Feasibility of NC approach for tableting applications (IV) . 51

5.3 Solid NC Formulation (III-IV)

5.3.2 Feasibility of NC approach for tableting applications (IV) . 51

Finally, the concept of solid NC formulation was further processed in order to expand the knowledge for higher amounts of NC formulations. Thus, ITC and IND NPSs were successfully manufactured by wet milling, increasing the batch scale 2-4 times, freeze-dried, and further developed into both direct compression (DC1-DC3) and granulated (G) tableting masses (Table 8). In order to find the optimal formulations for tableting, the powder and tablet properties of the ITC and IND, both DC and G compositions, were screened and compared in detail according to true density, powder flowability, dose uniformity, maximum upper punch force, tablet crushing strength, dissolution and disintegration behavior, and stability testings.

(^aPMs, NPS replaced with bulk ITC/IND, ^bTherapeutic dose included, ^cfDC compositions.)

The critical tableting parameters were optimized by manually compacting both ITC and IND DC1-DC3 compositions and PMs (n = approx. 30 tablets), whereas the G and fDC compositions were compressed using the automated process (n = approx.

300 tablets), which explains the differences in the forces and in the comparisons made in the data analysis. The tableting experiments with the ITC and IND DC1-DC3 compositions demonstrated informatively the effect of the varying amounts of NC powders. The existence of NCs improved the compressibility; with lower force, sufficiently hard tablets were provided. Figure 15 shows intriguing information about the compression force and tablet crushing strength with different compositions. An important factor explaining the results is the particle size. The smaller the particle size, the more there exists contact surfaces, and thus the greatest potential for bond formation, which in turn increases the hardness, i.e. crushing strength, of the tablets (MCKennan and MCCafferty, 1982;Velasco et al., 1999).

The increased number of contact surfaces and thus potential for bond formation explains the fact that the greater the load of nanocrystals in the composition, the lower force is required to produce hard tablets. Both the granulated compositions,

ITC G and IND G, facilitated significantly harder tablets, compared to the final ITC DC (P < 0.001 ) and IND DC compositions (P < 0.0001), with lower forces (P <

0.0001). This supports the well-known profitable properties of granulated tableting masses (Iveson et al., 2001), which can be compressed more easily and consume less energy (Faure et al., 2001;Hansuld and Briens, 2014).

Figure 15 The maximum upper punch forces (N, column) with each (A) ITC and (B) IND compositions (DC1-DC3, final (f) DC, G, PM) in comparison to the average crushing strengths (N, after 48 h from tableting, line) of the compressed 250 mg tablets.

Furthermore, the dissolution behavior of IND was dependent on the load of nanocrystal powder in the IND DC1-DC3 tablet formulations (Figure 16a). At 15 min detection time-point the released drug load from the IND DC1 tablets was clearly higher than from the DC2 and DC3 tablets (P < 0.0001). The drug release from DC2 was in turn significantly above DC3 tablets (P < 0.05). Taking into account the tablet properties, processablity, inclusion of adequate drug concentrations and dissolution profiles, the IND DC1 showed to be the best candidate for the final DC formula. ITC DC1 mini-tablets (30 mg) enabled the ITC dissolution study in sink-conditions, and thus related the ITC dissolution to its disintegration behavior. This relation between disintegration and dissolution was utilized to describe the dissolution behavior of the highly concentrated ITC DC2 and DC3 tablets, which were otherwise excluded from the dissolution analyses due to the high drug content.

Figure 16 The dissolution profiles of (A) IND DC1-DC3 tablets (250 mg) and powders, (B) IND NPS compared to final IND DC (fDC), G and PM tablets (250 mg), and (C) ITC NPS compared to DC1 tablets (30 mg) and powder and PM tablets (30mg).

The disintegration results demonstrated also the effect of the amount of nanocrystal powders in the tablets ( Figure 17): the less the formulation included nanocrystal powder (ITC DC1 // IND DC1), thus the more porous and less dense the structure, the faster was the medium penetration (diffusion), and the tablet disintegration. ITC and IND DC2s, and moreover the DC3s, provided more prolonged medium diffusion times. The disintegration times correlated in general well with the crushing strength values. The compositions of both the model substances showed comparable disintegration behavior in descending order according to the disintegration times (DC3 > DC2 > DC1 > PM and G > fDC, P ≤ 0.001). The disintegration results proposed the choice of ITC DC2 and IND DC1 for the final DC compositions. ITC DC2 offered the most suitable choice, since it provided an opportunity of inclusion of adequate drug concentrations in reasonable sized tablets, which would be disintegrated within acceptable time frames.

Figure 17 The disintegration times (min, column) versus crushing strengths (N, line) of the (A) ITC and (B) IND tablets.

In conclusion, the amount of the nanocrystal powder is critical for the formulation. When including excessive amounts of nanocrystals in the formulation, the benefits of the nanosized powders will be finally lost. Thus, there exists a maximum concentration, which provides good processability resulting in tablets with suitable strengths and drug release properties, i.e. dissolution behaviors and disintegration times. The DC designs of both the model drugs with compositions including 40% of freeze-dried nanocrystalline drug powder (ITC DC2 and IND DC1) outperformed the corresponding granulated tablets in all parameters after the stability surveillance. In the light of these evidences, both the model substances would benefit from nanocrystal tablet formulation approach.

6 Conclusions

Dissolution properties of the poorly soluble drugs (indomethacin, brinzolamide, itraconazole) were improved by preparing drug nanocrystals with universally applicable and industrially relevant, rapid wet media milling technique. High-quality nanocrystal suspensions, regarding particle size, size uniformity, morphology, stability and solid state were obtained. Dissolution study of freeze-dried nanocrystal compacts with the channel flow dissolution method and the novel UV imaging technique revealed the significance of the particle size for dissolution. UV imaging provided valuable new information about the concentration of the dissolved drug next to the sample surface: with the smallest nanocrystals the concentration next to the particle surface exceeded five-fold the thermodynamic solubility, creating supersaturated states. Even though the effect of the variation in the area available for dissolution was eliminated by studying smooth, constant surfaces instead of particulate samples, the differences between particle sizes were evident. This difference will be increased even further in actual drug formulation. This indicates that the solubility improvement itself, and not only the increased dissolution area, have a crucial role in higher dissolution rates of nanocrystal formulations.

Three ophthalmic BRA nanocrystal suspension formulations in PBS (pH 4.5 and 7.4) were successfully developed using HPMC as an effective stabilizer. The ophthalmic nanocrystal suspensions dissolved immediately in vitro and were homogenous and stable. The in vivo rat ocular hypertension model showed the significantly decreased intraocular pressure values by all the formulations. The IOP reduction was enhanced the most at pH 4.5, when the amount of free drug in the nanosuspension (formulation III) was at its highest. The actions of the formulations were proven against the commercial BRA product used as a control. The results revealed that nanocrystal suspensions are valid tools for ophthalmic drug delivery and therapeutic approaches.

Lastly, the results of the set of performed experiments answered to a wide range of questions regarding the feasibility and the preparation of solid oral nanocrystal formulations. Freeze-drying was proven over granulation to be an effective method to convert the nanocrystal suspension into dry powders. The compaction process of nanocrystal powders was performed successfully, maintaining the original characteristics of the nanocrystals, i.e. rapid dissolution. The up-scaling of wet milling was a straightforward process, and regarding the further formulation

development, it was clear that the amount of the nanocrystal powder in the solid formulation was critical in order to be able to fully utilize the benefits of the nanocrystals. Therefore, nanocrystal tablet formulation is an advantageous design with a fairly simple production process. However, the difficulty to predict the in vivo behavior on the basis of the in vitro analyses was demonstrated.

To conclude, NC suspensions offers a versatile platform to deliver poorly water soluble drugs via liquid and solid formulation. However, the formulation should be carefully considered in order to obtain an in vitro-in vivo correlation and, thus the transfer of the in vitro benefits to an in vivo environment.

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