TR201514760A1 - NEW ORAL SOLUTION FORMULATION WITH RUPATADINE - Google Patents

Abstract

The present invention relates to an orally administered, solubility improved and stable pharmaceutical aqueous solution comprising a therapeutically effective amount of rupatadine or a pharmaceutically acceptable salt thereof.

Description

DESCRIPTION NEW ORAL SOLUTION FOR MULATION WITH RUPATADIN Technical Area This invention relates to an oral pharmaceutical solution containing rupatadine. More specifically this The invention contains a therapeutically effective amount of rupatadine or their pharmaceutically acceptable An orally administered, improved solubility and stable relates to pharmaceutical aqueous solution.

Previous Technique Rupatadine, chemical name 8-Chl0r-11-{1-[(5-methylpyrid-3-yllmethylpiperid-4- ylidenl-6,11-dihydro-SH-benzo[5,6]cyclohepta[1,2-b]pyridine and its chemical structure Treatment of allergic rhinitis and chronic idiopathic urticaria as shown in Formula 1 It is a well-tolerated H1-receptor blocking antihistamine drug.

Formula 1 Rupatadine's active ingredient competes with histamines to bind to H1 receptors. It binds to receptors and histamine enters the gastrointestinal tract, uterus, large blood It shows by blocking its effects on blood vessels and bronchial smooth muscle. Rupatadine dual-action by blocking both histamine H1 receptors and PAF-receptors. It has been reported to have an antihistamine effect.

Original product in Turkish market, 10 mg rupatadine equivalent rupatadine fumarate salt containing RUPAFIN® 10 mg tablet (license under J. Uriach Compania S.A. /Spain) owner and producer Abdi Ibrahim Ilaç San. and Tic. A.S.) and also licensed in the market. In Europe, in addition to the tablet dosage form, 1 mg/ml rupatadine from J. Uriaeh The oral solution form containing Rupatall®, Wystammaji Tamalisasi Alergoliber®, Urtimed®, Pafinur®l on the market are available.

RUPAFIN® 1 mg/ml oral solution is administered to pediatric patients aged 2-11 years instead of 10 mg tablets. It allows the administration of lower doses (eg 2.5 and 5 mg). 25 5 ml (5 mg of rupatadine) once daily in children weighing kilograms (kg) or more] 2.5 ml once a day in children weighing less than 25 kg and weighing 10 kg or more. (2.5 mg of rupatadine).

Rupatadine is a white crystalline crystal with low solubility in water and pH dependent. it is dust. Solubility values in various pH environments, (pH 3.0 to 7.0 at 25°C) It has been reported to be in the range of 1.32 mg/mL to 0.84 mg/mL (Table 1). molecule and the first indication patent. In the patent application, in the form of syrup The amount of rupatadine fumarate used is 4g/L7 and auxiliary substances are sucrose, aroma, sweetener and water. The amount of rupatadine fumarate in the form of solution for injection. g/L” and auxiliary substances are benzyl alcohol, propylene glycol and water. In this reference pH values and solubility are not mentioned. But EP2402012A2 It has been reported that the solubility values are low according to the reference in the patent.

EP2402012A2 (European patent application I. URIACH & CIA. S.A1, rupatadine It is an oral pharmaceutical product with a pH value of the active ingredient fumarate between 4 and 6.5. mentions the formulation. This liquid pharmaceutical without cyclodextrin pH selected from formulation, rupatadine fumarate, co-solvent, buffers and bases Contains regulatory agent. In the mentioned invention, it causes stability problem. because co-solvents do not contain surfactant, especially It is mentioned that it does not contain pol Isorbate. The solubility of fumarate depends on the pH value and its solubility in acidic medium It has been stated that the solubility decreases as the pH shifts to a basic environment. This In the patent application, also referred to the disadvantages of the patent application numbered I957. has been found. In the patent, the solubility of rupatadine fumarate in water is 2.9g/L. specified. This solubility value saturates the use dose of rupatadine. close to its concentration. In this case, the stability problem due to saturation It has been mentioned that it could happen.

Chinese patent number CN Syrup with a pH in the range of 3.0 to 7.0 containing rupatadine or its salt It's about composition. The present invention is the ratio of rupatadine fumarate to water. 1:20 co-solvent, fumaric acid as pH regulating agent, boric acid, borax, citric acid, sodium citrate buffer systems, aspartame as sweetener, high Contains fuuctose, flavoring agent. In the invention, no surfactant is present.

Chinese patent number CN A liquid eye solution using cyclodextrin to increase the solubility of rupatadine. relates to the preparation.

Chinese patent application no. CN, from an ocular oral pharmaceutical formulation of the active ingredient rupatadine fumarate is talking about. In BLIlUS, in certain proportions, rupatadine fumarate, buffer salt, thickening agent, isotonic agent, bacteriostatic agent and solubilizing agent It contains polysorbate.

Chinese patent number CN application is a liquid drug that uses cyclodextrin to increase the solubility of rupatadine. It's about nasal preparation. This application also describes the low water content of rupatadine. has been reported and the solubility problem has been resolved with the use of cyclodextrin.

European patent application EP258 rupatadin or a different salt of rupatadine with better solubility than rupatadine fumarate (Related to Compound II].

The solubility of rupatadine in water decreases, especially with the increase of alkalinity of the medium. It is difficult to obtain an effective concentration in aqueous solutions. Because, As the pH value of the environment increases, such as stability, loss of active substance amount, increase in impurity, etc. problems appear.

One of the above problems encountered while preparing aqueous pharmaceutical solutions of rupatadine because; As a result of low concentration of rupatadine in pharmaceutical solutions, Ingestion of larger volumes of the oral solution is necessary to obtain the therapeutically effective dosage. required; If it is prepared in high concentration, the pharmaceutical solution various problems reflected on the patient, such as change in physical appearance (blurring) it is natural.

Therefore, rupatadine for oral administration has improved solubility and a stable aqueous solution. There is a need to develop a pharmaceutical formulation in solution form.

The present invention contains rupatadine at pH above 6.5, improved solubility and relates to stable aqueous oral solution formulation.

Brief Description of the Invention The aim of this invention is to treat allergic rhinitis and rupatadine or pharmaceuticals for use in the treatment of chronic idiopathic urticaria as a pharmaceutical aqueous solution containing the appropriate salt.

Another object of this invention is rupatadine suitable for oral use in pediatric patients. or a pharmaceutically acceptable salt with improved solubility above pH 6.5 and to obtain a stable pharmaceutical aqueous solution.

Detailed Description of the Invention The present invention is suitable for oral use by pediatric patients with allergic rhinitis and chronic rupatadine or pharmaceutically acceptable for use in the treatment of idiopathic urticaria It relates to an oral pharmaceutical aqueous solution containing a salt thereof.

As the alkalinity of the medium increases, the solubility of rupatadine in water decreases and the aqueous solution decreases. It is difficult to obtain effective concentration in solutions. your resolution One of the known solutions to achieve this is the use of cosolvent.

However, in basic settings, a single adjuvant in an appropriate amount for pediatric use The use of solvent is insufficient to ensure the solubility of rupatadine.

The use of high amount of co-solvent is not suitable for pediatric products.

The present invention, together with co-solvent in the range of pediatric use, contains surfactant.

The present invention uses rupatadine as the active substance or accepted as a pH value above 6.5. a co-solvent, at least one surfactant, and at least one It is an aqueous oral pharmaceutical solution containing a pH-regulating agent.

In one embodiment of the invention, rupatadine or its equivalent salt is used in the formulation. concentration value in the range of 0.01 mg/ml to 3 mg/ml, preferably 0.1 mg/ml - 1 mg/ml in the range, more preferably 1 mg/ml. Preferably, the active ingredient is rupatadine fumarate. 1.28 1 mg of rupatadine fumarate salt is equivalent to 1 mg of rupatadine free base.

In the preferred embodiment of the invention, the oral pharmaceutical solution formulation in the range of 0.01% to 4% by weight/volume (g/ml), preferably 0.2% to 2%, even more preferably 0.5% to 1% surfactant.

In a preferred embodiment of the invention, said invention is polysorbate, sodium laurii. sulfate. sorbitan ester, docusate sodium, poloxamer, fatty acid esters, polyoxyethylene at least one of the group of sorbitan fatty acid, polyoxyethylene monoalkyl ether, or pharmaceutically acceptable surfactant selected from mixtures contains. Preferably surfactant polysorbate 20, polysorbate 40, polysorbate 60, at least one or mixtures of the polysorbate 80 group. More preferably, surfactant the substance is polysorbate 80.

According to the present invention, oral pharmaceutical solution formulation by weight/volume (g/ml) between 5% and 40%, preferably between 10% and 25%, more preferably between 15%. Contains co-solvent.

Besides water as the present invention solvent, ethyl alcohol, cetyl alcohol, glyceryl stearate, isopropyl alcohol, glyceryl oleate, myristyl alcohol, benzyl alcohol, glycerin, maltitol, xylitol, inositol contains a co-solvent selected from the sorbitol group. Preferably, co-solvent from ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol any one. More preferably, the co-solvent is propylene glycol.

Preferably, the maximum amount of propylene glycol suitable for pediatric use usage is 40% by weight/volume (g/ml). Preferably between 5% and 40%, more contains.

In a preferred embodiment of the invention, propylene glycol and co-solvent are used. Polysorbate 80 is used as surfactant.

In a preferred embodiment of the invention, oral pharmaceutical solution formulation 0.01% to 4% by weight/volume (g/ml), preferably 0.2% to 2%, more preferably According to a preferred embodiment of the present invention, said oral pharmaceutical The solution has a pH value above 6.5. More preferably, the pH is 6.5 to 7.5.

Control of pH value of said oral pharmaceutical solution pH regulating agent (buffer) is provided. The pH regulating agent used, preferably one or more may be too much. In the said embodiment of the invention, the invention includes alkali metal citrate, citric acid/sodium citrate, potassium hydrogen tartrate, sodium hydroxide, hydrochloric acid/sodium hydroxide, disodium hydrogen phosphate, anhydrous sodium phosphate dibasic and citric pH regulating agent selected from at least one of the acid monohydrate group or mixtures thereof contains. In the preferred embodiment of the invention, the pH regulating agent anhydrous sodium phosphate dibasic and citric acid monohydrate. The present invention preferably has a pH value It contains a sufficient amount of pH regulating agent to adjust it.

In addition, in the preferred embodiment of the invention, Viscosity agents, preservatives, sweeteners, flavoring agents, taste-improving/masking agents selected from the group or more excipients can be used.

In the said embodiment of the invention, the invention includes carboxymethyl cellulose, carboxymethyl cellulose sodium, xanthan gum, carrageenan, modified starch, karaya gum, tragacanth gum, guar gum, gelatin, water-soluble carboxyvinyl polymer, methylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium alginate, propylene glycol Contains ViSkOZite agent selected from at least one of the alginate group or mixtures thereof.

In a preferred embodiment of the invention, said invention is sodium benzoate, potassium sorbate, benzoic acid, benzyl alcohol, methyl 4-hydroxybenzoate (methylparabenl, sodium paraben, ethyl 4-hydroxybenzoate (ethylparaben), propyl 4-hydroxybenzoate (propylparabenl, At least one of the butiii 4-hidrok5ibEnzoate (butylparaben) group or mixtures thereof Contains selected pharmaceutically acceptable preservative.

In one embodiment of the invention, said invention is saccharin sodium, sodium Cychiamate, containing xylitol, aspartame, acesulfame potassium, sucrolase and the like or the like Contains suitable sweetening agent.

The flavoring agent used is natural and/or semi-synthetic or synthetic citrus, lemon, lime, orange, tangerine, mint, apple, pear, plum, peach, apricot, strawberry, raspberry. cherry, banana, vanilla. honey. bubble gum flavors or are selected from suitable flavors containing the like.

In the preferred embodiment of the invention, rupatadine or pharmaceutically acceptable The oral pharmaceutical solution containing the salt is in the form of syrup or drops.

Unless otherwise stated, all ratios stated in % in the invention are %. weight/volume (means a/hl.

The following examples are to better explain the subject of the invention and the subject of the invention is not limited to examples.

Examples Example 1 Formulations Table 2. Rupatadine Fumarate Oral Solution Formulations Contents Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula fumaral Polysorbate 80 - 1 - - 1 l 1 monohydrate k.m: sufficient amount The pH value was measured at room temperature (20-25°C] and atmospheric pressure.

The above oral solution formulations are prepared by conventional methods known in the art. It is produced according to any of the methods described in detail and the desired dosage form is brought into the form and made available for use.

Example 2 and Table of the Site specified and % w/v amount of propylene glycol and/or polysorbate. Formulas different from Z, other excipients in Table 2 and active substance keeping the amount constant; amount of water and pH regulating agents (for appropriate pH) has been modified.

Example 2. Appearance of Rupatadine Fumarate Aqueous Solution Table 3. Appearance of Rupatadine Fumarate Aqueous Solution (pH 6.8) Propylene Glycol* Polysorbate-BO* Clarity (gr100mli (grloomn) 0 Fuzzy He is Blurred He is Blurred 50 0 Clear 60 0 Clear 1 clear 1 clear 40 1 Clear 60 1 Clear 2 clear 40 2 Clear *The amount of use in the formula.

Example 3. Stability Test Table 4. Impurity Analysis Results (10 days at 60°C) Usage in Formula o ` .. .

Quantities (Silver Û Total Impurite Propylene . _ Glycol Polysorbate 80 pH 5.0 pH 6.8 Table 4 shows the use of propylene glycol combined with 1% (w/v) polysorbate 80. The amount is above 50% (w/v) regardless of pH (pH 5 and pH 6.8). It does not make a significant difference in terms of impurity when used. But Since the use of propylene glycol causes side effects over 50%, its use is must be under/limited. with 1% (w/v) polysorbate 80 Use of propylene glycol below 50% at pH 6.8 (compared to pH 5) reduces impurity.

Table 5. Impurity Analysis Results (at pH 6.8) Usage in Formula o - .. .

Quantities Û Total Impurite Propylene . pH 6.8 pH 6.8 Glycol Polysurbate 80 Initial at 25°C 10 days at 60°C It is stated that polysorbate has a disadvantage in terms of impurity (EP2402012A2). despite. stress studies of the use of polysorbate in the formula according to this invention It was observed that the result did not cause an increase in the total impurity value (Table 5).

Accelerated stability studies are used to predict the stability of a compound in a short time. makes it happen. The stability test results in Table 4 and Table 57; at 25°C by performing impurity analysis at initial conditions and at 60°C for 10 days. has been obtained.

Around these basic concepts, the subject of the invention is “New Oral Solution Containing Rupatadine. It is possible to develop a wide variety of applications of "formulation". not limited to the examples described, essentially as claimed in the claims.

Claims (15)

REQUESTS It is a stable and improved solubility aqueous pharmaceutical solution containing rupatadine or a pharmaceutically acceptable salt as an active ingredient for oral use, and its feature is a. a co-solvent in the range of 5% to 40% (giml), b. It contains at least one surfactant in the range of 0.01% to 4% (g/ml), c. contains at least one pH regulating agent in sufficient amount to adjust the pH value, and d. the pH value is above 6.5. It is a pharmaceutical solution according to claim 1, characterized in that it contains rupatadine or its equivalent pharmaceutically acceptable salt at a concentration of 0.01 mg/ml to 3 mg/ml, preferably 0.1 mg/ml to 1 mg/ml. It is a pharmaceutical solution according to any of the above claims, characterized in that it contains rupatadine fumarate as an active ingredient. It is a pharmaceutical solution according to claim 3, and its feature is that it contains 1 mg/ml rupatadine equivalent rupatadine fu marate as an active ingredient. Pharmaceutical solution according to any of the above claims, characterized in that it is 0.2% to 2% (g/ml, preferably 0.5% to 1% (g/ml range, more preferably 1% (g/ml) It is a pharmaceutical solution according to claim 5, characterized in that it contains pOIISOI'bat 80 as surfactant. It is a pharmaceutical solution according to claim 6, characterized in that it contains 0.2% to 2% (g/ml), preferably 0.5% to 1% (g/ml), more preferably 1% (g/ml) polysorbate 80. . It is a pharmaceutical solution according to any of the above claims, characterized in that it contains a co-solvent in the range of 10% (giml), most preferably 20% (g/ml). 9- It is a pharmaceutical solution according to claim 8, characterized in that it contains propylene glycol as an auxiliary solvent. 10- It is a pharmaceutical solution according to claim 9 and its feature is between 10% and 25% (g/ml), preferably between 15% and 25% (g/ml), more preferably between 19% and 21% (g/ml), most preferably it contains 20% (g/ml) propylene glycol. It is a pharmaceutical solution according to any one of the above claims, characterized in that the pH value of the solution is between 6.5 and 7.5. 12- It is a pharmaceutical solution according to any one of the above claims, characterized in that the pH regulating agent is anhydrous sodium phosphate dibasic and citric acid monohydrate. 13- It is a pharmaceutical solution according to any of the above claims, and its feature is that it additionally contains one or more excipients selected from the group of viscosity agents, preservatives, sweeteners, flavoring agents, taste-improving/masking agents. 14- It is an aqueous pharmaceutical solution according to any one of the above claims, characterized in that it is in the form of syrup or drops. 15-It is an aqueous pharmaceutical solution according to any of the above claims. Its feature is that it is used as a medicine for the treatment of allergic rhinitis and chronic idiopathic urticaria.