Super quick disintegrating tablet formula for API miglitol. Miglitol is employed for the oral therapy of diabetes mellitus. It inhibits the rise in blood sugar level following supply of carbohydrate-containing food, by inhibiting alpha-glucosidase. For an optimum effect, the uniform distribution of the active ingredient in the food is advantageous. In order to achieve this, the possibility exists of using an orally disintegrating tablet. This then allows effective mixing in the chyme in the stomach itself.

In the field of tablets which disintegrate or dissolve rapidly in the mouth there is an extensive prior art. A noteworthy example here is a similar formulation which is described very generically and with a broad claim concerning the solubility of the active ingredient used (JP20091 14069A). Production of the new formulation ought not to necessitate any specialist technology, and the costs of the ingredients used ought to be low. The particular challenge, however, lies in the attainment of a short disintegrat ion t ime (softening time ) of the tablets in the mouth. The target figure is less than 100 seconds. This is made more difficult by the comparatively low volume of liquid in the mouth and also by the viscosity of the saliva, which is increased by comparison with that of water.

The mouth feel obtained is to be pleasant especial ly for the patient, consumer, in order to increase the acceptance of the formulation and the therapeutic compliance.

The composition described, surprisingly, achieves a tablet disintegration time in water (37°C, PhEU apparatus with disc) and in the mouth of less than 100 seconds. The activ e ingredient fraction of the formulation, at more than 25% (m/m), is high enough to allow production of appealingly small tablets. At the same time, the mechanical strength of the tablets, with a breaking load of more than 50 N and an abrasion of less than 0.5%, is sufficiently high to allow the tablets to be handled and packaged normally.

The combination of insoluble vehicle (a good 70% (m/m) overall is insoluble) combined with coarse API particle size results in rapid disintegration with pleasant mouth feel and contrasts with the otherwise used technology with easily and quickly soluble vehicle/active ingredients and/or high- porosity drug forms such as freeze-dried products. As a result of the production technology employed, moreover, the tablets obtained are significantly less expensive.

A surprising factor is the relationship between the disintegration times measured and the particle size of the active pharmaceutical ingredient (API). Favourable active ingredient agglomerates are compact (preferably crystallized) and are also achievable by customary granulation methods (preferably aqueous fluid-bed agglomeration and dry compacting) or crystallization. It is found that increasingly more compact active ingredient agglomerates with increasing average particle size lead to shorter disintegration times.

Figure 1 shows an example of the effect of the API particle size on the disintegration time (Ph. EU apparatus, water, 37°C). The left-hand column shows the disintegration time of crystalline miglitol, the second column that of fractionated miglitol with a particle size of <400 micrometers. The third column shows the disintegration time with fractionated miglitol, with a particle size of >400 micrometes, and the right-hand column shows that of granulated miglitol. Granulation took place by fluid-bed agglomeration, and the crystalline product was fractionated by sieving.

Surprisingly, in spite of the restrictive boundary conditions (methods and ingredients), success is achieved in developing a formulation which is equivalent or superior to many of the specialized technologies and/or ingredients described in the literature.

A tablet of the invention contains about 20% to 30% miglitol. 25% to 28% miglitol is preferred. Moreover, the tablet of the invention contains 65% to 78%, preferably 68% to 75%, of insoluble ingredients. The difference to 100% is made up by tableting auxiliaries such as, for example, disintegration assistants, excipients, fillers, lubricants and optionally flavours.

Production technologies employed are standard methods of the kind customary for tablet production in the pharmaceutical industry.

The tablets can be obtained preferably by the method of direct tableting. In this method the components are merely mixed and optionally sieved, and the resulting mixture is then tableted by compression. This method is notable in particular for low production costs.

It is also possible for some of the components or ail of the components to be mixed and to be compacted dry in the form of such a mixture or partial mixture. Such so-called "roll granules" are likewise inexpensive and easy to produce. Following dry compacting, the compacts are sieved and optionally mixed with the other, remaining, components, to give flowablc mixtures for tableting. This mixture is subsequently pressed into tablet form.

In order to utilize the positive effect described for the particle size of the active ingredient on the disintegration time, the active ingredient can also be processed, alone or in combination with other components of the composition described, in such a way as to form larger active ingredient agglomerates or active ingredient-containing agglomerates. Suitabi lity here as well is possessed by the above-described dry compacting or other common granulation techniques, such as fluid-bed agglomeration or high-speed mixer granulat ion. Granulating liquids used in such cases are preferably water or suitable organic solvents. i f, for any particular reason (e.g. availability of Migiitol drug substance or lack of technical equipment), M iglitol drug substance of a fine part icle size grade (for example mean particle size x ₅₀ at 3μ m-80μm, 10 μ m- 50 μ m or 15μm -30μ m ) has to be used in the described compositions, the flow properties of the resulting mixtures is markedly decreased. As a consequence the physical properties of the resulting tablets do change, but still remain within the desired range for sufficiently short disintegration time and sufficiently high mechanical resistance. The manufacturing process step of tablet compression however is negatively affected. The use of fine particle size grade of M iglitol (small crystals or milled material) results in powder segregation, which leads to inacceptabie content uni formity results for some time-points in tableting operation (content uniformity testing is a common testing approach of all major Pharmocopias like PhEU, PhJap, USP). Such a process has a high risk of producing tablets, which cannot be released/used for market supply, because of this non-compliance with the commonly employed binding regulations of content uniformity testing. Although the exact mechanism behind the observed powder segregation is not understood (e.g. difference in particle size of the mixture components, difference in density of the mixture components, irregular powder flow due to bridging etc.), the tableting process output and robustness can be surprisingly improved with respect to the content uniformity results of the produced tablets by using a flexible foil-tubing as a connection between the container (containing the ready-to-press mixture) and the tablet press feeder. The used material of this flexible foil-tubing has to be flexible enough to allow for a change in tube-diameter depending on powder flow and has to be made of suitable material for direct contact with food and pharmaceutical preparations (e.g. Polyethylene LDPE or H DPE, Polypropylene PP, Polyvinyl chlorine PVC, Polyetylenterephtalat PET, Cellulose, Si licon, Polystyrene PS, Polytetrafluoroethylene PTFE or combinations thereof). The maximum diameter of the flexible foil-tubing is in the range of 75mm-400mm, 100mm-350mm, 150mm-300mm. This described simple flexible foil-tubing is used to replace the standard metal tubing (usually stainless steel ) and all part inside the tablet press above the feeder ( forced feeder or gravity feeder). Thus a direct flexible connection with the possibility to alter its diameter between the container and the feeder of the tablet press is given. This set-up ensures that powder segregat ion of the mixture is reduced to an extent, that acceptance criteria for content uniformity testing are safely met and robustness of the tableting process is greatly improved.

The described simple and effective modification of the process equipment helps to av oid other technical efforts that are commercially av ailable (e.g. fixed quantity supplying units, that supply small defined quantities of powder mixture to the feeder of the tablet press), allows for long v ertical transport distances for powder mixture, eliminates the need for cleaning as it can be disposed after use and needs very low investment. The modified tableting process can be run with markedly improved robustness even with the fine particle size grade of Miglitol, which otherwise would not be possible.

Examples of the composition of tablets

Compacting to 8.5 mm flat tablet with facet to breaking load of 50-70 N (Schleuniger 6D)

*) M iglitol may be used alternatively as a fluid-bed granule product, in dry-compacted form (roll granules) or directly after crystallization (particularly preferred on account of no additional operating step).

**) Particularly suitable lubricants are magnesium stearate or sodium stearylfumaratc (PRUV).

The following are insoluble: maize starch, magnesium trisi licate, PVP CL.

Example of production by direct tableting

Example of agglomeration of partial mixtures by dry compacting: