HUT64216A - Process for producing cough diminishing medical preparative containing dextrometorphane - 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 present invention relates to novel antitussive pharmaceutical compositions containing dextromethorphan. More particularly, the present invention relates to compositions and methods for rapidly achieving a therapeutic systemic level of dextromethorphan.

Dextromethorphan (racemetorphan), i.e. 17-methyl-3-methoxymorphinan, is included in the 10th edition of the Merek Index [M. Windholz, ed., No.8009, (1983) p. 1170] as a cough suppressant.

Dextromethorphan hydrobromide is widely used as a cough suppressant in commercial products, as described in Physician's Desk Reference for Non-Prescription Drugs, 11th Edition (1990), E.R. Barnhardt pub., P. 306] and Physician's Desk Reference [44th Edition (1990), E.R. Barnhardt pub., P. 309]. Such products include Bayer Children's Cough Syrup (Glenbrook), Benylin DM (Parke-Davis), Benylin Expectorant (Parke-Davis), CeroseDM (Wyeth-Ayerst), Cheracol D Cough Formula (Upjohn), Cheracol Plus Head Cough / Cold Formula (Upjohn), Cough Formula Comtrex (Bristol-Myers Products), Comtrex Multi-Symptom Cold Reliever Tablets / Caplets / Liquid / Liquigels (Bristol-Myers Products), Contac Cough Formula (SmithKline Consumer), Contac Cough & Shore Throat Formula (SmithKline) Consumer), Contac Jr. Children's Cold Medicine (SmithKline Consumer), Contac Nighttime Cold Medicine (SmithKline Consumer), Contac Severe Cold Formula Caplets (SmithKline Consumer), Dimacol Caplets (Robins), Dorcol Children's Cough Syrup (Sandoz Consumer), Hold ( SmithKline Beecham), Naldecon DX Aduit Liquid (Bristol Laboratories), Naldecon DX Children's Syrup (Bristol Laboratories), Naldecon DX Pediatric Drops (Bristol Laboratories), Naldecon Senior DX Cough / Cold Liquid (Bristol Laboratories), Novahistine DMX (Lakeside) armaceuticals), Pediacare Cough-Cold Formula Liquid and Chewable Tablets, · »·

(McNeil Consumer Products), Pediacare Night Rest Cough-Cold Formula Liquid (McNeil Consumer Products), Robitussin Night Relief (Robins), Robitussin-CF (Robins), Robitussin-DM (Robins), Scot-Tussin Sugar-Free DM Cough & Cold Medicine (Scot-Tussin), Snaplets DM (Baker Cummins Pharmaceuticals), Snaplets-Multi (Baker Cummins Pharmaceuticals), St. Joseph Cuogh Suppressant For Children (Pluogh), St. Joseph Nighttime Cold Medicine (Pluogh), Sucrets Cough Control Formula (SmithKline Beecham), Sudafed Cough Syrup (Borroughs Wellcome), Triaminic Night Light (Sandoz Consumer), Triaminic DM Syrup (Sandoz Consumer), Triaminicol Multi-Symptom Cold Tablets (Sandoz Consumer), Triaminicol Multi-Symptom Relief (Sandoz Consumer) , Tylenol Cold Medication Caplets and Tablets (McNeil Consumer Products), Tylenol Cold Medication Liquid (McNeil Consumer Products), Tylenol Cold Medication No Drowsiness Formula Caplets (McNeil Consumer Products), Vicks Children's Cough Syrup (Richardson-Vicks, Inc.), VicksChildren's NyQuil (Richardson-Vicks, Inc.), Vicks Cough Silencer Cough Drops (Richardson-Vicks, Inc.), Vicks Daycare Daytime Colds Medicine Caplets (Richardson-Vicks, Inc.), Vicks Daycare Multi-Symptom Colds Medicine Liquid (Richardson) -Vicks, Inc.), Vicks Formula 44 Cough Control Disks (Richardson-Vicks, Inc.), Vicks Formula 44 Cough Medicine (Richardson-Vicks, Inc.), Vicks Formula 44D Decongestant Cough Medicine (Richardson-Vicks, Inc.). , Vicks Formula 44M Cough Medicine (Richardson-Vicks, Inc.), vicks NyQuil Nighttime Colds Medicine - Original & Cherry Flavor (Richardson-Vicks, Inc.), Vicks Pediatric Formula 44 Cough &

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- 4 Colds Medicine (Richardson-Vicks, Inc.), Vicks Pediatric Formula 44 Cough & Congestion Medicine (Richardson-Vicks, Inc.), Ambenyl-D Decongestant Cough Formula (Forest Pharmaceuticals), Bromarest DX Cough Syrup (Warner Chilcott), BromFed-DM Cough Syrup (Muro), Codimal DM (Central Pharmaceuticals), Dimetante-DX Cough Syrup (Robins), Guaifenesin w / D-Metrophan Hydrobromide Syrup (Lederle), Humibid DM Tablets (Adams), IoTuss-DM Liquid (Muro) ), Medi-Tuss DM Warner Chiclott, Phenergan Dexotromthorpan (Wyeth-Ayrest), Poly-Histine DM Syrup (Bock), Quelidrine Syrup (Abbott), Rondec-DM Clock Drops (Ross), Rondec DM Syrup (Ross) Tusibron -DM (RAM Laboratories), Tussar DM (Rorer Pharmaceuticals) and Tussi-Organidin DM Liquid (Wallace). Delsym Cough Suppressant Syrup (McNeil Consumer) contains dextromethorphan polystyrene as an antitussive. All of the above commercial products containing dextromethorphan are believed to have a neutral or lower pH formulation.

Beckett, A.H. and E.G. Triggs in Buccal Absorption of Basic Drugs and Its Application as an Invention Model of Passive Drug Transfer Through Lipid Membranes (Journal of Pharmaceutics and Pharmacology, Vol. 19, (Supplement) 31S-41S (1967)) states that higher For a significant proportion of pH formulations, oral absorption is significantly increased when the formulation is rotated in the mouth for 5 minutes. Dextromethorphan is not among the drugs studied by Beckett and Triggs. Beckett and Triggs' statement is less applicable to liquid formulations that are not usually held in the mouth but are rapidly used by the human body ·····················••••••••••••••• It is ingested and similar to solid products, such as lozenges, which dissolve in the mouth and are swallowed quickly.

U.S. Patent No. 4,892,877 discloses liquid cough suppressant compositions containing dextromethorphan and phenol and having a pH of from 5 to 9. United States Patent 4,427,681 discloses thixotropic cough suppressants containing dextromethorphan and Avicel ^R RC-591.

The present invention relates to dextromethorphan formulations for oral administration which exhibit a faster rate of cough suppression than commercially available formulations.

It is a further object of the present invention to provide a rapid cough suppressant effect in dextromethorphan formulations.

The pharmaceutical compositions of the present invention for oral administration consist essentially of a safe and effective amount of dextromethorphan and an acceptable pharmaceutical carrier for oral use and have a pH of about 8 to about 11.

The invention further encompasses pharmaceutical compositions for oral administration comprising a safe and effective amount of dextromethorphan, a safe and effective amount of a non-phenolic antitussive and antitussive agent, and a pharmaceutical carrier acceptable for oral administration having a pH of about 8 and between about 11.

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The present invention further encompasses pharmaceutical compositions for oral administration comprising a safe and effective amount of dextromethorphan, a safe and effective amount of phenol, and a pharmaceutically acceptable carrier for oral use having a pH above about 9 to about 11.

Thus, the compositions of the present invention contain a safe and effective amount of dextromethorphan and, optionally, other active ingredients. A safe and effective amount is an amount of active ingredient that is large enough to cause a definite positive change in the condition being treated, but small enough to avoid (at a reasonable effect / risk ratio) serious side effects within the medical judgment. The safe and effective amount of the active ingredient will depend on the age and physical condition of the patient to be treated, the severity of the condition being treated, the duration of treatment, the concomitant therapies and the like.

Dextromethorphan is a known antitussive. By dextromethorphan, the term racemtorfant, 17-methyl-3-methoxymorphanthine (dl-cis-1,3,4,9 ', 10,10a-hexahydro-10,4a- (imino-ethano) -11-methyl-6- methoxy-2H-phenanthrene, a compound of formula (A), and pharmaceutically acceptable salts thereof The hydrobromides are preferred among the salts of dextromethorphan.

The compositions of the invention preferably ^_ about 1 to about 50 mg, more preferably about 2.5 - contain about 30 mg dextromethorphan per dose. The liquid compositions preferably contain from about 0.02 to about 1.5%, more preferably from about 0.05 to about 1%, most preferably from about 0.1 to about 0.3% dextromethorphan. The usual dosage for liquid formulations is about 1 to about 30 ml. More preferably, the dose of the antitussive syrup is about 5 to about 20 ml, and the dose of the concentrated antitussive spray is about 2 to about 5 ml, most preferably about 3.5 ml.

Preferred pharmaceutical compositions of the present invention comprise a substantially safe and effective amount of dextromethorphan and an acceptable pharmaceutical carrier for oral use, having a pH of from about 8 to about 11, preferably from about 8.4 to about 10, more preferably from about 8.5 to about 9, Other preferred compositions of the invention comprise a safe and effective amount of dextromethorphan, a safe and effective amount of a non-phenolic antitussive and antifungal agents, and a pharmaceutically acceptable carrier for oral use having a pH of about 8 and from about 11, preferably from about 8.4 to about 10, more preferably from about 8.5 to about 9.5, most preferably from about 9. Further Preferred compositions comprise a safe and effective amount of dextromethorphan, a safe and effective amount of phenol, and a pharmaceutically acceptable carrier for oral use having a pH above about 9, about 9 to about 11, preferably about 9.5 to about 10, more preferably about It is between 9.1 and about 9.5.

It has been found that the compositions of the present invention achieve a therapeutically effective blood level and / or peak dextromethorphan blood levels that are faster and longer than conventional dextromethorphan formulations of lower pH.

Preferably, the compositions of the present invention exhibit a sufficiently high basic buffering effect sufficient to counteract the effects of the mouth and throat mucosa and mucous membrane, so that the composition, when mixed with saliva, maintains a pH within the above ranges while remaining in the mouth and throat. Thus, the base puff effect of the compositions of the invention is at least 0.01 milliequivalents (mEq) per unit dose, preferably about 0.05 to about 2.5 mEq / unit dose, more preferably about 0.1 to about

1.5 mEq / unit dose.

Preferably, the compositions of the present invention comprise a pharmaceutically acceptable carrier comprising a pharmaceutically acceptable buffer system. This may be, for example, a phosphate buffer system consisting of a mixture of monohydrogen and dihydrogen phosphates, sodium hydroxide / glycine or carbonate / bicarbonate buffer systems. Phosphate buffer systems are preferred for use in the compositions of the invention.

A preferred component of the carrier for use in the compositions of the invention is microcrystalline cellulose or a mixture thereof with sodium carboxymethylcellulose. A mixture of microcrystalline cellulose and sodium carboxymethylcellulose is available under the tradename Avicel ^R from FMC Corporation. In these mixtures, the ratio of microcrystalline cellulose to (carboxymethyl) cellulose sodium is from about 20: 1 to about 1: 1, preferably from about 15: 1 to about 3: 1, more preferably from about 10: 1 to about 5: 1 it is.

A preferred commercial blend of microcrystalline cellulose with carboxymethyl cellulose sodium is Avicel ^R RC591 microcrystalline cellulose, available from the Food and Pharmaceutical Products Division of FMC Corporation, Philadelphia, Pennsylvania. Avicel ^R RC591 is a colloid in which about 89% microcrystalline cellulose gel is mixed with about 11% dried (carboxymethyl) cellulose sodium; this product is highly dispersible in water. Partially soluble in water, organic solvents and dilute acids. Chemical and physical properties: less than 6% drying loss during transport; heavy metals: less than 10 ppm; the viscosity of the 1.2% solution is 65 ± 1%; particle size: sieve residue less than 0.1% on a sieve with a mesh size of 0.250 mm and less than 20% on a sieve with a mesh size of 0.044 mm; average particle size is about 28 micrometers. It has a bulk density of about 0.6 g / cm ^{3 with a} loose charge and about 0.8 g / cm ^{3 with a} solid charge. It has a density of 1.55, an ash content of about 2%, and a pH of 6 to 8 in an aqueous dispersion of 2%. Detailed description of the product is provided in Avicel ^R RC-CL Microcrystalline Cellulose, L-318, FMC Corporation.

The compositions of the present invention preferably contain from about 0.5% to about 3%, more preferably from about 1% to about 1.5%, of the microcrystalline target lulose or a mixture thereof with carboxymethylcellulose sodium.

The compositions of the invention may be administered orally. Such formulations include liquid formulations which may be advantageously employed, in particular aqueous formulations such as syrups, sprays and drops. Solid compositions which can be dissolved or chewed in the mouth, such as lozenges, chewable lozenges, powders or chewable tablets, are also preferably used. The pH of these solid dosage forms is determined by dissolving the solid composition in artificial saliva at a concentration of 10% and measuring the pH of the resulting solution or suspension. The composition of artificial saliva can be found in Fusayema, T., T. Katayori and S. Nomoto Artifical Salvia (Journal of Dental Research, 42, 1183-1197, 1963).

Dextromethorphan is relatively poorly soluble in water at the pH of the compositions of the invention. Therefore, it is preferable that the vehicle contains an appropriate amount of one or more co-solvents (co-solvents) to help dissolve the dextromethorphan content of the composition in the oral cavity. Preferred co-solvents for this purpose are ethanol, propylene glycol, polyethylene glycol, glycerol and sorbitol; of these, ethanol, propylene glycol and glycerol are particularly preferred.

The carrier of the liquid compositions of the present invention preferably comprises some of the following optional additives: water; sweeteners such as sucrose, corn syrup, invert sugar, dextrose, saccharin sodium, aspartame, sorbitol, honey or magnasweet; aromatic additives such as menthol, anethole (p-methoxypropenylbenzene), camphor, thymol (4-isopropyl-1-methylphenol), methyl salicylate, eucalyptus oil or peppermint oil; other flavorings; thickeners such as carboxymethylcellulose, carboxymethylcellulose sodium, cellulose, glycerol or polyethylene glycol; dyes; preservatives such as sodium benzoate or cetylpyridinium chloride; mixed additives such as potassium sorbate, sodium chloride, titanium dioxide, polysorbate 80, sodium citrate, sodium bicarbonate, sodium hydroxide, aluminum hydroxide or magnesium hydroxide.

The carrier of the solid compositions of the invention preferably contains one or more of the optional additives listed in the liquid compositions, and may additionally contain some of the following optional additives: solid diluents, binders, disintegrating agents, and opacifying agents, such as silicon. -dioxide, talc, povidone [polyvinylpyrrolidone], kaolin, dicalcium phosphate, calcium sulfate, lactose, starch; and mixed additives such as acacia, capsicum, mannitol, sodium alginate, alginic acid, veegum, guar gum, gelatin, ethyl cellulose, magnesium stearate, bentonite, sodium lauryl sulfate.

The compositions of the invention may further comprise one or more other active ingredients for the treatment of cough and / or colds. For this purpose, active compounds commonly used in commercial products with antitussive agents, such as antihistamines, bronchodilators, decongestants, expectorants, topical anesthetics, anti-inflammatory drugs and analgesics, are advantageously used for this purpose. The following are some examples of the active compounds that may be used in the compositions of the invention and their preferred dosage unit amounts: antihistamines such as chlormelipramine (preferably about 1 to about 8 mg, more preferably about 2 to about 4 mg) and salts (e.g. maleate); diphenhydramine (preferably about 6 to about 50 mg, more preferably about 12 to about 25 mg) and its salts (e.g. hydrochloride), brompheniramine (preferably about 1 to about 8 mg, more preferably about 2 to about 4 mg) and its salts, doxylamine (e.g. preferably about 2 to about 20 mg, more preferably about 6 to about 12 mg) and its salts (e.g. succinate), triprolidine (preferably about 0.5 to about 4 mg, more preferably about 1 to about 3 mg) and its salts (e.g. hydrochloride) ); bronchodilators such as ephedrine (preferably about 5 to about 50 mg, more preferably about 10 to about 25 mg) and its salts (e.g., hydrochloride, sulfate), antitussives such as pseudoephedrine (preferably about 10 to about 100 mg, more preferably about 30 to about 60 mg) and salts (e.g., hydrochloride), phenylephrine (preferably about 2 to about 20 mg, more preferably about 5 to about 10 mg) and salts (e.g., hydrochloride), phenylpropanolamine (preferably about 5 to about 50 mg); mg, more preferably about 12 to about mg) and its salts (e.g. hydrochloride), expectorants such as guaifenesin (preferably about 50 to about 400 mg, more preferably about 100 to about 200 mg), topical anesthetics such as anesthetic [p- ( ethylamino) benzoate, preferably about 1 to about 25 mg, more more preferably about 2 to about 15 mg], phenol (preferably about 10 to about 150 mg, more preferably about 20 to about 50 mg), diclonine (preferably about 1 to about 10 mg, more preferably about 2 to about 4 mg), and salts thereof (e.g. e.g. hydrochloride), lidocaine (preferably about 2 to about 20 mg, more preferably about 4 to about mg) and its salts (e.g. hydrochloride), butacaine (preferably about 5 to about 50 mg, more preferably about 10 to about 20 mg) and salts (e.g. dicucaine (preferably about 0.1 to about 4 mg, more preferably about 0.5 to about 2 mg), e.g. sulfate, hydrochloride), benzyl alcohol (preferably about 50 to about 750 mg, more preferably about 100 to about 500 mg) dicucaine (preferably about 0.1 to about 4 mg). and salts thereof (e.g. hydrochloride), tetracaine (preferably about 0.1 to about 4 mg, m.p. g more preferably about 0.5 to about 2 mg) and its salts (e.g., hydrochloride), sodium phenol (preferably about 10 to about 150 mg, more preferably about 20 to about 50 mg), salicyl alcohol (preferably about 20 to about 200 mg). mg, more preferably about 50 to about 100 mg), hexyl resorcinol (preferably about 1 to about 10 mg, more preferably about 2 to about 4 mg) or menthol (preferably about 2 to about 50 mg, more preferably about 5 to about 25 mg); anti-inflammatory and analgesic agents such as acetaminophen (preferably about 60 mg)

about 1000 mg, more preferably about 300 to about 650 mg), ibuprofen (preferably about 100 to about 800 mg, more preferably about 200 to about 400 mg) and its salts (e.g., sodium salts), aspirin (preferably about 75).

about 1000 mg, more preferably about 300 to about 650 mg) and its salts (e.g., sodium salts) or naproxane (preferably about 75 to about 500 mg, more preferably about 125 to about 300 mg) and its salts (e.g., sodium salts).

The invention further relates to a method of treating or preventing cough in humans or smaller animals by oral administration of one of the above compositions. The daily dose of dextromethorphan used in the process of the invention is preferably about 0.1 to about 10 mg / kg body weight, more preferably about 0.5 to about 5 mg / kg body weight, most preferably about 1 to about 3 mg / kg body weight. . The dextromethorphan composition is orally administered to the patient about 1 to about 10, preferably about 2 to about 8, and more preferably about 3 to about 6 times daily.

The following examples are intended to further illustrate the invention but are not intended to limit its scope. Liquid and tablet formulations are prepared by conventional techniques.

Example 1

Liquid stone cracking preparation

Ingredients Quantity per 15 ml dose Dextromethorphan HBr 30.0 mg propylene 1.74 g Ethanol (95%) 1.5 ml Menthol (natural) 12.5 mg eucalyptus 7.55 mg flavorings 0.05 ml saccharose 7.65 g (Carboxymethyl) cellulose (CMC) 7.5 mg Microcrystalline cellulose and sodium CMC (Avicel ^R RC591, FMC) 187.5 mg Polysorbate 80 3.0 mg Glycerol 300.0 mg sorbitol 300.0 mg F, D and C Red No.40 3.0 mg glycine 28.2 mg Sodium hydroxide 7.8 mg Cleaned water as required

The above liquid cough suppressant composition is generally prepared by mixing the following components into separate liquid phases: (1) dextromethorphan HBr, propylene glycol, ethanol, menthol, eucalyptus oil and flavoring agents; (2) sucrose, CMC, Avicel, polysorbate 80, glycerol, sorbitol and some water; and (3) dyes, glycine, sodium hydroxide and some water. The three liquid phases are then mixed with the remainder of the water to give a liquid antitussive composition.

Example 2

Liquid stone heat retardant

Ingredients Mennvisecr in a dose of 15 ml Dextromethorphan HBr 15.0 mg propylene 777.0 mg Ethanol (95%) 1.5 ml Polyethylene glycol (Carbowax 400) 750.0 mg flavorings 0.05 ml F, D and C Red No.40 5.1 mg Disodium hydrogen phosphate 231.0 mg Saccharin sodium 22.5 mg Cleaned water · as required Example 3 Liquid cough suppressant preparation Ingredients Mennvisécr In a dose of 15 ml Dextromethorphan HBr 30.0 mg propylene 1.74 g Ethanol (95%) 1.5 ml Menthol (natural) 22.5 mg eucalyptus 7.5 mg flavorings 0.05 ml F, D and C Red No.40 5.1 mg Disodium hydrogen phosphate 231.0 mg

Saccharin sodium

30.0 mg

saccharose

Glycerol

Sodium hydroxide

Cleaned water

8.16 g

750.0 mg

3.0 mg as needed

Example 4

Liquid-stone-cushioning composition

Ingredients Quantity In a dose of 15 ml Dextromethorphan HBr 30.0 mg saccharose 8.16 g (Carboxymethyl) -cellulose (CMC) 7.5 mg Microcrystalline cellulose and sodium CMC (Avicel ^R RC591, FMC) 187.5 mg Polysorbate 80 3.0 mg Glycerol 300.0 mg sorbitol 300.0 mg F, D and C Red No.40 3.0 mg Disodium hydrogen phosphate .T 231.0 mg Sodium hydroxide 3.6 mg Saccharin sodium 30.0 mg Ethanol (95%) 1.5 ml propylene 1.74  g Menthol (natural) 22.5 mg eucalyptus 7.5 mg flavorings 0.05 ml

Purified water as needed

- 18 Example 5

Liquid cough suppressant

ingredients Mennviséq In a dose of 15 ml Dextromethorphan HBr 20.0 mg saccharose 8.16 g CMC 7.5 mg Microcrystalline cellulose and sodium CMC (Avicel RC591, FMC) 187.5 mg Polysorbate 80 3.0 mg Glycerol 300.0 mg sorbitol 300.0 mg F, D and C Red No.40 3.0 mg Disodium hydrogen phosphate 231.0 mg Sodium hydroxide 5.0 mg Saccharin sodium 30.0 mg propylene 1.74 t g Phenol 100.0 mg Ethanol (95%) 1.5 ml Menthol (natural) 22.5 mg Eucalyptus oil 7.5 mg flavorings 0.05 ml Cleaned water need by

Example 6

Liquid cough and anti-coagulant Ingredients Quantity per 15 ml dose

Dextromethorphan HBr

30.0 mg

propylene 777.0 mg Ethanol (95%) 1.5 ml saccharose 8.16 g CMC 7.5 mg Microcrystalline cellulose and sodium CMC (Avicel ^R RC591, FMC) 187.5 mg Polysorbate 80 3.0 mg Glycerol 300.0 mg flavorings 0.05 ml F, D and C Red No.40 5.1 mg Disodium hydrogen phosphate 231.0 mg Sodium hydroxide 3.6 mg Saccharin sodium 22.5 mg Cleaned water as required

Example 7

Liquid cough suppressant

Ingredients Quantity in a dose of 15 ml

Dextromethorphan HBr 30.0 mg propylene 1.74 g Ethanol (95%) 1.5 ml Menthol (natural) 22.5 mg eucalyptus 7.5 mg saccharose 8.16 g CMC 7.5 mg Microcrystalline cellulose and sodium CMC (Avicel ^R RC591, FMC) 187.5 mg

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- 20 - Polysorbate 80 3.0 mg flavorings 0.05 ml F, D and C Red No.40 5.1 mg Disodium hydrogen phosphate 231.0 mg Saccharin sodium 30.0 mg Glycerol 300.0 mg Sodium hydroxide 3.6 mg Cleaned water as required Example 8

Liquid cough suppressant

ingredients Quantity per 15 ml dose Dextromethorphan HBr 25.0 mg saccharose 8.16 g Glycerol 300.0 mg sorbitol 300.0 mg F, D and C Red No.40 3.0 mg Disodium hydrogen phosphate 231.0 mg Sodium hydroxide 3.6 mg Saccharin sodium 30.0 mg propylene 1.74 g Ethanol (95%) 1.5 ml Menthol 22.5 mg eucalyptus 7.5 mg flavorings 0.05 ml Cleaned water as required

9, Example

Liquid stone heat retardant

Ingredients Quantity in a dose of 15 ml

Dextromethorphan HBr 30.0 mg

saccharose 8.16 g Glycerol 300.0 mg sorbitol 300.0 mg F, D and C Red No.40 3.0 mg Disodium hydrogen phosphate 231.0 mg Sodium hydroxide 3.6 mg Saccharin sodium 30.0 mg propylene 1.74 g Phenol 100.0 mg Ethanol (95%) 1.5 ml Menthol 22.5 mg eucalyptus 7.5 mg flavorings 0.05 ml Cleaned water as required

Example 10

Pressed solid heat retardant

Ingredients Mennviséq in a 2.25 q candy bar Dextromethorphan base 5.0 mg anesthesia 1.25 mg talc 90.0 mg flavorings 15.8 mg Caramel B&C No.40 69.4 mg

Trisodium phosphate dodecahydrate 40.0 mg Magnesium stearate 45.0 mg Saccharin 15.0 mg Emdex as required

Example 11

Liquid spray antitussive

Ingredients

Quantity per dose of 3.5 ml

Dextromethorphan base

25.0 mg

propylene

Ethanol (95%)

1.05 ml

Polyethylene glycol (Carbowax 400)

0.7 ml

Saccharin sodium

5.25 mg of flavoring agents

0.012 ml

F, D and C Red No.40

1.19 mg

Phenol

75.0 mg

Purified water as needed

Example 12

Liquid spray cough suppressant

Ingredients Quantity 3.5 ml dose Dextromethorphan base 10.0 mg propylene 0.7 ml Ethanol (95%) 0.7 ml Polyethylene glycol (Carbowax 400) 0.7 ml Sodium dihydrogen phosphate 8.4 . mg

Saccharin sodium

7.0 mg

flavorings

F, D and C Red No.40

0.14 ml

1.19 mg

Purified water as needed

The liquid of Example 12 was prepared by adding dextromethorphan base to propylene glycol with stirring followed by gradual addition of polyethylene glycol, alcohol, flavoring agents and saccharin sodium. Sodium dihydrogen phosphate in 10% aqueous solution is also added with stirring. An aqueous solution of the dye and a further volume of water are added with stirring.

It will be apparent to those skilled in the art that the above embodiments of the process of the present invention may be made with obvious modifications, without prejudice to the scope of the invention.

Claims (7)

PATENT CLAIMS CLAIMS 1. An oral cough suppressant pharmaceutical composition in unit dosage form comprising a safe and effective amount of dextromethorphan and an acceptable pharmaceutical carrier for oral administration having a pH of 8 and 11. preferably between 8.4 and 10. 2. An oral cough suppressant pharmaceutical composition in unit dosage form comprising a safe and effective amount of dextromethorphan, a safe and effective amount of another non-phenolic cough / rhinitis agent, preferably an antihistamine, bronchodilator, local anesthetic, antitussive, and an acceptable pharmaceutical carrier for oral administration and has a pH of 8 to 11, preferably 8.4 to 10. 3. An oral cough suppressant pharmaceutical composition in unit dosage form comprising a safe and effective amount of dextromethorphan, a safe and effective amount, preferably 20 to 50 mg of phenol per dose, and an acceptable pharmaceutical carrier at a pH of 9 to 11, preferably Values between 9 and 10 but greater than 9. 4. Composition according to any one of claims 1 to 3, characterized in that the basic buffer strength is at least 0.01, preferably 0.05 to 2.5 milliequivalents (mEq) base / dose, and contains 1 to 50 mg, preferably 2.5 to 30 mg dextromethorphan per dose. . «··· 5. Composition according to any one of claims 1 to 3, characterized in that it is an aqueous liquid, which preferably also contains 0.5 to 3% Avicel ^R RC591. 6. Composition according to any one of claims 1 to 3, characterized in that it contains an additional cough / cold product, namely 1 to 8 mg chlorpheniramine, 6 to 50 mg diphenhydramine, 1 to 8 mg brompheniramine, 2 to 20 mg doxylamine, 0.5 to 4 mg per dose. triprolidine, 5 to 50 mg ephedrine, 10 to 100 mg pseudoephedrine, 2 to 20 mg phenylephedrine, 5 to 50 mg phenylpropanolamine, 50 to 400 mg guaifenesin, 1 to 25 mg anesthetin, 1 to 10 mg diclonine, 2 to 20 mg lidocaine 5 to 50 mg butacaine, 50 to 750 mg benzyl alcohol, 0.1 to 4 mg dibucaine, 0.1 to 4 mg of tetracaine, 10 to 150 mg of sodium phenolate, 20 to 200 mg of salicyl alcohol, 1 to 10 mg of hexylresorcin, 2 to 50 mg of menthol, 60 to 1000 mg of acaminamine, 100 to 800 mg of ibuprofen, 75 to 1000 mg of aspirin, or 75 to 500 mg of naxoprene or mixtures thereof. Use of dextromethorphan according to one of claims 1-6. For the preparation of a composition according to any one of claims 1 to 6 for the treatment or prevention of cough in humans, orally.