Novel Noncompendial Methods for the Investigation of Drug Release

Obtaining an adequate prediction of in vivo performance may require a degree of biorelevance beyond that possible with a standard compendial test even when used in conjunction with appropriate biorelevant dissolution media. Apparatus described in a pharmacopeia are necessarily kept as simple as possible and are carefully specified in terms of equipment design, and will only mimic some aspects of the in vivo environment (e.g., temperature). With regard to other aspects (such as hydrodynamics, digestion or dynamic fluid mixing) a test using the standard apparatus will lack biorelevance, mainly because they are more difficult to mimic within the constraints of the equipment design. For instance, a rotating paddle or basket can hardly realistically mimic the motion or movement of fluids in the GI tract.

Once again, recent research in the dissolution test arena may provide direction for those scientists interested in the development of more realistic in vitro drug release tests. Recently, holistic dissolution systems have begun to be used in the development of oral dosage forms that aim to mimic many of the relevant dynamic and digestive features of the GI tract that might impact on in vivo performance. These systems, which include the TNO Intestinal Models TIM-1 [15] and TIM-2 [16], and the Institute of Food Research's Dynamic Gastric Model (DGM) [17], offer a significant improvement in the ability of the in vitro dissolution test to imitate the dynamics, fluid input and removal, food, enzyme-dependent digestive processes, and even, in the case of TIM-2, gut microflora in the GI tract that may impact dissolution (and stability) in vivo. They can be seen as attempts to recreate multifunctional aspects of the GI tract in the laboratory. Initially designed for use by the food industry, they offer the possibility of a more reliable, although not necessarily less expensive in vitro alternative to the use of in vivo animal models for the prediction of oral drug formulation performance in humans. However, sample throughput, cost and obtaining a significant number of replicates for improved confidence remain challenges for the widespread application of these systems, and the number of applications to pharmaceuticals reported in the literature is currently limited.

For the prediction of the performance of oral modified release dosage forms, the TNO-TIM-1, a gastric and small intestinal model (Fig. 5.1), has been shown to provide an improved prediction of the behavior of theophylline matrix tablets, whereas simpler methods needed retrospective adjustment of the agitation intensity in order to obtain a good IVIVC [18]. The DGM is a dual chamber gastric model (Fig. 5.2) designed to mimic both the fundus (lower agitation "storage" region of the stomach) and the antrum (higher agitation region). It has been used to characterize the differences between two different oral nifedipine products that use contrasting release mechanisms - an osmotic pump formulation and a matrix tablet formulation. These differences may explain the known differences between the in vivo robustness of these formulations [19].

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Fig. 5.1 Schematic representation of TNO's "TIM 1." From S. Blanquet, J. P. Meunier, M. Minekus, S. Marol-Bonnin, and M. Alric. Applied and Environmental Microbiology, May 2003, Vol. 69, No. 5, pp 2884-2892. Recombinant Saccharomyces cerevisiae Expressing P450 in Artificial Digestive Systems: a Model for Biodetoxication in the Human Digestive Environment. http://aem.asm.org/cgi/reprint/69/5/2884. See also TNO website: http://www.tno.nl/content. cfm?context=thema&content=markt_product&laag1=891&laag2=180&laag3=297&item_ id=874&Taal=2

Fig. 5.1 Schematic representation of TNO's "TIM 1." From S. Blanquet, J. P. Meunier, M. Minekus, S. Marol-Bonnin, and M. Alric. Applied and Environmental Microbiology, May 2003, Vol. 69, No. 5, pp 2884-2892. Recombinant Saccharomyces cerevisiae Expressing P450 in Artificial Digestive Systems: a Model for Biodetoxication in the Human Digestive Environment. http://aem.asm.org/cgi/reprint/69/5/2884. See also TNO website: http://www.tno.nl/content. cfm?context=thema&content=markt_product&laag1=891&laag2=180&laag3=297&item_ id=874&Taal=2

In addition to these "GI tract in a laboratory" systems, other dynamic systems of intermediate complexity that attempt to improve the biorelevance of key variables that are inadequately mimicked in more established dissolution tests have been developed in recent years [20-25]. These systems focus on factors such as dynamic fluid mixing [20, 21], improved mimicking of the impact of GI motion on

Fig. 5.2 The dynamic gastric model (DGM). From [26]. See http://pubs.acs.org/doi/ pdfplus/10.1021/mp1001203

Fig. 5.2 The dynamic gastric model (DGM). From [26]. See http://pubs.acs.org/doi/ pdfplus/10.1021/mp1001203

dosage form [22, 23], lipid digestion [24] or drug removal from the GI tract by absorption [25]. By focusing on improving the biorelevance of a specific aspect of the test, these methods tend to retain at least some of the simplicity of a pharmacopeia dissolution method such as the ability to test multiple replicates, and can be used to target and improve the biorelevance of the test for specific types of drug and formulation.

A fuller description of these emerging dynamic dissolution testing systems has recently been the topic of a useful and comprehensive literature review [26].

Dissolution apparatus attempting to improve the mimicking of the impact of GI motion have particular application to modified release dosage forms, especially when developing matrix tablets which may be vulnerable to some loss of their controlled release characteristics when subjected to the physical stresses associated with GI transit, such as during gastric empting and illeo-cecal transit. The physical stresses associated with gastric emptying, where the dosage form may be subjected to a short period of very high agitation, particularly upon passage through the pyloric sphincter, may be critical to the integrity of some modified release dosage forms [22]. These stresses are likely to be a significant contributory factor to differences in pharmacokinetics seen between the fasted

Fig. 5.3 Schematic representation of the dissolution stress test device described in [22]

Fig. 5.4 Representation of a modified paddle apparatus for mimicking gastric dynamics (paddle not shown for visual clarity)

and fed state in vivo with some modified release matrix tablets, which rely on erosion for drug release.

Garbacz et al. [22] have demonstrated that the irregular pharmacokinetic profiles seen with a Diclofenac modified release tablet can be mimicked using a novel dissolution test apparatus (Fig. 5.3) that uses both a rotary/dipping motion and an intermittent squeezing motion applied via an inflatable balloon. The system was devised to mimic the physical forces acting upon a matrix tablet, determined from pressure measurements exerted on a telemetric capsule [22]. The test apparatus was also used to examine modified release matrix nifedipine formulations marketed in Europe. Matrix formulations showed a higher susceptibility to variable and more extensive drug release during the applied biorelevant stress test than an osmotic pump formulation, particularly during the simulated high stress events associated with gastric empting [27].

Another device, also using two different means of agitation within the same apparatus and devised to mimic the physical forces in vivo in a more realistic way than established dissolution methods, is described by Burke et al. [28] (see Fig. 5.4).

This apparatus uses a plunger to apply stress to matrix formulations placed within a stationary basket. The basket is placed within a standard paddle dissolution apparatus.

These various approaches, although of different levels of complexity, offer the hope of greater accuracy in the prediction of the human pharmacokinetics for oral modified release dosage forms, and a much improved opportunity to prospectively predict likely in vivo profiles at the very earliest stages of modified release formulation development. If these approaches prove successful, they may help to reduce the development cycle times for new oral modified release dosage forms. However, more confirmatory work is needed.

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