JPH0262823A - Antitussive oral composition - Google Patents

Abstract

PURPOSE: To obtain an oral antitussive composition containing both an oral antitussive and tryptophan and improved in antitussive potency. CONSTITUTION: This oral antitussive composition contains (A) a safe and effective amount of tryptophan represented by the formula, and (B) a safe and effective amount of an oral antitussive, e.g. dextromethorphan, chlophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, and/or their pharmaceutically acceptable salts, in an A:B ratio of 2:1 to 5000:1, especially 16:1 to 100:1, exhibits an improved antitussive potency, and is useful for the treatment of tussis in man and animals in the form of e.g. syrup, emulsion, suspension, solution, tablet, lozenge, capsule, granule, or bulk powder suitable for the oral administration of a unit dosage.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to an antitussive oral pharmaceutical composition containing tryptophan together with an oral antitussive.

BACKGROUND OF THE INVENTION The cough reflex is an important mechanism by which secretions are cleared from the lungs and trachea. Generally, such secretions are removed by capillary muscle escalators. However, when this mechanism is defective or becomes difficult to counteract, for example due to excessive secretion, coughing becomes the primary means of secretion removal.

The cough-sucking reflex is initiated by stimulation of mechanical receptors and is controlled by afferent pathways in the vagus (X), glossopharyngeal (IX), and upper laryngeal nerves to cough centers in the brainstem. Cough, for example, is lower breathing.

caused by foreign objects, dust, mucus, residue, gas and smoke. Irritation of various sensory nerves in the nose, throat, pharynx, ears, stomach, six membranes, or septum can also produce a cough. However, in many of these conditions, chronic or paroxysmal cough becomes tiring and debilitating, especially if it impairs sleep.

Oral cough preparations such as H-containing antitussive tablets, lozenges, syrups, solutions, suspensions, etc. have been used for a long time to relieve cough symptoms. The most popular such formulations contain either dextromethorphan (or its hydrobromide salt) or codeine (or its sulfate salt) as the active antitussive agent. These treatments are described, among many others, in Drug Evaluations, Volume 6.
Edition, Chapter 21 [American Medical Association
tion), 1986].

It has now been discovered that tryptophan has antitussive activity in humans and lower animals. Additionally, it has been discovered that tryptophan in combination with oral antitussives exhibits improved antitussive efficacy in humans and animals.

The effectiveness of tryptophan in relation to cough has also not been reported;
Letin), Volume 17, Page 81, 1981 and Smith (S+++ith) and Proek.
up), New England Journal of Medicine (NcvEngland Journal
or Medicine), No. 2 6 7
Volume, page 1338. 1982] or calcium [WyaLt.
Specification No. 45] and carbohydrates (September 1983, 1411
Sleep inducers effective in combination with other substances such as Wurtman, European Method Application No. 88,621, published with: Appetite suppressants (1'9
US Method No. 4.210.637 of Wardman et al., July 1, 1980, Q40, Antidepressants: and Analgesics [Martindalc,
The Ext.
ra Pharmacopeia), 28th edition, 61st
-200, Pharmaceutical Press (Pharm
aceutical Press), 1 9 8
2)].

It has been found that the effectiveness of tryptophan in the above disorders is related to an increase in the level of serotonin in the brain, as serotonin is synthesized from tryptophan through the following metabolic pathway. Hydroxytryptamine (serotonin) Kamei et al.
! 1 [“Effect of methylsergide on cough II soft reflex”, Japanese Journal of Pharmacology, Vol. 42.

No. 450, 1986 (Japan Journal
o “Pharmacology.42:450.19
8B>) o In another study, Kamei et al.
TP administration leads to an increase in brain serotonin aim and activity. ) “Dose-response relationship between unit activities”, Neuro Armacology 1 Part 1 5
L i3 3 '14.

1976], the direct precursor of heptalotonin, 5-hydroxytryptophan (5-HT
P) It was proven that the cough reflex was not suppressed automatically (
“Involvement of central serotonergic mechanism in cough reflex”, Japanese Journal of) 7-Macology 9, No. 4
Volume 2 Volume 1 5 3 1 t'<.

(1986). Therefore, it was not 5-HTP but tryptophan that suppressed the cough reflex except for]-.

Therefore, it is an object of the present invention to provide a tryptophan dowel oral pharmaceutical composition that is highly effective in the treatment of cough II. Another object of the present invention is to provide a pharmaceutical composition containing tryptophan with an oral antitussive agent that has improved antitussive efficacy. Yet another object of the invention is to provide methods of using these pharmaceutical compositions in the treatment of cough in humans or animals.

SUMMARY OF THE INVENTION The present invention relates to an oral pharmaceutical composition for the treatment of cough adapted for oral administration in small doses, which composition comprises (a) a safe amount of tryptophan and (b) a safe and effective amount of tryptophan. Contains H as an oral antitussive.

Also provided is a method for treating cough in a human or animal, comprising administering to the human or animal a safe and effective pharmaceutical composition containing tryptophan and an oral antitussive agent.

All percentages and ratios used herein are by weight unless otherwise indicated.

Preferably, the oral antitussive agent is dextromethorphan, clophedianol, carbetapentane, caramiphene,
DETAILED DESCRIPTION OF THE DEVELOPMENT Selected from the group consisting of Noskabine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, pharmaceutically acceptable salts thereof and mixtures thereof. Oral antitussive pharmaceutical compositions and methods for antitussive treatment in animals are provided. The compositions of the present invention relate to oral pharmaceutical compositions for the treatment of cough adapted for unit dose oral administration containing (a) a safe and effective amount of tryptophan and (b) a safe and effective amount of an oral antitussive agent. A safe and effective amount indicates antitussive efficacy,
As with any medical treatment,
It has a benefit/risk ratio of '1' for the amount of cough relief or anti-tL strain. Obviously, the amount of antitussive pharmaceutical composition administered will depend on the specific condition being treated, the severity of the condition being treated,
It will vary depending on such factors as the duration of treatment, the physical condition of the patient, the nature of the combination therapy (if any), the particular formulation and carrier used, and the solubility and concentration of the antitussive agent used.

Tryptophan has the following general formula: H tryptophan It is generally believed that the biologically active isomer of tryptophan is the L isomer. Tryptophan is commercially available, for example, from Aji no Sakusha (11 bottles, Tokyo).

Several drugs have been shown to increase plasma and/or brain tryptophan concentrations, and these can be included in the desired formulation. Examples of these compounds include lithium, sodium salicylate, aminophylline and clofibrate, cursine, G, (C
urzon, G.) and knot.

P, J. (Knoll, P. J.), “Environmental, Toxicological and Related Aspects of Tryptophan Metabolism with respect to the Central Nervous System”, CRC Critical Reviews in Toxicology (CRCCri[1eal Rev.
ies in Toxieology), vol. 5, p. 187, 1977; Gessa, G.
essa, G, l, ) and Tadariamont A, (
Tagliamon Le, A.), ``Serum free tributophane: control of brain concentration of tryptophan and 5-hydroxytryptophan synthesis, aromatic amino acids in the brain (AromaLic Ate: no Ac1d).
s in Ll+e13rain), 1974,
Ciba Foundation Symposium (Ciba F
Foundation Symposium), -r-Elscvicr; Gessa, G. L., and Tagliamont A., “Possible role of free serum tryptophan on the control of brain tryptophan levels and serotonin synthesis”, Advances in Biochemical Psychopharmacology (A
dvaances in BiochcmicalPsy
chopbarn+aeology), Volume 11, Page 119.

It was written in 1974. All of the above is incorporated herein by reference.

As used herein, the term "oral antitussive" refers to a drug that is taken orally and acts systemically to relieve cough.
egistcr), Volume 52, No. 155.

August 12, 1987, page 30055].

Oral antitussives approved for several months are not particularly limited, but include, for example, dextromethorphan and its acid salts, preferably hydrobromic acid, clofibrate hydrochloride, carbetapentane citrate, calamiphene disilate, diphenhydramine and its salts. Non-narcotic types such as hydrochloride, hominoben etc., as well as codeine and its sulfate or phosphate salts,
There are narcotic types such as noskabine hydrochloride, hydrocodone and its bitartrate salt, hydromorphone hydrochloride, etc.

The usual adult doses of such antitussive agents are also used per dose in the present compositions or are listed in Table 1.

Table 1 Oral antitussive agent for regular adult use (mg) Dextromethorphan HB r to-30 Clophedianol HCI 15-25 Carbetapentane citrate 15-30 Calamifene didisylate +5-20 Noscabine HCL
15-30 diphenhydramine HCI
15-25 codeine sulfate
I (1-20 hydrocodone bitartrate
5-10 Hydromorphone HCI
2 Hominoben 8O-IGO
Preferred oral antitussive agents are dextromethorphan, codeine, diphenhydramine, pharmaceutically acceptable salts thereof, and mixtures thereof. Dextromethorphan and codeine, pharmaceutically acceptable salts thereof, and mixtures thereof are most preferred. Dextromethorphan and pharmaceutically acceptable salts thereof are most preferred.

Tryptophan and oral antitussives are about 2.1 to about 500
0:1, more preferably about 3:1 to about 5000:
1, even more preferably about 8=1 to about 400:1
, most preferably at a tryptophan to oral antitussive agent ratio of about 16:1 to about 100:1.

A variety of oral dosage forms are available, including solid forms such as tablets, capsules, granules, lozenges and bulk powders, and liquid forms such as syrups, suspensions and solutions. These oral forms contain safe and effective amounts, usually at least about 0. Contains 1% active ingredient H. The solid oral dosage form preferably has a molecular weight of about 5 to about 9596, preferably about 1
0 to about 9590. Most preferably from about 25% to about 95% of the active ingredient is gold. Liquid oral dosage forms preferably have a molecular weight of about 1 to about 5096, more preferably about 1 to about 2500.
Most preferably from about 3% to about 10% of the active ingredient is gold-plated.

Tablets can be compressed, packed with suitable binders, lubricants, bulking agents, disintegrants, coloring agents, flavoring agents, preservatives and flow agents.
Tablets can be crushed, enteric coated, coated, film coated or multi-compressed.

Liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, suspensions, solutions and/or suspensions prepared from boiling granules, in the presence of suitable solvents, preservatives, emulsifying agents, suspending agents, etc. Contains a clouding agent, a diluent, a flavoring agent, a coloring agent, and an aromatic agent. Preferred carriers for oral administration 111 include gelatin, propylene glycol, ethyl oleate, cottonseed oil and sesame seeds.

Pharmaceuticals that can be used to formulate oral dosage forms: 1. '1
Specific examples of acceptable carriers and excipients are found in RoberL, U.S. J', No. 3.90, published September 211, 1975, which is incorporated herein by reference.
No. 3,297 is described.

Techniques and compositions for making solid oral dosage forms are described by Mars
hal l), “Solid Oral Dosage Form” Modern
Modern Pharma
ceuties) Volume 7, [Bunker
) and Rhodes (eds.)], No. 359-4
Page 27, 1.97Q. Tablets (compressed,
Techniques and compositions for making capsules (hard and soft gelatin) and capsules (formed and molded) are described in Remington's Pharmaceutical Sciences (1?em i), which is incorporated herein by reference.
ny, Lon'sPharmaeuLi,ea
l 5eienies) (Arthur O'Toole (Ar
Edited by Lhur 0sol), No. 15') 3-1 '5
93, 1981D.

Since many oral antitussive agents are commonly used in the form of water-soluble salts, they can be easily incorporated into conventional aqueous squirt syrups and solution formulations.

Water-insoluble or sparingly soluble antitussives can be prepared, usually in base form, into dispersions, suspensions, 41ii solutions, oil-in-water emulsions, etc., each with suitable dispersing agents, suspending agents or emulsifying agents, each readily apparent to the pharmaceutical formulator. It can also be incorporated into an aqueous orally acceptable pharmaceutical carrier such as.

In preparing the pharmaceutical compositions of this invention, the oral antitussive and tryphan components are incorporated into an aqueous orally acceptable pharmaceutical carrier consistent with conventional pharmaceutical practice. An "aqueous orally acceptable pharmaceutical carrier" is a carrier whose entire or predominant solvent is water.

Typical carriers include simple aqueous solutions, syrups, dispersions, suspensions and liquid emulsions such as/in water. The most preferred carrier is suspension of the pharmaceutical composition in an aqueous vehicle with a suitable suspending agent.

A suitable suspending agent is Avicel RC.
Examples include 5Q1 (microcrystalline cellulose/sodium carboxydimethylcellulose mixture commercially available from FMC), guar gum, and the like. Such suspending agents are well known to those skilled in the art. The amount of water in the compositions of the invention can vary over a wide range depending on the total weight and volume of the two essential active ingredients and other optional non-active ingredients, but the total amount of water in the weight of the final composition may vary over a wide range. The water content usually ranges from about 20 to about 7,596, preferably from about 211 to about 4,096 by weight/'i'j.

Either water itself forms the perfect carrier or, in typical spray formulations, water is added to the composition to aid in the dissolution and introduction of water-insoluble ingredients, such as propylene glycol, glycerin, solubiol, etc., into the composition. It is preferable to use a co-solvent such as LFK, etc. Therefore, in general,
The compositions of the invention preferably range from about 5 to about 25 volumes/volume9.
6, most preferably from about 10 to about 20 volumes/volume 96 of the co-solvent.

To provide and maintain the pH of the composition from about 3 to about 9, preferably from about 4 to about 7, for example, sodium citrate t Mxj i (1, sodium phosphate buffer, etc.) consistent with conventional pharmaceutical practice. Compositions of the invention are optionally combined with one or more other known therapeutic agents, particularly those commonly used in cough/cold formulations, such as pseudoephedrine hydrochloride, phenylpropaturamine hydrochloride, Like phenylephedrine hydrochloride and ephedrine hydrochloride.

decongestants; analgesics such as acetaminophen and ibuprofen; expectorants or mucolytics such as glyceryl guaiacholate, guaiacolate, terpine hydrate, ammonium chloride, N-acetylcysteine and amproxol, and maleic acid. chlorpheniramine,
Antihistamines such as quinolamine succinate, prompheniramine maleate, and diphenhydramine hydrochloride may also be used as antihistamines, all of which are incorporated by reference herein. Sunshine et al., US Method No. 4,619,934. Bronchodilators such as theophylline and albutyrol are also used for a.

For example, natural or artificial flavoring agents, fragrances, colorants, etc. to obtain a finished product with good taste and good appearance; preservation (e.g. butylated hydroxyanisole or butylated hydroxytoluene to prolong and increase longevity). Thousands of other ingredients well known in the pharmaceutical industry, such as antioxidants such as methyl or propylparaben or preservatives such as sodium benzoate, may also be included in amounts commonly known for these ingredients. Can be done.

Treatment Method The present invention provides treatment for humans or lower animals by orally administering to humans or lower animals in need of treatment a pharmaceutical composition containing tryptophan in a safe amount along with an oral antitussive. It also relates to cough treatment methods. The amount of the pharmaceutical composition administered is dependent on the amount of tryptophan antitussive required per dose, the stability, release characteristics, and the proportion of the +19 component in the formula, which is a function of other pharmaceutical parameters. . Usually about 2~3 C) D (1
mg/kt 7 days, preferably about 6 to about 360 mK
/kg/D, most preferably from about 14 to about 180
mg/kg/l'l of the pharmaceutical composition is administered as described herein.

This amount can be given once or preferably repeatedly in multiple doses (2-6) or by sustained release administration throughout the treatment period. Generally, each individual dose of a pharmaceutical composition of the invention will be about 1,0 to about 500 mg/kg, preferably about 3 to about 60 mg/kg, most preferably about 7 to about 30 mg/kg.
It is within the range of g/kg. Higher steps than above. The same precautions as with any drug must be taken in some individuals to prevent side effects, even in small amounts that are effective in preventing coughs.

The compositions and compositions described herein are industry-recognized for exerting antitussive activity.

used according to the formula.

The following examples illustrate embodiments of the invention in which the essential and essential components are mixed.

Example 1 A suspension rB solution for oral administration is manufactured by mixing the following components: Ingredients
Tryptophan weighed 2000.0
mg dextromethorphan H B r 3
0.0+ng microcrystalline cellulose and carboxy
375.0mg Methylcellulose Sodium Sucrose 13.5g
Glycerin tioo. 0+n
g Sorbitol solution (70%) 1.5
g Potassium sorbate 30. Oo
+g saccharin sodium 60.
0mg gluconic acid 75
．． 0mg fragrance 45.
0mg colorant 5.
0mg purified ice appropriate amount all fii3
Mix 0.0 ml of the above ingredients to prepare a suspension with a pH of 4.3 and fill aseptically into 6 oz (approx. administration, thereby suppressing cough.

Substantially similar results indicate that dextromethorph 7 has therapeutically significant levels of clophedianol, carbetapentane,
It is also included when substituted with caramiphene, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, their pharmaceutically acceptable salts, and mixtures thereof.

Example 2 Syrup for oral administration is manufactured by the following ingredients: L-1-Lyptophan Dextromethorphan HB Glycerin citrate Sorbitol 1 volume/skin (709δ) Coloring agent and flavoring agent Amount to be mixed: 1000.0 +++ gr 30.0 mg 5.7111 + 12.0 mg Appropriate amount Total amount 30.0 mg Appropriate amount Dissolve citric acid in glycerin at a temperature of about 40 to 60°C. While stirring, add L-)ributophane to the mixture. The resulting mixture is cooled to room temperature and fragrance and color are added. Then, sorbitol solution is added, thereby obtaining a concentrated 1',' liquid. 30 ml of this liquid is administered to an adult in need of treatment, thereby suppressing cough.

Substantially similar results were obtained with dextromethorphan or therapeutically equivalent levels of clophedianol, carbetapentane,
It is also obtained when substituted with caramiphene, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, their pharmaceutically acceptable salts and mixtures thereof.

Example 3 Hard capsules for oral administration are manufactured as follows. 500 mg of L-tryptophan and 15 ff of dextromethorphan HB r as dry powders are packed into O+-3 hard shell capsules using techniques known in the art. One or two capsules are administered to a person in need of treatment, thereby suppressing cough.

Substantially similar results were obtained when dextromethorphan was used at therapeutic levels of clophenoanol, carbetapentane, caramiphene, noscabine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben,
They are also obtained when substituted with their pharmaceutically acceptable salts and mixtures thereof.

Example 4 A soft gelatin capsule composition for oral administration is prepared by mixing the following ingredients: Ingredients Amount L-) Liptophan 250.0m
gDextromethorphan HBr 15.0
■Gomaura 735. O
The mg L-tryptophan and Dex I lometorphan are mixed with sesame seeds and poured into soft gelatin capsules using the horn method known in the art. 1000mg of each composition
The resulting capsules 1 to 21 are administered to adults in need of treatment, thereby suppressing cough.

Substantially similar results were obtained with dextromethorphan or therapeutically equivalent levels of clofuenanol, carhetabentan,
It is also obtained when caramiphene, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, their pharmaceutically acceptable salts and mixtures thereof are substituted.

Example 5 A tablet for oral administration is manufactured by mixing the following ingredients.

Ingredients
Amount L-tryptophan 500
mg dextromethorphan HBr 15
mg malt dextrin 50m
gCroscarmellose 2511
1 Magnesium stearate 5m
gL-tryptophan and dextromethorphan
0 w/w! '． ci malt dextrin soluble relative [Malrin M-100”C
The resulting granules are dried overnight at a temperature of about 45°C. The dried granules are crushed and 1. The resulting powder blend is compressed into 580 mg tablets according to industry routines.i-) 1-2 tablets are administered to a human in need of treatment. , L, thereby suppressing cough.

Substantially similar results were obtained with dextromethorphan or with therapeutic agents such as clophedianol, carbetapentane, caramiphene, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben,
It is also included when substituted with their pharmaceutically available salts and mixtures thereof.

Example 6 Chewable tablets for oral administration are manufactured by mixing the following ingredients:
Amount L-tryptophan 500
mg Dextromethorphan adsorbent (10%) Malt dextrin 50 mg Crystal sorbitol 500 mg Magnesium stearate 1 m
Granulate with v% malt dextrin solution. The resulting granules are dried overnight at a temperature of approximately 45°C. Grind the dry granules;
Blend with remaining ingredients. The resulting powder blend is compressed into 1.05 g tablets as is routinely practiced in the art. Tablet 1~
Two doses are administered to a person in need of treatment, thereby suppressing cough.

Substantially between +. The results of 1 show that dextromethorphan is therapeutically effective at 11:1, compared with clofecyanol, carbetapentane, caramiphene, noskabine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, and their pharmaceutically acceptable salts. and mixtures thereof can be substituted to obtain t.

Claims (1)

Claims: 1. An oral pharmaceutical composition for the treatment of cough adapted for unit dose oral administration, comprising: (a) a safe and effective amount of tryptophan; and (b) a safe and effective amount of an oral antitussive agent. A composition characterized by containing; 2. Ratio of tryptophan to oral antitussive agent is 2:1-50
A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is within the range of 00:1. 3. Ratio of tryptophan to oral antitussive agent is 3:1-50
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is within the range of 00:1. 4. Ratio of tryptophan to oral antitussives is 8:1-40
4. A pharmaceutical composition according to claim 3, which is within the range of 0:1. 5. The pharmaceutical composition according to claim 4, wherein the ratio of tryptophan to oral antitussive agent is within the range of 16:1 to 100:1. 6. The oral antitussive agent is selected from the group consisting of dextromethorphan, clophedianol, carbetapentane, caramiphene, noskabine, diphenhydramine, codeine, hydrocodone, hydromorphone, hominoben, pharmaceutically acceptable salts thereof, and mixtures thereof. , a pharmaceutical composition according to claim 1, 2, 3, 4 or 5. 7. The pharmaceutical composition according to claim 6, which is in the form of a syrup, emulsion, suspension or solution. 8. A pharmaceutical composition according to claim 6, in the form of a tablet, lozenge, capsule, granule or bulk powder. 9. A method for treating cough in humans or animals: Claims 1, 2, 3, for humans or animals in need of such treatment.
7. A method comprising administering the pharmaceutical composition according to 4, 5 or 6. 10. A method for treating cough in humans or animals, which comprises: administering the pharmaceutical composition according to claim 7 to humans or animals in need of such treatment. 11. A method for treating cough in humans or animals, which comprises: administering the pharmaceutical composition according to claim 8 to humans or animals in need of such treatment.