SK42593A3 - Antitusic agents - Google Patents

Abstract

The subject invention involves antitussive pharmaceutical compositions for the peroral administration of dextromethorphan, the composition being at a pH of from about 8 to about 11.

Description

the invention relates to novel antitussive agents, i. cough supplements containing dextromethorphan. More particularly, the invention relates to a composition and method for rapidly achieving therapeutic levels of dextromethorphan in the system.

BACKGROUND OF THE INVENTION Fluoromethanate (racemetorphan), 3-methoxy-17-methylmorphinan, is disclosed in the Merck Index, 10th Edition (1983), by M. Windholz, eds. 8009, p. 11/0; is disclosed herein as an antitussive agent.

.... extromethorphan hydrobromide is widely used as an antitussive agent, i.e. a cough agent, in commercial products, the eye of which is given in the Physician's Desk Reference for Nonprescriptian..urugs, 11th edition (1990), ER barnhordt, pub., n . 306, av physician's vesk Reference, 44th edition (1990), F. h. tfanhardt, pub., p. j09: Bayer Ohildren's Cough oyrup by Glenbrook, áenylin dP 'oodla Parke-Davis, benylin Lxpectorant by Parke-Levis, Gerose-DM by Jl'yethAyerst, cheracol d Cough Formula by Uojohn, cheracol Plus Head cough / Cold Formula by Uojoh Formula Uomtrex according to Bristol-Myers Products, Comtrex Culti-Cold Re-Symptom. Liever Tablets / Calets / Liquid / Liquigels underXa Bristol-Myers Products, Oontac Cough Formula by SmithXTine Gonsumer, Gontac Cough and sor.e Throat Formula by Smit.hKiline · Gonsumer, oontac Jr. children's Gold Medicine by SmithXline Gonsumer, Oontac Fi'ghttime oold Medicine by SmithXline consumer, Oontac Severe Gold Formula Gaplets by smith \ line Gonsumer, dirracol Gaplets by dobins, uorcol children * with cough Syrup by oandoz _in onsumer, Hold by omith¾line deecham, Naldecon uX Adult niquid oodlo Bristol Laboratories, Naldecon DX Children 's oyrup by Bristol Laboratories, Naldecon T) X Pediatrics

Drops Podlg Bristol Laboratories, Naldecon Senior DX Cough /

Cold according to Bristol Laboratories, Novahistidine LKTX according to Lakeside Pharmateucitals, Pediacare cough-cold Formula Liquid and chewable rablets by McNeil uonsumer Products, Pediacare Night Rest uough - <, old Formula Liquid by McNeil Consumer Products, Robitussin Night Relief by Robins, Robitissin-uF Robins, Robitussin by Robins, Scot-Tassin Sugar-Free by Cough and Cold Medicine by Cot-Tussin, Snaplets-LM by Baker Cummins Pharma'Ceuticals, Snaplets-Multi by Baker Cummins Pharmaceuticals, St.JosephtDough Suppressant for Children Plow Joseph Nighttime Cold Medicine by Plow, Bucrets Cough control Formula by SmithKline Beecham, Sudafed Cough Syrup by Burroughs Wellcome, Triaminic Night by Sandoz Consumer, Triaminic-DM Syrup by Sandoz Consumer, Triaminicol Multi-Symptom Cold Tablet by Sandoz Consumer, Triaminicol Multi-Symptóm Relief by Sandoz Consumer, Tylenol Cold Medication Caplet and Tablet by McNeil Consumer Products, Tylenol Cold Medication Liquid by McNeil Consumer Products, Tylenol Cold Medication No Drowsiness Formula Caplets by McNeil Consumer Products, Vicks Children's Cough Syrup by Richardson-Vicks, Inc., Vicks Children's NyQuil by Richrdson-Vicks, Inc ,,

Vicks cough Silencers Cough Drops by Richrdson-Vicks, Inc., Vicks Daycare Daytime Colds Medicine Caplets by RichardsonVicks, Inc., Vicks Daycare Multi-Symptom Colds Medicine Liquid by Richardson-Vicks, Inc., Vicks Formula 44 Cough Control Discs by Richardson- Vicks, Inc., Vicks Formula 44 Cough Medicine by Richardson-Vicks, Inc., Vicks Formula 440 Decongestant cough Medicine by Richardson-Vicks, Inci, Vicks Formula 44M Multi-Symptom cough Medicine by Richardson-Vicks, Inc., Vicks NyQuil Nighttime Colds Medicine-Original and Cherry Flavor by Richardson-Vicks, Inc., Vicks Pediatrics Formula 44 Cough Medicine PadRichardson-Vicks, Inc., Vicks Pediatrics Formula 44 Cough and Colds Medicine by Richardson-Vicks, Inc., icks Pediatrics Formula.44 Cough and Congestion Medicine by Fichardson-ieki, inc., Ambenyl-D

Lecongestent Coufth Formula according to Forest Pharmsceuticnls, Bromarest DX Cough Syrup according to Warner Chilcott, BromFes-hM fourh Syruo according to turo, Codíasl according to Central Phermaceuticals, Dimetane-DX Courh Syruo according to Robin, Gualfeneain w / p-metorruoide dibromide by Adam, loTUss-Dfé _{iáid by} Muro, Medi-Tuss 7) M by Warner Chilcott, rhener ^ an wit.h Dextromethorphan by wyethAyerst, poly-Histine DM Syrup by Bock, Quelidrine Syrup by Abbot, Rondec-DM Oral Dropa Rosa, Tusibron-DM according to RAA 'Laboratories, Tussar DV nodla Rorer Pharmeceutieale and Tussi-Orphthanidine DM Liquid according to Wollnce. Delsym Coufth Suppreaaant Syrup according to Reil Conoumer contains an eye-opthalmic agent destromethorphan poliatirex. It is likely that

In addition, said corrective products containing dextromethorphan are among the compositions and pH neutral or low.

Beckett AH and Tri ^ s SG in his treatise Buccsl Absorption of Basic l'rufts and Its Application as an In Vi in Jododel of Psssiv © Drú # Transfer Throufth Lip.id Merr.branos': Jour nal of Pharmacy and Tharmacology, Vol. . 19 * Supplement / 1967 / JJl-S o? They have found that the buccal absorption of many drugs is substantially increased in the case of pharmaceuticals having a ph phi, when these medicines are swollen after administration for 5 minutes in the mouth. Dextromethorphan was not listed as one of the drugs tested in Beckett and Trlft.ro. According to the findings in Deckott and Triftra, the appropriate liquid products are not expected to be administered orally so that they can remain in the mouth but swallow rapidly, or in the case of solid lozenge products which dissolve in the mouth, then swallow rapidly in order to satisfy said condition of staying in the mouth for 5 minutes.

U. U.S. Pat. 4 69? No. 677, which was published in Gorentin on January 9, 1999, which discloses disclosed quaternary formulations acting on cachets which contain phenol as dextromethorphan, i.e., phenol having a pH of 9 and? 9th

U.3. U.S. Pat. 4 4? 7 681, which came out in lununi on January 24

1984 »discloses disclosed thixotroone duck-active compositions comprising both eye dextromethorphan and Avical® nc591. These patents have been incorporated by reference.

nature of the invention

It is an object of the present invention to provide dextroraethorphan compositions for oral administration having faster ontitusic effects than commercially available compositions.

It is a further object of the invention to provide a method for achieving a rapid antitussive effect of dextromethorphan compositions.

The present invention encompasses pharmaceutical compositions for oral administration which essentially consist of a safe, effective amount of dextromethorphan and any orally acceptable pharmaceutical carrier having a pH of from 8 to 11.

The present invention further encompasses pharmaceutical compositions for oral administration comprising a safe and effective amount of devtromethorphan, a safe and effective amount of a medicament that is effective to treat cold, other than phenol, and a further orally acceptable pharmaceutical carrier, wherein: the compositions also have a pH of from 8 to 11, the subject invention also includes pharmaceutical compositions for oral administration comprising a safe amount with an effective amount of dextromethorphan, a safe and effective amount of an orally acceptable pharmaceutical carrier, a composition having a pH greater than 9 e. 11th

The compositions and methods of this invention contain safe and effective amounts of dextromethorphan, and the possible active drug substance. The term &quot; safe and effective amounts &quot;, as used herein, means those amounts of the active drug that are so high as to provide a significant positive change in health conditions - i. the patient's health status - but too low to avoid serious side effects. risk-benefit / consistency and medical judgment. A safe and effective amount may vary widely depending upon the conditions of treatment, the age and physical condition of the patient, the severity of the disease, the course of treatment, the nature of the therapy, and similar factors.

dextromethorphan is known to be pharmacologically active as an antitussive agent. As used herein, dextromethorphan means 3-methyl-17-methyl-morphinan / 11-cis-1,3,4,9,10,10a-hexahydro-e-methoxy-11-methyl-2H-1,4,4o -iminoetenofenentrén /:

(recession torphan) and its pharmaceutically acceptable salts. such preferred dextromethorphan salts include the hydrobromide salt.

The composition of the present invention preferably comprises from 1 mg to 50 mg dextromethorphan per dose, more preferably from 2.5 wf to 30 mg dextromethorphan per dose, the liquid compositions preferably comprise from 0.02% to 1.5 T dextroreethorphan, even more preferably from 0 0.05% to 17% dertromethorphan, most preferably from 0.1% to 0.3% dextromethorphan. A typical dose for a liquid antitussive composition is from 1 ml to 30 ml. The dose of liquid cough syrup is more typical from 5 ml to 20 ml, in particular 15 ml. The dose of the concentrated cough spray is more typical from 2 ml to 5 ml, in particular 3.5 ml.

Preferred compositions of the present invention comprise as an essential safe or effective amount of deythromethorphan an orally acceptable pharmaceutical carrier. These funds have

PH 6 from Q to 11, preferably from 8.4 to 10, more preferably from 8.5 to 9.5, most preferably then 9. The preferred compositions of the present invention comprise a safe and effective amount of doxtromethorphan, a safe n effective amount of another cough and cold drug, wherein the active drug is other than phenol, and the composition comprises an orally administrable pharmaceutical carrier. These compositions have a pH of from 8 to 11, preferably from 8.4 to 10, more preferably from 8.9 to 9.5, most preferably then 9. Other preferred compositions of the present invention comprise a safe and effective amount of dextromethorphan, a safe and effective amount phenol and an orally acceptable pharmaceutical carrier. Such compositions have a pH of from 9 to 11, more preferably from 9.5 to 10, even more preferably from 9.1 to 9.5.

It has been found that the action of said agents of the present invention results in a more resistant attainment of therapeutic levels of dextromethorphan in the blood over a longer period of time and / or higher peak levels of dextromethorphan in the blood compared to conventional formulations and dextromethorphan. with lower pH.

The compositions of the present invention preferably have a basic creep force (capacity) suitable to overcome conditions and time for the development of salivary mucosa in the throat and throat, wherein said composition is mixed with saliva 0 at the above pH for the desired retention time. in the mouth and throat. As a result, the compositions of the present invention preferably have a basic buffer strength (also: a basic buffer strength (at least 0.01 milliequivalents) per unit dose, preferably from 0.05 nsd to 2.5 rofq per unit dose, most preferably thereafter from 0.1 mEq to 1.5 mKq per unit dose.

The compositions of the invention comprise a pharmaceutically acceptable carrier, preferably comprising a pharmaceutically acceptable buffer (buffer) system. Such pharmaceutical carriers that are useful in the compositions of the present invention include, but are not limited to, the following eystenias: phosphate and buffer systems which are a mixture of primary and secondary phosphate salts, Hydroxide / Lycin Buffer Systems Buffer systems consisting of a carbonate with a primary / acid / carbonate. For the compositions of the present invention, phosphate buffer systems are preferred as buffer systems.

For the compositions of the present invention, the carrier components are microcrystalline cellulose or a mixture of microcrystalline cellulose and sodium carboxymethylcellulose. Microcrystalline cellulose and mixtures of microcrystalline cellulose and sodium carboxymethyl cellulose are available from FMG Corooration o by the name of Avicel®. Such mixtures preferably have a ratio of microcrystalline cellulose and non-sodium carboxymethylcellulose of from 2C: 1 to 1: 1, preferably from 15: 1 to 3: 1, and even more preferably from 10: 1 to 5: 1.

A preferred blend of nicrocrystalline cellulose and non-sodium carboxymethylcellulose is Aviccl® PC59I, a commercially available microcrystalline cellulose, labeled FMC Corooration, Food and Pharmaceutical Products Division, Philadelphia, Philadelphia.

The product Avicel ® PC59I is said to be a colloidal form of 89% microcrystalline cellulose gel mixed with 11 nontruiracarboxymethylcellulose, which learns the product readily disperses in water, organic solvents and dilute acids, partially disintegrates in dilute bases. It has the following chemical and physical properties: do not lose on drying; less than 6% in the transport and loading of heavy metals: less than 10 parts per million (porc); viscosity of the 1,2X solution: f 9 + 1 particle size: less than 0.1% retained no 60 mesh site, less than 20µ retained no 3? 5 meeh.aite * Average particle size is 28 microns. The bulk material is 0.39? 7 kg dm @ 2 in terms of loose packaging and p

O »833O kg om in case of thin, firm and leak-proof packaging. The specific gravity is 1.53. The ash content is 2.times.value, the pH of the water dispersion in water is 6-8. This product is fully described by FMC Corporation Duilletin L-10 Avicel®

- 8 RC-Ci »Microcrystalline Celluloae, where appropriate reference is incorporated.

The amount of microcrystalline cellulose or of microcrystalline cellulose and sodium ethylcellulose incorporated into the sweat composition of the present invention is preferably from 0.5 to 3%, more preferably from 1 to 2%, more preferably 1.5%.

The compositions of the invention are intended for oeroral non-administration. Such compositions are, for example, preferably liquid compositions, in particular liquid compositions based on water, such as syrups, elixirs, ouepens, sprays. Preferred are those? solid compositions which dissolve or chew in the mouth, such as lozenges, chewable lozenges, powders and chewable tablets. The pH of the solid dosage aa is determined by dissolving the solid dosage in artificial saliva at a concentration of 10% solids and determining the pH in the resulting solution or suspension. The formulation of artificial saliva is given in; Fusayema T., Katayori T and Homoto S. Artifical Salivs ”, Journal of Dental Research Vol. 42 / 1963./ »PP · 1183 p - 1197» as incorporated herein by reference./

Pextromethorran is relatively insoluble in water at the pH of the compositions of the present invention. Therefore, it is preferred to incorporate a suitable amount of one or more cosolvents into the carrier to promote dissolution of the dextroraethorphan in the formulation and in the oral cavity. Preferred opolurosorbent or such purpose is ethanol, propylene glycol, polyethylene glycol, glycerin and eorbitol; more preferably include, for example, ethanol, for pyrene glycol and glycerin.

For the liquid compositions of the present invention, suitable carriers are, for example, the following suitable ingredient: water; sweetening agents such as sucrose, corn syrup, invert sugar, dextrose, sodium saccharin, aspartame, eorbitol, honey; and Reduce aromatic ingredients such as menthol, anethole, camphor thymol.1, methyl salicylate, eucalyptus? oil and peppermint oil, various flavors, various thickeners such as carboxymethylcellulose, natriuracarbovymatylcellulose, cellulose, glycerin and

9 polyethylene glycol preservatives such as sodium benzoate and cetylpyridinium chloride} various ingredients such as potassium eorbate, sodium chloride, titanium dioxide, polysorbate 8Π, sodium citrate, sodium bicarbonate, sodium hydroxide, aluminum hydroxide and magnesium hydroxide.

for solid compositions according to the present invention, a suitable carrier is preferred, which preferably contains one or more suitable ingredients listed above for liquid compositions and, for example, the following compositions have been used as urine additives: solid diluents, binders, blowing agents, disintegrating agents, disintegrating agents such as oxide silica, talc powder, kaolin, tartaric acid phosphate, lactose and starch; e a variety of ingredients such as resin, mannitol, sodium alginate, ©ginic acid, orabic gum, gelatin, ethylcellulose, magnesium otearate, bentonite and sodium lauryl sulfate.

The compositions of the present invention may also contain one or more medicaments that are effective but for treating a cough and / or a cold. Preferred are coughs / colds associated with antitussive agents in coral corpus products. The coughs / colds useful in the compositions of the present invention are selected from the group consisting of antihistamines, bronohodllatons, blood flow reducing agents, cough-relieving drugs, local anesthetics and anti-inflammatory analgesic agents. These preferred therapeutic agents are suitable in the following amounts in the compositions of the present invention: antihistamines such as chlorpheniramine (preferably from 1 mg to 3 mg, more preferably from 2 mg to 4 mg) and salts thereof (e.g. maleate (diphenylhadrarain) preferably from 6 mg to 50 mg, more preferably from 1 mg to 50 mg; mg to? 5 mg (and its salt (e.g. hydrochloride), bromopheniraraine), preferably from 1 mg to Sg, more preferably from 2 mg to 4 mg, and its salt, doxylamine (preferably from j mg to 20 mg, more preferably from 6 mg) up to 12 mg (e) of its salt (e.g. succinate), triprolidine (preferably from 0.5 mg to 4 mg, more preferably from 1 mg to 3 mg) and its salts (e.g. hydrochloride), bronchodiil, the eye being aphedrine (preferably

10 to 50 mg, more preferably from 10 mg to 25 mg (and its salts (e.g. hydrochloride, sulfate), a blood-reducing agent such as peeudoephedrine (preferably from 10 to loo mg, more preferably from 30 mg to 60 mg) and its salts (e.g. hydrochloride), phenylephridine (preferably from 2 to 20 mg). more preferably from 5 mg to 10 eg (and its salt (e.g. hydrochloride), phenyloro-aminolamine (preferably from 3 mg to 30 mg, more preferably from 12 mg to 25 mg) and its salts (e.g. hydrochloride) preferably from 50 mg to 400 mg, more preferably from 100 mg to 200 mg /; topical anesthetics such as benzocaine (preferably from 1 mg to 25 mg, more preferably from 2 mg to 15 mg), phenol (preferably from 1 mg to 150 mg, more preferably from 20 mg to 5 mg), dyolonine (preferably from 1 mg to 15 mg) 10 mg, more preferably from 2 mg to 4 mg (and its salt (e.g. hydrochloride), lidocaine), preferably from 2 mg to 22 mg, more preferably from 4 mg to 10 mg (and its salts (e.g. hydrochloride), butane), preferably from 5 mg to 50 mg, more preferably from 10 mg to 22 mg (and its salts (for example, airone, hydrochloride), benzyl alcohol (preferably from 50 mg to 750 mg, more preferably from 100 mg to 500 mg), dibucaine) 1 mg to mg, more preferably from 0.5 mg to 2 mg (and its salt (e.g. hydrochloride), tetracaine), preferably from 0.1 mg to 4 mg, more preferably from 0.5 mg to 2 mg, and its

Salts (e.g. hydrochloride), sodium phenolate (preferably from 10 mg to 150 mg, more preferably from 20 mg to 52 mg), sage, ethyl alcohol (preferably from 22 mg to 200 mg, more preferably from 50 mg to 100 mg), hexylresorcinol (preferably from 1 mg to 10 mg, more preferably from 2 mg to 4 mg) and menthol (preferably from 2 mg to 50 mg, more preferably from 5 mg to 25 mg); anti-inflammatory agents such as acetaminophen (preferably from 60 mg to 1220 mg, preferably Si® from 300 mg to 650 mg), ihuprofan (preferably from 100 mg to 900 mg, more preferably from 202 mg to 420 mg) and salts thereof (e.g. sodium salt, aspirin (preferably from 75 mg to 1000 mg, more preferably from 302 mg to 65 mg) and its salts (e.g. sodium salt) and naproxane (preferably from 75 mg to 520 mg, more preferably from 125 mg to 30 mg) and its salts (e.g. sodium salt).

The present invention further comprises methods.

For the treatment or prevention of cough in humans or certain animals by the oral route of administration, the daily dose of dertromethorphan is preferably from 0.1 rag / kg to 10 rag / kg of body weight, preferably greater than 0. 5 tna / kp; to 5 mg / kg, more preferably from 1 to 3 mg / kg. According to the method of the present invention, it is preferred to administer the methorphan composition orally once and once. deoalkrate daily, more preferably twice and? eight times a day and eSt® more preferably three times a? Sosl times a day.

The following are examples which illustrate the compositions n of the methods of the invention without, however, limiting the invention in any way. Liquid formulations and lozenges are prepared by conventional methods known in the art.

Methods of carrying out the invention

Example 1

Liquid anti-cat

Ingredient dose / lg ml dose

dextromethorphan HBr 30.0 mg propylene glycol 1.74 g ethanol / 95 $ / 1.5 ml menthol, natural 1.7,5 mg eucalyptus oil ^, 55 mg aromatic substances 0.05 ml sucrose 7.65 g carboxymethylcellulose (r, MO) 7.5 mg Microcrystalline cellulose and Sodium 0 (Avicel ^R HC591, FMC) 187.5 mg polysorbate 80 3.0 mg glycerin 700.0 mg sorbitol 300.0 mg F, T) and C Red t 40 7.0 mg

1?

glycine 78 * 2 mg sodium hydroxide 7.3 mg water, purified

A typical process for preparing the above cough liquid cough composition consists in preparing a separate

Ί liquid phase by combining the following components together: (1) destrometrophene ISr, propylene glycol, ethanol, menthol, eucalyptus oil and flavorings; sucrose, CMC, quail, Polysorbate 80, glycerin, sorbitol and part of water; n / 3 / dyes, glycine, sodium hydroxide and part of water. The three liquid phases e and are combined together with a reservoir with a plurality of water to prevent said cough liquid composition.

Example 2

Liquid anti-duck

ingredients .Kno £ etvo / l5 ml doses Dextromethorphan hydrochloride 15.0 mg propylánglykol 777.0 mg Ethanol (95%) 1.5 ml Polyethylene glycol / 'arbawax 499 / 759.3 mg Aromatic substances 3,3 ' 5 ml p, D, and Red * 49 5.1 mg Sodium dihydrogen phosphate ? 3l, 0 mr Saccharin sodium 23.5 mr

Water Purified Example 3 A liquid cough composition

Ingredicncia

Dextromethorphan hydrochloride Propylene glycol Ethanol (95%)

Menthol, natural .Knitting / 15 ml dose

w * V n <<< 1.74 rr 1.5 ml 3.5 mg

Eucalyptus oil 7.5 mg Aromatic substances 0.05 ml F, P and Red ä 43 5.1 mg Sodium dihydrogen phosphate 331.0 mg Saccharin sodium .30.0 mg sucrose Q, 16 g glycerin 7> 0.0 mg Sodium hydroxide 3.0 mg Water, purified Example 4 Liquid anti-sludge. Ingredients Quantity / 15 ml Pestromphorphan hydrochloride 30.0 me sucrose 6.16 p. Microcrystalline cellulose p .soda c? r / Avicel ppgol, i ^ / 167.5 mg KarbOTymetylcelulóza 7.5 mg Polysorbate PO 3.0 glycerin 2 00, P mg sorbitol 3 00.0 · mg F, D and Red 3.0 mg Sodium dihydroxyphosphine 231.0 mg Sodium cyanide 3.6 mg Sodium aol checkered 30.0 mg propylánglykol 1.74 jfir Ethanol / 95 X ^z 1.5 ml menthol 03,5 mg Eucalyptus oil 7.5 mg Aromatic substances Ο, 'Ό ml

Water, purified

Example 5

Liquid anti-cough agent

Ingredients Black / 15 ml < úextromethorphan hydrochloride 20.0 mg sucrose 8.16 e CMC 7,5 mg microcrystalline cellulose o CMC / Avicel ® KC591 sodium, F''C / 187.5 mg Polysorbate SO 3.0 mg glycerin 300.0 mg sorbitol 300.0 mg F, D, and C Red * 40 3.0 mg Sodium dihydrogeaphosphorus 231.0 mg Sodium hydroxide 5.0 mg It has a saccharin salt 30.0 mg Propylánglykol 1,74 g phenol 100.0 mg Ktanoi 1.5 ml menthol 7 2.5 mg Eucalyptus oil 7,5 mg Aromatic substances 0.05 ml

Water, purified

Example 6

Oroti liquid liquid formulation

Xngrediencie Knočstvo / P? ml dose Oextromethorphan hydrochloride 30.0 mg propylene glycol 777.0 mg Ethanol (95 *) 1.5 ml SGchnróze 8.16 7 g C vein of cry δ t © odd cellulose a 1 t J sodium salt CMC / Avicel © pcnol, PO / 187.5 Tľi'7 Polysorbate SO ·· '> mg glycerin 300.0 mg Aromatic substances 0.05 ml

F, D and Red and 40 Sodium dihydrogen phosphate Sodium hydroxide GOd aol of saccharin Water, Purified 5.1 231.9 3.6 2.?, 5 mg mg mg mg Example 7 Liquid anti-caffeine Ingredients ivno?, 8tvo / l5 ml dose Dextromethorphan h.hydrochloride 39.0 mg propylene 1.74 g Ethanol (95%) 1.5 ml Menthol, natural 27.5 m p Eucalyptus ,? oil 7.5 mg saccharose 6.16 g CMC 7.5 WP Microcrystalline cellulose; and Sodium CMC / Avicel © r? C5? l, FM9 / 167.5 mg Polyoorbát 3.0 mF Aromatic substances 0.05 ml F, T) and Red n 5.1 mg The hydrogenic gene was present 771.0 mg Worthy of saccharin ? · 9.0 mm glycerin 7 90.0 τη / r Sodium hydroxide 3.6 mr Water, purified Example 8 liquid anti-knock agent Ingredients t night / 15 roll dose Dextronethorphan hydrochloride 25.0 mg sucrose 6.16 g glycerin 300.0 mg

Sorbi tol 300.0 Nir F, p end Redt 4n n n * ·. ·· NSP Sodium hydrogen phosphate ? 3'1, C m r sodium hydroxide 3.6 we Saccharin sodium 30.0 mr propylene 1 -4 g Ethanol (95%) 1 ^sec ml .Mentol c- J,> MIF Fucslypt oil C ' »J rar Zvromatic substances Water, purified n J) ml Example 9 Liquid anticorrosive agent ingredients ** <knife / l5 1 rcl dose Dextromethorphan hydrochloride 30.0 mg sucrose 8.16 g glycerin 300.0 mg sorbitol J op, 0 mg F, P and Red ti 49 3.0 mg Sodium dihydrogen phosphate ? 3l, 0 mc sodium hydroxide 3.6 m? Sodium eol of saccharin 30.0 mg Propyl enlycol 1.74 g phenol 10 ^, 0 55Γ Ethanol / 95 V 1.6 ml menthol ??, 6 mm Fucalypt oil 7.5 DP Aromatic substances Water, purified 0.06 ml Example 10 Pressed composition tablets

17 g / 2.5 g lozenges

Ingredícncia

Dextromethorphan basic 5.0 mg ňenzokaín 1.25 mg Drilled talc 90.0 mg Aromatic substances 15.8 mg Caramel D end C * 40 69.4 mg Sodium phosphate dodecahydrate 40.0 mg Aagiiáziumateerát 45.0 mg saccharin 15.0 Iflff Eiiidex Example 11 Anti - cough agent in a liquid spray the ingredients of the Fodder / 1,5 ml dose Lextromethorphan basic ? 5.0 mg Propylene glyco 1 0.7 ml ethanol T 05 ml polyethylene glycol / Carbowax 400 / 0.7 ml Saccharin sodium 5.25 mg Aromatic substances by, inter alia; ? ml F, 1) and C Red # 40 1.19 mg phenol 75.0 mg Water, Cioteno. Example 12 Anti - cannula in a liquid gray Ingredients Anožstvo / O, 5 ml dose Pextromethorphan basic 10,0 mg pelyetylénglykol 0.7 ml Ethanol (95%) 0.7 ml polyethylene glycol / oarbotrax 400 / 0.7 ral Sodium phosphate 8.4 mg

- 18 Sodium saccharin Aromatics F, D and ped # 47 Water, purified

7.7 ml / ml, 14 ml 1.19 mg of liquid in Example 1? Axis is prepared by adding said basic dextromstorphan to propylene glycol or by continuous mixing. Gradually add the mieSenio polyetylénrly _the wheel, alcohol, aroma and saccharin sodium nol, stirring under nitrogen, the sodium phosphate jodnosýty-102 in neat Ný> water therein. A dye is added as an aqueous solution, while still mixing, adding purified water to make up the volume.

The foregoing embodiments of the present invention are merely descriptive and illustrative and allow for various modifications and variations, without thereby limiting or limiting the subject matter and scope of the invention.

Industrial use tqlnosl

The composition of the invention is a pharmaceutical composition for the treatment of certain diseases c is an antituaic agent. Its preparation is one of the methods of preparation in the pharmaceutical industry.

Claims (6)

1. Antitussive formulations in the form of a unit dose for peroral absorption, you Srhrft č, u-ji.jc € _{? R} a, FTTM,? ziíkladné contain the active safety of the oral xnočatvo dcxtron.etorfánu much prijotelnáho fermciceutického carrier wherein the viscosity is between 8 and 11, preferably 8.4 to 10. ?. Unit dose arithritic formulations for oral administration, characterized in that: 2e contain a safe and effective amount of another anti-cold and cold drug component other than phenol, preferably antihistcrin, bronchodilators, vascular blocking agents, coughing agents, topical anesthetic or anti-inflammatory or onalgesic agents; and wherein the pH of the composition is from about 10 to about 11, preferably from about 6.4 to about 10. 3. Unit dose antitussive formulations for oral administration, comprising a safe and effective amount of dextromorphan; an effective amount by a safe amount, preferably from rcg to 50 µm per dose of phenol; and further comprising an orally acceptable pharmaceutical carrier; the pH of this px-fraction is higher than 5 and g 11, preferably higher than 9 to 10. 4. The composition as claimed in claim 1, wherein said means has a pressure capacity of at least Ω, οΐ, preferably from 0.05 to 2.5% of base per liter. dose, e from 1 µg to 50 mg, preferably from 0.5 mg to 30 mg dextromethorphan per dose. 5. A composition according to any one of claims 1 to 4, characterized in that said composition is an aqueous base liquid, preferably containing from 0.5% to 3% of Avicel ®. · C '' CCL scatter / uy according to any one of claims 1 and 2 5 »I ^'to 7' of the 5 CISRI Ju? characterized in that said composition also comprises another medicament against cough and cold which is selected from: 1. P mp of chlorphentramine per dose, from C op to 5 o mp of diphenylamine per dose, from 1 wp to P mg of brophenrerine per dose, from 7 mp to 00 mg doxylamine per dose, from 7.5 v to 5 mg mp triprolidine np dose, from. 5 nip to 57 κρ ephedrine per dose, from 17 mg to 170; np paeudoephedrine per dose, from 7 mp to 7 7 pp phenyl e - 'e drin per dose, from 5 mg to 57 nv phenylpronenolsrcin per dose, from 50 T to 477 mp puaifenezin per dose, from 1 mp to 25 mp benaokein per dose, from 1 mp to 10 mp dyclonin. per dose, from 2 mp to 70 mp lidocaine per dose, from 5 rap to 57 mg butsk.aine per dose, from 50 mg to 750 rp bcr.alcohol alcohol dose, from 0.1 mp to 4 dibucine per dose, from 0 , 1 mp to 4 mp teiroctin per dose, from 10 mp to 157 mg sodium phenolate per dose, from PO mg to 700 aalicylalcohol per dose, from 1 mg to 10 mp hexyl? iug to 50 µl per dose, from CO mp to 1000 mp acetavduofen per dose, from. 170 mp ibuprofen no dose, from 75 mp to 1770 && aspirin no. a dose of from 75 µm to 5 µm for xene per dose of their mixture. 7. A method for the manufacture of a composition according to claim 1 for the treatment and prevention of ducks in humans by the oral administration of said composition.