Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-06-14
2004-04-27
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S489000, C514S570000
Reexamination Certificate
active
06726929
ABSTRACT:
The present invention relates to a novel pharmaceutical mixture comprising a profen.
In the development of pharmaceutical forms, in particular in the case of profens, 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 take, 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 fulfil 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 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 are present in the case of the profens. Thus the active compound ibuprofen, for example, is administered in high doses. The dose which is usually not subject to prescription is 200 mg, and in some countries recently 400 mg. For treatment of rheumatic disorders, even pharmaceutical forms having a dose of 600 mg or 800 mg are approved by the pharmaceutical authorities in very many countries.
A further disadvantageous aspect of the profens is that they do not dissolve well. Problems can therefore occur with respect to bioavailability. Therefore for ibuprofen US Pharmacopeia USP XXIII, for example, requires a dissolution rate of at least 80% of the active compound after 60 minutes. In order to achieve a rapid dissolution rate, large amounts of the auxiliaries described above must be added to the ibuprofen in order thus to attain the required high extent of release.
Ibuprofen further shows very poor tableting behavior. The added auxiliaries must therefore at the same time also compensate for this disadvantage. A check of most ibuprofen tablets available on the market 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 pressable 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 stabilizer is replaced by a surfactant such as sodium dodecylsulfate.
No tablets are known on the market which contain a high amount of ibuprofen. Although a few ibuprofen-containing tablets having a high active compound content are already known from the literature, these, however, are not available on the market. Thus in EP 0 607 467 A1 pellets are described which have an active compound content of over 90% and which release the active compound (measured according to USP XXII) after 50 minutes only to 15-28%.
In EP 0 456 720 B1 granules are described which have an ibuprofen content of over 90%. The granules were prepared using PVP. Formulations containing PVP, however, exhibit considerable stability problems. Thus the release of active compound from PVP-containing granules is only 20-30% of the original value even 3 months after preparation.
In WO/8902266, a process is described in which, with the aid of an aqueous granulating process in a fluidized bed granulator, granules are prepared which can be pressed directly to give tablets without further additives, but which can only contain up to 85% of ibuprofen. The process is involved and, like all fluidized bed granulating processes, laborious and expensive. Moreover, PVP is employed for binding the granules, which leads to stability problems as mentioned above.
A. Sakr et al. [Pharm. Ind. 60, No. 3 (1998) 257-262] describe an ibuprofen tablet which contains 95% ibuprofen and was prepared by roller compaction. This process, particularly when it is carried out on the plant scale, is very laborious and poorly reproducible. Moreover, these tablets again contain the incompatible PVP. These tablets also do not meet the requirement for a rapid onset of action, as is desired in the case of a painkiller.
Moreover, it is common to all these tablets that, for the preparation of the pressable tableting material, a conventional moist granulation or compaction must again be added as already mentioned above or that PVP must be employed, which admittedly has good binding ability, but does not guarantee stability.
Surprisingly, it has now been found that a specific mixture having a high profen content can be processed very simply to give tablets which meet the highest pharmaceutical demands. In the case of an analgesic this means: small and easy-to-swallow tablets, very rapid onset of action and rapid elimination of the pain. Both are very highly desirable from the point of view of the patient.
The invention relates to a profen-containing pharmaceutical mixture, which has a profen 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 also a lubricant and, if appropriate, celluloses and/or hydroxyalkylcelluloses.
HLB is understood as meaning the “hydrophilic-lipophilic balance”, cf. Sucker, Fuchs and Speiser in: Pharmazeutische Technologie [Pharmaceutical Technology], 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 “profen” means antiinflammatory substances containing the structural element
wherein the dotted lines are free bonds.
Examples of such compounds are preferably ibuprofen and its optically active S form. Further suitable profens are flunoxa-profen, flurbiprofen, ibufenac, ibuproxam, ketoprofen and loxo-rofen. 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 also salts with amino acids such as lysine. Preferred are the sodium salt
Eason Raymond
Einig Heinz
Hach Harald
Müller Bernd W.
Thompson Richard C.
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