MXPA97003734A - Oral compositions containing ondanset - Google Patents

Abstract

The present invention relates to a liquid composition for oral administration comprising ondansetron or a pharmaceutically acceptable derivative thereof, a sweetener and one or more pharmaceutically acceptable excipients, characterized in that the sweetener consists of sorbitol and the pH of the composition is at the range of 2.0 to 5

Description

ORAL COMPOSITIONS CONTAINING ONDANSETRON The present invention relates to a pharmaceutical composition containing, as an active ingredient, 1, 2, 3, 9-tetrahydro-9-methyl-3- [(2-methyl-lH-imidazol-1-yl) -methyl- 4H-car-bazol-4-one, specifically a liquid composition for oral administration.

In U-Patent No. 2153821B we disclose, inter alia, 1, 2, 3, 9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole -4-one, now known as ondansetron, which is represented by the formula (I). and physiologically acceptable salts, solvates or physiologically acceptable equivalents thereof In the aforementioned specification the compounds are described with potent and selective antagonists for the REF: 24758 5-hydroxytryptamine (5HT) receptors to 5-HT 'neuron-nale' receptors of the type located at the terminals of the primary afferent neurons, which are present in the central nervous system. The receptors of this type are now called 5HT ~ receptors. The compounds described being for use in the treatment of a subject, human or animal that results from a disturbance of neuronal 5HT function, for example in the treatment of migraine pain or a psychotic disorder such like schizophrenia. This also discloses that the compounds may be useful in the treatment of conditions such as anxiety, obesity and inania.

According to our European patent application publication No. 226266 the compounds have also been found to be selective because they are anti-emetic, and can be used in the treatment of the prevention of nausea and vomiting. The use of such compounds for the treatment of emesis is also described in European Patent No. 201165, which additionally refers to the use of the compounds for the treatment of irritable bowel syndrome.

Numerous clinical studies have demonstrated the effectiveness of ondansetron in the treatment of emesis, particularly nausea and vomiting associated with chemotherapy and radiotherapy of cancer and that occurs postoperatively, until now, the drugs have always been administered, both by injection or oral.

Oral administration in the form of conventional tablets, pills and capsules is the generally preferred route for drug administration, since this route is generally convenient and acceptable to patients. Unfortunately such compositions can be associated with certain disadvantages, particularly in the treatment of pediatric and geriatric patients, who may not like or have difficulty swallowing such compositions or where the administration of a conventional tablet, pill or capsule is not possible. This is highly desirable, particularly in the treatment of acute conditions, those pharmaceutical compositions have a rapid and consistent attack of combined action with uninterrupted activity and good bioavailability. Rapid absorption can be by direct injection, but this is unacceptable for some patients, particularly if the drug is to be administered with direct medical supervision, i. and. administered the same.

Alternative routes for administration of ondanse -tron are proposed in GB 2153821 which include liquid formulations for oral administration. GB 2153821 discloses a number of pharmaceutical formulations containing ondansetron, in the form of hydrochloride dihydrate, and formulations of sucrose and sucrose-free syrup for oral administration containing ondansetron hydrochloride dihydrate are specifically disclosed herein.

The present invention provides an advantageous pharmaceutical composition, particularly hitherto not specifically disclosed, which is a liquid composition of the ondansetron suitable for oral administration.

The present invention therefore provides in a first aspect a liquid composition for oral administration consisting of ondansetron or a pharmaceutically acceptable derivative thereof, a sweetener and one or more pharmaceutically-acceptable excipients, characterized in that, the sweetener consists of one or more polyhydric alcohols and the pH of the composition is in the range of 2.0 to 5.0.

By a pharmaceutically acceptable derivative this means any pharmaceutically acceptable salt or solvate of ondansetron, or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) ondansetron or an active metabolite or residues thereof.

Preferably the compositions according to the invention comprise ondansetron in the form of its hydrochloride, more particularly it is hydrochloride dihydrate.

It will be appreciated by those especially in the art that ondansetron contains a chiral center (shown by * in formula (I) and that ondansetron therefore exists in the form of optical isomers (e.g., enantiomers). all ondansetron isomers and pharmaceutically acceptable derivatives, which include all tautomeric and optical forms, and mixtures thereof, including racemic mixtures.

Unlike the compositions of the prior art, the sweetener of the compositions according to the invention comprises one or more polyhydric alcohols. Applicants have found that the use of one or more polyhydric alcohols provides a surprisingly disadvantageous pharmaceutical composition by virtue of this good stability and acceptable test.

It will be appreciated by those skilled in the art that the polyhydric alcohols referred to above will be pharmaceutically acceptable polyhydric alcohols or mixtures thereof, for example sorbitol, mannitol, xylitol and maltitol.

Preferably the sweetener for use according to the invention comprises sorbitol; more preferably, the sweetener-sorbitol and xylitol; more preferably the sweetener-sorbitol is sorbitol.

The total polyhydric alcohol content of the liquid composition, expressed in terms of polyhydric alcohol solids, conveniently lies in the range of 20 to 85% w / v (weight per volume), such as 30 to 70% p / v, preferably 35 to 50% w / v, for example about 40% w / v.

Each polyhydric alcohol can be used in the form of a liquid or in the form of a solution, it is preferably used in the form of a solution, such as an aqueous solution, for example sorbitol is conveniently used in the form of an aqueous solution. which is characterized in that the concentration of solids in the solution is in the range of 64 to 72% w / v (weight by weight).

The concentration of ondansetron in the liquid composition, expressed as free base, is convenient in the range of 0.005 to 1% w / v, such as 0.01 to 0.5% w / v, preferably 0.02 to 0.2% w / v, for example approximately 0.08% p / v.

The pH of the liquid compositions according to the invention conveniently lies between the range of 2.5 to 4.5, such as 3.0 to 4.0, for example about 3.5.

The composition according to the invention can be in the form of liquids, suspensions and syrups. Preferably the compositions are formulated as liquids.

Conventional excipients which can be employed in the compositions according to the invention include preservatives, cushioning systems, viscosity increasing agents, flavoring ingredients, coloring ingredients, additional sweeteners and mixtures thereof.

Suitable preservatives include one or more alkyl hydrobenzoates, such as methyl, ethyl, propyl and / or butyl hydroxybenzoates; sorbic acid or a salt of the same. Preferably the composition according to the invention comprises sodium benzoate.

Suitable buffer systems include combinations of citric acid and salts and solvates thereof, for example citric acid (anhydrous or monohydrate) combined with sodium citrate dihydrate. Preferably the compositions according to the invention comprise the buffer system of anhydrous citric acid and sodium citrate dihydrate.

Suitable viscosity-increasing agents include gums (e.g., xanthan gum); glycerol, polyvinyl alcohol; polyvinylpyrrolidine, cellulose derivatives, such as carboxymethylcellulose or a salt thereof, C1_, alkyl and / or hydroxy C / cellulose alkyl, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; and mixtures thereof.

Liquid compositions according to the invention conveniently have a viscosity which is in the range of 1 to 100 cps, such as 10 to 75 cps, for example almost 15 to 50 cps.

The convenient flavoring ingredients include strawberry, cherry and grape flavoring ingredients, specifically strawberry flavoring ingredients.

Suitable additional sweeteners, include, for example, sugars such as glucose; and cyclamate and salt thereof. Preferably the compositions according to the invention are substantially free of fructose or a saccharide containing fructose (eg sucrose), for example containing less than 5% w / v of the fructose unit, such as, less than 1% p. / v of the fructose unit.

In the subsequent preferred aspect, the invention provides a liquid composition for oral administration consisting of ondansetron hydrochloride dihydrate and sorbitol.

In a still further preferred aspect, the invention provides a liquid composition for oral administration consisting of ondansetron hydrochloride dihydrate, sorbitol, sodium benzoate and flavoring ingredients frequently.

In the later preferred aspects of the invention a liquid composition having a concentration of ondansetron, expressed as a free base, of 0.02 to 0.2% W / v, for example almost 0.08% W / V, a content of sorbitol expressed in terms of sorbitol solids, from 30 to 50% W / V, for example between 40% W / V and a pH 3.0 to 4.0, such as about 3.5, is especially preferred.

Liquid compositions for oral administration are conveniently prepared in a conventional manner, for example by mixing the aqueous solution of the sweetener with an aqueous suspension of the hydrochloride dihydrate of ondansetron and the excipients.

A further aspect of the invention provides a method of treating a mammal, including man, that suffer from a condition mediated through the action of 5HT to 5HT receptors, which consist of the administration of a liquid composition for oral administration consisting of ondansetron or a pharmaceutically acceptable derivative thereof, a sweetener and one or more pharmaceutically acceptable excipients or suspensions, characterized in that the sweetener consists of one or more polyhydric alcohols and the pH of the composition is in the range from 2.0 to 5.0, it will be to be appreciated that the treatment reference is intended to include prophylaxis as well as relief from stabilizing systems. Conditions mediated through the action of 5HT a5HT receptors include emesis, cognitive disorders such as dementia, particularly degenerative dementia (which includes senile dementia, Alzheimer's disease, Pic disease, Huntington's korea, Parkinson's disease and Creutzfeldt-Jakob disease) and vascular dementia (including multi-infarct dementia), as well as dementia associated with lesions that occupy the intracranial space, trauma, referred infections (including HIV infection), metabolites, toxins, anoxia, vitamin deficiencies, and mild cognitive impairment associated with age; particularly memory impairment associated with age; psi-cticos disorders, such as schizophrenia and inania; Anxiety disorders, includes panic disorders, agarophobia, social phobia, simple phobia, obsessive-compulsive disorders. post-traumatic stress disorders, mixture of anxiety and pressure, and generalized anxiety disorders, irritable bowel syndrome and dependence on drugs and substances of abuse. Other conditions mediated in this manner include particularly that it is induced by cholestasis, gastric stasis, gastrointestinal dysfunction symptoms such as occurs with peptic ulcer, reflux esophagitis, flatulence and dyspepsia, migraine, obesity and conditions such as bulimia; d lor and depression.

The emesis, i.e. nausea, nausea and vomiting, includes acute emesis, emesis release and anticipatory emesis. Ondansetron is useful in the treatment of emesis, however, induced. For example, emesis that can be induced by drugs such as cancer chemotherapeutic agents such as agejí renting, e. g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e. g. dactomycin, doxoru bicine, mitomycin-C and bleomycin; antimetabolites, e.g. citation-rabina, methotrexate and 5-fluoracil, vinca alkaloids e.g. eto-posida, vinblastina and vincristina; and others such as cisplati, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation diseases; radiotherapy, e.g. Chest and abdomen irradiation, such as in the treatment of cancer. poisons; toxin such as toxins caused by metabolic disorders or by infection, e.g. gastritis, or release during viral and bacterial gastrointestinal infections; pregnancy; vestibular disorders, such as motor diseases, vertigo, Meniere's disease and dyskinesia; postoperative disease; gastrointestinal obstruction; reduced intestinal gastro motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; reduced intracranial pressure, increased intracranial pressure (e.g., altitude sickness); opioid analgesics, such as morphine and gastro esophageal reflux disease, acid indigestion, overindulgence to foods and beverages, stomach acid, heartburn, waterbrash, regurgitation, heartburn, such as episodes of heartburn, nocturnal heartburn, and pain induced by heartburn and dyspepsia.

The pharmaceutical composition according to the invention have specific utility for the treatment of emesis, particularly associated with chemotherapy and radiotherapy of the case, but also that which exists postoperatively.

It will be appreciated that the precise therapeutic dose of the active ingredient will depend on the age and condition of the patient and the nature of the condition to be treated and will be the elemental discretion of the physician.

However, in general, the effective doses for treatment of conditions mediated through the action of 5-HT to 5HT receptors, for example emesis, which is located in the range of 0.05 to 100 mg, such as 0.1 to 50 mg, preferably 0.5 to 25 mg, for example 1.2.4 or 8 mg of the active ingredient per unit dose, which can be administered in single or divided for example 1 to 4 times a day.

The volume of the single dose of the liquid composition conveniently is in the range of 1 to 15 ml, such as 2.5 to 10 ml, for example about 5 ml.

The following non-limiting examples illustrate the invention Example 1 Ondansentron HCL.2H20 5.0 0.10 Sorbitol solution (USP.EP) 3000.02.3 60.00 Citric acid anhydride (USP.EP) 25.0 0.50 Diuretic citrate of sodium (USP.EP) 7.5 0.15 Sodium Benzoate (USP.EP) 10.0 0.20 Strawberry flavors 15.0 0.30 Purified water, qs for 5 mi 100.00 equivalent of ondansetron, as free base 2 Equivalent to 2.33 mi Equivalent to: 38.4% P / V sorbitol solids USP 40.8 to 43.2 P / V sorbitol solids, EP.

The sorbitol solution was mixed "with water and the anhydrous citric acid added to the mixture, the water was added to the hydrochloride dihydrate of ondansetron to form an aqueous suspension and the suspension was added to the mixture followed by citrate. Sodium benzoate was dissolved in water and the solution added to the mixture, followed by the strawberry flavor The mixture was made "increase in volume with filtered water and filled in bottles.

Example 2 A composition containing 2.5 mg of hydrochloride dihydrate of ondansentron (2 mg ondansetron, as free base) in 5 ml was prepared as described above in example 1.

Example 3. Mg / 5ml% W / V Ondansetron HCL.2H20 5. O1 0.10 Xylitol (USP) 3000.0 60.00 Sorbitol solution (USP) 500. O2 10.00 Anhydrous citric acid (USP) 25.0 0.50 Sodium citrate dihydrate (USP) 7.5 0.15 Sodium Benzoate (USP) 10.0 0.20 Strawberry flavors 15.0 0.30 Purified water, s for 5 mi 100.00% Equivalent to 4 mg ondansetron, as free base 'Equivalent to 0.39 mi The anhydrous citric acid was dissolved in water and then the ondansetron hydrochloride dihydrate was added followed by the sodium citrate. The sodium benzoate was dissolved in water and the solution added to the mixture. The xylitol was added to the mixture, then the sorbitol solution and finally the strawberry flavor. The mixture was made "increase its volume with water, filtered and filled the bottles.

Example 4 and 5 Compositions containing 1.25 and 10 mg of ondansetron hydrochloride dihydrate (1 to 8 mg of ondansetron, as ba free, respectively) in 5 ml are prepared as described above in example 1.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as an antecedent, what is contained in the following is claimed as property.

Claims (13)

CLAIMS.

1 . A liquid composition for oral administration consisting of ondansetron or a pharmaceutically acceptable derivative thereof, a bleaching solution and one or more pharmaceutically acceptable excipients, characterized in that the sweetener consists of one or more polyhydric alcohols and the pH of the composition. it is in the range of 2.0 to 5.0.

2 . A composition according to claim 1, characterized in that it consists of ondansetron in the form of this hydrochloride.

3. A composition according to claim 1 characterized in that it consists of ondasetron in the form of its hydrochloride dihydrate.

4. A composition according to any of any of claims 1 to 3, characterized in that the sweetener consists of sorbitol.

5. A composition according to claim 4 characterized in that it consists of ondansetron in the form of its hydrochloride dihydrate and sorbitol as the sweetener.

6. A composition according to any of claims 1 to 6, characterized in that the concentration of ondansetron in the composition expressed as free base, is in the range of 0.005 to 1% w /.

7. A composition according to any one of claims 1 to 6, characterized in that the content of the total polyhydric alcohol of the composition, expressed in terms of polyhydric alcohol solids, is in the range of 20 to 85% w / v.

8. A composition according to any of claims 1 to 7, characterized in that the pH is between the range of 2.5 to 4.5.

9. A composition according to any of claims 1 to 8, characterized in that the concentration of ondansetron in the composition; expressed as a free base, it is in the range of 0.005 to 1% P / V; The total polyhydric alcohol content of the composition, expressed in terers of polyhydric alcohol solids, is in the range of 20 to 85% P / V, and the pH is within the range of 2.5 to

10. A composition according to any of claims 1 to 9, characterized in that it has a viscosity that ranges from 1 to 100 cps.

11. A composition according to any of claims 1 to 10, characterized in that it is substantially free of fructose or a saccharide containing fructose.

12. A method of treating a mammal, including man, suffering from a condition mediated through the action of the 5HT to 5HT ~ receptors, characterized in that it comprises the administration of a composition according to any of claims 1 to eleven.

13. A method according to claim 12 for the treatment of emesis.