TR201620489A2 - STABİL BUTAMİRAT EFERVESAN TABLET FORMULATION - Google Patents

Abstract

The invention provides a more stable, homogeneous and pleasant taste of pharmaceutical compositions in the form of effervescent, powder or granules containing butamirate or pharmaceutically acceptable salts, hydrates, solvates, esters, amorphous or crystalline forms, or any water-soluble combinations thereof. characterized in that said production method is wet granulation.

Description

DESCRIPTION STABIL BUTAMIRAT EFERVESAN TABLET FORMULATION Technical Field of Invention The invention includes butamirate or its pharmaceutically acceptable salts, hydrates, solvates, esters, containing amorphous or crystalline forms, or any water-soluble combinations thereof More stable, homogeneous and pleasant taste of pharmaceutical compositions in the form of effervescent, powder or granules. describes the production method that a product with method is wet granulation.

State of the Art Butamirate, whose chemical structure is shown below, is chemically referred to as 2-phenylbutyric acid 2-(2- expressed as diethylamino)ethoxy)ethyl ester. Its empirical formula is C18H29NO3 and its molecular weight 307.428 g/mols.

Formula 1 Butamirate is known as Sinecod® in oral syrup and film-coated tablet dosage forms in Turkey. marketed below. The corresponding product is indicated for centrally acting antitussive disorders.

Butamirate citrate is chemically and pharmacologically unrelated to opium alkaloids. It is a cough suppressant. Butamirate citrate cough by inhibiting the cough center in the brain stem and with bronchospazinolytic effect.

Butamirate citrate is a white or yellowish crystalline powder, with little inium and little amine odour. Butamirate base It is sparingly soluble in water, soluble in 96% ethanol. Butamirate is the citrate salt. It is hygroscopic and has water-retaining properties. Butamirate citrate active ingredient has a very bitter taste.

In addition, butamirate citrate is a heat sensitive active ingredient.

BASE. Patent 3349114 describes the preparation process of butamirate and its salts. The same patent It also describes the preparation process of butamirate and its pharmaceutically acceptable compositions.

Pharmaceutical compositions applied by dissolving in water are in powder, granule or effervescent form. water or Liquids in which the respective forms dissolve are often water-soluble and/or hygroscopic agents in liquid form. They are used as carriers for application. General of effervescent, powder and granules One of its uses is the application of high doses of vitamins, minerals and active substances. in water These compositions, which are applied by dissolving, are rapidly absorbed by the human body of the active substance. are the galenic forms that allow

TR2012/06770 patent includes butamirate or its pharmaceutical salts, dissolving agent, basifying agent, Drinkable pharmaceutical solution for oral administration containing sweetening agent, flavoring and antioxidant, or discloses the manufacture of a pharmaceutical product in the form of a syrup.

TR2012/06772 patent butamirate or its pharmaceutically acceptable salts, hydrates, in water containing solvates, esters, amorphous and crystalline forms or a combination thereof describes the pharmaceutical composition in soluble form.

TR2014/12014 patent combines paracetamol with chlorpheniramine maleate and butamirate citrate. explains.

Water-soluble and orally administered pharmaceutical compositions are carbon dioxide when dissolved in water. They contain carbonate or hydrogen carbonate together with releasing acids or acid salts.

Thus, the active ingredient can act as acid or alkali metal compounds. Moreover, They show a faster onset effect compared to conventional dosage forms.

As it is known, the first step for the production of orally administered products dissolved in water is granules. is to create. However, such granules are difficult to produce because they are extremely sensitive to the they stand in between. Accordingly, the critical quality parameters of the product are appearance, taste, hardness and dispersion. time is homogeneity.

Studies have shown that powder, granule and effervescent tablets applied by dissolving in water When pharmaceutical compositions are produced by direct printing method, adhesion during tablet compression show problems. For this reason, the surface of the product cannot be homogeneous. Mourning The powder produced by the granulation method shows free-flowing properties and the tablet compression is very gives better results. In addition, the product obtained using the wet granulation method, With a high quality tablet press that prevents the sticking problem during tablet printing, the acid it contains and protects bases from environmental humidity.

In the process of oral pharmaceutical composition preparation containing butamirate, butamirate is homogeneously mixed. Wet granulation method is used for dispersion. However, after the wet granulation process The moisture source is removed from the environment to dry the granules and increase product stability. Removal of butamirate adversely affects the stability of the product since it is heat sensitive. affects.

Since the active ingredient of butamirate has a bitter taste, the film-coated tablet dosage available in the market When the form is administered orally, it leaves this taste in the mouth. Another dosage foririu In addition to the active ingredient, there are many auxiliary substances in the syrup to prevent this situation. substance is used. Butamirate active ingredient in powder, granule and effervescent dosage forms It contains less excipients than the syrup and syrup form, and when administered orally, this pain There is a need for a formulation that prevents the taste from being felt.

Appropriate dispersion time is one of the important parameters for powder, granule and effervescent forms. In addition to adding the necessary auxiliary substances to the formulation for size is also important. With its high particle size and elastic structure, butamirate It must have a particle size that allows it to dissolve.

Inventors surprisingly find that in the state of the art, it can be dissolved in water and taken orally. The above-mentioned problems for formulations applied via the wet granulation method butamirate and/or a pharmaceutically acceptable salt and granulation It can be overcome by optimizing the weight ratio between the solvent and the solvent.

Purpose and Brief Description of the Invention The present invention is stable, homogeneous and pleasant, containing butamirate citrate as the active ingredient. discloses a production method of a product in powder, granule and effervescent tablet dosage form having a taste.

Starting from the known state of the art, the aim of the invention is to solve all the above-mentioned problems. powder, granule and/or granules containing butamirate in which it is dissolved and/or a pharmaceutically acceptable salt thereof. is the choice of wet granulation method to produce products in effervescent dosage form.

The aim of the invention is to increase the product stability of the granulation process, the active substance and completely in the mixture of granulation solvent in ratios ranging from 0.5:1 to 13 by weight. mixing the resulting solution with at least one water-soluble auxiliary substance and obtaining Drying of the extracted wet granule at lower temperature and in less time depending on this ratio to explain the method.

Another object of the invention is to provide active substance and granulation in ratios ranging from 0.5:1 to 13 by weight. The use of solvent, hygroscopic butainirate citrate, less moisture retention. so that it is relevant for powder, granule and effervescent forms with high moisture sensitivity. to explain the method of easily removing the moisture source from the environment.

The present invention also includes oral administration of butamiratin in powder, granule and effervescent forms with a bitter taste. It should be formulated with the necessary auxiliary substances to leave a pleasant taste in the mouth when applied. It aims to explain.

Detailed Description of the Invention Invention, water-soluble powder, tablet containing butamirate or its pharmaceutically acceptable salts and granule formulations and the process for their preparation.

The term "butamirate" is used throughout the text to refer to butainirate and its pharmaceutically acceptable salt. means solvate, polymorph, hydrate or enantiomer, or a combination thereof is coming. Preferably, butamirate is used in the present invention in the form of the citrate salt.

Butamirate powder, effervescent and granules produced with the formulation subject to this invention are completely dissolved in water. butamirate water solution, which is soluble, has a homogeneous, pleasant taste and a more stable structure found to be created.

As a result of their studies, the inventors tried to use the wet granulation management. They found that the ratio of butamirate: granulation solvent is a very important parameter. Because butamirate has a highly elastic structure, it can be mixed with a high rate of granulation solvent. A long time at high temperature is required to dry the granules obtained when granulated. has been heard. Since butamirate is a heat sensitive active substance, it can be exposed to high temperatures. When it is left, stability problems arise.

If a small amount of granulation solvent is used, butamirate does not dissolve completely and the slurry is becoming. Butainirate in slurry form is further used to produce the lozenge formulation. It is very difficult and troublesome to use in subsequent processes and production optimization is not provided.

In addition, the inventors of the tablet lozenge obtained by using butamirate in the form of slurry It was determined that the problems of homogeneity and content uniformity appeared in the formulation. they did.

As a result of the work they have done to eliminate all the problems mentioned, the inventors Surprisingly, the ratio of butamirate to granulation solvent should be from 05:] to 1:3. they found it in this way. It is completely dissolved in butyramate granulation solvent in the specified ratios. It dissolves and is stable, homogeneous and content without the need for high temperature, long time. Lozenge formulation with uniformity can be produced. In the formulation subject to the present invention This solution is used as a granulation solution in wet granulation.

The object of the present invention is a solution containing 0.5:1 to 1:3 by weight butamirate and solvent. It is the production of butamirate lozenge form by using the solution in the wet granulation process.

The preferred weight ratio of butamirate and solvent with the present invention is 122, more preferably 1:1.

This invention also includes active ingredient and granulation ratios in the range 0.5 :1 to 1:3 by weight. The hygroscopic structure of the solution obtained with the mixture of solvent is less moisture than butainirate citrate. powder, granule and effervescent forms with high moisture sensitivity. explains the method of easily removing the relevant moisture from the environment.

Another object of the present invention is to dissolve completely in a small amount of granulation solvent. It is a production method that ensures homogeneous distribution of butamirate citrate in tablets.

This invention is a formulation that eliminates the bitter taste of butamirate and its explains the production method.

In addition, the active ingredient granulation process is 0.5:1 to 1:3 by weight to improve product stability. Preparation of the solution with a mixture of active ingredient granulation solvent in the range of mixed with at least one auxiliary substance and the wet granule obtained is further dried in the drying stage. describes exposure to heat at a lower temperature and for less time.

The wet granulation method subject to this invention includes the following steps: a) Preparation of effervescent base; acidifying agent, alkalizing agent, buffering agent wet granulation method in the presence of solvent by mixing the diluents and diluents implementation, b) Drying of the obtained wet granules, c) The dried granules will have a maximum particle size of 2000 microns. sifting through the appropriate sieve, d) Preparation of an effective material base; of the active substance into the vacuum granulator. 0.5:3, preferably 1:2, and more preferably 121 by weight butamirate citrate and taking the granulation solvent and mixing it to prepare a solution, e) mixing the solution obtained in step (d) with at least one excipient, and realization of the granulation process, f) The granules obtained in step (6) should be kept under vacuum of 0-100 millibars and at a temperature of 50-70°C. drying at appropriate values in the range, micron and more preferably 750 micron to 1000 micron particle size sifting through the appropriate sieve, h) Mixing effervescent and active substance bases i) At least one pharmaceutically acceptable excipient of the granule mixture obtained mixing with the substance, j) The particle size of the granules obtained in step (i) is between 100 micron and 2000 sifting through the appropriate sieve to be between microns, k) Compressing the obtained mixture in tablet form In an application of this invention, the solvent used during the granulation process is water, organic solvent. or a mixture of these. Organic solvents ethanol, isopropanol, propanol, may be selected, but not limited to, methanol, acetone, dichloromethane or a mixture thereof.

As used herein, the term "therapeutically effective amount" refers to cough caused by a variety of causes, medicine to treat cough and whooping cough before and after surgery or bronchoscopy is the amount of butainirate and its pharmaceutically acceptable salts that can be administered. therapeutic The effective amount depends on the component, the disease and its severity, and age, weight, physical condition. and the responsiveness of the mammal to be treated.

According to the invention, 5 mg to 50 mg in water-soluble powder, effervescent tablet and granule formulation butamirate or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof may be used. 50 mg in film-coated tablet dosage form The product containing butamirate citrate is 1 tablet 2-3 times a day in adults and a day in adolescents over 12 years old. It is applied 1-2 times as 1 time. Adults up to 150 mg of butamirate citrate per day Intake of butamirate citrate up to 100 mg per day in adolescents aged 12 years. has been approved by

Suitable pharmaceutically acceptable excipient used in the invention; acidifying agent, alkalizing agent, buffering agent, diluents, lubricant, flavoring, lubricant, sweetening agent, antioxidant agent and emulsifying agents or a mixture thereof, but with not angry.

Used in effervescent water-soluble powder, tablet and granule formulations prepared according to the invention. acidic agent acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof, but not limited to.

Used in effervescent water-soluble powder, tablet and granule formulations prepared according to the invention. sodium hydrogen carbonate, sodium carbonate, potassium carbonate and may be selected from basic agents such as potassium hydrogen carbonate, but is not limited thereto.

Pharmaceutically acceptable excipient binders, lubricant, humectant, dispersants, sweeteners and taste adjusting agents or a mixture thereof can be selected, but not limited to that.

Lubricant used in water-soluble powder, tablet and granule formulations prepared according to the invention calcium stearate, magnesium stearate, polyethylene glycol, PEG, polyvinyl alcohol, potassium benzoate and may be selected from, but not limited to, sodium benzoate or a mixture thereof.

Antioxidant agent used in powder, tablet and granule formulations prepared according to the invention ascorbic acid (Vitamin C), glutathione, lipoic acid, uric acid, carotenes, alpha-tocopherol (Vitamin E) and ubiquinol (Co enzyme Q) or a mixture thereof, but limited to is not.

The diluent used in the formulations of water-soluble powders, tablets and granules prepared according to the invention agent calcium carbonate, calcium sulfate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or can be selected from a mixture of these, but is not limited to this.

Acceptable lubricating agent in powder, tablet and granule formulations suitable according to the invention, magnesium stearate, polyethylene glycol, metal stearates, hydrogenated castor oil or their can be selected from the mix, but is not limited to it.

Aromatic agents, fruit flavors in powder, tablet and granule formulations suitable according to the invention can be selected from orange, banana, strawberry, cherry, lemon or a mixture of these, but limited to is not.

used in water-soluble powder, tablet and granule formulations prepared according to the invention. sweetener acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharin sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or can be selected from a mixture of these, but is not limited to this.

The present invention will be described in more detail by means of the following example. Sample, The light of the description detailed above is not intended to limit the scope of the invention. should be considered below.

Raw material name Functional category mg/tb Butamirate citrate Active ingredient 5 - 50 Sodium citrate dihydrate Emulsifying agent 0.1 - 2.0 Sodium hydrogen carbonate Basifying agent 600 - 800 Sodium carbonate anhydrous Buffering agent 100 - 200 Mannitol Diluting agent 700 - 1200 Ascorbic acid Antioxidant agent 50.0 - 125.0 Sucralose Sweetening agent 10.0 - 18.0 Lemon flavor Aroma 25.0 - 37.5 PEG Lubricating agent 100.0 - 140.0 Deionized water* Solvent Sufficient * Not found in the finished product.

The emulsifying agent required for the production of the effervescent base in the formulation of the invention, Wet granulation with acidifying agent, alkalizing agent and buffering agent granulation solvent The granules obtained by the process are dried. On the other hand, the active ingredient granulation solvent A solution is obtained by mixing with 122 by weight, preferably 1:1.5 and more preferably 1:1. The wet granulation process is performed by mixing it with a little auxiliary substance. Obtained at vacuum and temperature values optimized by granules formulation trial studies. dried. Afterwards, both granules are mixed dry, followed by at least one auxiliary It is also mixed with the substance and made ready for tablet printing. Mixture in tablet printing machine printed using the appropriate Staple.

Tablets prepared in accordance with the invention for stability monitoring at 25°C / 60%RH, 30°C / 65%RH and placed in stability cabinets at 40°C / 75%RH. 25°C from these conditions represents.

The tablets placed in the stability cabinets were analyzed and the results were presented in the table below. is summarized.

Beginning 3rd Month Beginning 3rd Month Beginning 3rd Month Quantity Determination Impurity C < LOQ T.E < LOQ T.E < LOQ T.E Unknown Impurity (RRT: * T.E.: Could not be determined.

LOQ: Below the calculation limit.

RRT: Relative retention time The products that were kept in stability cabinets for 3 months were analyzed and the shelf life of the results, intermediate conditions and from the analysis results obtained in the initial period even under accelerated stability conditions. It is understood that it does not show much deviation. Butamirate treated with heat and liquid during production Citrate has a pleasant taste that does not pose a problem in terms of moisture, quantification and impurity parameters. It has been achieved in the form of a quality product with high quality.

Claims (1)

REQUESTS It is the production method of an oral pharmaceutical formulation with improved stability, containing butamirate or a pharmaceutically acceptable salt as an active ingredient. In the production of the active substance phase, the solution is prepared by mixing the active substance with the granulation solvent in the ratios between 05:] to 1:3 and it is a wet granulation process applied by mixing it with at least one pharmaceutically acceptable excipient. It is an oral pharmaceutical composition production method according to claim 1, characterized in that the ratio of active substance and granulation solvent is preferably 1:1.5 by weight, and more preferably lzl, in the method of producing the active substance using wet granulation. It is an oral pharmaceutical composition according to claim 17, characterized in that the composition is in powder, granule and effervescent tablet form. Pharmaceutical composition according to claim 6, characterized in that diluent, lubricant, buffering, acidifying, alkalizing, emulsifying agents, antioxidants, flavoring and sweetening agents are used as pharmaceutically acceptable excipients. Pharmaceutical composition according to claim 7, characterized in that the diluent is calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, sucrose, maltodextrin, maltose, mannitol, sodium chloride, is selected from the group consisting of sorbitol, starch, and xylitol. A pharmaceutical composition according to claim 77, characterized in that the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, PEG, polyvinyl alcohol, amino acid, potassium benzoate and sodium benzoate. The pharmaceutical composition according to claim 7, characterized in that the acidifying agent is selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid and the like. It is a pharmaceutical composition according to claim 7, characterized in that the basifying agent is selected from the group consisting of sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate. It is a pharmaceutical composition according to claim 7, characterized in that the sweetener is selected from the group consisting of acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharin, saccharin sodium, sodium cyclamate, sucralose, sucrose and xylitol. It is a process for the preparation of water-soluble powder, granule and effervescent formulations according to any of the claims, and its feature is to make wet granulation of the effervescent base, which consists of a mixture of acidifying agent, alkalizing agent, buffering agent, using a granulation solvent and then drying it, on the other hand, granulation of the active substance in the wet solution granulation method. It includes the steps of mixing and drying the concentrated solution formed by dissolving with at least one auxiliary substance, combining both dried granules and mixing them dry with at least one auxiliary substance and compressing them into tablet form. The feature of the granules prepared for tablet compression according to claim 13 is that the particle is preferably between 750 microns and 1000 microns.