Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-01-14
2001-06-26
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06251945
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical mixture comprising a combination of a profen and other active compounds.
In the development of pharmaceutical forms, in particular in the case of profen-containing active compound combinations, the object is generally to find an optimum between 3 opposing objectives:
1. Both from the point of view of the pharmaceutical manufacturer and of the patient, it should be possible to prepare a pharmaceutical form as economically as possible. In the case of tablets, this means that with a fixed dose of active compound which is prespecified out of therapeutic necessity, the amount of the other auxiliaries which are added to the tablets should be kept as low as possible. The lower the amount of auxiliaries, the lower the production costs, which can likewise have an effect on the sale price. The production of tablets should also be as simple as possible and only comprise a few working steps in order likewise to be able to save costs in this way.
2. A tablet should optimally make available the active compound contained therein to the patient. This means an instant-release tablet should disintegrate very rapidly in the digestive fluids and rapidly release the active compound.
3. In order that it is easy to swallow, the tablet should have as small a form as possible (this applies particularly to high-dose active compounds). Small pharmaceutical forms are better accepted by patients and markedly increase so-called patient compliance.
It is almost impossible to fulfill these 3 requirements at the same time. When processing active compounds which are not extremely highly soluble, rapid release of an active compound from a tablet is achieved only by the addition of relatively large amounts of solubilizing auxiliaries and relatively large amounts of substances which bring about rapid disintegration and thus also rapid dissolution of the tablets. If the active compound can moreover only be tableted with difficulty, the production of a tablet is only possible using additional auxiliaries which compensate for the disadvantages of the poor tabletability. Moreover, in the production of ready-to-press tableting materials, in very many cases a laborious granulation step is also necessary beforehand. It is therefore usually impossible to develop a small and economical form.
All these disadvantages apply in particular to combinations of profens and other pharmaceuticals.
A further disadvantageous aspect of the profen monopreparations is that the profens contained therein do not dissolve well. Problems can therefore occur with respect to bioavailability. Therefore, for ibuprofen US Pharmacopeia USP XXIII, for example, requires a profen dissolution rate of at least 80% of the active compound after 60 minutes in order to ensures good bioavailability.
The profen ibuprofen, for example, further shows very poor tableting behavior. The added auxiliaries must therefore at the same time also compensate for this disadvantage. A check of most tablets available on the market which only contain ibuprofen shows that the amount of active compound in the total weight of the tablets as a rule is only 55-65%.
It is further common to all these tablets that, for the preparation of the compressable tableting material, a conventional granulation or compaction must be added, since otherwise adequate solidity cannot be achieved during tableting. Granulation, however, is expensive and time-consuming.
A further criterion of the quality of profen-containing tablets is the release of the active compound in vitro. Thus, according to Sucker, Fuchs and Speiser in: Pharmazeutische Technologie [Pharmaceutical Technology], Georg Thieme Verlag Stuttgart, 1978, page 283, the dissolution rate of poorly soluble substances can be increased in many cases by the addition of solubilizers. However, if it is attempted to increase the dissolution rate, for example, of ibuprofen by the addition of a solubilizer of the polyethylene glycol type, only minor success is achieved. The same applies if the solubilizer is replaced by a ionic surfactant such as sodium dodecylsulfate.
These abovementioned stipulations are additionally made difficult if profens are combined with one or other active compounds, which very often occurs in pharmaceutical practice. In this case, to the poor pharmaceutical processing properties of profens are added those of other active compounds.
Thus, for example, the combination of 200 mg of ibuprofen with 60 mg of pseudoephedrine hydrochloride, a nasal decongestant, has the problem that both active compounds are poorly tabletable. The poor tabletability of pseudoephedrine hydrochloride can be confirmed in that, with this active compound, the tablet in the so-called direct tableting process can only be prepared with up to at most 35% contents by weight of pseudoephedrine hydrochloride. If, in the case of pseudoephedrine hydrochloride, concentrations higher than 35% are desired, a more complicated and more expensive granulation step has to be performed before the tableting. Thus, the concentration of the two active compounds in a tablet can only be increased to 68% by a complicated granulation of ibuprofen and pseudoephedrine hydrochloride with further pharmaceutical auxiliaries, as demonstrated in Comparison Example 5. In this case, however, the release of ibuprofen is considerably worsened.
Some combination preparations of profens, in particular of ibuprofen, with other active compounds are already on the market, i.e. with pseudoephedrine hydrochloride, caffeine and, recently, a combination of 200 mg of ibuprofen and 7.5 mg of hydrocodone bitartrate. The tablet weight of this combination is 400 mg.
All these combination preparations have an active compound content, based on the tablet weight, of approximately 50-60%. This means that the tablets are all very large and are difficult to swallow.
BRIEF SUMMARY OF THE INVENTION
Surprisingly it has now been found that profens in combination with additional active compounds which can have a very high content in the total weight, can be processed very simply to give tablets which meet the very high pharmaceutical demands. These tablets are small and easy to swallow and exhibit a very rapid onset of action.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to a pharmaceutical mixture containing a profen and one or more other active compounds, which has a total active compound content of over 85%, preferably over 90%, and contains up to 1% of a nonionic surfactant having an HLB of ≧9 and a customary disintegrant and a lubricant and, if appropriate, celluloses and/or hydroxyalkylcelluloses.
HLB is understood as meaning the “hydrophiliclipophilic balance”, cf. Sucker, Fuchs and Speiser in: Pharmazeutische Technologie [Pharmaceutical Techology], Georg Thieme Verlag Stuttgart, 1978, page 305. The HLB in the mixture according to the invention is ≧9, preferably ≧11 and in particular ≧12.
The details in percent (%) relate to percentage by weight everywhere in the application.
The designation “Trofen” means antiinflammatory substances containing the structural element
in which the dashed lines represent free valences.
Examples of such compounds are preferably ibuprofen and its optically active S form. Further suitable profens are flunoxaprofen, flurbiprofen, ibufenac, ibuproxam, ketoprofen and loxoprofen. The compounds can optionally be present in the form of their physiologically tolerable salts. These are to be understood as meaning the alkali metal and alkaline earth metal salts and salts with amino acids such as lysine. Preferred salts are the sodium salt and the lysinate.
Other active compounds in the mixture which may be mentioned by way of example are pseudoephedrine, ephedrine, phenylpropanolamine, tripolidine, acetylcystire, ambroxol, azelaic acid, dihydrocodeine, hydrocodone and caffeine.
The amount of other active compound in the mixture is in the range from approximately 0.5 to 70% of the amount of profen. It is dependent on the strength of the active compound to whi
Eason Raymond
Einig Heinz
Hach Harald
Muller Bernd W.
Thompson Richard C.
Jones Dwayne C.
Keil & Weinkauf
Knoll Aktiengesellschaft
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