TR201620498A2 - PHARMACEUTICAL COMPOSITION CONTAINING ACETYLSISTE AND PARACETAMOL - Google Patents

Abstract

The present invention relates to the formulation of a pharmaceutical composition comprising acetylcysteine, paracetamol and at least one pharmaceutically acceptable excipient at high solubility and stability properties for treating effects caused by colds and influenza infections.

Description

DESCRIPTION PHARMACEUTICAL COMPOSITION CONTAINING ACETYLCISTEIN AND PARACETAMOL Technical Field of Invention The present invention provides treatment for the effects of colds and flu infections. acetylcysteine, paracetamol and at least one pharmaceutically acceptable high solubility and stability properties of an excipient-containing pharmaceutical composition State of the Art Paracetamol or Acetaminophen is a paraaminophenol derivative analgesic and antipyretic drug.

Acetaminophen is actually the active metabolite of phenacetin and its chemical name is 4'-Hydroxyacetanilide.

It is indicated by the Formula 1 mentioned below.

Formula 1 Acetaminophen is currently the first-line drug in cases of osteoarthritis of the hips and knees. recommended. As with other nonsteroidal anti-inflammatory drugs, a single dose of acetaminophen The analgesic effect provided by its administration is also limited by a ceiling; acetaminophen as a single dose Maximum analgesic effect is achieved when 1 g is given, and side effects at doses above this. increases. On the other hand, acetaminophen has been associated with oral surgery, episiotomy, headache, and dysmenorrhea. It is an effective analgesic against mild to moderate pain.

Acetylcysteine is the N-acetyl derivative of L-cysteine. Chemical name (R)-2-Acetamido-3-sulfanyl propionic acid and is represented by Formula 2 below.

Formula 2 Due to the ability of the sulfhydryl group in its structure to break the disulfide bonds in the glycoprotein. therefore, it has a mucolytic effect on mucoid and mucopurulent secretions. in the respiratory tract Cough as it reduces the density of accumulated sputum and facilitates the removal of mucus. It is also used as medicine. This means that acetylcysteine, which is abnormal in cystic fibrosis patients, is thick It makes mucus useful in thinning by breaking disulfide bonds. In addition, acute acetaminophen (paracetamol) is used for the treatment of overdose.

Since the active ingredient of acetylcysteine has a very bitter taste, even after drinking it. leaves an unpleasant aftertaste to the patient. It is used by many patients because of its bad smell. It is not preferred to drink drugs containing acetylcysteine.

Also, compounds containing acetylcysteine are stable throughout the shelf life due to impurity problems. problem is occurring. In addition, due to the bitter taste of acetylcysteine, patients' drug intake makes it difficult. It is described in “131”. The usage here is Paracetamol poisoning, that is the dose of Paracetamol. for the treatment of asimia.

Regulation of EP level with Acetylcysteine By increasing the therapeutic efficacy of paracetamol ingestion equivalent to standard dose and efficacy, The use of paracetamol in analgesic and antipyretic applications is mentioned.

When examined in detail, its purpose here is in fact, it is given before the overdose treatment. It's kind of about preventing it.

The definition of effervescent is carbon dioxide as a result of the reaction of acid and base in its formula in aqueous medium. It is in the form of a composition that disperses rapidly with its output and gives the active substance to the solution. easy use, With the easy applicability and the increasing number of people who cannot swallow drugs day by day, the demand for these products is rising. However, since the effervescent compounds are in solution form, the solutions visuality and taste are the defining features of the drug's quality.

Weitschies ,W, “Arzneiformenine Reise durch den Verdauungstrackt” Pharm. Ztg146 and Nümberger, B. and Brune, K.,”Buffering the stomach content enhances the With effervescent tablets, this passage from the stomach is accelerated with buffer solutions and it is given to the small intestine. stated that it reaches and absorbs earlier.

In addition, effervescent production is not an easy production, but it will be obtained. The quality of the solutions is important. Say, the effervescent composition should easily pass into solution form. (it should dissolve easily) and the resulting solution should be clear and pleasant in taste. It is also effervescent Preservation of the moisture value in the production methods throughout the shelf life of the drug, heat and humidity It should not cause loss of visibility in the connected composition.

EP0267809 Bllde is high when sucralose is dispersed at low concentrations. It is stated that it is resistant to temperatures. Again in the same patent, pure, dry, crystalline sucralose It has been stated that it is less resistant to temperatures. In GB, the hot water of crystalline sucralose and it has been explained that it changes color in dry conditions. with water-soluble maltodextrins. stated to have been resolved.

The condition described in the above-mentioned patents is mottling in the effervescent composition. is observed. Different sweeteners have been tried to prevent this. The present invention includes fever, joint pain, nasal congestion and prevention of dense sputum formation in the respiratory tract Solubility and stability of acetylcysteine and paracetamol fixed dose combination for relates to an enhanced pharmaceutical composition.

Purpose and Brief Description of the Invention The present invention includes fever, joint pain, nasal congestion and prevention of dense sputum formation in the respiratory tract Solubility and stability of acetylcysteine and paracetamol fixed dose combination for relates to an enhanced pharmaceutical composition.

The aim of the invention is to solve the technical problems mentioned above and to effervescent two factors. to obtain a composition with increased solubility and stability by combining it in the formulation.

Another object of the invention is that Paracetamol has a bitter taste and is left in the throat after swallowing. offensive taste and with it the unpleasant taste and odor of Acetylcysteine It is to mask it so that it is not felt after it dissolves.

The innovation mentioned in the preferred embodiment of the invention is the use of micronized Paracetamol. by using acidifying and alkaline agents and granulating with water or an organic solvent. increases the resolution. Hereby, inventors have made it clearer and clearer when dissolved in cold water. They have obtained a good-tasting composition that does not leave any residue. Incorporating these two factors together in the market There is a product and the resolution of the existing reference product and the test product is in this respect. evaluated and the values are shown in the table below.

In a preferred embodiment of the invention, the particle size of Paracetamol is below 250 µm. should preferably be below 200 µm, more preferably below 100 µm.

In the preferred embodiment of the invention, Paracetamol is between 500 mg and 2500 mg.

In the preferred embodiment of the invention, Paracetamol is preferably 500 mg to 1000 mg7.

In the preferred embodiment of the invention, Acetylcysteine is between 200 mg and 1200 mg.

In the preferred embodiment of the invention, Acetylcysteine is 200 mg to 600 mg.

Detailed Description of the Invention The present invention includes Acetylcysteine, Paracetamol and a pharmaceutically acceptable adjuvant. for the treatment of the effects caused by substances, colds and flu infections It is related to the formulation of the appropriate composition with increased solubility and stability and micronized Paracetamol can be mixed with water or an organic solvent using acidifying, alkaline agents and preferably a binder. or granulating them with a mixture.

As used herein, the term "effervescent composition" contains Paracetamol and Acetylcysteine. pharmaceutical composition is disclosed. This pharmaceutical composition is additionally pharmaceutically adjunct contains at least one or more excipients. In the preferred embodiment of the invention these excipients; acidifying agents, alkaline agents, binders, fillers, lubricants, antioxidants, stabilizers, sweeteners and flavorings or their It includes, but is not limited to, blends.

Pharmaceutical compositions disclosed by the invention; tablet (core, film-coated, effervescent, oral disperse, water soluble), capsule, sachet, lozenge, syrup, suspension, solution and solution, but not angry with them. The preferred form is effervescent tablet or sachet.

In the preferred embodiment of the invention, acidifying agents, citric acid, sodium citrate, potassium citrate, calcium citrate, tartaric acid, fumaric acid, malic acid, acetic acid, lactic acid, phosphoric acid, at least one selected from propionic acid, or mixtures thereof, but not angry with it. Preferably, they are aqueous and anhydrous mixtures of citric acid and sodium citrate.

In addition, citric acid and sodium citrate have high solubility in water and flavor. Synergy effect to mask the taste when this couple is used together. shows that it is a good choice.

In a preferred embodiment of the invention, alkaline agents; sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium glycine carbonate It may be in the form of at least one or a mixture of these, but is not limited to this. Preferably sodium is hydrogen carbonate.

In a preferred embodiment of the invention, the binders are; polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, xanthan gum, gelatin, polymethacrylate, carboxymethyl cellulose, methyl cellulose, other cellulose derivatives may be in the form of one or a mixture of these, but is not limited to this. Preferably polyvinylpyrrolidone.

In a preferred embodiment of the invention, the filler is inannitol, lactose, microcrystalline cellulose, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, sodium chloride, starch or modified starch (potato starch, wheat starch, corn starch, rice starch, including pregelatinized corn starch), sugar, sucrose may be at least one of sorbitol or mixtures thereof, but not limited to is not. Preferably it is mannitols.

Here the terms "filler" and "diluent" are used interchangeably. used.

In a preferred embodiment of the invention, the lubricant (lubricant), sodium oleate, sodium stearate, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, hydrogenated castor oil, glyceryl behenate, sodium benzoate may be at least one of the talc or mixtures thereof, but is not limited thereto.

Preferably it is polyethylene glycol.

In a preferred embodiment of the invention, the antioxidant stabilizer, ascorbic acid (Vitamin C), From glutathione, Lipoic acid, uric acid, carotenes, oi-Tocopherol (Vitamin E), Ubiquinol (coenzyme Q) at least one or a mixture of these, but not limited to. Preferably is ascorbic acid (Vitamin C). In the formulation subject to this invention, Vitamin C is used as an excipient or It can also be used as an active ingredient.

In a preferred embodiment of the invention, the sweetener is dispersed or dissolved in water. sucralose, aspartame, saccharin, acesulfame K, cyclamates, glucose, sucrose, fructose, lactose and other at least one or more of sugars, xylitol, erythritol, sorbitol, mannitol, and other sugar alcohols It includes, but is not limited to, blends. Preferably sodium cyclamate and saccharin together is use.

In a preferred embodiment of the invention, flavorings are orange, banana, strawberry, cherry, lemon. fruit flavors such as menthol, mint, cinnamon and at least one of the other flavorings, or It includes, but is not limited to, blends. It is preferably orange flavoring.

In a preferred embodiment of the invention, by total composition weight I. 5.0% - 30.0% by weight Acetylcysteine ii. 10.0- 65.0% by weight Paracetamol iii. 5.0 - 50.0 % by weight filler iv. O - 5.0% by weight binder v. 5.0% - 30.0% antioxidant by weight vi. 0.5 - 35.0 wt% acidifying agents Vii 0.5 -50.0% by weight alkaline agents viii 1.0 - 5.0 % by weight lubricants ix. 0.1 - 5.0 % by weight sweeteners x. 0.5 - 5.0 % by weight flavoring xi. 0-2.0% solvent by weight It is an effervescent composition containing effervescent and its feature is that inicronized Paracetamol does not contain acidifying, alkaline agents and granulate with water or an organic solvent or a mixture thereof, preferably using a binder. is to be done. Water or organic solvent or their mixture used during granulation its ratio to total granules is between 0% - 2.0%. Preferably 0% - 1.0%, more preferably 0% - 0.5“.

The term "solvent" as used herein means water or organic solvent or a mixture thereof. explains.

In a preferred embodiment of the invention, the mentioned organic solvent is ethanol, methanol, Contains, but is not limited to, at least one or mixtures of diethylforinamide, acetone, ethyl acetate is not.

The “intermediate product” used here is paracetamol, acidifying agent, alkaline agent and preferably binder. and solvent.

A preferred embodiment of the invention is the method for preparing the effervescent composition, a) One of the acidifying agents is dissolved in the solvent to obtain a granulation solution, b) Micronized Paracetainol, acidifying-alkaline agents and preferably binder into vacuum granulator transferred, c) Add some of the granulation solution from step (a), d) After the mixture turns into powder, it is wetted with the granulation solution in step (a). larger granules are obtained, c) The temperature is expected to drop and the vacuum is opened and the drying process is started, f) Drying continues until the moisture value is < 0.4%, g) The intermediate product is allowed to cool and sieved, h) The sieved intermediate product is transferred to the mixer and Acetylcysteine and other raw materials are sieved from the sieve. added to the mixer, mixed, i) Drying loss is checked and j) The effervescent composition may be in tablet form or in sachet form.

Claims (16)

REQUESTS l. It is an effervescent composition containing Acetylcysteine and Paracetamol, and its feature is that micronized Paracetamol is granulated with water or an organic solvent or a mixture of these, using acidifier, alkaline agents and preferably binder. 2. It is an effervescent composition according to claim 1, characterized in that the particle size of the Paracetamol is below 250 µm, preferably below 200 µm, more preferably below 100 µm. 3. It is an effervescent composition specified according to claim 1, and its feature is that Paracetamol is between 500 mg and 2500 mg. 4. It is an effervescent composition as claimed in claim 1, characterized in that Acetylcysteine is between 200 mg and 1200 mg. 5. It is an effervescent composition as specified in claim 1, and its property contains at least one or a mixture of acidifying agents, alkaline agents, binders, fillers, lubricants, antioxidants, stabilizers, sweeteners and flavorings. 6. A pharmaceutical composition according to any preceding claim, wherein said acidifying agents are at least one selected from citric acid, sodium citrate, potassium citrate, calcium citrate, tartaric acid, fumaric acid, malic acid, acetic acid, lactic acid, phosphoric acid, propionic acid. or mixtures thereof, preferably aqueous and anhydrous mixtures of citric acid and sodium citrate. 7. A pharmaceutical composition according to any preceding claim, wherein said alkaline agent comprises at least one selected from sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium glycine carbonate, or mixtures thereof, preferably sodium hydrogen carbonate. 8. A pharmaceutical composition according to any one of the preceding claims, wherein said binders contain at least one of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, xanthan gum, gelatin, polymethacrylate, carboxymethyl cellulose, methyl cellulose, other cellulose derivatives. or mixtures thereof. 9. A pharmaceutical composition according to any one of the preceding claims, wherein said filler is mannitol, lactose, microcrystalline cellulose, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, sodium chloride, starch or modified starch (potato starch, wheat starch). starch, corn starch, rice starch, including pregelatinized corn starch), sugar, sucrose, sorbitol, or mixtures thereof. 10. A pharmaceutical composition according to any one of the preceding claims, wherein said lubricant is sodium oleate, sodium stearate, stearic acid, sodium stearyl funiarate, calcium stearate, magnesium stearate, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, hydrogenated castor oil. Contains at least one of glyceryl behenate, sodium benzoate, talc, or mixtures thereof. 1. A pharmaceutical composition according to any one of the preceding claims, wherein said antioxidant stabilizer consists of at least ascorbic acid (vitamin C), glutathione, Lipoic acid, uric acid, carotenes, u-Tocopherol (vitamin E), Ubiquinol (coenzyme Q). contains one or a mixture of these. 12. A pharmaceutical composition according to any one of the preceding claims, wherein said sweetener is composed of dispersed or water-soluble sucralose, aspartame, saccharin, acesulfame K, cyclamates, glucose, sucrose, fructose, lactose and other sugars, xylitol, erythritol, sorbitol, mannitol and other alcohols. contains at least one or mixtures thereof, preferably a combination of sodium cyclamate and saccharin. 13. A pharmaceutical composition according to any one of the preceding claims, wherein said flavorings comprise at least one or mixtures of other flavorings such as orange, banana, strawberry, cherry, lemon, menthol, mint, cinnamon and the like, preferably orange flavoring. 14. By total composition weight i. 5.0 - 30.0 % by weight Acetylcysteine ii. 10.0- 65.0% by weight Paracetamol iii. 5.0 - 50.0 % by weight filler iv. 0 - 5.0 wt% binder V. 5.0 - 30.0 wt% antioxidant vi. 0.5 - 35.0 wt% acidifying agents vii 0.5 -50.0 wt% alkaline agents viii 1.0 - 5.0 wt% lubricants ix. 0.1 - 5.0 % by weight sweeteners x. 0.5 - 5.0 % by weight flavoring xi. It is an effervescent composition containing 0-2.0% solvent by weight, and its feature is that micronized Paracetamol is granulated with water or an organic solvent or a mixture of these, using acidifier, alkaline agents and preferably binder. 15. An effervescent composition as claimed in claim 14, characterized in that the ratio of water or organic solvent used during granulation or their mixture to the total granule is in the range of 0% - 2.0%, preferably 0% - 1.0%, more preferably 0 - 0.5%. "Truck. 16. A method for the preparation of effervescent composition according to any of the preceding claims, a) One of the acidifying agents is dissolved in the solvent to obtain a granulation solution, b) Micronized Paracetamol, acidifier, alkaline agents and preferably binder are transferred to the vacuum granulator, c) in step (a). Adding some of the granulation solution, d) After the mixture turns into powder, it is wetted with the granulation solution in step (a) to obtain larger granules, e) Waiting for the temperature to drop, opening the vacuum and starting the drying process, f) Until the moisture value is < 0.4% g) Allowing the intermediate product to cool and sieving, h) Adding and mixing the sieved intermediate product and Acetylcysteine and other raw materials sieved from the sieve into the mixer, i) Controlling the drying loss value, j) Effervescent composition in tablet form or in the form of sachets.