FIELD OF INVENTION

The present invention relates to peristaltic movement simulating stirring device for dissolution testing and relates to the field of dissolution testing and particular to dissolution testing device which simulates the movement in gastro-intestinal (GI) tract.

BACKGROUND OF THE INVENTION

Dissolution testing is frequently used for the evaluation of drug delivery systems, especially orally administered delivery systems, to predict the absorption profiles after oral application. This is reasonable for drugs with good permeability which are not the subject of other presystemic processes. Different apparatus and methods are used for dissolution testing, most frequently those included in different pharmacopeias. Apparatus 1 and 2 according to US Pharmacopeia are apparatus with basket and paddle stirring element, respectively, where dissolution is performed in thermostated vessel, usually with volume of 1 liter. Apparatus 3 is apparatus with reciprocating cylinders and Apparatus 4 is flow through apparatus using cells with different volumes and different flows of media. The mechanical forces which influence the dosage form are different in these apparatus; most frequently the dosage form is exposed to the flow of liquid and is not in direct contact with stirring device. Additionally, some improvements of these apparatus especially regarding the mode of stirring were described in patent application Qureshi: WO 03/026784 Al. Apart pharmacopeial apparatus and their modifications the use of other apparatus is also described, like complex, multicompartmental in vitro system in United States Patent No. 5525305, which is able to simulate well many conditions in GI tract and some other more simple apparatus represented in scientific literature. However, the mechanical forces to which the dosage form is exposed in GI tract are very difficult to simulate and all mentioned in vitro models simulate them only to a limited degree.

After administration dosage form is exposed to media in GI tract, it might float in these media, but it is most frequently in direct contact with GI mucosae. That means that the dosage form is exposed to forces due to the peristaltic movement of the musculature of GI tract. Thus, the apparatus / device, more precisely the mode of stirring which would consider and simulate the mechanical contact of the dosage form with mucosa and would be able to imitate also the movement of the musculature in GI tract is highly desirable. Additionally, this device should be simple enough to be used in any laboratory.

SUMMARY OF THE INVENTION

The main purpose of the present invention is to provide a dissolution stirring device which simultaneously enables gentle mechanical contact of solid dosage form with grounding and its peristaltic movement due to the movement of the grounding. This device can be used in any suitable flow - through or other system which uses magnetic or other stirrer for stirring the medium. Peristaltic movement of the grounding is achieved by a suitable amount of small inert beads which are settled at the bottom of the vessel and stirred by a stirrer in a suitable medium. Solid dosage form is put in the medium on the surface of the beads' layer. It moves around the vessel due to the stirring and additionally it moves up and down due to the movement of the beads' layer thus simulating peristaltic movement.

BRIEF DESCRIPTION OF THE DRAWINGS

The features and advantages of the present invention will become more fully apparent from the following detailed description and the accompanying drawings, in which:

FIG. 1 shows a front view of the vessel with stirrer bar and beads when no stirring is applied. FIG. 2 shows a front view of the vessel with stirrer bar and beads during stirring. FIG. 3, FIG. 4 and FIG. 5 show front views of the vessel, stirrer bar, beads, medium and solid dosage form i.e. tablet during stirring at three different successive positions of the stirrer bar. FIG. 6 shows the dissolution profile obtained using the device described herein as a part of flow-through system in comparison with dissolution profile obtained on USP apparatus 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention represents the device which simulates movements in gastro-intestinal tract to which the dosage form is exposed after oral application. The scheme of the device is shown in Figures 1 - 5.

The present invention comprises a thermostated round bottom vessel 1 with a stirrer as shown in Figure 1. Stirring is performed by a cylindrical stirrer bar 2 as seen on Figure 1. The length of the stirrer bar is allowed to be maximally 8-10 millimeters shorter than the inner diameter of the vessel. At the bottom of the vessel there is a suitable quantity of small beads 3 which are mechanically pushed by stirrer bar 2 and thus provide peristaltic movement during stirring in a suitable medium 4. Most usual stirrer device is magnetic stirrer; with this particular case, stirrer bar is a magnetic bar, driven by another magnet under the bottom of the vessel 1. According to the invention, any stirring device comprising a bar being driven magnetically or in any other way may be used.

The quantity, i.e. bulk volume of the beads 3 in the vessel 1 with inner bottom diameter 58 mm is 1O mL - 7O mL.

When a smaller or a larger vessel 1 is used, which means that the diameter i.e. surface of the bottom of the vessel 1 is smaller or larger than the mentioned one, equivalently smaller or larger quantity of beads 3 has to be used. Generally: the preferred quantity of the beads 3 used is to achieve the minimum amount which covers the bottom of the vessel 1 in one layer to maximum amount which represents the height of about 400% of the stirring bar 2 diameter, i.e. the height of the bar 2 in the working position.

The size of beads 3 has to be suitable to enable their homogeneous movement with stirring bar 2. The most suitable bead's 3 diameter is 0.2 - 2 mm. The beads 3 have to be of spherical shape and made of glass or other inert material which does not react with the vessel 1 or with any substance in the vessel 1, which does not release any substances or particles and prevents the adsorption of drug substance on the surface of the beads 3. Additionally, beads 3 must not adhere on the surface of the dosage form. Typical materials from which the beads 3 are made include - but are not limited to - glass, polytetrafluoroethylene (PTFE, Teflon ) or any other inert material. The beads 3 must have suitable density to settle on the bottom of the vessel 1, to avoid their floating and to enable magnetic bar 2 to push them. Preferred density of beads 3 is from 1.1 to 5 g/cm ³ . Stirring rates 5 - 150 rpm might be used. The volume of the medium 4 depends on the simulated conditions, dosage form 6 tested, desirability of sink conditions etc. and is a choice of a researcher; however the only limitation from the point of view of the device is the minimal volume which has to cover the beads 3 and the dosage form 6.

Figures 3, 4 and 5 show complete system with the dosage form 6 during stirring when the beads 3 are pushed by stirring bar 2 and thus forming an elevated part 5 which is moving around the vessel 1 during stirring. The solid dosage form 6 which settles on the surface of beads' 3 layer is moving around the vessel 1 and also up and down due to the movement of the beads 3. Dosage form 6 in the vessel 1 is thus in the contact with the beads 3 and exposed to their peristaltic movement. If the dosage form 6 is floating, it is also exposed to the flow of the medium 4 caused by stirrer bar 2 and movement of the beads 3.

Figure 6 shows dissolution profiles of diclofenac sodium from commercially available tablets, i.e one of possible form of the dosage form 6. Dissolution profile obtained in pharmacopeial apparatus with paddle stirring element (USP, apparatus 2, 100 rpm) is compared with the profile obtained using the device described in the present invention under the following conditions: 40 g i.e. bulk volume approx. 25 mL, of glass beads of 1.0 mm diameter and 2.43 g/cm ³ density, cylindrical magnetic stirring bar 2 with length 50 mm and diameter 8 mm and rate of stirring 50 rpm, inner diameter of the vessel lis 58 mm, volume of the medium 4 is 40 mL. The device represented a part of flow-through testing system with the flow of medium 4 of 2.0 mL/min. Medium 4 and the time of 1 hour in artificial gastric fluid were the same in both systems. Differences in the dissolution profiles from 120 minutes on are probably in a great extent a consequence of the way of movement and the mechanical contact of the tablet with glass beads 3 in the device described herein.