RU2427388C2 - Antitussive - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: antitussive pharmaceutical preparation contains dextromethorphan or its pharmaceutically acceptable salt as an antitussive and anisic drops of ammonium chloride in alcoholic solution as an expectorant. The pharmaceutically acceptable salt of dextromethorphan is dextromethorphan-hydrobromide-monohydrate preferentially. The weight relation of dextromethorphan-hydrobromide-monohydrate and anisic drops of ammonium chloride in the preparation makes 1:80-1:120, preferentially 1:90-1:110, especially preferentially 1:100. The preparation is intended for treating airway reflexes in asthmatics.

EFFECT: preparation does not cause excessive defluvium in this group of patients and simultaneously leads to appreciable cough reflex reduction.

10 cl, 2 ex

Description

FIELD OF THE INVENTION

The present invention relates to a cough preparation, in particular to one which contains an antitussive agent, preferably dextromethorphan or a pharmaceutically acceptable salt thereof, and an alcohol-containing expectorant, preferably ammonia drops. It also relates to a cough preparation containing dextromethorphan or a pharmaceutically acceptable salt and anise oil thereof.

State of the art

A cough is an arbitrary or due to coughing irritation involuntary jerking of air from the lungs. Coughing is one of the most common symptoms of illness. Cough causes can be respiratory diseases, such as bronchitis, colds, asthma or chronically obstructing pulmonary disease, as well as heart, stomach, medication (such as ACE inhibitors), or, in rare cases, mental disorders. A dry cough that is not accompanied by sputum production and occurs at an early stage of a cold due to an allergy or taking medications (for example, ACE inhibitors) is called a reflex cough. With a cold, a dry cough first appears, which then, after 1-3 days, passes into a wet cough, in which there is a separation of mucus (sputum) of a transparent or yellow-green color. In principle, the underlying cold should be treated. However, since the cough is often perceived painfully and often disturbs the night's rest, which delays the patient’s recovery and rest, there is a great need for medicines to treat dry (reflex) and wet types of cough. It should be borne in mind that a wet cough is a protective reflex that prevents obliteration of the respiratory tract, and therefore should be suppressed only in case of serious disturbance of night rest.

In principle, there are several types of cough remedies. Antitussive or soothing cough suppresses cough irritation. These substances act on the central nervous system, suppressing the cough center in the brain stem, and also have a sedative effect. Essentially, these are opiate derivatives. Mainly used are prescription codeine, dihydrocodeine or hydrocodone, partially covered by the law on narcotic drugs, which have a relatively high potential for irresistible pathological attraction and cause the risk of abuse of drug addicts.

Along with them, dextromethorphan or its salt is very widely used. This active substance is dispensed without a prescription and has a significantly lower potential for drug dependence than the above opiate derivatives. It is found in many commercial types of cough suppressants, such as 44 Wick® Cough Soothing, Wick® MediNait, Ratiopharm® Cough Soothing Capsules, Forte Contac® Liquid Cold, Silomat® DMP.

More modern antitussive agents are, for example, clobutinol or pentoxiverin. Clobutinol is an active substance for the treatment of dry reflex cough and has been used in this capacity for over 40 years. His leave is made without a prescription. By order of the Federal Institute of Medicines and Medical Products, from August 31, 2007 it is forbidden to put into circulation medicines containing clobutinol. He called on patients not to take medications containing clobutinol for a long time. The reason for this precaution was the fact that the Institute received new information and data from the owner of the license for the original drug, based on which it can be assumed that clobutinol in rare cases causes cardiac arrhythmias (pirouette type arrhythmia). In connection with this suspicion, the Federal Institute of Medicines and Medical Products demanded that appropriate experimental and clinical studies be conducted. He came to the conclusion, like the manufacturer of the original drug, that the ratio between the beneficial and harmful effects of clobutinol is such that the use of such drugs in medicine is unacceptable.

Thus, patients suffering from dry (reflex) cough are deprived of the active substance that has been used successfully for almost 50 years, as a result of which there is an acute need for well-tolerated and effective cough medicines.

As the next class of active substances used to facilitate the coughing up of bronchial mucus and bronchial secretion, so-called expectorant drugs are used. Among which there are distinguished secretolitic (mucolytic) agents that cause thinning of the bronchial secretion, and secretory agents that provide enhanced drainage of mucus (sputum).

As secretolytic (mucolytic) agents, for example, acetylcysteine, carbocysteine, bromhexine and its metabolite ambroxol, ammonium chloride and guaifenzin, as well as plant products such as fennel and anise oils are used.

The simultaneous use of expectorants (thinning mucus) and antitussive drugs (suppressing coughs) is counterproductive, since coughing up bronchial mucus is designed for an undisturbed cough reflex. If the resulting mucus cannot be cleared up, then complications, such as pneumonia, which must be prevented, can occur. Therefore, usually expectorant drugs are taken during the day, but no later than 5:00 p.m., and at night - drugs that suppress coughing to ensure night rest, i.e. both funds are taken in any case alternately and never simultaneously.

However, in the patent literature some combination preparations containing the active substances of dextromethorphan are described.

WO 92/07559 discloses a combination of dextromethorphan and guiafensin, an expectorant with a pH of 8 to 11.

WO 85/04589 describes a combination consisting of a non-steroidal anti-inflammatory active substance and at least one component selected from antihistamines, perfumes, antitussives or expectorants.

WO 99/32119 discloses an analgesic combination of an opioid agonist and an opioid antagonist, optionally in combination with an expectorant. This combination is designed to reduce the possibility of an irresistible pathological attraction caused by an opioid agonist.

WO 03/061642 describes a combination of an opioid and an antitussive agent of Ambroxol.

However, combinations consisting of an antitussive and an expectorant in an alcohol solution are unknown. Combinations of dextromethorphan or its pharmaceutically acceptable salts and anise oil or ammonia drops are also unknown in the prior art.

Especially for patients suffering from bronchial asthma, until now there was no appropriate medication for the treatment of reflex cough, since after taking traditional antitussive agents in this group of patients, an extremely high degree of bronchial mucus was usually observed.

Therefore, it is an object of the present invention to provide a cough preparation that is also suitable, in particular, for treating reflex cough in asthmatics.

Description of the invention

However, it was found that the combination of an antitussive and expectorant in an alcohol solution unexpectedly has a particularly positive effect as a cough remedy, especially in asthmatics suffering from a reflex cough, since this combination does not unexpectedly cause abundant mucus in this particular group of patients and at the same time leads to a noticeable decrease in the urge to cough. This is, in particular, a surprise, since the combination of expectorant and antitussive agents, as mentioned above, is considered in principle to be unsuitable and counterproductive in the treatment of cough. Especially highly effective was the combination of dextromethorphan or its pharmaceutically acceptable salts and anise oil, in particular ammonia and anise drops.

Therefore, according to the invention, a combination of dextromethorphan or a pharmaceutically acceptable salt and anise oil thereof, in particular ammonia drops, is preferably used.

Dextromethorphan is a known antitussive. It has the following chemical structure: (+) - 3-methoxy-N-methylmorphinan. We are talking about the (+) - enantiomer of racemetorphan. Its preparation is described, for example, in US 2,676,177. The active substance is a commercial product. Dextromethorphan is found in numerous over-the-counter coughs and colds. There is a danger of abuse; the active substance is also known among drug addicts under the name "DXM", "DM", "CCC", Triple C "," Candy "," Robo "," Velvet "or" Rojo ". If the active substance is in the dose prescribed in the cough treatment if it is well tolerated, it can cause severe side effects in case of a significant overdose.The American Drug Administration (FDA) indicates among the possible complications brain damage, epilepsy attacks, unconsciousness and heart rhythm disturbances.

As pharmaceutically acceptable salts, all commonly used salts are suitable according to the invention, such as salts of inorganic bases, for example halides (chlorides, bromides, iodides, fluorides), hydrohalides, for example hydrochloride, hydrobromide, hydroiodide, ammonium salts, sulfides, hydrosulfides, phosphates, diphosphates , sulfates, carbonates, hydrogen carbonates, nitrates, salts of organic bases, such as, for example, acetate, maleate, fumarate, tartrate, mesylate or toluene sulfonate, or basic amino acids. Hydrobromide, also used in conventional commercial preparations, is particularly preferred.

According to the invention, the term "dextromethorphan or its pharmaceutically acceptable salts" also includes hydrates or solvates. Most preferably, dextromethorphan hydrochloride monohydrate is used according to the invention.

There are some combination preparations on the market that contain dextromethorphan, for example Wick Medinalt®, which contains paracetamol, dextromethorphan hydrobromide, ephedringemisulfate and doxylamine succinate, and Wick DayMed® containing paracetamol, dextromethorphan hydrobromide, phenylpropanolamine as the active substance.

Combinations of dextromethorphan and home-based cold remedies such as honey, such as cough lozenges with Wick® reflex cough honey, are also on sale.

Ammonium anise drops are a standard ammonia anise extract obtained in accordance with the German Pharmacopoeia. It contains ethanol. Ammonium-ammonia drops are also called “containing aniseed oil with ammonia solution” or “complex anise alcohol”. Other synonyms are ammonia solution containing anise oil (German Pharmacopoeia), anise ammonia, Ammonil hydroxidi solution anisata, Spiritus ammonii anisatus, anise ammonia alcohol containing anise oil ammonia solution, anise ammonia, Liquor di ammonio anisato, containing anise oil, anise oil, ammonia complex anise alcohol, composition of anise alcohol, complex anise alcohol. All of these synonyms are included in the scope of the present invention and are suitable for use according to the invention. Ammonia-anise drops are obtained from anise oil, which, according to German Pharmacopoeia 9, is an essential oil obtained from ripe dried fruits of anise (Pimpnnella anisum) or illicium (Illicium verum) by steam distillation.

The preparation of ammonia-anise drops and their control are carried out in accordance with the German Pharmacopoeia 2003, A-100, as follows: 3.3 g of anise oil is dissolved in 80.0 g of ethyl alcohol (90% by volume) and then diluted with 16.7 g 10% (by volume) ammonia solution. Get a clear, colorless or faint yellow liquid with a pronounced smell of anise and ammonia.

Anise oil has been used for a long time as a home remedy for various ailments, it is attributed to, for example, thinning mucus, which promotes sputum separation, antispasmodic, carminative, diuretic, milk producing, promotes digestion, stimulates appetite and antibacterial action, it is used in folk medicine thanks to its mucus-dissolving action as a cough suppressant. Anise tea, obtained by boiling aniseed fruits with boiling water, helps with cramps and flatulence.

The preparation according to the invention is prepared, for example, by mixing dextromethorphan or a pharmaceutically acceptable salt thereof, such as hydrobromide monosolvate, with ammonia anise drops to form a uniform solution. To dissolve dextromethorphan, it is necessary that alcohol be present in the ammonia-anise drops. By alcohol according to the invention is meant any pharmaceutically acceptable alcohol that is liquid under normal conditions, but preferably ethyl alcohol. Then the alcohol can be removed in the usual way, for example by evaporation.

In the preparation according to the invention, in a combined form, preferably used are dextromethorphan or a pharmaceutically acceptable salt thereof and ammonia anise drops in an amount of: 0.005-0.1 g, preferably 0.01-0.04 g, particularly preferably 0.02 g dextromethorphan-hydrobromide monohydrate and 0.5-3.0 g, preferably 1.0-2.5 g, particularly preferably 2.0 g of ammonia-anise drops. Moreover, the weight ratio between the two active substances is preferably: dextromethorphan-hydrobromide monohydrate: ammonia drops = 1: 80-1: 120, preferably 1: 90-1: 110, particularly preferably 1: 100. Preferably, the combination is mixed with water to provide a convenient concentration for use. In this case, preferably Aqua purificata (purified water) is used. Water can be used in any quantity, but it is preferable to choose it so that the total concentration of active substances (the sum of the weight fractions of dexomethorphan-hydrobromide monohydrate and ammonia drops) is 5-50 wt.%, Preferably 10-25 wt.% and most preferably 20-21 wt.%. Therefore, it is particularly preferred that the preparation has the following composition:

dextromethorphan hydrobromide monohydrate 0.02 g ammonia drops 2.00 g Water up to 10.00 g

It was found that with this composition the most positive soothing cough effect is achieved with a slight mucus discharge.

Fennel oil, ivy extract, thyme oil, ambroxol, acetylcysteine, carbocysteine, bromhexine and guiafenesin used in accordance with the invention in an alcoholic solution are also suitable as expectorants.

According to the invention, the preparation is preferably in the form of drops, taken either in pure form or after dilution with water, juice or tea, or after application to a piece of sugar.

According to the invention, for the preparation of a cough syrup, a combination of active substances can be mixed with a suitable syrup base, for example, from sucrose, xylitol, D-xylose, maltose, D-glucose, sorbitol, glycerin, mannitol, Sirupus simplex, etc. In this case, the water is more not applicable for dilution. After that, the resulting preparation can be taken as a cough syrup without dilution.

According to the invention, the combination of active substances can also be prepared in the form of a filler for sweets or lozenges for sucking.

According to the invention, the combination of active substances may additionally contain conventional pharmaceutical excipients, such as indifferent substances, thickeners, diluents, emulsifiers, preservatives, antioxidants, flavors and flavorings, colorants, buffers, stabilizers, etc.

The cough drops described above according to the invention are preferably taken taking into account the age of the patient and the severity of the disease, in some cases, at a dose of 15-20 drops for children and 30-40 drops for adults. Typically, the daily intake schedule depends on the degree of ailment and ranges from 2 to 5 times the daily intake, preferably from 2 to 3 times a day.

Thanks to the combination of active substances according to the invention, an unexpectedly quick cure for reflex cough is achieved, which is not provided by other conventional cough remedies. Especially among asthmatics, a particularly positive softening of the reflex cough is noted, which is not accompanied by increased formation of mucus, which with this underlying disease has a particularly negative effect. This is a particularly unexpected effect, since a combination of antitussive and expectorant drugs is considered harmful and counterproductive.

Example 1

Cough drops

20.0 g of dextromethorphan hydrobromide monohydrate, 2.00 g of ammonia anise drops (finished product according to the German Pharmacopoeia 2003) and up to 10.00 g of water were stirred at room temperature until the solid components disappeared and poured into tinted glass droppers.

Example 2

Use for asthmatic with a reflex cough

A patient suffering from asthma for several years and therefore using terbutaline and cortisone medications complained of a reflex cough after a cold. He took the cough drops diluted in water, shown in Example 1, for 7 days three times a day. Within a few hours, he reported a noticeable decrease in reflex cough, which was not accompanied by increased mucus formation in the bronchi. This improvement described was much more effective than that achieved with conventional antitussive drugs,

Claims (10)

1. A pharmaceutical preparation for the treatment of cough containing an antitussive agent and an expectorant in an alcoholic solution as an active substance, in which the antitussive agent is dextromethorphan or a pharmaceutically acceptable salt thereof, and an expectorant agent in an alcoholic solution is ammonia anise drops. 2. The pharmaceutical preparation according to claim 1, wherein the dextromethorphan salt is dextromethorphan hydrobromide monohydrate. 3. The pharmaceutical preparation according to claim 2, in which the components are contained in the following weight ratios:
Destromethorphan hydrobromide monohydrate: ammonia anise drops = 1: 80-1: 120, preferably 1: 90-1: 110, particularly preferably 1: 100. 4. The pharmaceutical preparation according to any one of claims 1 to 3, made in the form of drops of an aqueous solution. 5. The pharmaceutical preparation according to any one of claims 1 to 3, in which the cough is a reflex cough of asthmatics. 6. The use of a combination of an antitussive agent and an expectorant in an alcoholic solution for the treatment of cough, in which the antitussive agent is dextromethorphan or a pharmaceutically acceptable salt thereof and an expectorant agent in an alcoholic solution is ammonia anise drops. 7. The use according to claim 6, according to which the dextromethorphan salt is dextromethorphan-hydrobromide monohydrate. 8. The use according to claim 7, according to which the active substances are contained in the following weight ratios:
Destromethorphan hydrobromide monohydrate: ammonia anise drops = 1: 80-1: 120, preferably 1: 90-1: 110, particularly preferably 1: 100. 9. The use according to claim 6, in which the combination is made in the form of drops of an aqueous solution. 10. The use according to any one of claims 6 to 9, in which the cough is a reflex cough of asthmatics.