MXPA00005129A

MXPA00005129A - Liquid and stable antihistaminic - anti-congestive pharmaceutical compositions

Info

Publication number: MXPA00005129A
Application number: MXPA/A/2000/005129A
Authority: MX
Inventors: Ulloa Lugo Sergio; De Jesus Villacampa Jose
Original assignee: Schering Corporation*
Filing date: 2000-05-24
Publication date: 2002-07-25

Abstract

Here are depicted liquid pharmaceutical compositions containing loratadine and an anti-congestive such as pseudoephedrine sulphate and at least a liquid vehicle pharmaceutically acceptable, which are stable to the physical and chemical degradation and the microbial contamination.

Description

ANTIHISTAMINIC PHARMACEUTICAL COMPOSITIONS - STABLE LIQUID ANTI-STAGES FIELD OF THE INVENTION The present invention relates to the formulation of pharmaceutical compositions, and more particularly, relates to stable liquid antihistamine-anti-congestive pharmaceutical compositions.

BACKGROUND OF THE INVENTION Loratadine is a long-acting non-sedating antihistamine with selective affinity for peripheral H1 histamine receptors, approved for the treatment of allergic reaction symptoms, for example, for the relief of nasal and non-nasal symptoms associated with seasonal allergic rhinitis, or for the treatment of chronic idopathic urticaria in human patients. Nasal anticongestives such as phenylpropanolamine, pseudoephedr and their pharmaceutically acceptable salts, such as the acid addition salts of hydrogen chloride or hydrogen sulfate, are useful for the treatment of symptoms associated with allergic conditions such as seasonal allergic rhinitis or rhinitis. allergic perennial, as well as symptoms associated with the common cold, including nasal congestion. Syrup formulations are commonly used to deliver drugs, particularly in cases where drugs will be delivered to pediatric patients. It has been found that the formulations of loratadine in syrup are chemically and physically unstable, and show proliferation of microbial agents such as molds, yeasts and bacteria. As a consequence of the above, it has been sought to provide a liquid pharmaceutical composition containing loratadine and an anticongestive, which is chemically and physically stable and resistant to microbial contamination. It would also be desirable to provide a liquid pharmaceutical composition containing loratadine and an anticongestive and which is free of sugar, eg, glucose or sucrose, and of ethanol, being suitable for pediatric use.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to liquid pharmaceutical compositions containing loratadine and an anticongestive and at least one pharmaceutically acceptable liquid carrier, which are chemically and physically stable and protected from microbial contamination after being stored at room temperature for up to 36 months. The liquid pharmaceutical compositions of the present invention are suitable for pediatric use.

OBJECTS OF THE INVENTION Taking into account the defects of the antihistamine-anticongestive pharmaceutical compositions of the prior art, it is an object of the present invention to provide an antihistamine-anticongestive pharmaceutical composition in stable solution. It is another object of the present invention to provide an antihistamine-anticongestive pharmaceutical composition in stable solution useful for the relief of symptoms associated with congestion of the upper respiratory tract associated with disorders such as seasonal and perennial allergic rhinitis, and for the relief of symptoms associated with upper respiratory tract infections, such as the common cold, including nasal congestion.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a stable liquid antihistamine-anticongestive pharmaceutical composition comprising an effective amount of loratadine or a pharmaceutically acceptable salt thereof, and an effective amount of anti-depressant or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically liquid carrier. acceptable. The present invention also provides a stable liquid antihistamine-anticongestive pharmaceutical composition comprising an effective amount of loratadine or a pharmaceutically acceptable salt thereof, and an effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof, and at least one carrier pharmaceutically acceptable liquid. The present invention provides a stable liquid composition comprising an effective amount of loratadine or a pharmaceutically acceptable salt thereof, an effective amount of pseudoephedrine or phenylpropanolamine or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable liquid carrier, and a combination of (1) a sweetener, (2) at least one pharmaceutically acceptable solvent, and (3) ) a sufficient amount of a pH regulator system to maintain the pH approximately within the range of 3.0 to 5.0. In a preferred embodiment of the present invention, the stable liquid antihistamine-anticongestive pharmaceutical composition comprises: Ingredient mq / ml Loratadine 0.4 to 0.6 Pseudoephedrine sulphate 5.40 to 6.60 Glycerin 160 to 240.00 Propylene glycol 280 to 420.00 Sorbitol solution at 70% 180 to 270.00 Sodium saccharin 0.32 to 0.48 Peach flavor No. 609 2.00 to 3.00 Anhydrous citric acid 0.51 a 0.77 Sodium Citrate 0.01 to 0.03 Purified Water cbp To obtain 1.00 ml In a second preferred embodiment of the present invention, the stable liquid antihistamine-anticongestive pharmaceutical composition includes: Ingredient mg / ml Loratadine 0.90 to 1.2 Pseudoephedrine sulphate 6.75 to 8.25 Glycerin 160 to 240 Propylene glycol 280 to 420 Sorbitol solution at 70% 180 to 270 Sodium saccharin 0.32 to 0.48 Peach flavor No. 609 2.00 to 3.00 Anhydrous citric acid 0.51 a 0.77 Sodium Citrate 0.01 to 0.03 Purified Water cbp To obtain 1.00 ml The stable liquid pharmaceutical compositions of the present invention are useful for the relief of symptoms associated with congestion of the upper respiratory tract associated with such disorders. as seasonal and perennial allergic rhinitis; and for the relief of symptoms associated with upper respiratory tract infections, such as the common cold, including nasal congestion.

The present invention further provides the use of loratadine and an anticongestive in the preparation of a liquid pharmaceutical composition for the treatment of symptoms associated with allergic reactions in a human. Another aspect of the present invention is to provide the use of loratadine and an anticongestive in the preparation of a liquid pharmaceutical composition for the treatment of symptoms associated with allergic rhinitis and the common cold in a human. Also, the present invention comprises the use of loratadine and an anti-depressant in the preparation of a liquid pharmaceutical composition for the treatment of symptoms associated with allergic rhinitis and the common cold, including nasal congestion, sneezing, rhinorrhea, pruritus and lacrimation in a human. In a preferred embodiment, the liquid pharmaceutical compositions of the present invention are substantially free of sugar, eg, glucose or sucrose, and of ethanol, and are thus suitable for pediatric use. It has surprisingly been found that it is possible to obtain liquid pharmaceutical compositions containing loratadine and an anticongestive, preferably pseudoephedrine, more preferably pseudoephedrine sulfate, as the active ingredients, which are stable to microbial contamination including, but not limited to, bacterial contamination , and physical and chemical degradation of the active ingredients for periods of at least 4 months, preferably up to 36 months of storage at room temperature (25 ° C). As shown in Table I, the preferred liquid pharmaceutical composition of Example 1 maintained a stable pH in the range of 3.3 to 4.3, and did not show a change in weight greater than about 3% in the original amounts of loratadine and pseudoephedrine sulfate. after being stored at room temperature for at least 4 months and up to 36 months. In addition, there was no change in the physical appearance and color of the liquid pharmaceutical compositions of the present invention. The Antimicrobial Preservative Efficacy Test ("APE") carried out in the liquid pharmaceutical compositions of the present invention, such as Example 1 (see table), demonstrated that the composition was free of microbial contamination after being stored at room temperature. for at least 4 months and up to 36 months. The anticongestives useful in the present invention include the nasal anticongestive pseudoephedrine, phenylpropanolamine, and / or pharmaceutically acceptable salts thereof, especially the acid addition salts of hydrogen chloride and hydrogen sulfate. In a further embodiment, the use of pseudoephedrine sulfate is preferred. Typically suitable sweeteners include sugar, for example glucose, as well as artificial sweeteners such as saccharin, for example, sodium saccharin, sorbitol, aspartame, sodium cyclamate, and mixtures thereof. Preferably, a combination of two artificial sweeteners is used; more preferably, a combination of sodium saccharin and sorbitol is used. Sorbitol is usually a 70% by weight aqueous solution of sorbitol in purified water. In preferred embodiments, the liquid pharmaceutical compositions of the present invention are substantially free of sugar, for example glucose or sucrose, and ethanol, and are thus suitable for pediatric use. The term "substantially free of sugar and ethanol", as used in the present description, means that the liquid pharmaceutical compositions of the present invention contain less than 1%, more preferably less than 0.5%, and most preferably contain less than 0.1% in weight, of sugar, for example, glucose or sucrose, and of ethanol, and in this way are suitable for pediatric use. Typical flavoring agents include those flavoring agents approved for use in pharmaceutical compositions, foods, sweets and sweetened beverages. These flavoring agents impart flavors such as grape, cherry, citrus, peach, strawberry, chewing gum, peppermint, and many others. Typically suitable pharmaceutically acceptable solvents include alcohols and glycols, especially propylene glycol, ethanol and glycerin. The liquid pharmaceutical compositions indicated for pediatric use should be substantially free of, and more preferably should not contain, ethanol. The use of a combination of propylene glycol and glycerin is preferred. Typical pH regulator systems include those capable of maintaining a pH in the range of 3.0 to 5.0, preferably approximately 3.3 to 4.3. Preferred pH buffer systems include citric acid / sodium citrate; and acetic acid / sodium acetate. In a specific embodiment, the use of sodium citrate / citric acid as the pH regulating system is preferred. Typically, the pharmaceutically acceptable liquid carrier is purified water. Even when it is not desired to be limited by any therapy, it is thought that the unique combination of glycerin, propylene glycol, sorbitol and a pH regulator system of sodium citrate / citric acid, provides chemical and physical stability to the liquid pharmaceutical compositions of the invention. present invention, and provides the liquid pharmaceutical compositions of the present invention with antimicrobial protection effective against microbial contamination for periods of at least 4 months and up to 36 months, when stored at room temperature (see Table I). This particularly surprising and unexpected result is achieved without the use of any standard preservative such as sodium benzoate. The present invention is further described by the following examples, which are not intended to limit the scope of the present invention as defined by the appended claims.

EXAMPLE 1 A solution containing the following ingredients was formulated: Ingredient mg / ml g / 1000 Loratadine 0.50 500 Pseudoephedrine sulphate 6.00 6,000 Glycerin 200.00 200,000 Propylene glycol 350.00 350,000 Sorbitol solution at 70% 225.00 225,000 Saccharin sodium 0.40 400 Peach flavor No. 609 2.50 2.500 Anhydrous citric acid 0.64 640 Sodium citrate 0.02 20 Purified water cbp c.b.p To obtain 1.00 ml 1, 000 I A batch of 1000 I of the solution of Example 1 was prepared using the following procedure: 1. In a stainless steel kettle of suitable size equipped with a stainless steel stirrer, the propylene glycol was charged, stirred slowly and warmed to 40 ° C ± 5 ° C. 2. The loratadine was charged to the propylene glycol heated in step 1, the stirring being continued until it completely dissolved. 3. The mixing was maintained and the USP glycerin and the sorbitol solution were loaded to the batch in step 2. Mixing was continued until the batch remained homogeneous. 4. - In a stainless steel vessel of adequate size, equipped with a stainless steel stirrer, 40 liters of purified water were charged and stirring was started. The following ingredients were charged to the purified water: sodium saccharin, sodium citrate, citric acid and pseudoephedrine sulfate, making sure that each ingredient was dissolved before starting the addition of the next. 5.- The active solution from step 4 was added to the batch in step 3; using purified water to rinse the container of the active solution several times (2 to 3 liters, three times); and adding the rinses to the batch. It was mixed until the batch was homogeneous. 6.- Agitation was maintained and a peach flavor was loaded to the batch in step 5, mixing until homogeneous. 7.- The pH was checked and adjusted to a value of 3.5 ± 0.1 using citric acid as a 10% solution in purified water. 8.- The batch was brought to the volume (1, 000 liters) with purified water, and mixed until homogeneous. 9.- The batch was filtered through an Ertel filter press (or its equivalent) equipped with a suitable asbestos-free filter, circulating the batch back in the tank until the outgoing filtrate was clear and bright. The batch was then filtered in a suitable stainless steel container tank. 10.- It was filled in approved containers. Typically suitable containers for the liquid compositions of the present invention include amber type III glass containers and a high density polyethylene ("HDPE") container. The containers obtained in the example can be stored in conditions between 2 ° and 30 ° C.

EXAMPLE 2 The procedure of example 1 was used to prepare the next solution.

Ingredient mg / ml Loratadine 1.0 Pseudoephedrine sulphate 7.50 Glycerin 200.00 Propylene glycol 350.00 Sorbitol solution at 70% 225.00 Sodium saccharin 0.40 Peach flavor No. 609 2.50 Anhydrous citric acid 0.64 Sodium citrate 0.02 Purified water c.b. To obtain 1.00 ml The solution formulation was also stored in 30 ml amber type III glass bottles with a dropper assembly cap, although it is possible to store it in white opaque bottles with 30 ml polyethylene. high density (HDPE). Some samples of the solution obtained in Example 1 in 30 ml amber type III glass bottles with tin foil lid with additional cover of vinyl-coated cardboard at room temperature, were stored at temperatures between 35 ° and 45 ° C. Samples were removed and analyzed for degradation by HPLC, using loratadine and pseudoephedrine standards. PH, APHA color and APE tests were also carried out. The results are summarized in table I.

Similar results were obtained for the solution formulation of Example 2. The solution formulations of Examples 1 and 2 are indicated to be useful for treating pediatric patients from 2 to 8 years of age., for the relief of symptoms associated with allergic rhinitis and the common cold, including nasal congestion, sneezing, rhinorrhea, pruritus and tearing. Additionally, the solution formulations of the present invention are useful when both the antihistaminic properties of loratadine and the anticongestive properties of pseudoephedrine sulfate are desired in any patient, including pediatric patients 2 to 8 years of age or older. In this manner, the stable liquid pharmaceutical compositions of the present invention are useful for the relief of symptoms associated with congestion of the upper respiratory tract associated with disorders such as seasonal and perennial allergic rhinitis, and for the relief of symptoms associated with upper respiratory tract infections, such as the common cold, including nasal congestion. The precise dose and dosing regimen will be determined by the attending physician based on the age and medical condition of the patient, as well as the severity of the symptoms associated with congestion of the upper respiratory tract and the severity of associated symptoms. with upper respiratory tract infections, such as the common cold, including nasal congestion. The liquid pharmaceutical compositions of the present invention in the form containing 0.90 to 1.1 mg / ml of loratadine and 5.40 to 6.60 mg / ml of pseudoephedrine sulfate, can be administered to a pediatric human patient from 2 to 8 years of age according to with the following regime: The liquid pharmaceutical compositions of the present invention containing 0.9 to 1.1 mg / ml of loratadine and 6.75 to 8.25 mg / ml of pseudoephedrine sulfate, can be administered to a pediatric human patient from 2 to 8 years of age according to the following regime: Other modifications well known to those skilled in the art may be made in the solution formulations of the present invention. For example, other suitable typical drugs include analgesics such as aspirin, acetaminophen, buprofen, naproxen or ketoprofen for pain relief and, except in the case of acetaminophen, for the relief of inflammation. It is also known that antitussives such as codeine, hydrocodone, or dextromethorphan for the relief of cough, and expectorants such as guaifenesin or ambroxol to increase the productivity of cough, can also be included in the syrup formulations to form combination products . Any of these additional drugs including salts thereof, and other drugs of the same therapeutic classes, may be added to the solution formulations of the present invention without departing from the scope of the present invention.

TABLE 1 Loratadine-pseudoephedrine sulfate solution of example I Amber glass bottles s \

Claims

NOVELTY OF THE INVENTION CLAIMS

1. A stable liquid antihistamine-anticongestive pharmaceutical composition, characterized in that it comprises an effective amount of loratadine or a pharmaceutically acceptable salt thereof, and an effective amount of anti-depressant or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable liquid carrier .

2. The pharmaceutical composition according to claim 1, further characterized in that the anticongestive is selected from phenylpropanolamine and pseudoephedrine, or a pharmaceutically acceptable salt thereof.

3. A stable liquid antihistamine-anticongestive pharmaceutical composition, characterized in that it comprises an effective amount of loratadine or a pharmaceutically acceptable salt thereof, and an effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof, and at least one carrier pharmaceutically acceptable liquid.

4. The pharmaceutical composition according to claim 3, further characterized in that it contains an effective antimicrobial amount of a sweetener, propylene glycol and glycerin.

5. The pharmaceutical composition according to claim 1 or 3, further characterized in that it contains approximately 0.4 to 0.6 mg / ml of loratadine.

6. The pharmaceutical composition according to claim 3, further characterized in that it contains an amount of a pH regulator system to maintain a pH approximately within the range of 3 to 5. 7.- A stable liquid antihistamine-anticongestive pharmaceutical composition to microbial contamination, characterized in that it comprises an effective amount of loratadine or a pharmaceutically acceptable salt thereof, an effective amount of pseudoephedrine or phenylpropanolamine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable liquid carrier, and a combination of (1) a sweetener, (2) at least one pharmaceutically acceptable solvent, and (3) an amount of a buffer system sufficient to maintain the pH approximately within the range of 3.0 to 5.0. 8. The pharmaceutical composition according to claim 7, further characterized in that it contains approximately 0.4 to 1.2 mg / ml of loratadine. 9. The pharmaceutical composition according to claim 7, further characterized in that it contains pseudoephedrine sulfate in an amount of about 5.40 to 6.60 mg / ml. 10. The pharmaceutical composition according to claim 7, further characterized in that it is suitable for oral administration. 11. The pharmaceutical composition according to claim 7, further characterized in that the sweetener is a combination of sodium saccharin and sorbitol. 12. The pharmaceutical composition according to claim 7, further characterized in that the pH is in the range of about 3.3 to about 4.3. 13. A stable liquid antihistamine-anticongestive pharmaceutical composition for the treatment of symptoms associated with allergic reactions, allergic rhinitis and the common cold, including nasal congestion, sneezing, rhinorrhea, pruritus and lacrimation in a human, characterized in that it comprises, for every 1.00 ml: from 0.40 to 0.60 mg / ml of loratadine; from 5.4 to 6.6 mg / ml of pseudoephedrine sulfate; from 160.00 to 240.00 mg / ml glycerin; from 280.00 to 420.00 mg / ml of propylene glycol; from 180.00 to 270.00 mg / ml of 70% sorbitol solution; from 0.32 to 0.48 mg / ml of sodium saccharin; from 2.00 to 3.00 mg / ml of peach flavor No. 609; from 0.51 to 0.77 mg / ml of anhydrous citric acid; from 0.01 to 0.03 mg / ml of sodium citrate; and, c.b.p. of purified water to complete 1.00 ml. 14. The liquid pharmaceutical composition according to claim 13, further characterized in that it comprises, for each 1.00 ml: 0.5 mg / ml of loratadine; 6.0 mg / ml pseudoephedrine sulfate; 200.00 mg / ml glycerin; of 350 mg / ml of propylene glycol; of 225 mg / ml of 70% sorbitol solution; 0.4 mg / ml sodium saccharin; 2.5 mg / ml peach flavor No. 609; 0.64 mg / ml anhydrous citric acid; 0.02 mg / ml sodium citrate; and, c.b.p. of purified water to complete 1.00 ml. 15. The liquid pharmaceutical composition according to claim 13, further characterized in that the human is a pediatric patient from 2 to 8 years of age. 16. The liquid pharmaceutical composition according to claim 15, further characterized in that when the pediatric patient has an age range of 2 to 5 years and a body weight of 12.5 to 18.5 kg, an effective amount of the composition to supply the Patient corresponds to 2.5 ml every 12 hours. 1

7. The liquid pharmaceutical composition according to claim 15, further characterized in that when the pediatric patient has an age range of 6 to 8 years and a body weight between 18.5 and 30 kg, an effective amount of the composition to supply the Patient corresponds to 5.0 ml every 12 hours. 1

8. A stable liquid antihistamine-anticongestive pharmaceutical composition for the treatment of symptoms associated with allergic reactions, allergic rhinitis and the common cold, including nasal congestion, sneezing, rhinorrhea, pruritus and lacrimation in a human, characterized in that it comprises, for every 1.00 ml: from 0.9 to 1.1 mg / ml of loratadine; from 6.75 to 8.25 mg / ml pseudoephedrine sulfate; from 160.00 to 240.00 mg / ml glycerin; from 280.00 to 420.00 mg / ml of propylene glycol; from 180.00 to 270.00 mg / ml of 70% sorbitol solution; from 0.32 to 0.48 mg / ml sodium saccharin; from 2.00 to 3.00 mg / ml of peach flavor No. 609; from 0.51 to 0.77 mg / ml of anhydrous citric acid; from 0.01 to 0.03 mg / ml of sodium citrate; and, c.b.p. of purified water to complete 1.00 ml. 1

9. The liquid pharmaceutical composition according to claim 18, further characterized in that it comprises, for every 1.00 ml: 1 mg / ml of loratadine; 7.5 mg / ml pseudoephedrine sulfate; 200.00 mg / ml glycerin; of 350 mg / ml of propylene glycol; of 225 mg / ml of 70% sorbitol solution; 0.4 mg / ml sodium saccharin; 2.5 mg / ml peach flavor No. 609; 0.64 mg / ml anhydrous citric acid; 0.02 mg / ml sodium citrate; and, c.b.p. of purified water to complete 1.00 ml. 20. The liquid pharmaceutical composition according to claim 19, further characterized in that the human is a pediatric patient from 2 to 8 years of age. 21. The liquid pharmaceutical composition according to claim 20, further characterized in that when the human patient has an age of 2 years and body weight of 12.5 kg, an effective amount of the composition to be delivered to the patient corresponds to 2 ml every 12 hours. 22. The liquid pharmaceutical composition according to claim 20, further characterized in that when the human patient has an age of 3 years and body weight of 14.5 kg, an effective amount of the composition to be delivered to the patient corresponds to 2.5 ml every 12 hours. 23. The liquid pharmaceutical composition according to claim 20, further characterized in that when the human patient has an age of 4 years and body weight of 16.5 kg, an effective amount of the composition to be delivered to the patient corresponds to 3 ml every 12 hours. 24. The liquid pharmaceutical composition according to claim 20, further characterized in that when the human patient has an age of 5 years and body weight of 18.5 kg, an effective amount of the composition to be delivered to the patient corresponds to 3.5 ml every 12 hours. 25. The liquid pharmaceutical composition according to claim 20, further characterized in that when the human patient has an age of 6 years and a body weight of 20.5 kg, an effective amount of the composition to be delivered to the patient corresponds to 4 ml every 12 hours. 26. The liquid pharmaceutical composition according to claim 20, further characterized in that when the human patient has an age of 7 years and a body weight of 23.6 kg, an effective amount of the composition to be delivered to the patient corresponds to 4.5 ml every 12 hours. 27. The liquid pharmaceutical composition according to claim 20, further characterized in that when the human patient has an age of 8 years and body weight between 26 and 30 kg, an effective amount of the composition to be delivered to the patient corresponds to 5 ml every 12 hours. 28. The liquid pharmaceutical composition according to any of the preceding claims, further characterized by being stable to microbial contamination for periods of at least 4 months, preferably up to 36 months of storage at room temperature (25 ° C). 29. The liquid pharmaceutical composition according to any of the preceding claims, further characterized by being stable to the physical and chemical degradation of the active ingredients for periods of at least 4 months, preferably up to 36 months of storage at room temperature. (25 ° C). 30. The liquid pharmaceutical composition according to any of the preceding claims, further characterized in that it is stable to microbial contamination and physical and chemical degradation of the active ingredients for periods of at least 4 months, preferably up to 36 months of storage at room temperature (25 ° C). 31. The liquid pharmaceutical composition according to any of the preceding claims, further characterized in that it is substantially free of sugar such as glucose or sucrose and of ethanol, and is suitable for pediatric use. 32.- The use of loratadine and an anticongestive in the preparation of a liquid pharmaceutical composition for the treatment of symptoms associated with allergic reactions in a human. 33.- The use of loratadine and an anticongestive in the preparation of a liquid pharmaceutical composition for the treatment of symptoms associated with allergic rhinitis and the common cold in a human. 34.- The use of loratadine and an anticongestive in the preparation of a liquid pharmaceutical composition for the treatment of the symptoms associated with allergic rhinitis and the common cold, including nasal congestion, sneezing, rhinorrhea, pruritus and lacrimation in a human. 35.- The use as claimed in claims 32, 33 or 34, wherein the anticongestive is phenylpropylamine or pseudoephedrine or a pharmaceutically acceptable salt thereof. 36.- The use as claimed in claims 32, 33 or 34, where the human is a subject in pediatric age from 2 to 8 years of age. 37.- The use as claimed in any of claims 32 to 36, wherein the liquid pharmaceutical composition is stable to microbial contamination, for periods of at least 4 months, preferably up to 36 months of storage at temperature Environment (25 ° C). 38.- The use as claimed in any of claims 32 to 36, wherein the liquid pharmaceutical composition is stable to the physical and chemical degradation of the active ingredients for periods of at least 4 months, preferably up to 36 months. months of storage at room temperature (25 ° C). 39.- The use as claimed in any of claims 32 to 36, wherein the liquid pharmaceutical composition is stable to microbial contamination and physical and chemical degradation of the active ingredients for periods of at least 4 months, preferably up to 36 months of storage at room temperature (25 ° C).