1. Field of the Invention
The present invention concerns an innovative pharmaceutical form for controlled drug release. In particular, it refers to systems obtained by the assembly of individual release modules, of which the capacity to release the drug in time and in space depends on the way in which the modules have been assembled. The modular structure offers high reproducibility of manufacture and flexibility of release.
2. The Prior Art
The pharmaceutical industry views with great interest the new forms of administration, which are able to release the drug in a pre-programmed way. This technology is known as controlled drug release and it has provided numerous innovative products for the industry and the market. Despite the solutions proposed for the various problems of administration, the variety of the existing drugs and their different requirements continuously create the need for new forms of administration. It is therefore of great interest to be able to find a drug release system that can be adapted to different active principles, changing its characteristics by simple modifications in manufacture.
The number of drugs that have to overcome important problems of administration in order to become products is increasing constantly. It is reasonable to imagine that the near future of pharmacological therapy belongs to the drugs of biotechnological origin which, on account of their chemical structure, present important problems of administration. Nor must one forget the economic and medical value linked to the revaluation of the old molecules, which in innovative forms of administration often find new therapeutic applications. Lastly it is now a common practice to propose the new drugs in the opportune release package, delivering the same through the most suitable pharmaceutical form.
As a result of this scenario, there are various problems to be dealt with concerning drug release control in time and in space. A high number of formula would therefore be necessary, in particular for products intended for administration by mouth, which are the majority of the forms of dosing used in pharmacotherapy, since they are well accepted by patients.
Many of these oral pharmaceutical forms with controlled release have however demonstrated low bioavailability in studies in vivo. This has often been attributed to an unsuitable release speed, to the incomplete liberation of the active principle by the form itself, or to a too short period of permanence in the gastroenteric tract in which absorption takes place.
The patent literature is full of inventions which attempt to solve these problems in an innovative manner.
However, a characteristic shared by all these solutions of the prior art is that a determined drug release curve is obtained with a specific therapeutic formula characterized by a weighted quantity of excipients which are mixed with (or added to) the active principle in such a way as to influence its release. Consequently a modification, even only a marginal one, of the release characteristics generally requires reformulation of the product. For example, in the ambit of coated tablets, a modification of the thickness of the outer layer is necessary, or a modification of the layer's composition, if the speed of release is to be modified. Consequently, the formulae known in the prior art do not allow an adaptation of their release curve to certain requirements without the simultaneous modification of their composition. This general principle also applies in cases where the modification of the release characteristic does not occur by modifying the excipients contained in the formula, but, instead, by choosing determined polymorphs or suitable granule sizes of the active principle.
These products generally come up against a precise problem of controlled release which is overcome with specific means for the environment in which release must occur. For example, in the documentation collected according to the International Patent Classification (IPC), in particular in the groups PCT A61K 9/00, 9/20, it is possible to find quoted numerous patents dedicated to the problem of release with space control, by means of gastro-retentive formulae.
This case deals with the necessity of having a release system, for oral drug administration, that is able to delay the gastrointestinal transit, for example by prolonging the time of permanence in the stomach. To achieve the aim of delayed transit in the digestive tract, various technological solutions have been proposed.
For example, the adhesive properties of certain polymers have been used in order to interact with the gastric and intestinal epithelium. This has allowed the construction of so-called bioadhesive systems. However, these involve certain problems, due in particular to the too localized release of the drug, with possible irritations of the mucosa.
Another solution has concentrated on the planning of systems that are able to float on the gastric content, remaining longer in the stomach. Systems of this type have been formulated with polymers that are able to swell, forming a stable gel in contact with the gastric fluid. The drug is released from these systems by diffusion through the barrier of gelled polymer. These systems therefore present an overlapping between the release of the drug and the mechanism which determines floating.
Other solutions have led to “double layer” systems, in which one layer, containing a hydrophilic polymer and an effervescent mixture, is intended to give floatability to the system, while the other layer is composed of the active principle incorporated in a hydrophilic matrix to prolong its release. This solution, instead, presents the limitation that the floating layer is activated slowly and develops a weak buoyancy. Two objects therefore do not appear to have been solved in the development of these floating systems: the first is the possibility of lifting a high quantity of substance, the second is the object of making the time of immersion necessary to obtain floating as short as possible.
The control of gastrointestinal transit is however only part of the characteristics which a versatile and innovative controlled drug release system ought to possess. In fact most of the systems are made to control the drug release speed, irrespective of the area in which it occurs. In this case too, the patent literature is rich in examples. Among these, one example is illustrated in U.S. Pat. No. 5,534,263.
So, from what has been seen above, there is still a necessity for systems which, my means of simple and reproducible manufacture, allow a variation of drug release in different areas of the gastroenteric tract, with easily modifiable kinetics. Preferably, these kinetics should be modifiable without varying the composition of the systems. There is also the necessity to have a system that is able to satisfy the requirements of release in a certain area of the gastrointestinal tract, controlling the kinetics with which said release occurs, so as to have a constant or pulsating release, adapted to the type of drug carried and to the therapy that is to be provided.
It is therefore an aim of the present invention to overcome the disadvantages of the prior art and to provide systems for the controlled release of an active principle which are more versatile than the currently known forms of administration and which allow the modification not only of the site but also of the kinetics of release of the active principle in the gastrointestinal tract without requiring important contrivances during their manufacture. Preferably, these systems for the controlled release of an active principle should be adaptable to the site and to the release kinetics desired in the gastrointestinal tract without any modification of their composition.
USPTO Backgrounds
USPTO Backgrounds