ES2684594A1 - Aqueous solution of ranitidine free of ethanol (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Aqueous solution of ranitidine free of ethanol. The present invention relates to an aqueous solution of ranitidine free of ethanol and to the use thereof for the preparation of a medicament for the prevention and/or treatment of duodenal and gastric ulcer, prevention and/or treatment of gastrointestinal hemorrhages. and the treatment of peptic esophagitis. The solution is particularly appropriate for administration to patients under 3 years of age. Said solution comprises a taste masking system based on sucrose and/or sorbitol, and a combination of a buffering system with a preservative which gives it a high stability despite having a high concentration of active principle. (Machine-translation by Google Translate, not legally binding)

Description

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DESCRIPTION

Ethanol-free ranitidine aqueous solution.

Technical field

The present invention relates to a pharmaceutical composition of ranitidine in the form of an aqueous solution for oral administration, which is free of ethanol.

Prior art

Ranitidine is the DCI of the compound called (E) - / V- (2 - ((5- 10 ((dimethylaminomethyl) furan-2-yl) methylthio) ethyl) -W, -methyl-2-nitroethane-1,1 -diamine, which responds to the structure:

image 1

Ranitidine is a histamine H2 receptor antagonist drug that inhibits gastric acid secretion.

Said active principle was originally described in 1978 in a family of patents of the Allen & Hanburys company (for example, in the US patent US4128658). Ranitidine hydrochloride was described in British patent application GB-A-2084580.

Its main therapeutic indications are the treatment of gastroduodenal ulcers, as well as the treatment and prevention of gastrointestinal bleeding and the treatment of peptic esophagitis.

According to the information available on the AEMPS website, in Spain the marketed specialties of ranitidine are mostly in the form of tablets and no oral specialty is marketed in liquid form. The only liquid formulations available are injectable.

In other countries, however, ranitidine is marketed in the form of syrup. For example, in the US, according to the information available on the FDA's website, the Glaxo company markets the Zantac® Syrup specialty, and other companies also market equivalent generic ranitidine syrup specialties.

The composition of Zantac® Syrup comprises hydroxypropylmethylcellulose (HPMC), ethanol, propylparaben, butylparaben, monopotassium phosphate, disodium phosphate, sodium chloride, sorbitol, mint flavor and water.

Liquid formulations are appropriate for administration to pediatric or geriatric patients, who prefer them to tablets or capsules, or due to difficulties in taking oral solid forms.

Various liquid formulations of ranitidine have been described in the state of the art.

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For example, the preparation of a syrup comprising 2.0% active ingredient, hydrochloric acid to obtain a pH of 5.0, sorbitol solution, aroma and distilled water is already described in the same basic patent of ranitidine.

In US patent US4585790 an oral composition of ranitidine (15 mg / ml) in the form of hydrochloride is described, having a pH between 6.5 and 7.5. Said composition includes as excipients hydroxypropylmethylcellulose, parabens, potassium dihydrogen orthophosphate, disodium hydrogen orthophosphate, sweetener, flavoring and water. It is noted that with pH adjustment, the stability of the formulation is significantly increased.

In British patent application GB-A-2198352 aqueous formulations of ranitidine of improved stability are described thanks to the addition of ethanol, preferably in an amount comprised between 2.5 and 10%, expressed in weight / volume. The compositions preferably have a pH between 6.5 and 7.5. They may also contain an agent to increase viscosity, such as xanthan gum, sorbitol, glycerol, or cellulose derivatives. Appropriate sweeteners include sodium saccharin, sodium cyclamate, sorbitol and sucrose, and parabens among preservatives. An illustrative example of a liquid formulation of ranitidine of 15 mg / ml concentration, with an ethanol content of 75 mg / ml, and a pH value of approximately 7 is provided.

European patent application EP-A-0193400 describes liquid compositions for oral administration with the synergistic antiulcer combination of ranitidine and sodium polyacrylate.

In the patent application WO-A-95/10274, aqueous solutions of ranitidine are described, both for parenteral and oral administration, where the problem of the stability of said active principle is addressed, the degradation thereof being minimized by the use of a buffer formed by the salt of an organic acid (citrate, tartrate or succinate, for example) and an additional buffering component that can be an organic acid or organic acid salt, to obtain a pH between 5.5-6.5. The compositions may additionally contain other conventional excipients, such as preservatives, viscosifiers, sweeteners and aromas. A solution containing 28 mg / ml of ranitidine hydrochloride is described.

Ranitidine and its salts have a bitter taste and represent a drawback for existing oral compositions, for example those described in GB-A-1565966, US4585790, GB-A-2198352, or WO-A-95/10274.

The problem of taste masking was addressed from non-aqueous solutions or suspensions, as, for example, in international patent applications WO-A-92/04893, WO-A-94/08576, WO-A-96 / 06599, WO-A- 97/33621, or in emulsions of the water-in-oil type (W / O) as, for example, in the international patent application WO-A-01/93834.

The problem of masking the taste of aqueous solutions of soluble ranitidine salts has been addressed from different approaches in the state of the art.

European patent application EP-A-0721785 addresses the problem of the bad taste of ranitidine using a drug salt with a polycarboxylic acid of molecular weight between 1,000 and 200,000 dalton. It is noted that in this way the characteristic bitter taste of ranitidine is significantly reduced.

In the international patent application WO-A-99/04788 the problem of bad taste and instability of ranitidine liquid compositions (5-10 mg / ml) is addressed and proposed

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Compositions containing a type of sucrose called LCMT (low color, metal, turbidity) that contains a smaller number of impurities, thereby achieving a good masking of the bad taste and good stability using a lower proportion of ethanol in the composition.

US patent application US-A-2006/0100271 refers to the preparation of aqueous solutions of ranitidine (15 mg / ml) that are stable without the need to use ethanol in the formulation, by using hydroxyethylcellulose as a stabilizing agent. Among the preferred excipients are parabens, and sorbitol or sucrose.

In the international patent application WO-A-2007/022105, aqueous formulations of ranitidine (15 mg / ml) are described which are stable without the need to use ethanol and which instead contain certain saccharides, starch, and / or derivatives of cellulose.

Aqueous ranitidine compositions (15 mg / ml) without ethanol are described in the international patent application WO-A-2008/039792, which are stable. Said compositions contain a combination of preservatives, and starch and / or celluloses as stabilizers.

In aqueous patent application WO-A-2009/008895 aqueous compositions of ranitidine (15 mg / ml) are described which are stable and do not contain ethanol, and which comprise a citrate salt, preferably sodium citrate. Additionally, they contain other excipients, such as saccharin, sodium chloride, and aromas, and optionally also preservatives (parabens), thickeners (sodium carboxymethyl cellulose) or buffers.

Article E. Alía, Pediatric oral solution of ranitidine, Professional Pharmacy, 2006, 20 (1), 63-66 describes a pediatric oral solution of ranitidine comprising 13.4 mg / ml of ranitidine, a simple syrup formed by sucrose and water, which acts as a preservative, and water. The pH of the 1.5% aqueous solution is between 5 and 6. It is noted that said solution has a weak bitter taste and lasts for a week.

Greek patent application GR-A-2015/0100003 describes compositions with a high ranitidine content (20-40 mg / ml) in a vehicle containing hydroxyethyl cellulose, sorbitol, ethanol, water, and one or more sweeteners selected from between the group formed by sucralose, aspartame, stevioside and rebaudioside. It is indicated that the composition has a synergistic taste masking effect.

Thus, there remains a need for a pharmaceutical preparation based on ranitidine, which keeps masked the bitter taste that the active ingredient generates in the mouth and throat, with a high content of active ingredient, that has a good stability, and that is appropriate to also be administered to patients under 3 years.

Object of the invention

The object of the present invention is an aqueous solution of ethanol-free ranitidine.

Another aspect of the invention is the use of said composition for the preparation of a medicament for the prevention and / or treatment of duodenal and gastric ulcer, the prevention and / or treatment of gastrointestinal hemorrhages and the treatment of peptic esophagitis.

Detailed description of the invention

The object of the present invention is an aqueous solution of ranitidine comprising:

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a) Between 2% (w / v) and 6% (w / v) of ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base.

b) Between 10% (w / v) and 60% (w / v) of a sweetener selected from the group consisting of sucrose, sorbitol and mixture thereof.

c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) Water.

wherein the solution is substantially free of ethanol.

The authors of the present invention have developed a pharmaceutical composition of ranitidine hydrochloride in the form of an aqueous solution for oral administration which, surprisingly, has good organoleptic properties, and good stability, despite having a high content of active ingredient and being substantially free of ethanol. These characteristics make it appropriate to be administered even to children under 3 years.

The composition developed is a transparent solution, ready for use, and which is especially suitable for pediatric application because it contains the active ingredient in the right proportions to facilitate proper administration in children, facilitating dose adjustment according to body weight of each patient, and with good organoleptic qualities for acceptance by the pediatric patient.

Definitions

Throughout the present description, unless expressly stated otherwise, the proportions of the components of the composition of the invention are expressed as percentages by weight / volume (w / v), that is, expressed, for example , as grams of each component per 100 ml of composition, for example.

Throughout the present description, unless expressly stated otherwise, the amounts of ranitidine hydrochloride are expressed as the equivalent amount of ranitidine base. The person skilled in the art will not have difficulty converting the values properly, based on the molecular weights of said substances.

Throughout the present description, any numerical figure preceded by the term "approximately" indicates that said figure also includes a variation of 5% above and below the indicated value.

The composition object of the invention is characterized in that it is substantially free of ethanol. Substantially free of ethanol means either a preparation that does not contain ethanol, or a preparation that contains a small amount of ethanol, which may come, for example, from the excipients constituting the composition. In any case, the content of ethanol in the formulation does not exceed 0.5% (w / v) ethanol, preferably 0.1% (w / v), and more preferably 0.05% (w / v ).

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In the aqueous solution of ranitidine, purified water is usually used, according to the specifications, for example, of the European Pharmacopoeia (Ph Eur) or of the United States Pharmacopoeia (USP).

Ranitidine hydrochloride

Ranitidine hydrochloride constitutes the active ingredient of the composition. By active ingredient, active ingredient, or drug, is meant the substance to which the pharmacological effect of a pharmaceutical preparation is due.

With the designation ranitidine hydrochloride or ranitidine hydrochloride, its solvated forms, including hydrated forms, are also included.

Ranitidine hydrochloride is commercially available, or it can be prepared, for example, as described in British patent application GB-A-2084580, by adding concentrated hydrochloric acid to a solution of ranitidine in a mixture of isopropyl alcohol and water.

The content of ranitidine hydrochloride in the solution of the invention is between 2% (w / v) and 6% (w / v), more preferably between 2.5% (w / v) and 5 , 5% (w / v), even more preferably between 3.5% (w / v) and 4.5% (w / v), where the percentages of ranitidine hydrochloride are expressed as the equivalent percentage of ranitidine base .

In a preferred embodiment of the invention, the ranitidine hydrochloride content is approximately 4% (w / v), expressed as an equivalent percentage of ranitidine base, that is, it is comprised between 3.8% (w / v) and 4.2% (w / v).

Sweetener

The aqueous ranitidine solution of the invention comprises a sweetener selected from the group consisting of sucrose, sorbitol and mixture thereof.

The sweetener content in said solution is between 10% (w / v) and 60% (w / v), preferably between 15% (w / v) and 50% (w / v).

In a preferred embodiment, the solution contains only sucrose as a sweetener. In a more preferred embodiment the sucrose content is between 20% (w / v) and 40% (w / v), preferably between 25% (w / v) and 30% (w / v), more preferably between 25% (w / v) and 26% (w / v), and even more preferably it is 25.6% (w / v).

In another preferred embodiment the solution contains only sorbitol as a sweetener. In a more preferred embodiment the sorbitol content is between 12% (w / v) and 30% (w / v), more preferably between 15% (w / v) and 25% (w / v) , still more preferably between 17% (w / v) and 20% (w / v), and even more preferably it is 18.67% (w / v).

In another preferred embodiment, the solution contains a mixture of sorbitol and sucrose as a sweetener. In a more preferred embodiment the sorbitol content is between 12% (w / v) and 30% (w / v), more preferably between 15% (w / v) and 25% (w / v) , still more preferably between 17% (w / v) and 20% (w / v), and even more preferably it is 18.67% (w / v), and the sucrose content is between 1% (w / v) and 40% (w / v), preferably between 1% (w / v) and 30% (w / v) and even more preferably between 1% (w / v) and 25 , 6% (w / v).

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Buffering system

The aqueous ranitidine solution of the invention comprises a buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

The buffering system allows the pH of the solution to be adjusted to a range between 6.5 and 7.5, preferably between 6.7 and 7.3, and more preferably between 6.8 and 7.1.

The person skilled in the art can determine by routine tests the amount of buffer system that is added to the ranitidine solution to adjust the pH to a specific value within the cited range. The description of the preparation of buffer solutions is described in chemistry manuals such as, for example, Handbook of Chemistry and Physics, 65th Edition, CRC-Press, 1984, or in pharmaceutical technology manuals such as, for example, Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Pennsylvania, 1990.

In a preferred embodiment, the ranitidine aqueous solution comprises between 0.05% (w / v) and 0.15% (w / v) potassium dihydrogen phosphate, preferably between 0.075% (w / v) and the 0.125% (w / v), more preferably between 0.09% (w / v) and 0.1% (w / v), and even more preferably 0.095% (w / v).

In a preferred embodiment, the aqueous ranitidine solution comprises between 0.1% (w / v) and 0.6% (w / v) of disodium hydrogen phosphate, preferably between 0.2% (w / v) and 0.5% (w / v), more preferably between 0.3% (w / v) and 0.4% (w / v), and even more preferably 0.35% (w / v ).

Preservative system

The aqueous ranitidine solution of the invention comprises domifen bromide as a preservative system.

Domifene bromide (CAS 538-71-6) is a quaternary ammonium compound that has antiseptic properties.

The content of domifen bromide is generally between 0.02% (w / v) and 0.5% (w / v), preferably between 0.05% (w / v) and 0.25% (w / v), more preferably between 0.075% (w / v) and 0.15% (w / v), and even more preferably between 0.09% (w / v) and 0.11% (p / v).

The combination of domifene bromide with the potassium dihydrogen phosphate buffer and disodium hydrogen phosphate buffer system provides a good stability of the ranitidine aqueous solution despite having a high concentration in active principle and being substantially free of ethanol.

Other components

The aqueous ranitidine solution may comprise other additional compounds, such as flavorings or dyes.

Flavoring

The aqueous solution of the invention may optionally contain flavoring agents to improve sensation on the palate. Said flavoring substances may be, for example, essential oils of natural origin such as peppermint, eucalyptus, lime or lemon, among others, or

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their mixtures The flavoring can also be of synthetic origin, of different flavors, for example, strawberry, banana, pineapple, caramel, vanilla, cinnamon, apricot, among others. Water soluble flavoring substances are preferably used.

In a preferred embodiment, the solution of the invention further includes a flavoring.

If present, the flavoring, or mixture of flavorings, are used in suitable concentrations, usually between 0.05% (w / v) and 1.5% (w / v).

Colorant

The aqueous solution of the invention may optionally contain a dye to improve the visual appearance thereof.

If present, the dye is used in suitable concentrations, usually between 0.01% (w / v) and 0.2% (w / v).

In a preferred embodiment of the invention, the ranitidine aqueous solution comprises:

a) Between 2% (w / v) and 6% (w / v) of ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base, preferably between 2.5% (w / v) and 5.5 % (w / v), even more preferably between 3.5% (w / v) and 4.5% (w / v), and even more preferably between 3.8% (w / v) and the 4.2% (w / v).

b) Between 10% (w / v) and 60% (w / v) sucrose, preferably between 20% (w / v) and 40% (w / v), more preferably between 25% ( w / v) and 30% (w / v), more preferably between 25% (w / v) and 26% (w / v), and even more preferably 25.6% (w / v).

c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) Water.

wherein the solution is substantially free of ethanol.

In a more preferred embodiment, the aqueous solution further comprises a flavoring agent.

In a particularly preferred embodiment, the aqueous ranitidine solution comprises:

a) Between 3.8% (w / v) and 4.2% (w / v) ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base.

b) 25.6% (w / v) sucrose.

c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) A flavoring.

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f) Water.

wherein the solution is substantially free of ethanol.

In a particularly preferred embodiment, the aqueous ranitidine solution consists of

essentially in:

a) Between 3.8% (w / v) and 4.2% (w / v) ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base.

b) 25.6% (w / v) sucrose.

c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) A flavoring.

f) Water.

wherein the solution is substantially free of ethanol.

In another preferred embodiment of the invention, the aqueous ranitidine solution comprises:

understands:

a) Between 2% (w / v) and 6% (w / v) of ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base, preferably between 2.5% (w / v) and 5.5 % (w / v), even more preferably between 3.5% (w / v) and 4.5% (w / v), and even more preferably between 3.8% (w / v) and the 4.2% (w / v).

b) Between 10% (w / v) and 60% (w / v) of sorbitol, preferably between 12% (w / v) and 30% (w / v), more preferably between 15% ( p / v) and 25% (p / v), even more preferably between 17% (p / v) and 20% (p / v), and even more preferably 18.67% (p / v) .

c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) Water,

wherein the solution is substantially free of ethanol.

In a more preferred embodiment, the aqueous solution further comprises an agent.

flavoring

In another particularly preferred embodiment, the aqueous ranitidine solution comprises:

a) Between 3.8% (w / v) and 4.2% (w / v) ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base.

b) 18.67% (w / v) sorbitol.

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c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) A flavoring.

f) Water.

wherein the solution is substantially free of ethanol.

In another particularly preferred embodiment, the aqueous ranitidine solution consists of

essentially in:

a) Between 3.8% (w / v) and 4.2% (w / v) ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base.

b) 18.67% (w / v) sorbitol.

c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) A flavoring.

f) Water.

wherein the solution is substantially free of ethanol.

In another preferred embodiment of the invention, the aqueous ranitidine solution comprises:

understands:

a) Between 2% (w / v) and 6% (w / v) of ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base, preferably between 2.5% (w / v) and 5.5 % (w / v), even more preferably between 3.5% (w / v) and 4.5% (w / v), and even more preferably between 3.8% (w / v) and the 4.2% (w / v).

b) Between 12% (w / v) and 30% (w / v) of sorbitol, more preferably between 15% (w / v) and 25% (w / v), still more preferably between 17 % (w / v) and 20% (w / v), and even more preferably it is 18.67% (w / v), and between 1% (w / v) and 40% (w / v ) of sucrose, preferably between 1% (w / v) and 30% (w / v) and even more preferably between 1% (w / v) and 25.6% (w / v).

c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) Water.

wherein the solution is substantially free of ethanol.

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In a more preferred embodiment, the aqueous solution further comprises a flavoring agent.

In another particularly preferred embodiment, the aqueous ranitidine solution comprises:

a) Between 3.8% (w / v) and 4.2% (w / v) ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base.

b) 18.67% (w / v) sorbitol, and between 1% (w / v) and 25.6% (w / v) sucrose.

c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) A flavoring.

f) Water.

wherein the solution is substantially free of ethanol.

In another particularly preferred embodiment, the aqueous ranitidine solution consists essentially of:

a) Between 3.8% (w / v) and 4.2% (w / v) ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base.

b) 18.67% (w / v) sorbitol, and between 1% (w / v) and 25.6% (w / v) sucrose.

c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate.

d) Domifen bromide.

e) A flavoring.

f) Water.

wherein the solution is substantially free of ethanol.

Characteristics and use of the composition

The solution according to the present invention is a ranitidine hydrochloride solution and has good organoleptic properties, and good stability despite having a high content of active ingredient and being substantially free of ethanol. A characteristic of the solution developed is the absence of the formation of crystals and / or aggregates after a prolonged period of time of at least 12 months.

The masking effect of flavor is achieved even in solutions with a relatively high content of the active ingredient, for example, up to 6% (w / v). The high concentrations of active ingredient in the solution of the invention together with the absence of ethanol in the formula are the key that allows the administration of the preparation to patients

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even under 3 years old, in manageable and adjustable volumes that contain the exact doses required according to the body weight of each pediatric patient.

Therefore, another aspect of the invention is the aqueous solution of the invention for its use for the prevention and / or treatment of duodenal and gastric ulcer, the prevention and / or treatment of gastrointestinal hemorrhages and the treatment of peptic esophagitis.

Or formulated in another way, another aspect of the invention is the use of the aqueous solution of the invention for the preparation of a medicament for the prevention and / or treatment of duodenal and gastric ulcer, the prevention and / or treatment of hemorrhages. gastrointestinal and treatment of peptic esophagitis.

Or formulated in another way, another aspect of the invention is a method for the prevention and / or treatment of duodenal and gastric ulcer, prevention and / or treatment of gastrointestinal bleeding and the treatment of peptic esophagitis in a patient in need of this, which comprises the administration of the composition of the invention.

In particular, in the case of adults, the aqueous ranitidine solution of the invention is indicated for the treatment of duodenal ulcer and benign gastric ulcer, including that associated with non-steroidal anti-inflammatory drugs; for the prevention of duodenal ulcers associated with the use of nonsteroidal anti-inflammatory drugs; for the treatment of post-operative ulcers, Zollinger-Ellison syndrome and gastroesophageal reflux disease including long-term treatment of reflux esophagitis. It is also indicated for patients with chronic episodic dyspepsia, characterized by pain (epigastric or retrosternal), related to meals or sleep disturbances, but not associated with previous pathologies, and for pathologies in which a reduction in gastric secretion is required and acid production; Prophylaxis of gastrointestinal bleeding due to stress ulcer in severe patients, prophylaxis of recurrent bleeding in patients with bleeding ulcer and in the preoperative period, in patients at risk of acid aspiration syndrome (Mendelson syndrome), especially obstetric patients during childbirth.

For the pediatric population aged 3 to 18 years, the ranitidine solution of the invention is indicated for the short-term treatment of peptic ulcer, the treatment of gastroesophageal reflux, including reflux esophagitis and symptomatic relief of gastroesophageal reflux.

The dose of active substance administered may vary according to the specific indication and the severity of the condition as well as, particularly in the pediatric patient, depending on body weight.

For pediatric patients under 3 years of age, the daily dose of ranitidine is generally 2 mg / kg for term infants (RNT) and for preterm infants (RNPT); between 12 and 27 mg / kg divided into 2 or 3 doses for infants with an age between 1 day and 1 month; between 6 and 27 mg / kg divided into 2 or 3 doses for children aged between 1 and 6 months, and between 8 and 16 mg / kg divided into 2 doses for children aged between 6 months and less than 3 years.

For pediatric patients between 3 and 18 years of age, the recommended daily starting dose of ranitidine is generally between 4 and 10 mg / kg, divided into two individual doses. For the treatment of duodenal ulcer the initial daily dose is preferably between 4 and 8 mg / kg and for the treatment of gastroesophageal reflux between 5 and 10 mg / kg. The daily maintenance dose of ranitidine is usually

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between 2 and 5 mg / kg of weight. For the treatment of duodenal ulcer the daily maintenance dose is preferably between 2 and 4 mg / kg and for the treatment of gastroesophageal reflux between 2.5 and 5 mg / kg.

Orientatively, the recommended dosage of ranitidine in adults is 300 mg per day, divided into two doses of 150 mg. In the case of an aqueous solution containing 4% (w / v) ranitidine, 150 mg corresponds to 3.75 ml.

The composition of the invention is suitable for use for said use or method of treatment in patients of any age, although its specific characteristics in terms of its presentation, organoleptic qualities and concentration of the active ingredient, make it particularly suitable for administration to Pediatric patient, particularly children under 3 years. Thus, a preferred embodiment of the invention relates to said use or method of treatment in the pediatric patient.

In the context of the present invention, the pediatric patient covers children under 3 years of age up to 18 years of age, approximately, in particular the range of children under 3 years, and the range between 3 years and 18 years.

An example is given below, by way of illustration of the present invention, but which should not be construed as limiting it.

Examples

Examples 1-3.- Aqueous solution of ranitidine hydrochloride

250 ml of different oral ranitidine solutions were prepared according to the present invention, using the components detailed in Table I:

TABLE I

 COMPONENT / EJEM PLO

 1% (p / v) 2% (p / v) 3% (p / v) 4% (p / v)

 Ranitidine hydrochloride

 4,464 4,464 4,464 4,464

 (as ratidine)

 (4.00) (4.00) (4.00) (4.00)

 Saccharose

 25.60 13.00 0 25.60

 Sorbitol

 18.67 18.67 18.67 0

 Domifen Bromide

 0.10 0.10 0.10 0.10

 Potassium Dihydrogen Phosphate

 0.095 0.095 0.095 0.095

 Disodium hydrogen phosphate

 0.35 0.35 0.35 0.35

 Flavoring

 c.s. c.s. c.s. c.s.

 Purified water

 c.s.p. 100.00 c.s.p. 100.00 c.s.p. 100.00 c.s.p. 100.00

For the preparation of the composition ranitidine hydrochloride was dissolved in 100 ml of purified water. Then the domifene bromide was dissolved in the above solution, as well as potassium dihydrogen phosphate and disodium hydrogen phosphate. In a separate container, sucrose (if carried) was dissolved in 36 ml of purified water, and over this solution was added

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sorbitol (if you carry it). This solution was added to the solution containing the active ingredient, the preservative and the buffer system and mixed until complete homogenization. The aroma was then added and homogenized. Finally 250 ml with purified water was brought to volume.

In all the examples, the solution obtained contained 40 mg / ml of ranitidine, and was transparent in a yellowish color.

The composition was assessed from an organoleptic point of view by a panel formed by three people. The panelists agreed that the organoleptic perception in the mouth was slightly sweet and with virtually no bitterness.

Example 4.- Stability of the ranitidine hydrochloride aqueous solution

Three 300 I batches of the ranitidine solution of Example 4 were prepared. With said solution, they were filled in 30 ml and 100 ml amber glass jars, capped with a low density polyethylene shutter, and a high polyethylene stopper. Childproof density. These bottles were tested for stability in accordance with the conditions set out in Table II:

TABLE II

 Stability

 Time Temperature Relative humidity

 Long term (climatic zones I and II)

 12 m 25 ° C ± 2 ° C 60% ± 5%

 Long term (climatic zones III and IVa), and, intermediate stability (climatic zones I and II)

 12 m 30 ° C ± 2 ° C 65% ± 5%

 Long term (climate zone IVb)

 12 m 30 ° C ± 2 ° C 70% ± 5%

One of the lots was also subjected to a complementary test in a refrigerator at a temperature of 5 ° C ± 3 ° C, a photostability test, a product stability test as a bulk, and a stability study in use.

The parameters that were evaluated to determine long-term stability were the following: appearance, pH, ranitidine analysis, domifen bromide analysis, impurity content, and microbiological assay.

It was observed that after 12 months under the conditions of long-term stability the solution maintained its initial appearance of transparent solution without the appearance of crystals and / or aggregates, of a slightly yellow color, free of foreign substances and with the characteristic smell of the flavoring agent employee, in this case strawberry aroma. The contents of ranitidine, domifen bromide and impurities were kept within the established specifications.

After six months at a temperature of 2-8 ° C in a refrigerator, the solution also met the specifications.

The ranitidine solution also met the specifications after being subjected to photostability test 5 at 1.2 million lux and an integrated UV energy of 200 watts / m2. Thus,

it can be concluded that if the product is directly exposed to light, its deterioration does not occur.

The bulk product packed in a double bag of low density polyethylene and 10 placed in a high density polyethylene canister, closed with a polypropylene lid, is

subjected to a stability test for 2 months at a temperature of 25 ° C ± 2 ° C and under a relative humidity of 60% ± 5%, and at a temperature of 30 ° C ± 2 ° C and under a relative humidity of 60 % ± 5%. In both cases, the product as a bulk complied with the specifications.

fifteen

The stability in use was carried out in amber glass bottles of 100 ml capacity, covered with a low density polyethylene shutter, and a child resistant high density polyethylene stopper for a period of 90 days. The temperature and humidity conditions were those mentioned in Table II for long-term stability. In all three trials, the ranitidine solution met the specifications, so it can be concluded that under the conditions of use, the ranitidine solution is stable at least 3 months from the first use.

Claims (24)

5 10 fifteen twenty 25 30 35 40 Four. Five fifty 1. Aqueous ranitidine solution characterized in that it comprises: a) Between 2% (w / v) and 6% (w / v) of ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base. b) Between 10% (w / v) and 60% (w / v) of a sweetener selected from the group consisting of sucrose, sorbitol and mixture thereof. c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate. d) Domifen bromide. e) Water. wherein the solution is substantially free of ethanol. 2. Solution according to claim 1, characterized in that the content of ranitidine hydrochloride is between 3.5% (w / v) and 4.5% (w / v), expressed as an equivalent percentage of ranitidine base. 3. Solution according to claim 2, characterized in that the content of ranitidine hydrochloride is between 3.8% (w / v) and 4.2% (w / v)), expressed as an equivalent percentage of ranitidine base . 4. Solution according to any one of claims 1 to 3, characterized in that the solution contains only sucrose as a sweetener. 5. Solution according to claim 4, characterized in that the sucrose content is between 20% (w / v) and 40% (w / v). 6. Solution according to claim 5, characterized in that the sucrose content is between 25% (w / v) and 26% (w / v). 7. Solution according to claim 6, characterized in that the sucrose content is 25.6% (w / v). 8. Solution according to any of claims 1 to 3, characterized in that the solution contains only sorbitol as a sweetener. 9. Solution according to claim 8, characterized in that the sorbitol content is between 12% (w / v) and 30% (w / v). 10. Solution according to claim 9, characterized in that the sorbitol content is between 17% (w / v) and 20% (w / v). 11. Solution according to claim 10, characterized in that the sorbitol content is 18.67% (w / v). 12. Solution according to any of claims 1 to 3, characterized in that it contains a mixture of sorbitol and sucrose as a sweetener. 5 10 fifteen twenty 25 30 35 40 Four. Five fifty 13. Solution according to claim 12, characterized in that the sorbitol content is between 12% (w / v) and 30% (w / v), and the sucrose content is between 1% (w / v ) and 40% (p / v). 14. Solution according to claim 13, characterized in that the sorbitol content is 18.67% (w / v), and the sucrose content is preferably between 1% (w / v) and 25.6% ( p / v). 15. Solution according to any of the preceding claims, characterized in that it comprises between 0.05% (w / v) and 0.15% (w / v) potassium dihydrogen phosphate, and between 0.1% (w / v) and 0.6% (w / v) disodium hydrogen phosphate. 16. Solution according to any of the preceding claims, characterized in that the content of domifen bromide is between 0.02% (w / v) and 0.5% (w / v). 17. Solution according to claim 1, characterized in that it comprises: a) Between 3.8% (w / v) and 4.2% (w / v) ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base. b) 25.6% (w / v) sucrose. c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate. d) Domifen bromide. e) A flavoring. f) Water. wherein the solution is substantially free of ethanol. 18. Solution according to claim 1, characterized in that it comprises: a) Between 3.8% (w / v) and 4.2% (w / v) ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base. b) 18.67% (w / v) sorbitol. c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate. d) Domifen bromide. e) A flavoring. f) Water. wherein the solution is substantially free of ethanol. 19. Solution according to claim 1, characterized in that it comprises: 5 10 fifteen twenty 25 30 35 a) Between 3.8% (w / v) and 4.2% (w / v) ranitidine hydrochloride, expressed as an equivalent percentage of ranitidine base. b) 18.67% (w / v) sorbitol, and between 1% (w / v) and 25.6% (w / v) sucrose. c) A buffer system formed by potassium dihydrogen phosphate and disodium hydrogen phosphate. d) Domifen bromide. e) A flavoring. f) Water. wherein the solution is substantially free of ethanol. 20. Use of a composition according to any of claims 1 to 19 for the preparation of a medicament for the prevention and / or treatment of duodenal and gastric ulcer, the prevention and / or treatment of gastrointestinal bleeding and the treatment of peptic esophagitis . 21. Use according to claim 20, characterized in that the treatment is performed on a pediatric patient. 22. Use according to claim 21, characterized in that the pediatric patient is less than 3 years old. 23. - Use according to claim 21, characterized in that the pediatric patient is 5 between 3 years and 18 years. 24. - Use according to claim 22, characterized in that the daily dose of ranitidine is 2 mg / kg for term infants and for preterm infants; between 12 and 27 mg / kg divided into 2 or 3 doses for infants with an age between 0 and 1 month; between 6 and 27 mg / kg divided into 2 or 3 doses for children aged between 1 and 6 months, and between 8 and 16 mg / kg divided into 2 doses for children aged between 6 months and less than 3 years.