Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-07-06
2001-08-07
Dees, Jose'G (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S400000, C424S470000
Reexamination Certificate
active
06270798
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a pharmaceutical lozenge for the modified release of active compounds in the gastrointestinal tract, with active-compound-containing particles which have a first coating controlling the release and a further, outer coating with saliva-resistant properties.
2. Description of the Prior Art
Orally administrable presentation forms having modified active compound release can serve various therapeutic aims. The most frequent aims are the protection of the gastric mucosa from a harmful active compound or the protection of the active compound from the acidic medium in the stomach on the one hand, which is brought about by enteric coatings; moreover the control of the release rate over a relatively long time, which can be achieved by various release-delaying measures and leads to plasma levels with relatively low variations, a better tolerability as a result and a longer efficacy of the administration.
A formulation with modified active-compound release cannot be equally easily developed in the case of all pharmacologically suitable active substances. As a rule, it necessitates a number of additives with the aid of which the desired effects can be achieved. These additives correspondingly clearly increase the mass of the presentation form. In presentation forms with prolonged release of active compound, the dose to be administered is additionally increased compared to a simple presentation form. In the case of various active compounds, on account of their dose, no presentation forms having prolonged release of active compound could be developed using the possibilities known until now, since they could not be swallowed in the form of a capsule or tablet because of the resulting dimensions. Thus various antibiotics, for example, must still be orally administered three to four times daily although it is known that in the case of administration more than twice daily the reliability of taking by patients is low. In the case of antibiotics, the non-delayed-release single dose is frequently already 500 to 1000 mg, which together with the auxiliaries necessary for pharmaceutical formulation leads to capsules or tablets which can only be swallowed with difficulty. A delayed-release preparation prepared on the basis of conventional techniques with more than 1000 mg of active compound and an increased content of auxiliaries can virtually no longer be swallowed.
The provision of a presentation form which is easy and pleasant to take with modified release of active compound, which is also suitable for active compounds which have to be taken in high single doses, is desirable.
According to the invention, the problem of the taking of high doses should first of all be solved by administering a multiparticulate active compound preparation which is compressed to give a lozenge, whose particles are individually coated to achieve a modified release. The coated particles are released in finely divided form on sucking the tablet in the mouth and can be easily swallowed with the saliva.
The presentation form of the lozenge has been known for a long time and is frequently used in order to deliver active compounds to the diseased oral and pharyngeal mucosa. The lozenge can also be suitable for systemically active substances if the substances have a pleasant taste and are to be absorbed without delay. For the solution of the problem, the presentation form of the lozenge is employed, since it is able to accommodate more active-compound and auxiliary mass without loss of its administrability than a tablet intended for swallowing. Lozenges having a mass of more than 4 g are on the market and are apparently accepted by patients without problem.
In principle, the prior art allows the compression of coated particles having modified release of active compound, although the intended use according to the invention with its advantages—administration as a lozenge with suitability even for high doses of active compound—was neither recognized nor described as a solution of the problem presented above.
Thus the Patent Applications EP 153 104 and EP 355 247 teach, for example, the compression of release-delaying coated particles containing active compound to give tablets, a process which is also described in other sources. Moreover, the Patent Specification U.S. Pat. No. 5,464,632 discloses a rapidly disintegrating tablet intended for sucking or for disintegration in the mouth, which contains the active compound optionally in the form of coated particles for modified release. However, with this tablet in the case of disintegration in the mouth it is to be expected that portions of the active compound have already been released through the coating of the particles into the oral cavity and in the course of this leaves behind an adverse taste impression.
Analogously, the presentation form of the lozenge, as is claimed in the present invention, does also solve, on the one hand, the problem of the administrability of relatively large amounts of active compound and auxiliaries, but on the other hand creates new problems. For one thing, in the case of enteric-coated particles the coatings are exposed to the pH-neutral saliva, as a result of which they prematurely disintegrate and can no longer achieve the desired protective effect in the stomach. For another thing, in the case of particles which are provided with release-delaying coatings, portions of the active compound have already been released in the oral cavity by diffusion, which is not acceptable, in particular in the case of unpleasantly tasting substances.
SUMMARY OF THE INVENTION
A need therefore exists for a further improved presentation form having modified release of active compound for administration of high doses of active compound, which does not have the disadvantages mentioned. This object, on which the invention is based, is achieved by a pharmaceutical-presentation form according to one of the two main claims: in addition to the special design as a lozenge, the tablet according to the invention overcomes the disadvantages of the prior art in that its active compound is present in the form of doubly or two-layer coated particles, a first, inner coating serving for the release of the modified active compound, while a further, external coating is saliva-resistant, but dissolves in the acidic medium of the stomach and thereby ensures that during the sucking of the tablet active compound is not released into the oral cavity. The first, inner coating of the particles can modify the release of active compound according to one of the two main claims either in that the release commences only after the gastric passage of the particle, or it can be designed as a membrane which is insoluble in the gastric and intestinal juice, but through which the active compound can slowly diffuse outwards and be released with a delay.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
According to the invention, the active-compound-containing particles are pressed together with suitable auxiliaries to give lozenges which, owing to their composition, slowly erode in the mouth and in the course of this release the particles into the saliva. The saliva containing the coated particles is then swallowed. Self-experiments showed that particles of up to approximately 100-200 &mgr;m in diameter are perceived to be only moderately troublesome on swallowing.
Film-forming polymers which can be employed for the production of a saliva-resistant coating are known to the person skilled in the art. Frequently, a copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters having the trade name Eudragit E (Röhm) is employed for this purpose. The basic character of the dimethylaminoethyl methacrylate provides for solubility in the acidic medium, such as, for example, in the gastric juice, while the solubility in the relatively neutral saliva is rather low. If the thickness of the film is suitable, a coating can therefore be produced using this copolymer which resists disintegration in the saliva for a longer tim
Dees Jose'G
George Konata M
Hochberg D. Peter
Holt William H.
LTS Lohmann Therapie-Systeme AG
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