared according to conventional techniques and excipients, such as those described in "Remington's Pharmaceutical Sciences Handbook", Hack Pub. Co., NY, U.S.A.. The compositions of the invention can be administered one or more times daily, according to the severity of the disease to be treated and to the conditions of the patient. The results from a pharmacokinetic study effected on guinea pigs under urethane anesthaesia, to which dextrorphan citrate and tartrate had been administered by the oral route, are reported hereinbelow in order to show the good bioavailability of dextrorphan salts. Dextrorphan dosages were effected by a high pressure liquid chromatography method. The plasma samples were subjected, before the extraction, to enzymatic hydrolysis with β-glucuronidase, according to the method reported by T.EAST and D.DYE (Journal of Chromatography Biomedical Applications 388, 99 - 112, 1985). After hydrolysis, plasma samples were alkalinized with sodium carbonate and extracted with benzene; benzene was re-extracted with 0.5 ml of 0.1 N HCl and 100 µl were chromatographed under the following conditions: COLUMN: Lichrosorb RP Select B Merck 5 µm, 25 cm x 4 mm inn. d. MOBILE PHASE: Octanesulphonic acid sodium salt 0.01 M solution in water. Acetonitrile mixture (68-32%). The solution was then buffered to pH 3 with phosphoric acid. FLOW: 0.8 ml/minute DEVELOPER: F 1000 MERCK HITACHI Fluorimeter exc. = 280 nm ; em. = 310 nm Dextrorphan citrate turned out to be effectively absorbed, as evidenced in Table 1 which follows. The following examples further illustrate the pharmaceutical compositions according to the invention. Example 1 SYRUP 100 ml of syrup contains: Dextrorphan citrate 0.1-1 g Benzoic acid 0.090 g Sodium benzoate 0.050 g Flavours 0.160 g Saccharose 72 g Depurated water q.s. to 100 ml Example 2 DROPS FOR ORAL USE 100 ml of solution contain: Dextrorphan citrate 1-5 g Parabens 0.1 g Flavours 1,5 g Depurated water q.s. to 100 ml Example 3 TABLETS One of tablet contains: Dextrorphan citrate 5-50 mg Maize starch 90 mg Lactose 20 mg Talc 10 mg Magnesium sterate 0.2 mg Example 4 CONTROLLED - RELEASE TABLETS One tablet contains: Dextrorphan citrate 5-50 mg Hydroxypropylmethylcellulose 117 mg Anhydrous lactose 80 mg Magnesium stearate 5 mg Precipitated silica 3 mg Example 5 SUBLINGUAL TABLETS One sublingual tablet contains: Example 6 CHEWABLE TABLETS One tablet contains: Example 7 SUGAR-DROPS One sugar-drop contains: Dextrorphan citrate 5-50 mg Flavours 20 mg Glucose 1 mg Saccharose 1,5 g Example 8 SACHET FOR EXTEMPORARY DISSOLUTION 5 g of granulate contain:

Claims: Oral pharmaceutical compositions containing as the active ingredient dextrorphan citrate. Pharmaceutical compositions according to claim one, in form of tablets, controlled - release tablets, sublingual tablets, chewable tablets, sugar-drops, sachets, syrup and drops. Pharmaceutical compositions according to claim one, containing 1 to 100 mg of dextrorphan citrate per unitary dose.

Inventors: BANDI, GIANLUIGI, FOSSATI, ANTONIO, PASSAROTTI, CARLO, VALENTI, MAURO
Applicants: PRODOTTI FORMENTI S.R.L.
Application year: 1989
Main classification: A61K31
IPC codes: A61K31, A61K9, A61P11, A61K47