Double phase time-controlled release system سیستم آزادسازی با کنترل زمان دو فاز

The invention relates to a delivery system for active ingredients which comprises a swellable phase defining at least one void. In this void an active ingredient may be present. The active ingredient may be substantially enclosed by the swellable phase, optionally with a degradable layer present between the gel phase and the active ingredient. The invention further relates to a method for providing such delivery systems, a method for non-medical administration of active ingredients, as well as to the use of a swellable phase in controlled release systems.

Through recent advances in biotechnology, therapeutic compounds based on protein, peptide and nucleotide sequences structures have become readily available in reasonable quantities and prices. Disadvantages that these compounds share is their instability against acidic, alkaline and/or enzymatic degradation upon systemic uptake and additionally their poor intestinal absorption due to their high hydrophilicity. Therefore, these compounds are almost exclusively administered by parenteral injection, which has the disadvantages of painful application, risk of infections, low patient compliance and the need of trained personnel.

Usually, peroral application is the easiest and most preferred way of drug administration. For most drugs or other active ingredients of high molecular weight, however, systemic absorption is hindered by low intestinal epithelial permeability and by enzymatic degradation. An ideal delivery system for these drugs would enhance epithelial permeability and/or restrict enzymatic or other chemical activity at a pH value where these hydrophilic compounds are the most stable.

Attempts employing mucoadhesive polymers have been rather successful in vitro and in vivo (see for example: H.L. Lueßen et al.; Pharm. Res. 1995, 12: 1293-1298; H.L. Lueßen et al.; Pharm. Res. 1996, 13:1668-1672). However, the turn-over of intestinal mucus covering the epithelium led to a rapid delocalization of the polymeric delivery system (C.-M. Lehr et al.; Int. J. Pharm. 1991, 70:235-240). It would thus be desirable to have a system that is retained in the lumen such as at specific sites in the gut, e.g., by controlled swelling over a predetermined and extended period of time. Such systems would have distinct advantages over delivery systems for active ingredients, such as drugs, known so far.

One objective of the present invention is to obtain such a delivery system; that is a delivery system that keeps the dosage form mechanically fixed at the site of action.

Another objective is to get an appropriate time-controlled drug release profile with a suitable lag time, which is necessary for absorption of certain compounds such as peptide drugs.

In Figure 1-A a release profile of a conventional drug release system is shown schematically. This profile is characterized by the immediate start of release (at time = 0) once the system is applied and comes into contact with the gastro-intestinal fluids.

However, in some cases, e.g. with peptide drugs, a suitable lag time is mandatory to inactivate enzyme activities and to open tight junctions. Thereafter, a burst release is necessary in which substantially the whole amount of drug can be released in a very short period of time, for example in order to achieve optimal bio-availability of the active ingredients, e.g. peptide drugs. This profile is depicted in Figure 1-B and is referred to as a "time-controlled release profile". It is another objective of the present invention to obtain a system that enables this type of release profile.

It has now been found that the above mentioned objectives can be met by a delivery system comprising a swellable phase, such as a superporous hydrogel (SPH) phase and/or a swellable superporous hydrogel composite (SPHC) phase, defining at least one void suitable to contain an active ingredient. Preferably, the dimensions of the delivery system and the chemical composition of the phases it comprises are chosen such that application of the system in a lumen results in swelling of the phase(s), which results in mechanical fixing of the system at a predetermined site in the lumen, such as of the gut.

Instead of SPH and/or SPHC other polymers can be used in the delivery system of the present invention, provided these polymers have similar swelling characteristics and have other properties that are also comparable to SPH(C).