Containing ondansetron formulations for oral administration

 

(57) Abstract:

The invention relates to chemical-pharmaceutical industry and relates to a liquid composition for oral administration. The invention consists in that the composition contains the ondansetron or pharmaceutically acceptable derivative, sweetener and one or more pharmaceutically acceptable excipients, and the sweetener is one or more polyhydric alcohols, and the pH of the composition is in the range from 2.0 to 5.0. Also describes how the use of such compositions in the treatment of conditions mediated by the action of 5-hydroxytryptamine (NT) NT3the receptors. The invention provides fast action combined with continued activity and good bioavailability. 2 C. and 10 C.p. f-crystals, 2 tab.

The present invention describes a pharmaceutical composition containing as an active start 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl - 1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one, in particular a liquid composition for oral administration.

Described (patent UK N 2153821B) 1,2,3,9-tetrahydro-9-methyl-3-[(2 - methyl-1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one, currently known as ondansetron, which may be represented by forms of the s.

In the above-mentioned source of these compounds are described as potent and selective antagonists of 5-hydroxytryptamine (5HT) on "neuronal" 5HT receptors subspecies, localized on the endings of primary afferent nerves, and is also present in the Central nervous system. The receptors of this subspecies now known as 5HT3the receptors. Describes the use of these compounds for the treatment of human or animal suffering from a condition caused by a disorder of neuronal 5HT transmission, for example in the treatment of migraine or of such mental disorders such as schizophrenia. It is also claimed that these compounds may be useful in the treatment of such conditions as anxiety, obesity and mania.

It is also known (publication of a European patent application N 226266) that these compounds are antiemetic drugs and can be used in the treatment or prevention of nausea and vomiting. Described (European patent N 201165) the use of these compounds for the treatment of vomiting, as well as their use for the treatment of intestinal dyskinesia.

Numerous clinical studies have demonstrated the effectiveness of ondansetron in the treatment of vomiting, especially nausea and vomiting due to chemo - the x drug always used either in injectable form, or oral.

Oral administration in the form of conventional tablets, pills or capsules is usually a preferred way of application of medicines, because this method is usually convenient and acceptable to patients. Unfortunately, such compounds may have some drawbacks, in particular in the treatment of patients of children and elderly who may not like or which may be difficult to swallow such compositions, and also in those cases where the application of conventional tablets, pills or capsules impossible. It is highly desirable, particularly when treating acute conditions, to pharmaceutical compositions were characterized by a rapid and predictable onset of action combined with continued activity and good bioavailability. Rapid absorption can be achieved by parenteral injection, but this is unacceptable for some patients, especially in those cases where the medicine is applied without direct medical supervision, it is applied by the patient.

Proposed (GB 2153821) alternative use of ondansetron, including liquid formulations for oral administration. Described (GB 2153821) multiple farmatsevticheskii and nesadurai sugar syrups, contains ondansetron hydrochloride dihydrate.

The present invention is described particularly useful pharmaceutical composition, which has not previously been separately described, and which is a liquid medication ondansetron suitable for oral administration.

Thus, the first aspect of the present invention is a liquid composition for oral administration containing the ondansetron or pharmaceutically acceptable derivative, sweetener and one or more pharmaceutically acceptable excipients, and sweetener contains one or more polyhydric alcohols, and the pH of the composition is in the range from 2.0 to 5.0.

Under the pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or MES ondansetron, or any other compound which upon application by the recipient is able to form (directly or indirectly) ondansetron, or its active metabolite or residue.

Most preferred is that described in the present invention the compositions contain ondansetron in the form of the hydrochloride, in particular the hydrochloride dihydrate. Specialists know that ondansetron contains one chiral CE is on there enantiomers). This invention includes all isomers of ondansetron and its pharmaceutically acceptable derivatives, including all tautomeric and optical form, or any mixture of ondansetron, including racemic mixtures.

In contrast to previously known compositions, the sweetener composition described in this invention contains one or more polyhydric alcohols. Applicants have discovered that the use of one or more polyhydric alcohols allows to obtain a surprisingly high-quality pharmaceutical composition due to their good stability and acceptable taste.

Specialists it is obvious that the above-mentioned polyhydric alcohols should be a pharmaceutically acceptable polyhydric alcohols or mixtures thereof, for example sorbitol, mannitol, xylitol and ▫ maltitol. Preferably, the sweetener for use in accordance with this invention include sorbitol; more preferred is a sweetener, representing sorbitol and xylitol; however, the most preferred sweetener is sorbitol.

Convenient to the total content of the polyhydric alcohols in the liquid composition, expressed in terms of polyhydric alcohols in solid sustaninable, about 40% of m/O.

Each polyhydric alcohol may be used in solid form or in the form of a solution. Preferred is the use in the form of a solution such as an aqueous solution. For example, sorbitol is conveniently used in the form of an aqueous solution in which the concentration of solids in the solution is in the range from 64 to 72% m/m (mass).

Convenient to the concentration of ondansetron in the liquid composition in terms of free base was in the range of 0.005 to 1% m/o, for example from 0.01 to 0.5% m/o, and preferably from 0.02 to 0.2% m/o, for example around 0.08% m/O.

It is convenient that the pH of the liquid compositions described in this invention were in the range from 2.5 to 4.5, preferably from 3 to 4, for example about 3.5.

Described in this invention, the compounds may be presented in the form of liquids, suspensions or syrups. Preferably, these compositions are presented in the form of liquids.

Conventional components that may be used is described in this invention, the compounds include preservatives, buffer systems, increasing viscosity, flavorings, dyes, additional sweeteners, and mixtures thereof.

Praml is/or butylperoxybenzoate; sorbic acid or its salt; benzoic acid or its salt; and mixtures thereof. The most preferred composition according to the invention contains sodium benzoate.

Acceptable buffer systems include combinations of citric acid and its salts and solvate, for example citric acid (anhydrous and monohydrate) in combination with dihydrate sodium citrate). Preferably the compositions according to the invention contain a buffer system consisting of anhydrous citric acid and sodium citrate.

Acceptable substances that increase the viscosity include resins (for example, xanthan gum resin), glycerin, polyvinyl alcohol, polyvinylpyrrolidine, cellulose derivatives such as carboxymethylcellulose and its salt, C1-4is an alkyl and/or hydroxy-C2-4is an alkyl cellulose ether such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose and hypromellose and mixtures thereof.

Convenient to the viscosity of the liquid compositions described in this invention were in the range from 20 to 100 centipoise (CP), for example from 10 to 75 centipoise, in particular from 15 to 50 centipoise.

Acceptable flavors include strawberry, cherry, plastically include, for example, sugars such as glucose; cyclamate and its salts. Preferably the compositions according to the invention practically does not contain fructose or fructosidase of sugars (e.g. sucrose), for example, contain less than 5% fructose, and preferably less than 1% of fructose.

In a further preferred aspect according to this invention proposed a liquid composition for oral administration containing hydrochloride dihydrate ondansetron and sorbitol.

According to the following preferred aspect of the proposed liquid composition for oral administration containing hydrochloride dihydrate ondansetron, sorbitol, sodium benzoate, anhydrous citric acid, dihydrate sodium citrate and strawberry flavoring.

In accordance with the foregoing preferred aspects of the invention, a liquid composition with a concentration of ondansetron (in terms of free base) from 0.02 to 0.2% m/o, for example around 0.08% of the content of sorbitol (in terms of solid sorbitol) from 30 to 50% m/o, for example about 40% m/o, and pH from 3.0 to 4.0, for example about 3.5, is particularly preferred.

Liquid compositions for oral administration can be suitably prepared in the usual way, aprimary of excipients.

In a further aspect of the invention, a method for treating mammals, including humans, suffering from conditions, the indirect effect on 5HT 5HT3receptors, consisting in applying a liquid composition for oral administration containing the ondansetron or pharmaceutically acceptable derivative, sweetener and one or more pharmaceutically acceptable carriers or excipients, and sweetener contains one or more polyhydric alcohols, and the pH of the composition is in the range from 2.0 to 5.0. Assumes that under treatment is understood as the prevention and alleviation of established symptoms.

State, the indirect effect on 5HT 5HT3receptors include vomiting; disorders of cognitive function, such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, a disease of the Peak horey of Huntington, Parkinson's disease Creutzfeldt-Jakob disease) and vascular dementia (including multifocal dementia), as well as dementia associated with intracranial volume lesions, trauma, infections and such conditions (including HIV infection), metabolism, toxins, anoxia and deficit vitengeni memory; mental disorders such as schizophrenia and mania; anxiety disorders, including panic disorder, agoraphobia, social phobia, simple phobia, binding disorder, posttraumatic stress disorder, mixed anxiety-depressivnii disorder and generalized anxiety; syndrome, intestinal dyskinesia, as well as drugs and drug addiction. Other conditions mediated in the same way, include itching, especially caused by cholestasis; gastroparesis; symptoms of gastrointestinal dysfunction characteristic of peptic ulcers, reflux esophagitis, flatulence and dyspepsia; migraine; obesity and conditions such as bulimia, pain, and depression.

Emesis, i.e. nausea, hiccups and vomiting, are divided into acute, delayed and expected. Ondansetron useful in the treatment of vomiting of any nature. For example, vomiting can be caused by drugs such as agents for cancer chemotherapy, namely alkylating agents (e.g. cyclophosphamide, carmustin, lomustin, and chlorambucil); cytotoxic antibiotics (e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin); antimetabolites drugs (e.g., cytarabine, methotrexat and 5-formazin, procarbazine, hydroxyurea, and their various combinations; radiation sickness; radiotherapy, for example by irradiation of the thorax or abdomen in the treatment of cancer; poisons; toxins such as toxins formed by metabolic disorders or by infection, such as gastritis, or released by bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as air, Maritime and transport sickness, vertigo, dizziness and trouble Miniera; postoperative weakness, obstruction of the gastrointestinal tract; paralysis of the gastrointestinal tract; visceral pain (e.g. myocardial infarction or peritonitis); migraine; increased intracranial pressure; low intracranial pressure (for example, when altitude sickness); opioid analgesics, such as morphine; gastroesophageal reflux; indigestion; the abuse of food or alcohol; high acidity, belching/regurgitation; heartburn (such as episodic heartburn, nocturnal heartburn, heartburn after a meal), and dyspepsia.

The pharmaceutical compositions described in this invention are useful in the treatment of vomiting, especially in the o what precise therapeutic dose of the beginning of the current will depend on the age and condition of the patient and the nature of the disease and to be determined solely by the treating physician.

In General, however, the effective dose for treating conditions mediated by the action on 5HT 5HT3receptors, such as vomiting, are in the range from 0.05 to 100 mg, for example from 0.1 to 50 mg, and preferably from 0.5 to 25 mg, for example, 1, 2, 4, or 8 mg per reception, which can be applied once or several times a day, for example from 1 to 4 times.

Convenient to the volume of liquid composition per unit intake was in the range from 1 to 15 ml, for example from 2.5 to 10 ml, in particular about 5 ml.

The following examples illustrate the invention but are not restrictive.

Example 1. The composition shown in table. 1.

The solution of sorbitol was mixed with water and the resulting mixture was added anhydrous citric acid. To the hydrochloride dihydrate ondansetron added water to the formation of aqueous suspension and this mixture added to the above mixture, and then added the dihydrate of sodium citrate. Sodium benzoate dissolved in water and added this solution to the mixture, and then added strawberry aromatised the holding of 2.5 mg of the hydrochloride dihydrate ondansetron (2 mg of ondansetron in the form of free base) in 5 ml was prepared by the method described in example 1.

Example 3. The composition shown in table. 2.

Anhydrous citric acid dissolved in water, then added the hydrochloride dihydrate ondansetron, and then sodium citrate. Sodium benzoate dissolved in water and added the solution to the above mixture. To the mixture was added xylitol, then sorbitol and finally strawberry flavoring. The mixture is added to the desired volume with water, filtered and bottled.

Examples 4, 5. Compositions containing 1.25 and 10 mg of the hydrochloride dihydrate ondansetron (1 and 8 mg of ondansetron in free base form, respectively) in 5 ml were prepared by the method described in example 1.

1. A liquid composition for oral administration containing the ondansetron or pharmaceutically acceptable derivative, sweetener and one or more pharmaceutically acceptable excipients, characterized in that the sweetener contains sorbitol, and the pH of the composition is in the range from 2.0 to 5.0.

2. Composition under item 1, characterized in that it contains ondansetron in the form of hydrochloride.

3. Composition under item 1, characterized in that it contains ondansetron in the form of the hydrochloride dihydrate.

4. The composition according to any one of paragraphs.1 to 3, characterized in that the>

5. The composition according to any one of paragraphs.1 to 4, characterized in that the concentration of ondansetron in terms of free base is 0.005 to 1% weight/volume.

6. The composition according to any one of paragraphs.1 to 5, characterized in that the total content of sorbitol in the specified composition in terms of solid sorbitol is from 20 to 85% weight/volume.

7. The composition according to any one of paragraphs.1 - 6, characterized in that the pH is from 2.5 to 4.5.

8. The composition according to any one of paragraphs.1 to 7, characterized in that the concentration of ondansetron in the specified composition in terms of free base is from 0.02 to 0.2% weight/volume; the total content of sorbitol in the specified composition in terms of solid sorbitol is from 30 to 50% weight/volume, and the pH is in the range from 3.0 to 4.0.

9. The composition according to any one of paragraphs.1 to 8, characterized in that its viscosity is from 1 to 100 centipoise (CP).

10. The composition according to any one of paragraphs.1 to 9, characterized in that it contains almost no fructose or fructosidase saccharides.

11. A method of treating mammals, including humans, suffering from conditions mediated by the action NT on T3receptors, which affect the composition according to any one of paragraphs.1 - 10.

12. The method according to p. 1

 

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