Kollidon SR: A polyvinyl acetate based excipient for DCsustained-release oral dosage forms by Dr. Bernhard Fussnegger BASF Aktiengesellschaft, Ludwigshafen Strategic Marketing Pharma Excipients Introduction Sustained-release oral dosage forms are in the focus of interest for several reasons. Customer compliance with the trend to simplicity and more comfort of use, the prolonged drug release with more reliable blood levels than those obtained with conventional dosage forms and life-cycle management of existing APIs directed the pharmaceutical development towards sustained release formulations [1, 2]. Due to the permanent cost pressure for newly developed pharmaceutical formulations the selection of the right excipient becomes a very crucial factor. No doubt that the production of a sustained release dosage form by direct compression offers several advantages such as rapid and easy formulation processes in combination with reduced manufacturing costs. Existing polymers for sustained-release formulations show some draw-backs and none of them can be used easily for direct compression technology. These reasons led BASF to develop a series of new excipients based on polyvinyl acetate for an easy and more reliable formulation of sustained-release oral dosage forms. The product for the DC-Technology is Kollidon SR Kollidon SR: Product Properties Kollidon SR is derived from a polyvinyl acetate-dispersion (Kollicoat SR 30D) and appears as a spray dried, non hygroscopic powder consisting of polyvinyl acetate (8 parts w/w) and polyvinyl pyrrolidone (2 parts w/w). As shown in table 1 the product proofs to have excellent flow properties. The angle of repose was determined to be far below 30 and the flow time of 150 ml powder passing a Pfrengle-funnel was fast and consistent. Table 1: Powder properties of Kollidon SR Angle of repose 21,0 Flow time 9,5 s Bulk density 0.37 [g/ml] Tap density 0.44 [g/ml] Hausner ratio 1.13 Medium particle size approx. 100 µm The powder properties such as bulk and tap density was determined using an Erweka SVM volumeter, the angle of repose and the flow time were measured with a Pfrengle funnel. The particle size was investigated by means of a Malvern Mastersizer.
These product characteristics allow Kollidon SR to be used in the manufacture of direct compressed, non-erodible tablets and when considering the bulk and tap densities, only small variations of the tablet weight are expected. Due to the extreme dry-binding capacity, matrix tablets can be achieved either with a high apparent density or they can be manufactured as very porous, floating systems with apparent densities below 1.0 [g/cm 3 ]. The latter dosage form is particularly suitable when a drug is intended to exert its actions locally in the stomach or is absorbed in the stomach or upper part of the small intestine. Floating systems prolong gastric and intestinal transit time and can thereby enhance bioavailability especially for drugs with an absorption window. Sustained-Release Tablets To demonstrate the potential of Kollidon SR sustained release matrix tablets were formulated using Kollidon SR (BASF); propranolol-hcl (Formulation A), caffeine (Formulation B) (Knoll); Mg-stearate (Bärlocher); Aerosil 200 (Degussa) in the quantities listed in table 2. To manufacture the tablets the ingredients were weighed, blended for 10 min in a turbula mixer and passed through a 800 µm sieve. The mixtures were compressed using an instrumented rotary press Korsch PH 106, rotation speed 30 rpm, with the compression forces 10, 18 and 25 kn, tablet diameter 10 and 12 mm, beveled edge. Table 2: Tablet compositions with Kollidon SR and the model drugs (amount per tablet [mg]) Formulation A Formulation B Kollidon SR 160.0 160.0 Propranolol-HCl 160.0 -- Caffeine -- 160.0 Aerosil 200 3.4 3.4 Mg-stearate 1.6 1.6 tablet weight [mg] 325.0 325.0 Table 3 shows the results. The tablets with an extremely high hardness, and a low friability showed a very acceptable content uniformity. According to the chemical composition and the adjusted particle size distribution, the marked dry binding capacity in combination with the good flow properties, are regarded as additional benefits when using Kollidon SR as sustained release excipient.
Table 3: tablet parameters of Kollidon SR tablets (compression force 18 kn) Formulation A Formulation B Hardness [N] 241 279 Hardness stand. dev. [%] 3.7 4.9 Friability [%] 0.05 0.04 Disintegration time [min] > 120 > 120 Content uniformity [%] 1.2 1.1 Even with the highly water soluble drug caffeine the test on the release characteristics revealed a sustained-release action over a period of more than 16 h. Moderate swelling of the tablets was observed, but the tablet shape remained intact due to the water insoluble polyvinyl acetate. The release mechanism can be assumed as diffusion controlled. Furthermore it is obvious that neither different ph-values, the variation of the ionic strength or the change of the paddle speed imitating different hydrodynamic conditions, influenced the release profile of caffeine tablets with Kollidon SR (Figure 1) 100 released drug [%] 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 time [h] 0.08 N HCl ph 1 PBS ph 7.4 PBS ph 7.4 + 2.5 % NaCl 0.08 N HCl (2h) + PBS ph 6.8 PBS 7.4 100 rpm Figure 1 Influence of dissolution medium on the release profile of caffeine tablets with Kollidon SR (diameter 12 mm) When checked for the influence of the compaction force on the release profile of caffeine and propranolol-hcl tablets, overall no influence could be detected. Figure 2, show the situation for propranolol-hcl formulation with Kollidon SR.
100,0 90,0 released drug [%] 80,0 70,0 60,0 50,0 40,0 30,0 18kN 25kN 20,0 10,0 0,0 0 2 4 6 8 10 12 14 16 18 time [h] Figure 2 Influence of compression force on the release profile of Kollidon SR tablets with propranolol-hcl (diameter 12 mm) When a drug is intended to exert its actions locally in the stomach or is absorbed in the stomach or upper part of the small intestine floating systems are particularly suitable. These systems prolong gastric and intestinal transit time and can thereby enhance bioavailability especially for drugs with an "absorption window". Floating Sustained-Release Systems To date only few manufacturing techniques for floating systems are known, all of them very demanding. In contrast to HPMC based floating tablets, which are observed to sink in the dissolution test medium after a certain time [3], Kollidon SR floating tablets manufactured by direct compression at very low compression forces show uniform behaviour. A formulation with the model drug diltiazem consisting of diltiazem HCl, 120.0 mg, Kollidon SR, 200.0 mg, Aerosil 200, 3.2 mg and Mg stearate, 3.2 mg was used for the tests. The final tablet weight was 326.4 mg.
Compression force [kn] Apparent density [g/mm_] Floating behaviour 2.36 0.81 immediately 2.94 0.91 immediately 3.76 0.97 immediately 4.11 0.99 after 45 min/immediately 4.79 1.03 after 90 min 6.61 1.09 24 to 48 hours Table 4 Influence of compression force on apparent density and floating behaviour of Dilitiazem tablets The density of the tablets correlates with the floating behaviour (Table 4): If their density after manufacture is below 1.0g/ml they immediately float on the surface and do not sink again even during an observation period of 48 hours. When increasing the compression force the volume of the tablets asymptotically approaches a value of 300 mm_ (Figure 3), hardness increases linearly over the entire measured range. In case of a diltiazem formulation compression forces of less than 4 kn result in stable tablets with a hardness exceeding 90 N, however with the ability to float. When the formulation is compressed with around 4,5 kn, the apparent density of the diltiazem tablets approximates the density of the dissolution medium, the tablets sink. volume [mm ] 450 425 400 375 350 325 300 210 180 150 120 90 60 30 hardnes [N] 275 1 2 3 4 5 6 7 compression force [kn] 0 Figure 3 Hardness and tablet volume of Diltiazem tablets as a function of compression force In the range investigated the compression force has hardly any influence on the dissolution of diltiazem HCl floating tablets (Figure 3). There is thus no risk that minor deviations in compression pressure within a tablet batch would result in pronounced changes in the dissolution period.
Summary Kollidon SR, an excipient for drug delivery matrices based on Polyvinyl acetate, possesses good controlled release properties. The release profiles of tablet formulations with Kollidon SR were not influenced by different dissolution media or compression forces. The excellent flow properties and the dry binding activity of Kollidon SR, provide easy handling and effective development and production of sustained release tablets. By applying low compression force floating tablets with a longer residence time in the stomach can be achieved. Floating times exceeding 24 h can be achieved easily. Furthermore it can be shown that even for low compression forces dissolution is independent of the pressure applied Literature [1] M. J. Vasquez; Drug Dev. Ind. Pharm., 18; 1355, (1992) [2] U. Gundert-Remy, Oral controlled release products, WVG, Stuttgart, (1990) [3] Baumgartner S., _mid-korbar J., Physical and technological parameters influencing floating properties of matrix tablets based on cellulose ethers, S.T.P. Pharma Science 8 (5), 285-290 (1998).