DD295986A5 - IBUPROFEN SHOWER PREPARATIONS - Google Patents

Abstract

The invention relates to ibuprofen effervescent formulations which contain a) a basic granulate consisting of a water-soluble ibuprofen salt, traegerstoffstoff, stabilizer and sodium or potassium carbonate and b) an acid component, in the form of granules and tablets and processes for the preparation.

Description

Effervescent ibuprofen preparations

The invention relates to clear dissolving ibuprofen effervescent preparations and to processes for their preparation.

Ibuprofen is a drug with an analgesic and anti-inflammatory effect, similar to acetylsalicylic acid irritates the gastric mucosa and is absorbed relatively slowly. In addition, the taste of ibuprofen is so poor that usually tablets are provided with a taste-covering coating. Since acetylsalicylic acid has to be treated with the problems of irritation of the gastric mucosa and its slow absorption by the use in the form of effervescent tablets and granules, it has been considered that this dosage form should also be used for ibuprofen. It turned out, however, that the use of conventional effervescent mixtures does not lead to success.

Despite many efforts, it was not possible to quickly and completely dissolve the extremely sparingly soluble ibuprofen crystals from an effervescent formulation in a glass of water, resulting in always quite unattractive appearing forms of application.

EP-A 228164 describes an ibuprofen or. their salts-containing effervescent preparation, which contains ibuprofen after the brewing reaction in suspended form in the glass of water. This preparation has the disadvantage that the benefits of an analgesic effervescent tablet, such as better digestibility and rapid onset of action, not given from the outset

DE-A 3638414 describes the addition of arginine or lysine in an amount exceeding the molar fraction in order to obtain a soluble form of ibuprofen. The Effervescent contains as acid component sodium hydrogen tartrate. The addition of these components has major disadvantages. Arginine and lysine are too expensive for use as a pharmaceutical excipient and exceed the cost of the active ingredient ibuprofen. Sodium hydrogen tartrate acts as an acid so weak that at a pH of about 6.5 for the entire system, the intensity of the brewing reaction leaves something to be desired and is almost unrecognizable. Thus, the patient positively responding effervescent effect is practically not achieved.

EP-A 203768 describes a therapeutic effervescent composition which may contain paracetamol, acetylsalicylic acid or ibuprofen. This invention proposes to granulate the active ingredient (eg ibuprofen) with a granulation auxiliary (eg PVP), to mix this granulate with a part of a component of the effervescent mixture and then to mix this premix with an effervescent system. The procedure described is suitable for the preparation of clearly soluble effervescent preparations of paracetamol and aspirin, but not ibuprofen. According to this invention, it is not possible to prepare effervescent formulations containing 200 mg of ibuprofen which dissolve so rapidly and clearly in 100 to 200 ml of water from 15 to 25 ° C. that more than 95% of the active ingredient is dissolved after 2 minutes.

In the preparation of ibuprofen effervescent preparations by conventional methods, the principal difficulty is that at a pH of the final dissolved preparation of 6.8 (7.2), which is necessary to add 200 (400) mg of ibuprofen in solution halt the brewing reaction between the carbonate component and the acid component. If ibuprofen is used in the acid form, the dissolution rate is low, so that unresolved residues remain in the glass of water for a long time to come. The rate of dissolution can be increased if the sodium, potassium or ammonium salt of ibuprofen is used. However, it then comes by the direct contact of dissolved ibuprofen salt with the acid component of the effervescent mixture to precipitates, which go very slowly back into solution. There has now been found an effervescent preparation which eliminates all the aforementioned disadvantages and is suitable for the production of fast and clearly soluble ibuprofen effervescent preparations. The effervescent preparation according to the invention has the following composition:

a) Basic granules consisting of

1 part by weight of water-soluble ibuprofen salt,

2 to 10 parts by weight, preferably 4 to 7 parts by weight of carrier,

0.3 to 0.8 parts by weight, preferably 0.4 to 0.7 parts by weight of stabilizer and

0.2 to 1 part by weight, preferably 0.4 to 0.7 parts by weight of sodium or potassium carbonate.

b) acid component

1 to 4 parts by weight, preferably 1.5 to 2.5 parts by weight, based on 1 part by weight of water-soluble ibuprofen salt.

The water-soluble ibuprofen salts used are preferably sodium, potassium and ammonium salts of ibuprofen. Particularly preferred are the sodium and potassium salts of ibuprofen. Also suitable are water-soluble salts of ibuprofen with amino acids, such as. As arginine, lysine or ornithine or with others

pharmaceutically acceptable organic amino compounds such. N-methylglucosamine, piperazine, N- (2-hydroxyethyl) piperazine or tris (hydroxymethyl) aminomethane.

The water-soluble ibuprofen salts can Ibuprofen as a racemate (R (-] - form and S [+] - form) but also only in the form of

pure S (+) - enantiomers or only in the form of the pure R (-) - enantiomer.

The effervescent preparation according to the invention offers a solution to the problems mentioned. Surprisingly, it has been found that a clearly dissolving, clearly effervescent ibuprofen preparation can be ordered,

when ibuprofen is granulated in the form of its water-soluble salts, preferably sodium or potassium salts, together with the carrier and the stabilizer, and then the granules are sprayed with a 5-20%, preferably 15-18% solution of the carbonate and then dried , To this basic granules is added a suitable amount of

Acid component mixed. Particularly preferred for the preparation of the ibuprofen effervescent preparation is the sodium salt of ibuprofen. From the

inventive preparation, consisting of basic granules and acid component, powder, granules or

Tablets are made. Preference should be given to granules and tablets. According to the invention, the carrier may be a water-soluble, non-effervescent component, such as. Sucrose, lactose, Mannitol, monosodium citrate and trisodium citrate or a effervescent component such. B. sodium or Potassium bicarbonate, sodium carbonate or potassium carbonate or mixtures of these components. Preferably Sodium hydrogen carbonate used. In the invention, the importance of the stabilizer is to keep dissolved ibuprofen in solution and to precipitate it

prevent. For this purpose, water-soluble polymers such. As polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone

Polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, preferred Polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer and cellulose ether, are preferred Hydroxypropylmethylcellulose suitable. Polyvinylpyrrolidone is particularly preferably used as stabilizer. The acid components which can be used are the organic acids customary for effervescent formulations, such as, for example Citric acid, tartaric acid, succinic acid, maleic acid, malic acid, malonic acid, adipic acid, fumaric acid, ascorbic acid, Monosodium citrate, disodium citrate, potassium hydrogen tartrate or sodium hydrogen phosphate. Citric acid is preferred

or tartaric acid.

The effervescent preparation may contain further additives such as binders, eg. As glycine, sweeteners, z. B. saccharin or Cyclamate, flavoring agents, wetting agents, e.g. Dioctyl sodium sulfosuccinate or sodium lauryl sulfate and antifoaming agents, e.g. Contain silicone oil. For the production of effervescent tablets from the effervescent granules, the addition of a lubricant is necessary. If this lubricant is missing in the composition and the tabletting tools are exposed to powder constituents, they show

the resulting tablets have a rough, unsightly surface. The selection of a suitable one for effervescent tablets

Lubricant is generally found to be extremely difficult. Water-insoluble lubricants such. As magnesium stearate, stearic acid, talc, paraffin and hydrogenated castor oil cloud the

as a clearly desired solution. As more or less readily water-soluble, but usually not very effective lubricants come

Polyethylene glycol, fumaric acid, adipic acid, sodium benzoate and Natriumstearylfumarat in question. Polyethylene glycol has insufficient lubrication properties and prolongs the dissolution times of effervescent tablets

considerably. In addition, the substance reduces the internal strength of the tablets.

Fumaric acid and adipic acid must be added in a relatively high concentration (10 to 15%). They precipitate in ibuprofen · Effervescent tablets, due to their acid character, the active ingredient in its sparingly soluble acid form, which

unsightly opacities arise. At the same time, the two lubricants reduce the hardness of the tablets.

Sodium stearyl fumarate is only about 1% soluble in water. Therefore, for example, in a 3g heavy effervescent tablet

not more than 3% of this substance are used. In this amount, the effect as a lubricant is often insufficient.

Sodium benzoate must be declared as an effective adjuvant and is therefore not suitable.

It has been found that pharmaceutically acceptable salts of fumaric acid and adipic acid, such as the sodium, potassium, ammonium, calcium and magnesium salts, preferably the sodium or potassium salts, in a concentration of 3 to 10%, preferably 5 to 8% , based on the entire preparation, are particularly suitable as a lubricant for the preparation of ibuprofen effervescent tablets. These lubricants are generally admixed as fine powders having a particle size less than 50, preferably less than 20 microns of effervescent formulation consisting of basic granules and acid component. It is also possible to spray the lubricant from an aqueous solution onto the basic granules and then to mix in the acid component

 Disodium fumarate is particularly preferred as a lubricant

 The invention will be illustrated by the following examples.

example 1 An ibuprofen effervescent granule with which 200 mg ibuprofen is to be administered is composed as follows:

Ibuprofen Natnumsalz 221.3 mg polyvinylpyrrolidone 120.0 mg Natriu m hydrogenca rbonat 1 363.7 mg sodium 100.0 mg citric acid 395.0 mg

In the container of a fluidized bed granulator 136.37 kg of sodium bicarbonate are weighed. 22.13 kg of ibuprofen, sodium salt, 12.0 kg of polyvinylpyrrolidone and 80 kg of water are weighed into a stirred vessel and stirred until a clear solution is formed. The solution is sprayed onto the sodium bicarbonate at a hot air temperature of about 100 ^° C., resulting in a granulate. On top of this granulate is then sprayed a solution of 10 kg of sodium carbonate in 50 kg of water. As thus coated with a layer of sodium carbonate basic granules are then dried.

To the basic granules 39.5kg of citric acid are mixed to obtain the finished ibuprofen effervescent granules. The assembly can be done in aluminum bags in single quantities of 2.2g. The granules contained in a bag then dissolved in 100 ml of water after one minute gives a clear Ibuprofen solution with a pH of 6.7.

Example 2

It is prepared according to the preparation method as in Example 1, a basic granules having the following composition:

Ibuprofen sodium salt 22.13 mg Polyvinylpyrrolidone 8.00 mg Sodium hydrogencarbonate 135.00 mg Sodium carbonate 15.00 mg

180.13 kg of this granulate are sprayed with a solution of 15 kg of disodium fumarate in 100 kg of water in a fluidized bed apparatus and then dried. The pretreated granules are mixed with 54.87 kg of citric acid and then pressed into effervescent tablets with a single weight of 2.5 g. The tablets have a dissolution time of 2 minutes in 100 ml of water to give a clear solution with a pH of 6.8.

Claims (10)

1. ibuprofen effervescent preparation containing a) a basic granule consisting of 1 part by weight of water-soluble ibuprofen salt, 2 to 10 parts by weight of carrier, 0.3 to 0.8 parts by weight of stabilizer and 0.1 to 1 part by weight of sodium or potassium carbonate and b) 1 to 4 parts by weight of acid component. 2. ibuprofen effervescent preparation containing a) a basic granule consisting of 1 part by weight of water-soluble ibuprofen salt, 4 to 7 parts by weight of carrier, 0.4 to 0.7 parts by weight of stabilizer and 0.4 to 0.7 parts by weight of sodium or potassium carbonate and b) 1.5 to 2.5 parts by weight acid component. 3. ibuprofen effervescent preparation according to claim 1 or 2, characterized in that the water-soluble ibuprofen salt, the sodium, potassium or ammonium salt is used. 4. ibuprofen effervescent formulation according to claim 1 to 3, characterized in that a water-soluble polymer is used as a stabilizer. 5. ibuprofen effervescent preparation according to claim 1 to 4, characterized in that is used as a stabilizer polyvinylpyrrolidone. 6. ibuprofen effervescent formulation according to claim 1 to 5, characterized in that is used as the acid component citric or tartaric acid. 7. ibuprofen effervescent preparation according to claim 1 to 6 in the form of tablets or granules. 8. ibuprofen effervescent tablets according to claim 7, characterized in that they additionally contain a lubricating agent. 9. ibuprofen effervescent tablets according to claim 8, characterized in that are used as the lubricant sodium or potassium salts of fumaric or adipic acid. 10. A process for the preparation of ibuprofen effervescent formulations according to claim 1 to 6, characterized in that granulating the water-soluble ibuprofen salt together with the carrier and the stabilizer, the granules then sprayed with the sodium or potassium carbonate solution, dried, and to this basic granules, the acid component admixed.