Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-01-06
2001-01-09
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S489000, C514S784000, C514S951000
Reexamination Certificate
active
06171617
ABSTRACT:
The invention relates to the subject matter stated in the claims.
In particular, the invention relates to a new, clearly dissolving ibuprofen effervescent formulation and a process for the preparation of this formulation.
Ibuprofen or (±)2-(4-isobutylphenyl)-propionic acid has the following structural formula
and has been for years a proven, non-steroidal antiphlogistic from the group of phenylpropionic acid derivatives, which shows effectiveness in veterinary experimental inflammation models by inhibiting prostaglandin synthesis. In human therapy, ibuprofen reduces pain caused by inflammation, swellings and fever. It shows the undesired side-effects typical for non-steroidal antirheumatics.
The pharmacokinetic properties of the substance are well-studied. Several clinical studies have also indicated that the start and the intensity of the analgetic effects correlate to the plasma-ibuprofen-concentration. In the case of ibuprofen, Laska et al. have shown that particularly in the first two hours after application, an increased plasma-ibuprofen level results in an increased analgetic effect. Another study has shown that soluble ibuprofen starts to relieve pain earlier than ibuprofen tablets. In the case of ibuprofen, it is also evident that the galenic formulation exerts a great influence on the adsorption rate and on the start of the analgetic effect. Several studies have also shown that effective ibuprofen-plasma levels appear significantly earlier with ibuprofen-lysinate compared to ibuprofen acid (G. Geisslinger et al. in Drug Invest. 5 (4), 238-242 (1994).
As can be seen from the above structural formula, ibuprofen has an asymmetrical carbon atom and is present as the racemate in the therapeutically used form. As is known for several drug agents having one or more asymmetrical carbon atoms, one of the enantiomeric forms is often far more effective than the other. It is known that R-(−)ibuprofen is essentially less pharmacologically active than S-(+)ibuprofen. It was established, however, that the S(+)-form of ibuprofen has an essentially greater pharmacologic potential in the absence of the R(−)-form as had been hypothesized (cf. DE-OS 36 39 038).
However, drugs for pain-relief should have reasonable prices. At the moment, there is the situation that water soluble salts such as ibuprofen-lysinate and ibuprofen-sodium are far more expensive than ibuprofen acid itself and other widely used analgetics such as aspirin and paracetamol.
Thus, great efforts have been made to formulate ibuprofen galenically in such a way that the cheap ibuprofen acid dissolves rapidly and completely. However, these efforts have ended in failure until now. Ibuprofen is an organic acid having a poor solubility. Only just at a pH-value of about 7 does the acid form a salt whereby the solubility is increased significantly (pK-value of ibuprofen acid: 4.5). Because of the immense circulation of ibuprofen it would be substantially helpful if ibuprofen acid could be made to dissolve more rapidly and less pH-dependently by the skillful choice of adjuvants and without complicating the preparation of the drugs. This becomes more important since ibuprofen has a low melting point and can only be processed with difficulty.
The taste of ibuprofen acid is bad and remains for a long period of time in the mucous membranes which are irritated by the active ingredient. Therefore, all solid forms of ibuprofen have to be processed into film tablets or in several cases even into dragees in order to avoid the bad taste during swallowing. Of course, this leads to a further extension of the disintegration and dissolution of the active ingredient.
EP-A-0 228 164 (Boots) describes an ibuprofen effervescent formulation giving rise to a suspension of ibuprofen after decrease of the effervescent reaction. The resulting suspension contains the active ingredient in form of fine particles which stick partially on the mucous membrane of the oral cavity after drinking and lead to burning and local irritations after swallowing of the solution.
DE-A-36 38 414 discloses the addition of arginine or lysine in an amount exceeding the molar level to obtain a soluble form of ibuprofen. The addition of these amino-acid-components causes great disadvantages. Arginine and lysine are very expensive for use as a pharmaceutical adjuvant and exceed by far the costs of the active ingredient ibuprofen itself. The effervescent part contains sodium hydrogen tartrate as an acid component. Sodium hydrogen tartrate exerts such a poor acidic effect that the intensity of the effervescent reaction at a pH-value at above 6.5 for the complete system is low. Therefore, the typical appropriate effervescent effect expected by the patient is not achieved.
EP-A-203 768 discloses an effervescent composition, which can contain paracetamol, acetylsalicyl acid or ibuprofen. It is therein proposed to granulate the active ingredient with an adjuvant for granulation (e.g. PVP) wherein the granules are mixed together with a part of a component of the effervescent mixture, then mixing this pre-mixture together with an effervescent system. The described procedure is suitable for the preparation of clearly soluble effervescent formulations of paracetamol and aspirin, however, not ibuprofen. According to this procedure, 200 mg ibuprofen containing effervescent formulations which dissolve in 150 ml water at about 20° C. within 2 minutes to give more than 90% dissolved ibuprofen cannot be prepared. In order to achieve this in general, the ibuprofen would have had to have been granulated together with basic adjuvants. Otherwise the ibuprofen is dispersed undissolved in the effervescent tablet solution, but which is, however, not desired.
EP-B-0 351 353 discloses ibuprofen effervescent tablets wherein the active ingredient is prepared in combination with sodium hydrogen carbonate and citric acid. Sodium hydrogen carbonate is used excessively to increase the solubility of ibuprofen. There are great doubts as to whether effervescent solutions are formed by this simple composition in which the active ingredient is completely dissolved within the usual time of a few minutes. All practical experiences have shown that dissolved ibuprofen in the form of its salt is again precipitated by the relative strong citric acid. The precipitated ibuprofen rises to the water surface in the form of small oil droplets, gathers together and crystallizes gradually in form of coarse crystals which redissolve again very slowly. The process described in EP-A-0 351 353 has been well-known for years. Acetylsalicylic acid, for example, is prepared as effervescent tablets by adding sodium hydrogen carbonate to the effervescent composition in order to enhance the dissolution of the organic ASS-acid.
EP-A-369 228 (Bayer) discloses an ibuprofen effervescent preparation with the following composition:
1 part by weight of a water soluble ibuprofen salt,
2-10 parts by weight of a excipient,
0.3-0.8 parts of weight of a stabilizer,
0.1-1 parts by weight of sodium carbonate or potassium carbonate.
The Bayer process for the preparation of the aforementioned preparation is extremely expensive since the water soluble ibuprofen salt has to be first of all processed into a clear solution by PVP and a great amount of water. This clear solution is sprayed onto sodium hydrogen carbonate in a fluidized bed granulator. These granules are then sprayed with sodium carbonate, which is dissolved again in a great amount of water. When these granules are processed into effervescent tablets, they should be sprayed once more with an aqueous disodium fumarate solution according to EP-A-0 369 228. These steps are very expensive and require spraying at high temperatures lasting for hours. Sodium carbonate, dissolved in water, tends to hardly release water at all as a result of hydrate formation. Therefore, the drying process requires a long period of time and high temperatures. With this preparation process one cannot rule out that yellow coloured granules are obtained. Concerning the amounts of water requ
Losan Pharma GmbH
Spear James M.
Standley & Gilcrest LLP
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