MXPA00011834A - A stabilized antihistamine syrup containing aminopolycarboxylic acid as stabilizer - Google Patents

Abstract

An antihistaminic syrup is stabilized against degradation of the active ingredient, by the addition of and about 0.05 to about 5 mg/mL of an aminopolycarboxylic acid such as a salt of ethylenediaminetetraacetic acid.

Description

STABILIZED ANTIHISTAMINIC SYRUP CONTAINING AMINOPOLYCARBODYL ACID AS A STABILIZER FIELD OF THE INVENTION The present invention pertains to the field of liquid pharmaceutical formulations, and more particularly to syrup formulations containing antihistamines.

BACKGROUND OF THE INVENTION Syrup formulations are commonly used for the administration of pharmacological agents, particularly where the agents should be administered to pediatric patients. Traditional syrups are concentrated solutions of sugar (usually sucrose) in purified water, such as NF syrup, prepared with 850 grams of sucrose and enough water to reach 1,000 mL according to the procedure provided in the official monograph in the page 1990 of NF XVII The National Formula, United States Pharmacopeial Convention, Inc., Rockville, Maryland USA, 1990. However, for the purposes of the present invention, the term "syrup" will also encompass those liquid formulations that have a sweet taste provided wholly or in part by artificial sweeteners, such as saccharin, sorbitol, aspartame, sodium cyclamate and the like, to avoid medical and dental problems that may be aggravated by sweeteners with more calories. As is well appreciated in the art, syrups are frequently flavored, as for example with fruit or peppery flavors, in general to mask an unpleasant taste caused by the presence of a dissolved or suspended pharmacologically active substance. A pleasant taste is particularly important when the formulation is intended to be ingested by children. Typical flavoring agents that are commonly used in sweetened pharmaceuticals, foods, confectionery, beverages and the like are also useful in the present invention; These materials impart flavors such as grape, cherry, lemon, peach, strawberry, chewing gum, mint and many others. Syrups frequently must contain antimicrobial components to ensure safe storage without the proliferation of pathogenic molds, yeasts, bacteria and the like; A typical antimicrobial considered suitable for use in foods and other essential substances is sodium benzoate. Additionally, those syrups that do not contain sugar, or that contain a mixture of sugar and another sweetener, may contain thickeners (such as hydroxypropyl methylcellulose, some forms of which are available from Dow Chemical, Midland, Michigan USA, under the trademark). METHOCEL) to provide a viscous mouthfeel similar to that of a traditional syrup.

An example of a currently marketed syrup contains 1 mg / mL of the antihistamine drug loratadine, together with citric acid, artificial flavor, glycerin, propylene glycol, sodium benzoate, sucrose and water; this formulation typically has a pH value between about 2 and 4. However, under certain storage conditions involving contact with air, loratadine content losses, and a concomitant generation of impurities have occurred. Similar problems can occur with formulations containing other chemically related drugs, such as descarboethoxyloratadine and azatadine. JS Naim, "Solutions, emulsions, Suspensions and Extracts", chapter 83 in AR Gennaro, ed., Remington's Pharmaceutical Sciences, Ed. No. 18, Mack Publishing Co., Easton Pennsylvania USA, 1990 on pages 1519-1520 The problem of the stability of the active agent in aqueous media is described. It is noted that oxidation reactions initiated by trace metals can be minimized through the use of citric acid or EDTA sequestering agents. It is desired to provide a stable storage syrup formulation of loratadine or related antihistamine components, which contains only components recognized as safe for human ingestion.

BRIEF DESCRIPTION OF THE INVENTION According to the invention, there is provided a syrup formulation containing loratadine or a chemically related antihistamine, which includes any pharmaceutically acceptable salt thereof, together with a stabilizing amount of an aminopolycarboxylic acid. Suitable aminopolycarboxylic acids include ethylenediaminetetraacetic acid ("EDTA") and its salts, such as the disodium salt. The acid or salt is generally present in the formulation in concentrations of about 0.05 mg / mL to about 5 mg / mL.

DETAILED DESCRIPTION OF THE INVENTION Loratadine is the pharmacological name given to the compound known as 4- (8-chloro-5,6-dihydro-11 H -benzo [5,6] cyclohepta [1,2- b] pyridin-11-iinden) -1 ethyl-piperidinecarboxylate and having the empirical formula C22H23CIN2O2. A structure for this compound is: The compound descarboethoxyloratadine is an active antihistamine metabolite of loratadine, which has the following structure.

A closely related antihistamine is azatadine, which has the following structural formula: The degradation of the syrup formulations containing loratadine or related antihistamines is observed during the storage stability test, as evidenced by the decreasing concentrations of the active ingredient and a concomitant formation of impurities. Two of the impurities that are formed in loratadine syrups have been identified as 2-hydroxymethilloratadine ("2-HML") and 4-hydroxymethilloratadine ("4-HML"), while other unidentified impurities are produced on a regular basis and Group A7 these materials amount to approximately 5 to 7 and are washed together in an HPLC analysis, in retention times indicating a polarity higher than that of loratadine.The severity of the degradation may be at least approximately to the volume in a bottle of the product that is not loaded with syrup, that is, the "upper space." As it is not practical to fill each bottle completely up, an assay has been carried out where the upper space was filled with gas nitrogen, the results were not conclusive, possibly due to the inevitable oxygen permeability of the closure of the polymeric bottle, another test was carried out, in which They prayed antioxidant additives common in the syrup. Ideally, the antioxidant will be soluble in the syrup and is safe to use in foods and pharmaceutical preparations. Among the water-soluble materials, it was found that ascorbic acid at 0.1 and 1 mg / mL reduced degradation in some way, but also caused an unacceptable strong color change in the product, while sodium bisulfite imparted a strong odor unpleasant. The soluble antioxidants and butylated hidoxytoluene oil and tocopherol were not soluble in the syrup, therefore they were not found acceptable either. It has been found that the addition of small amounts of an aminopolycarboxylic acid, including the term specifically salts of the acids, can stabilize the syrups against degradation. The aminopolycarboxylic acids and their useful salts are those which are safe for ingestion and which have sufficient solubility in the syrup formulations to prepare a stable single-phase composition. Commercially available compounds that could be used include iminodiacetic acid, methyliminodiacetic acid, nitrilotriacetic acid, ethylenediaminetetraacetic acid ("EDTA"), diethylenetriaminepentaacetic acid, 1,2-diaminocyclohexane tetraacetic acid, N-hydroxyethylene diaminetriacetic acid, and related compounds. Mixtures of two or more of the foregoing compounds are suitable for use. From the aspects of easy availability, safety, efficiency and cost, the alkali metal salts of EDTA are currently preferred, and the rest of this description will be centralized in these materials. An aminopolycarboxylic acid or salt will typically be present in a syrup of about 0.05 mg / mL to about 5 mg / mL. More preferably, the level of aminopolycarboxylic acid will be from about 0.1 mg / mL to about 1 mg / mL. As with any additive component in a formulation for ingestion, it is convenient to incorporate the minimum level that will provide the desired result. This level can easily be determined by means of an accelerated storage stability test, in which containers of the final product are stored at elevated temperatures above the usual storage temperatures at which the product is expected to be exposed.; the inventors of the present have used temperatures of up to 55 ° C for this purpose, although such temperatures tend to cause a minor discoloration (darkening) of the syrups, probably due to some caramelization of the contained sucrose. It is expected that most of the drug degradation reactions will be accelerated by the elevated temperature. At predetermined intervals, some of the containers are opened and analyzed to determine the amount of active ingredients and impurities present in the formulation. Antihistamine syrup formulations often also contain other drugs, for obtaining more than one therapeutic result from a single dose. Typical pharmacological substances included with antihistamine are decongestants of sympathomimetic amines, such as pseudoephedrine or phenylpropanolamine (for the relief of congestion of the upper respiratory tract that often accompany disorders such as rhinitis and upper respiratory infections), and analgesics, such as aspirin, acetaminophen, buprofen, naproxen or ketoprofen (for pain relief and, except in the case of acetaminophen, to reduce inflammation). Antitoxives, such as codeine, hydrocodone or dextromethorphan, for the relief of cough, and expectorants such as guaifenesin, to increase the productivity of cough, are also included in combination products. Any of these additional ingredients, including their salts and other drugs of the same therapeutic classes, are suitable for inclusion in the syrups of the present invention.

The invention will be further described by means of the following examples, which are not intended to limit the scope of the invention as defined by the appended claims. When the term "percent" is used herein, it is intended to represent percent by weight, unless the context clearly indicates otherwise.

EXAMPLE 1 A syrup was formulated to contain the following ingredients, wherein the amounts of all but water are expressed in milligrams.

Inquired Quantity Loratadine, micronized 1 Citric acid 8.78 Flavoring agent 2.5 Glycerin 100 Propylene glycol 100 Sodium benzoate 1 Disodium EDTA 0.25 Sucrose 600 Water To reach 1.0 mL This syrup is prepared using the following procedure: (a) approximately 80 percent of the water is placed in a container, heated to 75-85 ° C, loaded with sugar and stirred to form a solution; (b) the citric acid is charged to the solution and stirring is continued to form a solution, then sodium benzoate is added and dissolved; (c) the solution is cooled to 30-35 ° C, with continuous stirring, and disodium EDTA is added and dissolved; (d) glycerin is added and stirring is continued while the solution is cooled to 25-30 ° C; (e) in a separate vessel, combine the propylene glycol and loratadine and shake to form a solution (note that the use of micronized loratadine particles decreases the time required to achieve dissolution), then the flavoring agent is added and stirred until achieving homogeneity; (f) the product of step e is combined with the product of step d, with stirring to ensure homogeneity, and sufficient water is added to provide the weight of the appropriate formulation; and (g) the resulting syrup is passed through lightening filters. The syrup is a clear, colorless liquid (which can be easily colored as desired, such as by adding a suitable pharmaceutically acceptable water-soluble dye in the sugar solution of step a) and is referred to as sample A. Another syrup is formulated from similarly, except that it additionally contains 1 mg / mL of the disodium salt of EDTA. This is called sample B. Twenty-five ml servings of the two syrups are placed in 50 ml flint glass jars, then closed with rubber stoppers and aluminum lids. The closed bottles are stored at 55 ° C until their removal and analysis by high performance liquid chromatography. The results of the analyzes are the following, where "NQ" indicates a result below the limit of quantification (0.1%) but above the limit of detection (0.02%): Storage Percentage of degradation products Sample (weeks) 2-HML 4-HML Total A 3 0.23 0.19 0.42 6 0.33 0.32 0.81 a B 3 0.11 NQ 0.1 1 6 0.10 NQ 0.10 12 0.15 0.14 0.62 a The sample contained 0.16% of an unidentified degradation product. b The sample contained two unidentified degradation products at levels of 0.21% and 0.12%. These results indicate a significant inhibition by EDTA of the degradation of loratadine during the severe storage conditions of the assay.

EXAMPLE 2 Sample A of the preceding example and syrups prepared in a similar manner which also contain 0.1, 0.25, 0.5 or 0.75 mg / mL disodium EDTA are packaged as in the previous example and are stored and tested in a similar manner. The following results are obtained, where "ND" indicates a concentration below the detection limit previously indicated.

EDTA Storage Percentage of products of deqradación (mq / mL) (weeks) 2-HML 4-HML Total 0 3 0.25 0.21 0.69"6 0.29 0.24 0.65b 9 0.49 0.53 1.54 ° 0.1 3 NQ NQ NQ 6 0.10 NQ 0.10 9 0.12 0.11 0.33d 0.25 3 NQ NQ NQ 6 NQ NQ NQ 9 0.10 NQ 0.10 0.5 3 NQ ND NQ 6 0.10 ND 0.10 9 0.1 1 0.10 0.21 0.75 3 NQ NQ 6 0.10 ND 0.10 9 0.10 0.10 0.20 a The sample contained 0.11% degradation products of group A and 0.12 % of an unidentified degradation product b The sample contained 0.14% of an unidentified degradation product c The sample contained three unidentified degradation products at levels of 0.17%, 0.13% and 0.22%. The sample contained 0.10% of an unidentified degradation product. These results suggest that 0.25 percent disodium EDTA would be a reasonable level for storage protection of the analyzed syrup.

EXAMPLE 3 A stabilized syrup was formulated according to the general procedure previously described to contain the following ingredients, wherein the amounts of all but water are expressed in milligrams.

Inqredient Amount Loratadine, micronized .1 Citric acid 8.78 Flavoring agent 1.5 Glycerin 100 Propylene glycol 100 Sodium benzoate 1 Disodium EDTA 0.25 Coloring agent 1 Sucrose 400 Water To reach 1.0 mL This syrup was found to exhibit acceptable storage stability. EXAMPLE 4 A stabilized syrup was formulated according to the general procedure previously described to contain the following ingredients, wherein the amounts of all but water are expressed in milligrams.

Ingredient Amount Loratadine, micronized 1 Citric acid 0.48 Sodium citrate 0.6 Flavoring agent 1.5 Glycerin 350 Propylene glycol 100 Sorbitol 150 Sodium benzoate 1 Disodium EDTA 0.25 Sodium cyclamate 0.75 Hydroxypropyl methylcellulose 0.5 Dye agent 1 Water To reach 1.0 mL This syrup was found to exhibit acceptable storage stability. The commercially named METHOCEL K100M, K4M and A4M from Dow Chemical are among the hydroxypropyl methylcellulose products which are suitable for use in the invention; substituting the various available products can cause changes in the viscosity of the syrup, then experiments must be carried out to determine the appropriate degree and the amount needed to prepare a certain syrup with desired properties.

EXAMPLE 5 A stabilized syrup was formulated according to the general procedure previously described to contain the following ingredients, wherein the amounts of all but water are expressed in milligrams.

Inqredient Amount Loratadine, micronized 1 Citric acid 0.48 Sodium citrate 0.6 Flavoring agent 1 Glycerin 350 Propylene glycol 100 Sorbitol 150 Sodium benzoate 1 Disodium EDTA 0.25 Saccharin 0.75 Hydroxypropyl methylcellulose 0.5 Water To reach 1.0 mL This syrup was found to exhibit acceptable storage stability.

EXAMPLE 6 A stabilized syrup was formulated according to the general procedure previously described to contain the following ingredients, wherein the amounts of all but water are expressed in milligrams.

Inqredient Amount Loratadine 1 Citric acid 0.48 Sodium citrate 0.6 Flavoring agent 2.5 Glycerin 450 Sorbitol 250 Propylene glycol 100 Sodium benzoate 1 Disodium EDTA 0.25 Water To reach 1.0 mL This syrup was found to exhibit acceptable storage stability.

EXAMPLE 7 A stabilized syrup was formulated according to the general procedure previously described but substituting descarboethoxyloratadine for loratadine, to contain the following ingredients, wherein the amounts of all but water are expressed in milligrams.

Inqredient Amount Descarboetoxiloratadine 1 Citric acid 8.78 Flavoring agent 2.5 Glycerin 100 Propylene glycol 100 Sodium benzoate 1 Disodium EDTA 0.25 Sucrose 400 Water To reach 1.0mL This syrup was found to exhibit acceptable storage stability.

EXAMPLE 8 A stabilized syrup was formulated according to the general procedure previously described but substituting azatadine for loratadine, to contain the following ingredients, wherein the amounts of all but water are expressed in milligrams.

Ingredient Quantity Azatadine 1 Citric acid 8.78 Flavoring agent 2.5 Glycerin 100 Propylene glycol 100 Sodium benzoate 1 Sucrose 600 Water To reach 1.0 mL This syrup was found to exhibit acceptable storage stability.

EXAMPLE 9 A stabilized syrup was formulated for pediatric use according to with the general procedure previously described to contain the following ingredients, where the amounts of all but water are expressed in milligrams.

Inqredient Amount Loratadine 0.5 Pseudoephedrine Sulfate 3 Acetaminophen 32 Dextromethorphan Hydrobromide 1 .5 Citric Acid 8.78 Flavoring Agent 1.5 Glycerin 100 Propylene Glycol 100 Sodium Benzoate 1 Disodium EDTA 0.25 Coloring Agent 1 Sucrose 400 Water To reach 1.0mL This syrup was found to exhibit stability in acceptable storage.

Claims (23)

NOVELTY OF THE INVENTION CLAIMS

1. - An antihistamine syrup formulation containing about 0.05 to about 5 mg / mL of an aminopolycarboxylic acid, including its salts.

2. The syrup according to claim 1, which contains an antihistamine ingredient selected from the group consisting of: loratadine; descarboethoxyloratadine; azatadine; and any combination of two or more thereof.

3. The syrup according to claim 1, which contains the antihistamine ingredient loratadine.

4. The syrup according to claim 1, which contains the antihistamine ingredient descarboethoxyloratadine.

5. The syrup according to claim 1, which contains the antihistamine ingredient azatadine.

6. The syrup according to claim 1, wherein the aminopolycarboxylic acid is selected from the group consisting of: iminodiacetic acid; methyliminodiacetic acid, nitrilotriacetic acid, ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid, 1,2-diaminocyclohexane tetraacetic acid, N-hydroxyethylenediaminetriacetic acid and any combination of two or more thereof.

7. - The syrup according to claim 1, wherein the aminopolycarboxylic acid comprises ethylenediaminetetraacetic acid.

8. The syrup according to claim 1, wherein the aminopolycarboxylic acid comprises approximately 0.1 to 1 mg / mL.

9. The syrup according to claim 7, wherein the aminopoxycarboxylic acid comprises about 0.25 to about 0.5 mg / mL.

The syrup according to claim 1, further comprising a therapeutically effective amount of a decongestant, an analgesic, an antitoxant, an expectorant or any combination of two or more thereof.

11. The syrup according to claim 1, further comprising a decongestant selected from the group consisting of pseudoephedrine and phenylpropanolamine.

12. The syrup according to claim 1, which also contains the decongestant pseudoephedrine.

The syrup according to claim 12, which contains the antihistamine ingredient loratadine.

14. An antihistamine syrup formulation containing loratadine or descarboethoxyloratadine and about 0.05 to about 5 mg / mL of an aminopolycarboxylic acid or a salt thereof.

15. The syrup according to claim 14, wherein the aminopolycarboxylic acid is selected from the group consisting of: iminodiacetic acid: methyliminodiacetic acid, nitrilotriacetic acid, ethylenediaminetetraacetic acid, dientylenetriaminepentaacetic acid, 1,2-diaminocyanohexan-tetraacetic acid, N-hydroxyethylenediaminetriacetic acid, and any combination of two or more of them.

16. The syrup according to claim 14, wherein the aminopolycarboxylic acid comprises ethylenediaminetetraacetic acid.

17. The syrup according to claim 14, wherein the aminopolycarboxylic acid comprises approximately 0.1 to 1 mg / mL.

18. The syrup according to claim 14, wherein the aminopolycarboxylic acid comprises from about 0.25 to about 0.5 mg / mL.

19. The syrup according to claim 14, further comprising an analgesic.

20. The syrup according to claim 14, further containing a decongestant by selecting from the group consisting of pseudoephedrine and phenylpropanolamine.

21. The syrup according to claim 20, further comprising an analgesic.

22. An antihistamine syrup formulation containing loratadine and about 0.05 to about 5 mg / mL of an aminopolycarboxylic acid or a salt thereof.

23. An antihistamine syrup formulation containing descarboethoxyloratadine and about 0.05 to about 5 mg / mL of an aminopolycarboxylic acid or a salt thereof.