Orally disintegrating tablets

Abstract

The present invention relates to rapidly disintegrating oral dosage forms, more particularly to rapidly disintegrating tablets containing (1S,2S,3R,5S)-3-[7-{[1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5 5-(2-hydroxyethoxy)cyclopentane-1,2-diol and a disintegrating excipient. Blister packs suitable for use with the rapidly disintegrating oral dosage form are also disclosed.

Claims

1. A tablet comprising: (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo-pentane-1,2-diol; and at least one disintegrating excipient; wherein the tablet has a hardness of from about 50 to about 150N and a disintegration time of less than about 3 minutes.

2. The tablet according to claim 1, wherein the tablet has a disintegration time of less than about 60 seconds.

3. The tablet according to claim 1, wherein the at least one disintegrating excipient comprises a fast oral disintegrating excipient.

4. The tablet according to claim 1, wherein the at least one disintegrating excipient comprises at least one carbohydrate filler and at least one disintegrant.

5. The tablet according to claim 1, wherein the at least one disintegrating excipient comprises mannitol.

6. The tablet according to claim 1, wherein the at least one disintegrating excipient comprises crospovidone.

7. The tablet according to claim 1, wherein the at least one disintegrating excipient comprises mannitol, xylitol, anhydrous dibasic calcium phosphate, crospovidone and microcrystalline cellulose.

8. The tablet according to claim 1, wherein the at least one disintegrating excipient is a disintegrating excipient pre-mix that is present in an amount ranging from about 50% to about 80% by weight of the tablet.

9. The tablet according to claim 1, wherein the (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol is present in an amount of from about 10 to about 18% by weight.

10. The tablet according to claim 1, wherein the tablet comprises about 60 mg or about 90 mg of (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol.

11. The tablet according to claim 10, wherein the tablet comprises about 90 mg of (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol.

12. The tablet according to claim 1, wherein the tablet has a hardness of from about 55 to about 90N.

13. The tablet according to claim 1, wherein the tablet further comprises at least one anti-caking agent.

14. The tablet according to claim 13, wherein the at least one anti-caking agent is present in an amount of from about 0.5 to about 1% by weight of the tablet.

15. The tablet according to claim 1, wherein the tablet is obtainable by a process comprising wet granulation of: (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo-pentane-1,2-diol; and an anti-caking agent.

16. The tablet according to claim 9, wherein the tablet has a disintegration time of less than about 60 seconds.

17. The tablet according to claim 11, wherein the tablet has a disintegration time of less than about 60 seconds.

18. The tablet according to claim 1, wherein the tablet comprises: (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo-pentane-1,2-diol at from about 10 to about 18% by weight of the tablet; hydroxypropyl cellulose at from about 0.9 to about 2% by weight of the tablet; colloidal anhydrous silica at from about 0.5 to about 1% by weight of the tablet; mannitol at from about 47 to about 67% by weight of the tablet; xylitol at from about 2.5 to about 4% by weight of the tablet; anhydrous dibasic calcium phosphate at from about 2 to about 3.5% by weight of the tablet; microcrystalline cellulose at from about 9 to about 15% by weight of the tablet; crospovidone at from about 5 to about 9% by weight of the tablet; and sodium stearyl fumarate at from about 1 to about 2% by weight of the tablet.

19. The tablet according to claim 18, wherein the tablet has a disintegration time of less than about 60 seconds.

20. The tablet according to claim 1, wherein the (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-[1,2,3]-triazolo[4, 5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol has a D (v, 0.9) particle size distribution of from about 5 m to about 50 m.

21. The tablet according to claim 1, wherein the (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol is substantially present in the form of polymorph II.

22. A process for the preparation of a tablet as defined in claim 1, wherein the process comprises the step of mixing together (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol and at least one anti-caking agent along with, or in, a liquid, so providing a wet granulate.

23. A blister pack containing one or more tablets as defined in claim 1.

24. The blister pack of claim 23, wherein the blister pack comprises a blistered base sheet comprising one or more cavities, and a lidding sheet bonded to the base sheet, wherein the edge of the blister pack comprises at least one break in the blistered base sheet and the lidding sheet such that the blister pack is tearable at the break to expose the cavity.

25. The blister pack according to claim 23, wherein the one or more tablets have a disintegration time of less than about 60 seconds.

26. The blister pack according to claim 24, wherein the one or more tablets have a disintegration time of less than about 60 seconds.

27. A method of treating atherothrombotic events in patients with cardiovascular disease, which method comprises administration of a tablet as defined in claim 1 to a patient suffering from or susceptible to such a disorder.

28. The method according to claim 27, wherein the tablet has a disintegration time of less than about 60 seconds.

Description

FIGURES

(1) FIGS. 1A and 1B show plan views of a blister pack. Tablets are shown within the blister pack in FIG. 1B.

(2) FIGS. 2A and 2B show side views of a single blister. A tablet is shown within the blister in FIG. 2B.

(3) FIG. 3A shows a plan view of a portion of a blister pack with a cleft. FIG. 3B shows a plan view of a portion of a blister pack with an incision.

(4) FIG. 4 shows FBRM data for ticagrelor granules.

(5) FIG. 5 shows FBRM data for F-Melt granules.

(6) FIG. 6 shows FBRM and dissolution data for batches of ticagrelor prior to storage.

(7) FIG. 7 shows FBRM and dissolution data for batches of ticagrelor following storage at 40 C., 75% RH.

(8) FIG. 8 shows the dissolution of ticagrelor orodispersible and film-coated tablets 90 mg dosed in clinical study A in 0.2% (w/v) Tween 80, mean values (n=6). Error bars represent min and max values.

(9) FIG. 9 is a photograph of a push-through type blister pack which has been modified to include triangular breaks (as tear notches).

ANALYTICAL METHODS

(10) In the examples described below, various parameters were measures according to the following analytical methods.

(11) Friability was measured in accordance with the method set out in USP monograph 1216 (Tablet Friability).

(12) Hardness was measured in accordance with the method set out in USP monograph 1217 and PhEur 2.9.8 (Resistance to Crushing of Tablets).

(13) Disintegration time was measured in accordance with the method set out in USP monograph 701 (Disintegration).

(14) Dissolution time was measured in accordance with the method set out in USP monograph 711 (Dissolution).

(15) Particle size distributions for the ticagrelor as received from suppliers and for granulates used in the tableting processes were measured using a laser diffraction method (in wet and dry conditions). In wet methods, particles of drug were suspended in a suitable suspending fluid (e.g. 0.5% v/v sorbitan trioleate in cyclohexane) and laser diffraction particle size analysis of the suspension was conducted using a Malvern Mastersizer 2000. In dry methods, particles size distribution measurements (typically for granules) were made by laser diffraction using dry material, i.e. without the aid of a suspending fluid. Unless otherwise specified, particle size measurements were made under standard measurement conditions appropriate for the technique.

(16) Focused Beam Reflectance Measurement (FBRM) analyses were conducted in dissolution studies. The FBRM technique involves the insertion of a probe directly into a process stream, at an angle, to ensure particles can flow easily across the probe window where the measurement takes place. A laser beam is launched down the probe tube through a set of optics and focused to a tight beam spot at the sapphire window. The optics rotate at a fixed speed (typically 2 m/s) resulting in the beam spot rapidly scanning across particles as they flow past the window. As the focused beam scans across the particle system, individual particles or particle structures will backscatter the laser light to the detector. These distinct pulses of backscattered light are detected, counted, and the duration of each pulse is multiplied by the scan speed to calculate the distance across each particle. This distance is defined as the chord length, a fundamental measurement of the particle related to the particle size, and a precise and highly sensitive chord length distribution can be reported in real time, thus tracking how particle size and count change over time. In the measurements, the probe diameter was approximately 6 mm and has a sapphire window at the probe end. The integration time was set to 5 seconds. The instrument was set on coarse mode and focal spot scan rate on 2 m/sec. The probe was placed 2 cm above the paddle.

(17) The invention may by illustrated by the following non-limiting examples.

(18) In these examples, F-melt type M and F-melt type C (also referred to herein as F-melt in the Examples) were supplied by Fuji Chemicals, Ludiflash was supplied by BASF, and GalenIQ (Grade 721) was supplied by Beneo-Palatinit, Mannitol was supplied by Roquette, crospovidone (Kollidon CL-SF and Kollidon CL-F) was supplied by BASF. Sodium stearyl fumarate was supplied by JRS Pharma, Hydroxypropyl cellulose was supplied by Ashland, colloidal anhydrous silica was supplied by Cabot GmbH.

Example 1Assessment of Direct Compression Tablets

(19) Four 500 g batches of direct compression (DC) tablets were produced using the formulation compositions detailed in Table 1.

(20) TABLE-US-00001 TABLE 1 Compositions of direct compression tablet batches Batch Component 1 2 3 4 Ticagrelor 15.0 15.0 15.0 15.0 F-MELT, type M 71.0 F-MELT, type C 10.0 Ludiflash 81.0 GalenIQ 81.0 75.0 Crospovidone 7.0 Silica, collodial 1.0 1.0 1.0 1.0 anhydrous sodium stearyl 3.0 3.0 3.0 3.0 fumarate Total 100.0 100.0 100.0 100.0 All values are weight percentages.

(21) The first three batches varied in the use of fast oral disintegrating excipient. F-MELT type M and C, Ludiflash or GalenIQ was used. Colloidal anhydrous silica was added to overcome the adhesive and cohesive nature of ticagrelor. As lubricant, sodium stearyl fumarate was included. The formulation containing GalenIQ was shown to have long disintegration time, for that reason a fourth experiment with a composition containing GalenIQ and 7% of the disintegrant crospovidone was carried out.

(22) The major observation during tablet compression was that the compositions including F-MELT (Batch 1) and Ludiflash (Batch 2) had poor flowability whereas the GalenIQ formulations (Batch 3 and Batch 4) had good flowability (see Table 2). This is reflected in the hardness and weight analysis where the F-MELT and Ludiflash formulations had high variability (RSD-value), whereas the opposite was observed for the two GalenIQ formulations.

(23) TABLE-US-00002 TABLE 2 Observations and results Batch 1 2 3 4 Quality attribute F-MELT Ludiflash GalenIQ GalenIQ + cros. Flowability poor poor good good Picking/Sticking no no no no Hardness, n = 10 Average (N) 60.3 67.4 37.3 35.4 RSD (%) 21.6 27.2 7.78 9.60 Tablet weight, n = 10 Average (mg) 617.9 613.4 605.8 598.0 RSD (%) 4.35 3.54 1.04 1.95 Friability (%) 0.8 0.9 1.9 1.2 Disintegration (s), 28 29 62 60 n = 6

(24) Typically preferred RSD values for the hardness measurements are less than 20%. Typically preferred RSD values for the tablet weight measurements are less than 4.0%. Typically preferred friability values are less than 1.0%. Typically preferred disintegration times are less than 30 seconds.

(25) None of the tablet formulations showed any sign of sticking or picking tendencies. The analysis of friability and disintegration showed that F-MELT and Ludiflash provided tablets with good disintegration properties (disintegration time of about 30 seconds), and acceptable friability (less than 1%). The GalenIQ composition on the other hand had neither acceptable disintegration time nor friability. Adding 7% of the disintegrant crospovidone did not significantly shorten the disintegration time of the GalenIQ composition.

(26) With tablets containing F-MELT or Ludiflash there was a risk of not meeting the (Critical Quality Attributes) QCA of uniformity of dosage units because of the low flowability. With tablets containing GalenIQ there was on the other hand a risk of not meeting the CQAs of assay (because of high friability) and disintegration. Further studies were conducted (see Examples 2 to 6) in which the ticagrelor particles were incorporated in granules to try to counter the flowability difficulties.

Example 2Assessment of Wet-Granulation Tablets

(27) This experiment was designed to assess wet granulation of ticagrelor, followed by dry-mixing with the other excipients prior to tablet compression. Included in the formulation was the fast oral disintegrating excipient of either F-MELT or Ludiflash, shown to provide favourable disintegrating properties. In this and all subsequent examples, only F-melt type C has been evaluated, rather than F-melt type M. References to F-melt in the compositions used in this and subsequent examples are references to F-melt type C, unless otherwise specified.

(28) Table 3 details the composition of the granulation batches in this example. Water was chosen as the granulation liquid and the binder hydroxypropylcellulose was added dry. In order to reduce the cohesive and adhesive nature of ticagrelor, colloidal anhydrous silica was used as anticaking agent. Three 100 g batches of ticagrelor granules were composed. The two last batches were duplicates in order to evaluate the granules both with Ludiflash and F-MELT in the tablet composition.

(29) TABLE-US-00003 TABLE 3 Composition of granulation batches Batch Component 5 6 7 Ticagrelor 95.0 95.0 95.0 Hydroxypropylcellulose 5.0 4.5 4.5 Silica, colloidal 0.5 0.5 anhydrous Water, purified.sup.a 30.0 30.0 30.0 .sup.aremoved during manufacturing process All values are weight percentages.

(30) The ticagrelor granules were included in two 500 g tablet batches, one containing Ludiflash and the other F-MELT, see Table 4 for the compositions. In order to further improve the disintegration time of the tablets, 5% of crospovidone was added to the formulation. Sodium stearyl fumarate and colloidal anhydrous silica were also included, as lubricant and glidant, respectively.

(31) Granulation of ticagrelor without colloidal anhydrous silica showed poor manufacturability. The powder adhered to the walls of the granulator and was subjected to caking formation. For that reason the ticagrelor granule batch without silica (Batch 5) was not evaluated for tablet compression. When 0.5% (w/w) of silica was added to the granulation blend the problem was decreased and the two other batches of ticagrelor granules could be evaluated in tablet compositions.

(32) TABLE-US-00004 TABLE 4 Composition of tablet batches Batch (granulation batch) Components 6 7 Ticagrelor granules 15.8 15.8 F-MELT type C 77.0 Ludiflash 77.0 Crospovidone 5.00 5.00 Sodium stearyl fumarate 2.00 2.00 Silica, colloidal anhydrous 0.20 0.20 All values are weight percentages.

(33) Table 5 summarises the results and observations from tablet compression of the two granules, blended with either Ludiflash or F-MELT and compares the results with the results of the two batches in Example 1, with either Ludiflash or F-MELT where ticagrelor was not granulated. The attributes of picking, sticking and flowability in Table 5 are visual observations during compression whereas the other four quality attributes are analysis of the manufactured tablets.

(34) Both F-MELT and Ludiflash compositions showed improved flowability when ticagrelor was granulated compared to the non-granulated powder blend in Example 1. This is reflected in the lower variability of tablet hardness and weight, see RSD-values in Table 5. Out of the two compositions including granules, the one containing F-MELT showed better flowability than the one containing Ludiflash, but both compositions provided tablets with disintegration of less than about 30 second and acceptable friability of less than 1%.

(35) Including granules of ticagrelor in the formulation reduced the risk of not meeting the CQA of uniformity of dosage unit and maintained the desired CQAs of assay (connected to a low friability) and disintegration. This finding supports the incorporation of a granulation step for ticagrelor in the manufacturing process for ticagrelor orodispersible tablets. Only F-melt was evaluated further as it showed better flowability than Ludiflash, as is evident from the improved RSD value for the hardness. The RSD value for the weight was also better for batches containing F-melt rather than Ludiflash, and this is further evidence of the improved flowability observed when using F-melt in place of Ludiflash.

(36) TABLE-US-00005 TABLE 5 Results and observations from Examples 1 and 2 Batch (explanation) 6 1 7 2 F-MELT F-MELT Ludiflash Ludiflash Quality attributes (gran) (DC) (gran) (DC) Picking/Sticking no no no no Flowability good poor moderate poor Hardness, n = 10 Average (N) 44.0 60.3 46.0 67.4 RSD (%) 6.8 21.6 21.3 27.2 Tablet weight, n = 10 Average (mg) 603.4 617.9 606.4 613.4 RSD (%) 1.95 4.35 2.57 3.54 Friability (%) 0.5 0.8 0.6 0.9 Disintegration (s), 28 28 29 28 n = 6

(37) Typically preferred RSD values for the hardness measurements are less than 20%. Typically preferred RSD values for the tablet weight measurements are less than 4.0%. Typically preferred friability values are less than 1.0%. Typically preferred disintegration times are less than 30 seconds.

Example 3Assessment of Granulation Composition

(38) The aim of this study was to build knowledge around, as well as improving the granulation and tablet composition. The granulation process was scaled up from 100 g to 500 g batches. The tablet batch size was still 500 g.

(39) Table 6 details the composition of the granulation batches included in the study. The granules contain different amount of ticagrelor, 95% (Batch 8), 64% (Batch 10) and 48% (Batch 9) were evaluated. In the last two of the three batches a part of the ticagrelor was exchanged to the filler mannitol, where a small sized grade was chosen in order to get homogenous granules.

(40) TABLE-US-00006 TABLE 6 Composition of granulation batches in Example 3 Batch Components 8 9 10 Ticagrelor 95.0 48.38 64.30 Mannitol 48.38 32.20 Hydroxypropylcellulose 4.50 3.00 3.00 Silica, colloidal anhydrous 0.50 0.25 0.50 Water, purified.sup.a 30.0 30.0 30.0 .sup.aRemoved during process. All values are weight percentages.

(41) The granulation batches were evaluated in subsequent tablet compression. Table 7 details the composition of the tablet batches included in the study. The tablet compression experiment was divided into two sub-experiments. The first was two tablet batches (Batches 9A and 10A) included granules of either 48% (from Batch 9) or 64% (from Batch 10) ticagrelor, respectively. Scale up of the 95% ticagrelor granules showed poor manufacturability in the granulation process step, and therefore these granules were not compressed into tablets, see section conclusions for details.

(42) Secondly, the granule containing 48% ticagrelor (Batch 9) was used for additional five tablet batches (Batches 9B to 9F) where the excipients in the tablet formulation were varied, see Table 7. In one batch colloidal anhydrous silica was excluded (Batch 9B), in one batch the amount of sodium stearyl fumarate was decreased from 1% (w/w) to 0.5% (Batch 9C), and in three batches the quality and quantity of disintegrant was examined. In Batch 9D the amount of disintegrant was increased from 5% (w/w) to 8%, in Batch 9E half the amount of crospovidone was exchanged to croscarmellose sodium, and in Batch 9F the crospovidone, which in all batches so far has been of a super fine particle size quality, was exchanged to a somewhat coarser quality of crospovidone. In the evaluation of the two crospovidone qualities, they are called crospovidone SF (as in super-fine) and crospovidone F (as in fine), respectively.

(43) TABLE-US-00007 TABLE 7 Composition of tablet batches Tablet batch (granulation batch included in the tablet composition) Components 9A 10A 9B 9C 9D 9E 9F Ticagrelor granules 31.0 23.3 31.0 31.0 31.0 31.0 31.0 F-MELT, type C 62.8 70.5 63.0 63.3 59.8 62.8 62.8 Crospovidone SF 5.00 5.00 5.00 5.00 8.00 2.50 Crospovidone F 5.00 Croscarmellose 2.50 sodium Sodium stearyl 1.00 1.00 1.00 0.50 1.00 1.00 1.00 fumarate Silica, colloidal 0.20 0.20 0.20 0.20 0.20 0.20 anhydrous All values are weight percentages.

(44) Scale up of the 95% ticagrelor granule composition (Batch 8) from 100 g to 500 g affected manufacturability during the granulation process step. A lot of material adhered to the vessel walls as well as to the impeller causing strong friction between the impeller and the bottom of the vessel. The process had to be stopped several times to scrape off material. It was judged that the composition would never work in production scale and therefore these granules where never compressed into tablets.

(45) Decreasing the amount of ticagrelor in the granule composition and instead adding mannitol as filler was found to improve the manufacturability, with less adhesion of material to vessel walls and impeller. It was still necessary to stop the process a few times and scrape off some material, but the composition was judged to be processable. Granules containing 64% (Batch 10) and 48% ticagrelor (Batch 9) with mannitol as filler were evaluated and the adhesion of material was more extensive when 64% ticagrelor was used. With granulation batches including 48% ticagrelor, just some material adhered to the vessel and impeller.

(46) Table 8 summarises the results and observations from tablet compression of the different granules. As for the visual observations during compression, the only two batches with manufacturability problems were Batch 9C, where the amount of lubricant was decreased from 1.0% to 0.5% (w/w) that showed moderate flowability and tendencies of picking and sticking, and Batch 9B, where no glidant was included in the formulation and poor flowability was observed during tablet compression. All other batches showed excellent manufacturability. It was therefore concluded that a proper amount of lubricant corresponds to 1.0% (w/w) where no sticking or picking tendencies were observed and the flowability was good and that the amount of silica should be 0.2% (w/w) in order to generate a powder blend with good flowability.

(47) Comparing tablet containing granules of 64% and 48% (w/w) ticagrelor, revealed that a higher amount of ticagrelor in the granules results in a slightly shorter disintegration time, see tablet Batch 9A and tablet Batch 10A. With a higher drug load in the granules, a smaller amount of granules is included in the tablet formulation (that should always carry a set amount of ticagrelor) and hence a larger amount of fast oral disintegrating excipient. Even though a short disintegration time is important for the product, it was decided that Batch 9 including 48% ticagrelor and mannitol as filler should be used for further formulation evaluation studies in view of the manufacturability problems shown in the granulation process step earlier.

(48) Comparing Batch 10A (5% crospovidone SF), with Batch 9D (8% crospovidone SF), Batch 9E (2.5% crospovidone SF and 2.5% croscarmellose sodium), and 9F (5% crospovidone F) revealed that an increase of the disintegrant from 5% to 8% did not shorten the disintegration time, on the contrary it increased from 28 to 43 seconds. Exchanging half of the disintegrant with croscarmellose sodium did not affect the disintegration time (both batches 28 seconds). However, exchanging crospovidone SF with crospovidone F shortened the disintegration time from 28 to 22 seconds and resulted in selection of crospovidone F for use in the tablet composition.

(49) TABLE-US-00008 TABLE 8 Observations and results from Example 3 9A 10A 9B 9C 9D 9F 48% 64% No 0.5% 8% 9E 5% Quality attributes gran gran glidant lubric. C-SF 2.5% + 2.5% C-F Flowability good good poor moderate good good good Picking/Sticking no no no yes no no no Hardness, n = 10 Average (N) 52.6 54.3 61.8 64.8 60.3 59.1 61.6 RSD (%) 3.68 3.29 12.2 4.80 9.90 8.41 5.11 Tablet weight, n = 10 Average (mg) 603.2 605.7 595.9 598.9 600.3 603.4 602.9 RSD (%) 0.51 0.49 1.26 0.52 0.99 0.82 0.52 Friability (%) 0.5 0.5 0.6 0.5 0.4 0.5 0.5 Disintegration (s), n = 6 31 28 38 29 43 28 22

(50) Typically preferred RSD values for the hardness measurements are less than 20%. Typically preferred RSD values for the tablet weight measurements are less than 4.0%. Typically preferred friability values are less than 1.0%. Typically preferred disintegration times are less than 30 seconds.

(51) In summary, the manufacturability of the ticagrelor granules was improved by lowering the ticagrelor content from 95% to 48%. Exchanging the crospovidone to a somewhat coarser quality gave a better margin to meeting the CQA of disintegration. With a lubricant content of 1.0% and a glidant content of 0.2% the flowability during tablet compression was assured and thereby the risk of not meeting the CQA of uniformity of dosage unit was decreased. Based on these results, the tablet composition of Batch 9F was selected for further evaluation, see Table 9.

(52) TABLE-US-00009 TABLE 9 Prototype composition of ticagrelor orodispersible tablet, 90 mg Quantity per Quantity per Components batch (%) tablet (mg) Function Ticagrelor.sup.a 15.0 90.0 Drug substance F-MELT, type C.sup.b,c 62.8 377 Filler Mannitol.sup.a 15.0 90.0 Filler Crospovidone.sup.b 5.00 30.0 Disintegrant Sodium stearyl fumarate.sup.b 1.00 6.00 Lubricant Hydroxypropylcellulose.sup.a 0.93 5.58 Binder Silica, colloidal 0.28 1.68 Glidant/anti- anhydrous.sup.a,b,d caking agent Water.sup.e qs qs Granulation liquid .sup.aIncluded in the granules. The granule consists of ticagrelor (48.4%), mannitol (48.4%), hydroxypropylcellulose (3.00%) silica (0.25%). .sup.bDry-mixed with the ticagrelor granules (31.25%) to form the final tablet composition. .sup.cF-MELT type C is a mixture formed by a co-spray drying of mannitol (65%), microcrystalline cellulose (18%), crospovidone (8%), xylitol (5%), and anhydrous dibasic calcium phosphate (4%) .sup.dtotal amount of silica, both intragranular (0.08%) and extragranular (0.20%). .sup.eRemoved during the manufacturing process qs quantum satis

Example 4Assessment of Disintegrant

(53) Since disintegration is one of the primary characteristics for an orodispersible tablet, Example 4 was set up in order to evaluate quantity and quality of disintegrant to be used.

(54) The lead composition from previous studies included 5% of the disintegrant crospovidone, of a fine particle size grade, here called crospovidone F[1]. It was compared to a crospovidone from another supplier, here called crospovidone F[2] (Table 10). Both have about the same particle size distribution. The amounts included were 0%, 2% and 5% (w/w) crospovidone and the amount was compensated with F-MELT type C in the composition. All batches contained the same batch of ticagrelor granules, with a composition as follows: 48.4% ticagrelor, 48.4% mannitol, 3.00% hydroxypropylcellulose, and 0.25% silica, all expressed in weight percentage.

(55) TABLE-US-00010 TABLE 10 Disintegrant in tablet batches Amount Batch Disintegrant (crospovidone) (wt %) 11 0.0 12 Crospovidone F [1] 5.0 13 Crospovidone F [2] 5.0 14 Crospovidone F [1] 2.0 15 Crospovidone F [2] 2.0

(56) Table 11 summaries the outcome of the disintegrant evaluation experiments in Example 4.

(57) TABLE-US-00011 TABLE 11 Observations and results Batch (quantity and quality of crospovidone) 11 12 13 14 15 Quality attributes 0% 5% F [1] 5% F [2] 2% F [1] 2% F [2] Flowability good good good good good Picking/Sticking no no no no no Hardness, n = 10 Average (N) 63.3 61.0 65.8 62.3 58.9 RSD (%) 7.06 6.73 10.1 4.59 5.04 Tablet weight, n = 10 Average (mg) 604.6 607.9 602.8 598.0 595.3 RSD (%) 0.74 0.68 1.10 0.48 0.50 Friability (%) 0.3 0.5 0.7 0.5 0.5 Disintegration (s), 29 26 25 21 21 n = 6 Dissolution at 45 min (%) 92.9 94.5 NT 94.3 NT at 60 min (%) 93.9 95.4 NT 95.2 NT NT not tested

(58) Typically preferred RSD values for the hardness measurements are less than 20%. Typically preferred RSD values for the tablet weight measurements are less than 4.0%. Typically preferred friability values are less than 1.0%. Typically preferred disintegration times are less than 30 seconds. Typically preferred dissolution thresholds are at least 75% at 45 min and at least 80% at 60 min.

(59) As can be seen all five batches showed good manufacturability with good flowability and no picking or sticking to tablet punches. The good flowability is reflected in the low variability in tablet hardness and weight (RSD-value) and all three quality attributes are good indicators for that the risk of not meeting the CQA of uniformity of dosage unit in production scale process is low. Disintegration was clearly affected by the amount of crospovidone. As can be seen 2% of either Crospovidone F[1] or Crospovidone F[2] gave the shortest disintegration time. Comparing dissolution of the tablets containing 0, 2 and 5% crospovidone F[1] revealed that the amount of crospovidone did not appear to have a major impact on the dissolution. In view of these findings it was decided that Crospovidone F[1] should continue to be included in the formulation and that the preferred quantity of crospovidone is closer to 2% than 5%.

Example 5Assessment of Tablet Composition

(60) The objective of this study was to investigate the tablet composition of the formulation. A 4+3 fractional factorial experimental design was carried out with three factors; amount of sodium stearyl fumarate, colloidal anhydrous silica and crospovidone.

(61) The compositions of the tablet batches in this study are detailed in Table 12. Crospovidone was varied between 1.0 to 4.0% (w/w), sodium stearyl fumarate between 1.0 to 3.0% (w/w) and finally silica between 0.2 to 0.6% (w/w). One granulation batch of 600 g was manufactured to support all tablet compositions in the study. The composition of the granules was as follows: 48.4% ticagrelor, 48.4% mannitol, 3.00% hydroxypropylcellulose, and 0.25% silica, all expressed in weight percentage.

(62) TABLE-US-00012 TABLE 12 Composition of tablet batches in Example 5 (% w/w) Batch Components 16 17 18 19 20 21 22 Ticagrelor granules 31.0 31.0 31.0 31.0 31.0 31.0 31.0 F-MELT, type C 63.8 64.8 66.4 61.4 64.1 64.1 64.1 Crospovidone 4.00 1.00 1.00 4.00 2.50 2.50 2.50 Sodium stearyl 1.00 3.00 1.00 3.00 2.00 2.00 2.00 fumarate Silica, colloidal anhyd. 0.20 0.20 0.60 0.60 0.40 0.40 0.40 Total 100 100 100 100 100 100 100 All values are weight percentages.

(63) The observations and results from the study are detailed in Table 13. Visual observations during tablet compression such as flowability and picking/sticking were noticed. The tablets were analysed for weight and hardness variation, friability, disintegration, and dissolution. The results were studied and compared individually as well as evaluated using the experimental design tool Modde (v 9.0 Umetrics AB, Sweden).

(64) As can be seen in Table 13 all seven batches showed good manufacturability with good flowability and no picking or sticking to tablet punches. The good flowability is reflected in the low variability in tablet hardness and weight (RSD-value). All batches met the preferred threshold value for friability.

(65) The results indicated that less of both crospovidone and sodium stearyl fumarate gives shorter disintegration time. The amount of silica did not significantly affect the disintegration time but both sodium stearyl fumarate and silica improved the flowability. Increased amount of both sodium stearyl fumarate and crospovidone gave slightly faster dissolution rate, although all complied with the preferred dissolution thresholds of Q=70 at 45 min and Q=75 at 60 min.

(66) TABLE-US-00013 TABLE 13 Observations and results Batch Quality attributes 16 17 18 19 20 21 22 Flowability good good good good good good good Picking/Sticking no no no no no no no Hardness, n = 10 Average (N) 45.8 55.4 54.1 47.2 49.6 52.3 55.0 RSD (%) 9.21 4.97 4.49 4.98 4.49 4.81 5.57 Tablet weight, n = 10 Average (mg) 593 604 599 602 592 605 607 RSD (%) 1.24 0.58 0.86 0.99 0.53 0.62 0.57 Friability (%) 0.5 0.5 0.5 0.5 0.5 0.3 0.5 Disintegration (s), n = 6 28 28 23 30 24 25 23 Dissolution at 45 min (%) 92.5 91.3 89.9 92.9 91.0 NT NT at 60 min (%) 93.2 92.0 90.8 93.8 91.8 NT NT NT not tested

(67) Typically preferred RSD values for the hardness measurements are less than 20%. Typically preferred RSD values for the tablet weight measurements are less than 4.0%. Typically preferred friability values are less than 1.0%. Typically preferred disintegration times are less than 30 seconds. Typically preferred dissolution thresholds are at least 75% at 45 min and at least 80% at 60 min.

(68) These findings lead to a tablet composition for further trials where the amount of crospovidone was lowered from 5.0% to 2.0% as it was shown to give the shortest disintegration time, and as both sodium stearyl fumarate and (extragranular) silica improved the flowability the amounts were slightly increased, for sodium stearyl fumarate from 1.00% to 1.50% and for silica from 0.20% to 0.40%.

Example 6Assessment of Granulation Composition and Drying Method

(69) In order to further investigate the composition of the granules a fractional factorial experimental design with 4+3 trials was carried out. The factors varied were amount of ticagrelor, hydroxypropylcellulose, and colloidal anhydrous silica.

(70) In the studies detailed in Examples 2 to 5, the granules have been tray dried. Duplicates of two trials were carried out where the granules were dried in a fluid bed drier in order to find out if that had any impact on the tablet quality. The use of fluid bed driers is typical in commercial scale manufacture.

(71) The compositions of the granulation trials in the study are detailed in Table 14 below. The content of ticagrelor was varied between 38 and 58%, hydroxypropylcellulose between 2 and 6%, and finally silica between 0.25 and 0.75%. As the tablet should always carry 90 mg ticagrelor, the composition of the tablet included between 25.9 and 39.5% of ticagrelor granules, see Table 15 below. The varying amount of granules was compensated with F-MELT type C in the tablet compositions. As for the other tablet excipients all tablets batches contained 2.0% crospovidone, 1.5% sodium stearyl fumarate and 0.4% silica. All expressed in weight percentage.

(72) TABLE-US-00014 TABLE 14 Composition of granule batches Batch (Trial number) 23 24 25 26 27 28 29 Components N1 N2 N3 N4 N5 N6 N7 Ticagrelor 38.0 58.0 38.0 58.0 48.0 48.0 48.0 Mannitol 59.25 39.75 55.75 35.25 47.50 47.50 47.50 Hydroxypropylcellulose 2.00 2.00 6.00 6.00 4.00 4.00 4.00 Silica, colloidal anhyd. 0.75 0.25 0.25 0.75 0.50 0.50 0.50 Total 100 100 100 100 100 100 100 All values are weight percentages.

(73) TABLE-US-00015 TABLE 15 Composition of tablet batches Batch (Trial number).sup.a 30 32 34 35 36 31 33 Components N1 N3 N5 N6 N7 N2 N4 Ticagrelor granules 39.47 31.25 25.86 F-MELT, type C 56.63 64.85 70.24 Crospovidone 2.00 2.00 2.00 Sodium stearyl 1.50 1.50 1.50 fumarate Silica, colloidal 0.40 0.40 0.40 anhyd. Total 100 100 100 .sup.aTrial Nos. N1 and N3 contains granules of 38% ticagrelor, number N5-N7 granules of 48% ticagrelor and number N2 and N4 granules of 58% ticagrelor. All values are weight percentages.

(74) Observations during the manufacturing process such as processability during granulation, and flowability as well as picking/sticking during tablet compression were noticed. The tablets were analysed for hardness, weight, friability, disintegration and dissolution. The results were studied and compared individually as well as evaluated using the experimental design tool Modde (v 9.0 Umetrics AB, Sweden). Table 16 summarise the outcome of the observations and results from Example 6.

(75) During the granulation process, increasing the amount of ticagrelor included in the granules lead to an increase in processing difficulty. The adhesive, cohesive and small sized ticagrelor particles tended to adhere to the walls of the granulator and it was necessary to stop the process and scrape off material from the walls a couple of times during the process. On the other hand, the results from the analysis of the tablets revealed that the larger the amount of ticagrelor in the granules the shorter the disintegration time of the tablets, which occurs as the inclusion of greater amounts of ticagrelor in the granules leads to the need for smaller amounts of granules being included in the tablet formulation and hence more F-MELT which helps the disintegration. These findings confirm the results from Example 3, where granules of 95%, 64% and 48% (w/w) ticagrelor were compared.

(76) The disintegration time was also decreased by adding a larger amount of hydroxypropylcellulose in the granules. This could be explained by that a larger amount of hydroxypropylcellulose makes the granules harder and less prone to crush during tablet compression. Crushing of granules would generate small particles that would bind to F-MELT and thereby increase the disintegration time. It was also shown that a larger amount of hydroxypropylcellulose slightly increased the dissolution rate of ticagrelor.

(77) As can be seen in Table 16 all batches showed good manufacturability with good flowability and no picking or sticking to tablet punches. The good flowability is reflected in the low variability in tablet hardness and weight (RSD-value), all indicating that the risk of not meeting the CQA of uniformity of dosage unit in production scale process is low. It is also noticed that all tablets met the preferred threshold values for friability.

(78) The amount of silica in the granules did not appear to impact the tablet quality, but as a larger amount facilitates the granulation process by reducing the adhesive and/or cohesive nature of ticagrelor particles it was decided that a larger amount of silica was to be included in the granules.

(79) After the study the following changes were made to the granulation composition. The amount of hydroxypropylcellulose was increased from 3.0 to 4.0% as it was shown that a higher amount shortened the disintegration time. The amount of silica in the granules was increased from 0.25% to 0.75% in order to reduce the adhesive and/or cohesive nature of ticagrelor particles. The amount of ticagrelor was not changed as a higher amount appeared to have a negative impact on the processability whereas a smaller amount appeared to have a negative impact on the disintegration time.

(80) TABLE-US-00016 TABLE 16 Observations and Results Batch (Trial No (amount ticagrelor in granules)) 30 31 32 33 34 35 36 N1 N2 N3 N4 N5 N6 N7 Quality attribute (38%) (58%) (38%) (58%) (48%) (48%) (48%) Flowability good good good good good good good Picking/Sticking no no no no no no no Hardness, n = 10 Average (N) 56.7 59.6 47.4 50.6 48.8 50.8 54.7 RSD (%) 8.64 4.36 5.70 5.73 6.97 5.91 5.30 Tablet weight, n = 10 Average (mg) 604.5 610.6 605.5 601.5 599.3 593.5 603.9 RSD (%) 0.61 0.24 0.54 0.53 0.55 0.62 0.63 Friability (%) 0.3 0.5 0.3 0.5 0.5 0.5 0.3 Disintegration (s), 31 22 26 23 24 26 23 n = 6 Dissolution at 45 min (%) 92.3 88.7 95.2 93.1 NT 93.7 NT at 60 min (%) 93.5 90.1 95.8 94.3 NT 94.5 NT NT not tested

(81) Typically preferred RSD values for the hardness measurements are less than 20%. Typically preferred RSD values for the tablet weight measurements are less than 4.0%. Typically preferred friability values are less than 1.0%. Typically preferred disintegration times are less than 30 seconds. Typically preferred dissolution thresholds are at least 75% at 45 min and at least 80% at 60 min.

(82) Tables 17 and 18 below show the analysis of the granules and tablets containing the granules that were either tray dried or fluid bed dried. The granules in N1 and N1b contain 38% ticagrelor, whereas the granules in N4 and N4b contain 58% ticagrelor. N1 and N4 are tray dried and N1b and N4b are fluid bed dried. As can be seen in Table 17, N4 and N4b have a larger particle size distribution than N1 and N1b but in both cases does fluid bed drying generate smaller particles than tray drying which also results in a higher Carr's index for both the fluid bed dried granules. On the other hand the two drying methods generate no major difference in tablet quality, see Table 18. Hence it was found that fluid bed drying is potentially suitable for commercial manufacturing without significantly affecting tablet quality.

(83) TABLE-US-00017 TABLE 17 Comparing tray dried and fluid bed dried granules Granule Batch 23 23A 26 26A Trial No N1 N1b.sup.a N4 N4b.sup.a Carr's index (%) 29.1 32.0 31.3 33.3 Particle size distribution d (0.1) 8.05 6.64 7.70 7.18 d (0.5) 73.0 57.3 194 132 d (0.9) 874 709 1168 1020 .sup.aTrial Nos. N1b and N4b contain fluid bed dried granules (Trial Nos. N1 and N4 contain tray dried granules)

(84) TABLE-US-00018 TABLE 18 Comparing tablets containing either tray dried or fluid bed dried granules Tablet Batch 30 30A 33 33A Trial No N1 N1b.sup.a N4 N4b.sup.a Flowability good good good good Picking/Sticking no no no no Hardness, n = 10 Average (N) 56.7 55.8 50.6 56.8 RSD (%) 8.64 9.89 5.73 5.85 Tablet weight, n = 10 Average (mg) 604.5 614.5 601.5 610.9 RSD (%) 0.61 1.28 0.53 0.70 Friability (%) 0.30 0.45 0.45 0.30 Disintegration (s), n = 6 31 30 23 26 Dissolution at 45 min 92.6 91.8 93.1 91.3 (%) .sup.aN1b and N4b contain fluid bed dried granules (N1 and N4 contain tray dried granules)

Example 7Tablet Compositions

(85) The composition shown in Table 19A has been prepared and is intended to illustrate the invention.

(86) TABLE-US-00019 TABLE 19A 90 mg Ticagrelor Tablet Composition Quantity per Quantity per tablet Ingredient batch (%) (mg) Ticagrelor.sup.a 15.0 90.0 F-MELT type C.sup.b,c 64.8 389 Mannitol.sup.a 14.8 88.6 Crospovidone.sup.b 2.00 12.0 Sodium stearyl fumarate.sup.b 1.50 9.00 Hydroxypropylcellulose.sup.a 1.25 7.50 Silica, colloidal 0.63 3.81 anhydrous.sup.a,b,d Core tablet weight 100 600 .sup.aIncluded in the granules. The granule consists of ticagrelor (48.0%), mannitol (47.25%), hydroxypropylcellulose (4.00%) silica (0.75%). .sup.bDry-mixed with the ticagrelor granules (31.25%) to form the final tablet composition. .sup.cF-MELT type C is a mixture formed by a co-spray drying of mannitol (65%), microcrystalline cellulose (18%), crospovidone (8%), xylitol (5%), and anhydrous dibasic calcium phosphate (4%) .sup.dtotal amount of silica, both intragranular (0.23%) and extragranular (0.40%). .sup.eRemoved during the manufacturing process qs quantum satis

(87) The composition shown in Table 19B may also be prepared.

(88) TABLE-US-00020 TABLE 19B 60 mg Ticagrelor Tablet Composition Quantity per Quantity per tablet Ingredient batch (%) (mg) Ticagrelor.sup.a 15.0 60.0 F-MELT type C.sup.b,c 64.8 259 Mannitol.sup.a 14.8 59.1 Crospovidone.sup.b 2.00 8.00 Sodium stearyl fumarate.sup.b 1.50 6.00 Hydroxypropylcellulose.sup.a 1.25 5.00 Silica, colloidal 0.63 2.54 anhydrous.sup.a,b,d Core tablet weight 100 400 .sup.aIncluded in the granules. The granule consists of ticagrelor (48.0%), mannitol (47.25%), hydroxypropylcellulose (4.00%) silica (0.75%). .sup.bDry-mixed with the ticagrelor granules (31.25%) to form the final tablet composition. .sup.cF-MELT type C is a mixture formed by a co-spray drying of mannitol (65%), microcrystalline cellulose (18%), crospovidone (8%), xylitol (5%), and anhydrous dibasic calcium phosphate (4%) .sup.dtotal amount of silica, both intragranular (0.23%) and extragranular (0.40%). .sup.eRemoved during the manufacturing process qs quantum satis

Example 8Tablet Manufacture

(89) 600 mg tablets containing 90 mg ticagrelor, according to Example 7, were manufactured according to the following method. Silica, colloidal anhydrous, ticagrelor, hydroxypropylcellulose and mannitol were dry mixed in a high shear mixer for about 5 minutes to give a total mass of 9 kg of dry ingredients. Then, a wet granulation was carried out by adding a granulating liquid (water, 18.4% (w/w)) to the dry ingredients. The wet granule mix was milled in a rotating impeller screening mill and then dried in a fluid bed dryer with an inlet air drying temperature of 50 C. This was followed by milling in a rotating impeller screening mill. Final blending was performed in a diffusion mixer. Ticagrelor-containing granules, silica, colloidal anhydrous, F-MELT type C, crospovidone and sodium stearyl fumarate were then blended together for about 20 minutes. The final blend was compressed into tablets using a power assisted tablet press.

(90) Tablet compaction forces of between 7.9 kN and 13.1 kN were found to be sufficient to provide tablets having an appropriate hardness (approximately 65N). These tablets had acceptable disintegration time, dissolution rate, hardness, and friability values.

(91) This process has also been scaled up using batch sizes of the final blend in the region of 256 kg. These tablets also had acceptable disintegration time, dissolution rate, hardness, and friability values.

Example 9Assessment of Drug Particle Size and Manufacturing Parameters on Tablet Properties

(92) The impact of (i) drug substance particle size, (ii) granulation liquid amount and (iii) water addition time on tablet manufacture were evaluated. The tablet composition was in accordance with Example 7, and the manufacturing method was in line with Example 8 except where specified otherwise. The tablets produced in this study were round and flat bevelled edged, 14 mm in size. 8 out of the 10 batches tested were also embossed.

(93) Two drug substance batches were selected with a low and high D (v, 0.9) value. The water addition time was varied by using 2 or 4 spray nozzles. The experimental design is outlined in Table 20. The major responses were assay, Acceptance Value (AV) for content variation, disintegration and dissolution.

(94) TABLE-US-00021 TABLE 20 Experimental design for the granulation step Drug substance Water addition particle size, Water Calculated time, Number Batch D (v, 0.9), m amount, kg minutes of nozzles 37 22 10 4.3 4 38 11 12 10.3 2 39 22 10 4.3 4 40 22 10 8.6 2 41 11 10 8.6 2 42 11 12 5.2 4 43 22 12 5.2 4 44 11 10 4.3 4 45 11 12 10.3 2 46 22 12 10.3 2

(95) All batches were sampled at three or four different compaction forces prior to commencing tablet batch compression. In addition, disintegration was analysed for each compaction force. Tablet hardness was tested as diametric compression breaking force.

(96) The sample tablets were withdrawn for UoDU from a composite sample and the AV value was calculated.

(97) In addition, the tablets were sampled and analysed according to the method proposed by Garcia (Garcia, Thomas et. al. Recommendations for the assessment of blend and content uniformity: modifications to withdrawn FDA draft stratified sampling guidance, J. Pharm. Innov., 2014, (DOI) 10.1007/s12247-014-9207-0), see below. Samples from 40 locations were withdrawn, 20 locations were selected for analysis (n=3). The samples were assayed for 4 of the 10 batches.

(98) To meet the acceptance criteria for blend uniformity, according to Garcia, the RSD of all individual results should be 3.0% (n=1 on 10 locations) or 5.0% (n=3 on 10 locations provided that the reason is not of analytical or sampling error). This criterion was used to gain knowledge to assess homogeneity.

(99) Sampling and analysis for appearance was performed at 4 to 5 occasions. For disintegration and friability sampling and analysis was performed at approximately 5 occasions.

(100) Analyses of dissolution were performed from a composite sample.

(101) Final Blend

(102) The overall objective of the final blend is to produce a uniform blend which can be compressed into tablets consistently containing the required dose of ticagrelor. Four batches were analysed, comprising trials with low/high water amount, small/large particle size drug substance and short/long water addition time. The results of the powder blend uniformity, shown in Table 21, confirms that the powder blend is adequately homogenous after final blend.

(103) TABLE-US-00022 TABLE 21 Final blend assay Assay, % Minimum, % of Maximum, % of Batch of nominal nominal nominal SD, % of target 39 96.9 93.3 101.0 2.4 53 98.1 95.6 100.2 1.4 44 98.3 95.2 102.2 2.4 46 99.1 95.4 103.5 2.5

(104) Tablet Compression

(105) The purpose of this unit operation was to compress the blended powder into tablets that consistently provide the target CQAs. Tablet properties results include assay and UoDU, weight, hardness, thickness, friability, disintegration and dissolution.

(106) Assay and Uniformity of Dosage Units

(107) In order to assess UoDU more thoroughly an assessment based on the method suggested by Garcia was used: All individual assay results should be within the range of 75.0% to 125.0% of target strength. Pass the ASTM E2709/E2810 using an acceptance criterion of 90% confidence and 95% coverage for the total number of dosage units assayed.

(108) All batches that were evaluated with this method were successful in meeting the criteria, see Table 22.

(109) TABLE-US-00023 TABLE 22 Individual Assay and acceptance test of ASTM E2709/E2810 Accept- Pass sample ance Min. Max. or Fail loca- Average, interval individual individual accept- tions % of for tablets, % tablets, % ance Batch assayed nominal average.sup.a of nominal of nominal test 39 20 97.2 94.1-105.9 93.0 104.6 Pass 53 20 97.4 96.2-103.8 90.5 106.8 Pass 44 20 98.8 90.8-109.2 95.4 103.7 Pass 46 40 97.8 96.2-103.8 87.5 107.1 Pass .sup.aCalculated interval for batch mean that would pass the acceptance test, based on the number of assayed tablets and their content distribution.

(110) The assay results are shown in Table 23. The results show that all batches except one were within an assay interval of 95% to 105%.

(111) TABLE-US-00024 TABLE 23 Assay Average, % Min, % of Max, % of Batch Sample of nominal nominal nominal RSD, % 37 Composite 97.2 94.6 101.7 2.2 38 Composite 98.6 92.8 109.0 4.7 39 Composite 94.5 88.4 97.2 3 40 Composite 98.1 90.2 102.8 3.4 41 Composite 97.4 92.4 100.5 2.1 42 Composite 100.6 94.5 107.1 4.4 43 Composite 97.4 93.2 101.8 2.9 44 Composite 99.4 97.1 102.9 2 45 Composite 95.4 91.1 98.8 2.8 46 Composite 97.5 91.1 98.8 3.3

(112) Tablet Weight

(113) The results are shown in Table 24 below. The batches were within 571 mg to 615 mg and had a mean value between 597 and 602 mg. The low variation in tablet weight indicates good powder flow which contributes to the ability of consequently deliver the right amount of ticagrelor in the final product.

(114) TABLE-US-00025 TABLE 24 Tablet weights Batch Mean, mg Min, mg Max, mg RSD, % 37 597 571 614 1.0 38 599 587 608 0.8 39 598 584 607 0.9 40 597 583 604 0.7 41 598 586 610 0.9 42 601 587 615 0.9 43 599 580 613 0.9 44 602 586 613 0.8 45 600 584 610 1.0 46 600 588 611 0.9

(115) Tablet Hardness, Thickness, Friability, and Disintegration

(116) The tablet hardness and disintegration in relation to compaction force was studied by obtaining a compaction profile for each batch, see Table 25.

(117) TABLE-US-00026 TABLE 25 Disintegration time in seconds (n = 6) as a function of compaction force Batch 8 kN 11 kN 14 kN 37 20 23 26 38 24 22 26 39 21 23 28 40 21 26 29 41 18 19 23 42 18 18 18 43 19 21 21 44 23 24 29 45 18 20 22 46 16 18 24

(118) The compaction forces needed to obtain a hardness of 65N were between 7.9 kN to 13.1 kN between the batches. It was found that the more fine sized material, measured as D (v, 0.1) in the drug substance granules the lower the compaction force was to achieve the same tablet hardness, here 65 N.

(119) The tablet disintegration time for all batches during the continuous tablet compression run was below the CQA target of 30 seconds. The disintegration dependence of compaction force is shown in Table 25 above. There is a slight curvature with a minimum approximately at the press force used for each batch.

(120) During the continuous batch manufacture the tablet average hardness and friability were monitored. The results are shown in Table 26.

(121) TABLE-US-00027 TABLE 26 Tablet hardness, friability and thickness Mean Min Max RSD Friability Thickness, Batch (N) (N) (N) (%) (%, n = 11) mm RSD, % 37 67 51 73 7.5 0.1 3.80 0.6 38 66 57 74 6.6 0.1 3.70 0.3 39 61 46 72 8.2 <0.1 3.85 0.4 40 64 51 71 7.5 <0.1 3.80 0.3 41 64 56 70 6.7 <0.1 3.78 0.5 42 63 55 75 8.3 <0.1 3.76 0.4 43 61 50 67 7.4 <0.1 3.83 0.6 44 64 57 70 5.2 0.1 3.84 0.4 45 63 49 70 8.3 <0.1 3.75 0.3 46 68 58 84 8.6 0.1 3.75 0.3

(122) The tablet friability was 0.1% or less which is low in comparison with the requirement in the pharmacopeia (<1.0%). The disintegration time was below the CQA target for all batches.

(123) The results show only a small variation between and within batches. The height was 3.7 to 3.8 mm in general. The slightly greater thickness in these tablets compared to earlier tested tablets is due to a short granulation time and low granulation liquid amount, which gives less dense granules and smaller particle sizes. Less compaction is needed to obtain the target hardness of 65 N used for these studies, hence the slightly thicker tablet.

(124) To conclude, the low variation in tablet height is an indicator of the product robustness with respect to the evaluated changes of scale, process parameter settings and drug substance particle size.

(125) Tablet Appearance

(126) The appearance of the tablets was visually assessed. Edge damage related to the adjustment of the scrape off mechanism was discovered in a few cases, after the adjustment damages disappeared. Hardly visible spots of slightly pink colour have been seen in one case and were most likely related to the drug substance colour. Overall there were no observations of picking, sticking, capping or lamination for any of the batches.

(127) Tablet Dissolution

(128) The amount of dissolved ticagrelor after 45 and 60 minutes is summarised in Table 27.

(129) TABLE-US-00028 TABLE 27 Dissolution at 45 and 60 minutes, % of label claim, (n = 6) Mean Min Max Mean Min Max Batch 45 minutes 60 minutes 37 83 81 87 85 83 89 38 82 80 84 85 82 87 39 84 82 88 86 84 90 40 81 79 83 83 81 85 41 85 80 88 87 82 90 42 84 81 88 86 83 91 43 85 80 87 87 84 89 44 89 87 92 91 89 94 45 84 81 88 87 84 92 46 83 82 86 85 84 89

(130) The amount of dissolved ticagrelor met the target in all batches. It was noted that the granulation factors that were evaluated influenced the dissolution rate slightly. Increased dissolution appears to come from a short granulation time, a low amount of granulation liquid and a drug substance with small particle size.

(131) Conclusion of Tablet Compression

(132) The results show that tablet compression step is adequate to compress the blended powder into tablets that provide the target Critical Quality Attributes (CQAs). In addition, the use of punch tools with embossing in this study appeared to have no impact on the tablet quality.

Example 10Assessment of Tablet Dissolution Mechanism

(133) Focused beam reflectance measurements were conducted on a series of ticagrelor granules and F-melt type C granules, each with a range of particle sizes.

(134) Tablet Dissolution Mechanism

(135) In the FBRM apparatus, the probe diameter was approximately 6 mm and had a sapphire window at the probe end. The integration time was set to 5 seconds. The instrument was set on coarse mode and focal spot scan rate on 2 m/sec. The probe was placed 2 cm above the paddle and slightly tilted towards the flow. The primary data set contains full particle size distributions 1-1000 m at 5 sec time resolution. From that dataset kinetic curves were calculated showing different size fractions and the fraction 40-100 m was the fraction selected for comparison. This fraction was selected since the amount of counts was higher for this fraction. In addition, the variability in between the kinetic profiles was low for the fractions with larger amounts of counts.

(136) The measurements were conducted with a UV probe that was placed in the bath having a 2 mm gap. Dissolution media was 900 ml of water with 0.2% tween 80. 75 rpm paddle speed. In addition a FBRM probe was placed in the bath in order to simultaneously measure the particles in the bath.

(137) The results are shown in FIGS. 4 and 5.

(138) The FBRM results in FIG. 4 show different particle size fractions from API granules in the dissolution bath. For all sizes the amount of counts are initially increasing in the bath and thereafter decreasing to only a few percent after 60 min. The initial increase in counts depend on that the granules are added to the bath at time zero and the kinetic of dissolving the particles is slower than the time it takes for the particles to be distributed in the bath. The time where the peak of counts appear would probably be different dependent on the way and time the granules are added to the bath and hence it is not relevant where on the time-axis the peak appears. However, the kinetics of the decreasing slopes indicates at what rate the particles dissolve and hence it can be seen that the dissolution of particles is faster during the first 30 min and thereafter the kinetic is slower.

(139) The FBRM results in FIG. 5 show different particle size fractions from F-melt in the dissolution bath. For all sizes an initial increase in amount of particles can be seen during the first minutes, thereafter a small decrease during a few minutes before the number of counts stays at a somewhat constant value. The initial increase in counts depends on that the granules are added to the bath at time zero. However, the almost constant value of particles after that indicates that the dissolution of the F-melt particles is happening quite fast, during the first minutes and simultaneously as the particles are distributed in the bath and therefore a further decrease in counts of particles is not observed. This seems to be in line with the material of F-melt that to a large extent contains spray dried mannitol and hence is designed to dissolve fast.

(140) In summary, tablet dissolution is found to be dominated by the API granule properties, whereas F-Melt is causing the rapid disintegration typical of an orodispersible tablet. It is therefore important to prevent aggregation of the API particles during disintegration and dissolution.

(141) Influence of Storage

(142) Model granules containing ticagrelor were stored in 40 C. at 75% relative humidity (RH) for 1 month in order to study the dissolution behaviour using the FBRM method described above. Fresh, i.e. non-stored (model), granules were prepared for comparison. The results are shown in FIGS. 6 and 7. Ticagrelor particles were received from three different suppliers: supplier 1 (AZ); supplier 2 (DSM); supplier 3 (Omnichem).

(143) For both the model granule batch and the stored granule batch containing ticagrelor supplied by AZ, both profiles show an increase in particles followed by a decrease in counts. However, for the material that has been stored at 40 C. and 75% RH for one month, a slower particle dissolution is observed. In addition, there are more particles left in the bath after 60 mins from the stored material. A similar overall pattern was observed for the material supplied by the other suppliers. The slower particle dissolution from the material that had been stored correlates to the release rates of ticagrelor. A comparison of the data shown in FIGS. 6 and 7 shows that ticagrelor has a slower release from granules that have been in storage for one month compared to the non-stored granules.

(144) In summary, it was found that the behaviour of the model granules containing ticagrelor following storage matched that of the aged tablets. From this, it was concluded that the drug granules cause dissolution changes in aged in tablets.

Example 11Effect of Storage on Drug Granule Porosity

(145) The pore volume and the pore size distribution were determined using mercury intrusion porosimetry (Micromeritics AutoPore III 9410). The determination was performed within the pore diameter interval 115 m0.0030 m (30 ). The surface tension and the contact angle of mercury are set to 485 mN/m and 130, respectively. Blank correction has been used to compensate for compaction of parts of the penetrometer system at high pressures. The test materials used were: ticagrelor granules (3606), final tablet blend (3606 FB); F-melt type C granules (F-melt); Ticagrelor particles from supplier 1 (AZ); Ticagrelor particles from supplier 2 (DSM); Ticagrelor particles from supplier 3 (Omnichem).

(146) To ensure that the porosimeter shows correct intrusion a test with an alumina silica reference material was done prior to the analyses. One of the penetrometers used for analysis of the granules was used for the reference test. The result gave a cumulative pore volume of 0.55 cm.sup.3/g and a median pore diameter (based on volume) of 73 . The reference values are 0.560.02 cm.sup.3/g and 755 , respectively. Results are shown in Table 28.

(147) TABLE-US-00029 TABLE 28 Hg porosity data for test materials before and after storage (1 month at 40 C./75% RH) Median Median pore Pore pore diameter Pore volume, diameter (area), area, cm.sup.3/g (vol), m m/ m.sup.2/g Specimen >8 <8 >8 <8 >8 <8 >8 <8 Pre- 3606 0.53 0.22 41 0.6 28 42 <0.1 10 storage 3606 FB 0.67 0.28 29 1.8 20 43 0.1 10 AZ 0.62 0.23 24 0.9 21 45 0.1 14 DSM 0.59 0.28 19 1.2 15 44 0.1 13 Omnichem 0.53 0.28 35 0.5 26 41 <0.1 12 F-melt 0.76 0.23 25 2.9 19 41 0.1 3 Post- 3606 0.55 0.20 40 0.6 24 39 <0.1 8 storage 3606 FB 0.69 0.26 35 1.7 28 40 <0.1 8 (1 AZ 0.69 0.23 27 1.1 21 41 0.1 14 month) DSM 0.64 0.29 20 1.5 16 41 0.1 12 Omnichem 0.61 0.18 36 0.5 26 38 <0.1 9 F-melt 0.80 0.21 28 1.6 23 44 0.1 5

(148) Hg porosity data for granules coupled with the data in Example 10 indicates that decreased porosity and/or increased aggregation causes a decrease in the dissolution rate for aged tablets. Drug particle size and particle surface properties appear to interact with wet granulation process parameters resulting in a specific aggregation size distribution, which in turn affects tablet dissolution.

Example 12Effect of Particle Size on Dissolution Following Storage

(149) Four tablet batches were assessed to study the effects of particle size on tablet dissolution rates before and after storage.

(150) The tablets were made according to the composition in Example 7. Parameters associated with the API (D (v, 0.9)) and the tablet manufacture (granulation fluid and mixing time) are shown in Table 29.

(151) TABLE-US-00030 TABLE 29 effect of porosity on dissolution following storage Batch 38 40 43 44 DOE local. D (v, 0.9) D (v, 0.9) D (v, 0.9) D (v, 0.9) 11 m 22 m 22 m 11 m 12 kg H.sub.2O 10 kg H.sub.2O 12 kg H.sub.2O 10 kg H.sub.2O 10 min 8.6 min 5.2 min 4.3 min Dissolution data 0 month data, 82.9 83.4 84.0 86.7 45 min 40 C., 75RH, 72.0 73.1 73.0 77.8 1 month open, 45 min 40 C., 75RH, 76.0 77.0 77.9 81.0 1 month closed, 45 min Porosity data Porosity (<8 um 0.411 0.588 0.516 0.572 0 month data

(152) The reduction in dissolution following 1 month of storage was typically no more than about 10 to 11%, though in Batch 44 the reduction was about 7%.

Example 13Effect of Ticagelor Particle Size and Surface Properties

(153) This study was conducted to assess the possible effects of raw material variability between suppliers, mainly physical characteristics such as particle size/habit and surface properties on tablet quality and disintegration time.

(154) The batches of drug substances tested are shown in Table 30.

(155) TABLE-US-00031 TABLE 30 Drug substance batches Particle Size (m) Supplier Batch D (v, 0.1)/D (v, 0.5)/D (v, 0.9) AZ Ops (EFA) 128 3/8/19 AAUA 3/7/18 AAAU 3/7/18 AAAS 3/8/23 Omnichem (AOC) 605770005 2/5/13 605770021A 2/6/14 DSM LHCYAA4005 3/5/9 LHCYAA5002 3/6/10

(156) TOF-SIMS surface characterization was conducted on the various drug batches. TOF-SIMS spectra were acquired in positive and negative ion modes in high mass resolution mode for all powders. TOF.SIMS (ION-TOF GmbH, Germany) was used for the experiments. 30 keV Bi.sub.3.sup.+ ion clusters were the primary ions. An electron flood gun was used for charge compensation of the sample surface.

(157) The samples were analysed as-received by dropping the powder from a mini-spatula onto double-sided tape on a 1 cm.sup.2 aluminium plate. The plates were vibrated to allow the powders to settle onto the tape. The excess powder was blown away by clean CO.sub.2. These samples were: batch 12801, batch AAAU, Omnichem batch 300000-01, and DSM batch LHCYAA4005. In addition to being analysed as received, DSM batch LHCYAA4005 was cryomilled by hand in a mortar filled with liquid nitrogen to expose the interior of the particles. The cryomilled powder which resulted was mounted as with the as-received powders.

(158) The high mass resolution spectra of the as-received samples were obtained from 500 m500 m areas with 128128 pixels. The high mass resolution spectra of the cryomilled powder were obtained from 200 m200 m areas with 6464 pixels. The nominal primary beam size in high mass resolution mode is approximately 5-6 m.

(159) Additionally, high spatial resolution images were obtained of the DSM batch LHCYAA4005 powder before and after cryomilling. The high spatial resolution images were 200 m200 m (at 10241024 pixels) for the as-received sample and 100 m100 m (at 512512 pixels) for the cryomilled sample. Thus, all images were matched to the nominal 0.2 m primary beam diameter of high spatial resolution mode.

(160) The data analysis was performed using the software provided by the instrument supplier (Surface Lab 6.3, Measurement Explorer, ION-TOF GmbH, Germany).

(161) Particle Size Distribution: about 3 ml dry powder was measured at 0.1 bar using a Malvern Mastersizer 2000.

(162) Ticagrelor powders are characterised by poor flowability, for example as indicated by a large Hausner ratio (tap density/bulk density 1.8-2.0). Particle size distributions (PSD) typical for the three drug substance manufacturers are given in Table 30.

(163) The larger D (v, 0.9) size fraction detected for AZ Ops supply corresponds to a more extended particle habit which, in turn, gives the lowest flowability (highest Hausner ratio).

(164) For the ticagrelor rapidly disintegrating formulation, drug substance variability is likely to be important to control in the formulations.

(165) In addition to drug substance PSD variations, it is believed that ticagrelor surface properties of different batches may also contribute to the tablet attributes, especially dissolution rate. TOF-SIMS analysis of a various batches of drug revealed a slightly different surface composition for one batch from DSM in comparison to AZ Ops and Omnichem materials.

(166) In summary, it is important to control the physical properties of the drug in order to obtain a robust large-scale manufacturing process. Variations in particle habit and potentially particle surface properties were judged to be particularly capable of affecting the properties of the final product.

Example 14Assessment of Tablet Stability

(167) The effects of storage on the tablets of Example 7 were studied following both open storage under various conditions, as well as storage in aluminium/aluminium blister packs with aluminium laminate form foil and aluminium lid foil (Al/Al blister). The tablets were manufactured using a process in line with that in Example 8 above.

(168) Investigational Stress Stability Study

(169) The performance of ticagrelor orodispersible tablets under stressed open conditions has been demonstrated during development. The study exposed ticagrelor orodispersible tablets in an open dish to different temperature and humidity conditions. By storing the tablets in an open dish they were subject to additional humidity stress than would be encountered when packaged in Al/Al blister.

(170) Stability Protocol

(171) Storage Conditions and Sampling Protocols

(172) The primary stability batches and the supportive batch have been stored in accordance with ICH guideline Q1A. Details of the sampling time points for each condition are presented in Table 31.

(173) TABLE-US-00032 TABLE 31 Sampling and storage protocol for primary stability studies Storage condition Time (months) ( C./% RH)/container 0.5 3 6 9 12 5 - control (+) (+) (+) (+) 25/60 - blister + + + + 25/60 - bulk + + + + 40/75 - blister + + 40/75 - bulk + + 50/AH - blister + Photo stability.sup.a + RH Relative Humidity. AH Ambient Humidity. + Sample tested to appropriate schedule. No sampling. Blister Al/Al blisters. Bulk Al bags 5 C. Control sample to be used as a reference sample when performing the description test. ( ) Optional testing if changes seen at other conditions. .sup.a1.2 million lux-hours of visible light and 200 watt-hour/m.sup.2 UV light; stressed condition. Tested on tablets stored in open dish covered with aluminium foil.

(174) Temperature is controlled to 2 C. and humidity is controlled to 5% RH. The investigational stability batch have been stored in open dish for up to 1 month in the following climates 25 C./60% RH, 30 C./65% RH, 40 C./75% RH and 50 C./amb.

(175) Photo Stability

(176) Photo stability has been performed on one batch from the primary stability study in accordance with ICHQ1B.

(177) Stability Tests and Acceptance Limits

(178) The stability of ticagrelor orodispersible tablets 90 mg has been assessed by monitoring appropriate chemical and physical characteristics during the stability study. Testing performed included: assay by HPLC, degradation products by HPLC, disintegration, dissolution (0.2% Tween 80), microbial limits and tablet hardness. Microbial limits testing was applied at 6 month for 40 C./75% RH and at 12, 24 and 36 month time point for 25 C./60% RH in the ICH primary stability studies of the Al/Al blister.

(179) Results

(180) The ICH primary stability data and the supportive stability data obtained for tablets of Example 7 in Aluminium/Aluminium (Al/Al) blister packs are presented in Tables 32 to 39.

(181) The ICH pivotal photo stability data obtained for tablets of Example 7 stored in open dish directly exposed to light are presented in Table 40.

(182) The stability of tablets of Example 7 was tested at stressed conditions, 50 C./ambient humidity (amb) for up to 3 months in Al/Al blister. The results of this study are presented in Tables 41 to 44.

(183) The stability of tablets of Example 7 was tested at stressed conditions, open storage (investigational study) for up to 1 month in different climates. The results can be found in Tables 45 to 48. The stability of tablets of Example 7 stored in a 4 layered aluminium bag (Al bag, bulk pack) was tested under various conditions for up to 6 months. The results can be found in Tables 49 to 54.

(184) TABLE-US-00033 TABLE 32 Stability data for 25 C./60% RH of tablets, Batch 51, stored in Al/Al blisters Stability pull times (months) Test Initial 3 6 9 12 Description White, circular, NCH NCH NCH NCH convex tablet Assay 100 100 100 100 98 (% label claim) Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 <0.05 <0.05 Disintegration 15-28 21-27 21-31 19-33 19-29 (seconds) Dissolution (% label claim) Mean (45 min) 85 85 92 86 85 Range (45 min) 83-88 84-87 91-93 84-87 84-86 Mean (60 min) 88 90 95 89 88 Range (60 min) 86-91 89-91 93-96 88-91 87-90 Water content 0.88 0.87 0.87 0.87 0.90 (% (w/w)) Hardness (N) 62 65 57 65 56 Mean Range 48-79 53-82 48-64 50-88 45-76 Microbial Complies NT NT NT Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(185) TABLE-US-00034 TABLE 33 Stability data for 40 C./75% RH of tablets, Batch 51, stored in Al/Al blisters Time (months) Test Initial 3 6 Description White, circular, NCH NCH biconvex tablet Assay 100 98 99 (% label claim) Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration 15-28 17-35 17-23 (seconds) Dissolution (% label claim) Mean (45 min) 85 78 88 Range (45 min) 83-88 77-79 85-92 Mean (60 min) 88 83 92 Range (60 min) 86-91 82-83 89-95 Water content 0.88 0.86 0.89 (% (w/w)) Hardness (N) 62 58 60 Mean Range 48-79 40-81 46-76 Microbial Complies NT Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(186) TABLE-US-00035 TABLE 34 Stability data for 25 C./60% RH of tablets, Batch 52, stored in Al/Al blisters Time (months) Test Initial 3 6 9 12 Description White, circular, NCH NCH NCH NCH biconvex tablet Assay 99 101 101 101 98 (% label claim) Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 <0.05 <0.05 Disintegration 15-25 16-44 19-31 19-39 23-24 (seconds) Dissolution (% label claim) Mean (45 min) 83 79 86 80 77 Range (45 min) 79-85 77-81 85-89 79-80 76-79 Mean (60 min) 87 84 91 84 82 Range (60 min) 83-89 82-85 89-93 84-85 80-83 Water content 0.82 0.80 0.80 0.82 0.83 (% (w/w)) Hardness (N) 72 81 76 67 64 Mean Range 55-90 66-91 62-86 46-83 54-81 Microbial Complies NT NT NT Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(187) TABLE-US-00036 TABLE 35 Stability data for 40 C./75% RH of tablets, Batch 52, stored in Al/Al blisters Time (months) Test Initial 3 6 Description White, circular, NCH NCH biconvex tablet Assay 99 101 102 (% label claim) Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration 15-25 17-22 13-50 (seconds) Dissolution (% label claim) Mean (45 min) 83 82 80 Range (45 min) 79-85 81-83 78-82 Mean (60 min) 87 88 84 Range (60 min) 83-89 87-89 83-85 Water content 0.82 0.76 0.79 (% (w/w)) Hardness (N) 72 73 66 Mean Range 55-90 63-84 58-80 Microbial Complies NT Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(188) TABLE-US-00037 TABLE 36 Stability data for 25 C./60% RH of tablets, Batch 53, stored in Al/Al blisters Time (months) Test Initial 3 6 9 12 Description White, circular, NCH NCH NCH NCH biconvex tablet Assay 98 100 98 100 99 (% label claim) Degradation products (% (w/w)): Unspecified 0.06.sup.b 0.05.sup.b 0.06.sup.b 0.06.sup.b 0.06.sup.b Total 0.06 0.05 0.06 0.06 0.06 Disintegration 15-31 25-40 14-32 23-31 22-25 (seconds) Dissolution (% label claim) Mean (45 min) 87 86 94 87 86 Range (45 min) 87-89 84-87 91-96 86-88 83-87 Mean (60 min) 91 90 97 91 90 Range (60 min) 90-92 89-91 94-100 90-91 88-92 Water content 0.83 0.84 0.84 0.85 0.84 (% (w/w)) Hardness (N) 75 73 69 64 64 Mean Range 60-92 60-84 60-83 50-77 45-81 Microbial Complies NT NT NT Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) .sup.bImpurity RRT 1.84 NCH No change NT Not tested

(189) TABLE-US-00038 TABLE 37 Stability data for 40 C./75% RH of tablets, Batch 53, stored in Al/Al blisters Time (months) Test Initial 3 6 Description White, circular, NCH NCH biconvex tablet Assay 98 100 99 (% label claim) Degradation products (% (w/w)): Unspecified 0.06.sup.b 0.06.sup.b 0.07.sup.b Total 0.06 0.06 0.07 Disintegration 15-31 17-25 15-37 (seconds) Dissolution (% label claim) Mean (45 min) 87 91 87 Range (45 min) 87-89 88-94 85-90 Mean (60 min) 91 94 92 Range (60 min) 90-92 92-96 89-94 Water content 0.83 0.81 0.84 (% (w/w)) Hardness (N) 75 69 66 Mean Range 60-92 55-89 52-78 Microbial Complies NT Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) .sup.bImpurity RRT 1.84 NCH No change NT Not tested

(190) TABLE-US-00039 TABLE 38 Stability data for 25 C./60% RH of tablets, Batch 54, stored in Al/Al blisters Time (months) Test Initial 3 6 Description White, circular, NCH NCH flat bevelled tablet Assay 98 99 98 (% label claim) Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration 26-52 35-45 29-41 (seconds) Dissolution (% label claim) Mean (45 min) 93 86 86 Range (45 min) 91-94 84-88 85-88 Mean (60 min) 95 86 89 Range (60 min) 94-95 85-88 86-90 Water content 0.82 0.80 0.80 (% (w/w)) Hardness (N) 55 NT 66 Mean Range 45-66 NT 58-71 Microbial Complies NT NT quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(191) TABLE-US-00040 TABLE 39 Stability data for 40 C./75% RH of tablets, Batch 54, stored in Al/Al blisters Time (months) Test Initial 3 6 Description White, circular, NCH NCH flat bevelled tablet Assay 98 98 98 (% label claim) Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration 26-52 17-43 29-35 (seconds) Dissolution (% label claim) Mean (45 min) 93 77 78 Range (45 min) 91-94 75-79 77-80 Mean (60 min) 95 .sup.80.sup.b .sup.80.sup.b Range (60 min) 94-95 .sup.76-85.sup.b .sup.79-82.sup.b Water content 0.82 0.79 0.80 (% (w/w)) Hardness (N) 55 NT 63 Mean Range 45-66 NT 55-71 Microbial Complies NT Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) .sup.bStage 2 requirements have been met (12 units tested), NCH No change NT Not tested

(192) TABLE-US-00041 TABLE 40 Stability data for photo stability of tablets, Batch 51 Time (months) Test Initial 0.5 (sample) 0.5 (reference) Description White, circular, NCH NT biconvex tablet Assay 100 98 NT (% label claim) Degradation products (% (w/w)): Unspecified <0.05 0.15.sup.b <0.05 Total <0.05 0.15 <0.05 Disintegration 15-28 16-34 NT (seconds) Dissolution (% label claim) Mean (45 min) 85 84 NT Range (45 min) 83-88 82-86 NT Mean (60 min) 88 86 NT Range (60 min) 86-91 84-88 NT Water content 0.88 1.6 NT (% (w/w)) Hardness 62 54 NT (N) Mean Range 48-79 46-78 NT Microbial Complies NT NT quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) .sup.bImpurity at RRT 0.88 NCH No change NT Not tested

(193) TABLE-US-00042 TABLE 41 Stability data for stressed condition, 50 C./amb for tablets, Batch 51 stored in Al/Al blister Test Initial 3 months Description White, circular, White, circular, biconvex tablet biconvex tablet Assay 100 99 (% label claim) Degradation products (% (w/w)): Unspecified <0.05 <0.05 Total <0.05 <0.05 Disintegration 15-28 17-25.sup. (seconds) Dissolution (% label claim) Mean (45 min) 85 .sup.80.sup.b Range (45 min) 83-88 73-88.sup.b Mean (60 min) 88 .sup.85.sup.b Range (60 min) 86-91 78-93.sup.b Water content 0.88 0.87 (% (w/w)) Hardness 62 52 (N) Mean Range 48-79 46-61.sup. Microbial Complies Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) .sup.bStage 2 requirements have been met (12 units tested)

(194) TABLE-US-00043 TABLE 42 Stability data for stressed condition, 50 C./amb for tablets, Batch 52 stored in Al/Al blister Test Initial 3 months Description White, circular, White, circular, biconvex tablet biconvex tablet Assay 99 101 (% label claim) Degradation products (% (w/w)): Unspecified <0.05 <0.05 Total <0.05 <0.05 Disintegration 15-25 13-30 (seconds) Dissolution (% label claim) Mean (45 min) 83 .sup.74.sup.b Range (45 min) 79-85 .sup.68-81.sup.b Mean (60 min) 87 .sup.80.sup.b Range (60 min) 83-89 .sup.74-87.sup.b Water content 0.82 0.77 (% (w/w)) Hardness 72 64 (N) Mean Range 55-90 56-80 Microbial Complies Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) .sup.bStage 2 requirements have been met (12 units tested)

(195) TABLE-US-00044 TABLE 43 Stability data for stressed condition, 50 C./amb for tablets, Batch 53 stored in Al/Al blister Test Initial 3 months Description White, circular, White, circular, biconvex tablet biconvex tablet Assay 98.4 99.3 (% label claim) Degradation products (% (w/w)): Unspecified 0.06.sup.b 0.06.sup.b Total 0.06 0.06 Disintegration 15-31 14-26 (seconds) Dissolution (% label claim) Mean (45 min) 87 87 Range (45 min) 87-89 84-89 Mean (60 min) 91 91 Range (60 min) 90-92 88-95 Water content 0.83 0.82 (% (w/w)) Hardness 75 58 (N) Mean Range 60-92 48-74 Microbial Complies Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) .sup.bImpurity RRT 1.84

(196) TABLE-US-00045 TABLE 44 Stability data for stressed condition, 50 C./amb, for tablets, Batch 54 stored in Al/Al blister Test Initial 3 months Description White, circular, NCH flat bevelled tablet Assay (% label claim) 98 99 Degradation products (% (w/w)): Unspecified <0.05 <0.05 Total <0.05 <0.05 Disintegration (seconds) 26-52 15-22.sup. Dissolution (% label claim) Mean (45 min) 93 .sup.74.sup.b Range (45 min) 91-94 73-76.sup.b Mean (60 min) 95 .sup.78.sup.b Range (60 min) 94-95 76-79.sup.b Water content 0.82 0.78 (% (w/w)) Hardness (N) Mean 55 57 Range 45-66 52-63.sup. Microbial quality .sup.a Complies Complies .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) .sup.bStage 2 requirements have been met (12 units tested) NCH No change

(197) TABLE-US-00046 TABLE 45 Stability data for stressed condition, 25 C./60% RH for tablets, Batch 45 stored open Test Initial 1 week 2 weeks 1 month Description White, circular, NCH NCH NCH flat bevelled tablet Assay (% label claim) 101 NT NT 97 Degradation products (% (w/w)): Unspecified <0.05 NT NT <0.05 Total <0.05 NT NT <0.05 Disintegration 60 60 60 60 (seconds) Dissolution (% label claim) Mean 83 78 79 77.sup.a Range 81-87 75-82 78-82 73-80.sup.a Water content 0.9 2.7 2.3 2.2 (% (w/w)) Tablet Hardness (N) 56 23 26 28 .sup.aStage 2 requirements have been met (12 units tested) NCH No change NT Not tested

(198) TABLE-US-00047 TABLE 46 Stability data for stressed condition, 30 C./65% RH for tablets, Batch 45 stored open Test Initial 1 week 2 weeks 1 month Description White, circular, NCH NCH NCH flat bevelled tablet Assay (% label claim) 101 NT NT 100 Degradation products (% (w/w)): Unspecified <0.05 NT NT <0.05 Total <0.05 NT NT <0.05 Disintegration 60 60.sup. 60.sup. 60 (seconds) Dissolution (% label claim) Mean 83 76.sup.a 75.sup.a 74.sup.a Range 81-87 73-78.sup.a 72-77.sup.a 71-76.sup.a Water content 0.9 2.9 2.4 2.2 (% (w/w)) Tablet Hardness (N) 56 18 19 20 .sup.aStage 2 requirements have been met (12 units tested) NCH No change NT Not tested

(199) TABLE-US-00048 TABLE 47 Stability data for stressed condition, 40 C./75% RH for tablets, Batch 45 stored open Test Initial 1 week 2 weeks 1 month Description White, circular, NCH NCH NCH flat bevelled tablet Assay (% label claim) 101 NT NT 99 Degradation products (% (w/w)): Unspecified <0.05 NT NT <0.05 Total <0.05 NT NT 0.10 Disintegration 60 60.sup. 60.sup. 60 (seconds) Dissolution (% label claim) Mean 83 73.sup.a 74.sup.a 72.sup.a Range 81-87 70-74.sup.a 71-76.sup.a 69-75.sup.a Water content 0.9 3.4 2.7 2.4 (% (w/w)) Tablet Hardness (N) 56 15 16 15 .sup.aStage 2 requirements have been met (12 units tested) NCH No change NT Not tested

(200) TABLE-US-00049 TABLE 48 Stability data for stressed condition, 50 C./amb for tablets, Batch 45 stored open Test Initial 1 week 2 weeks 1 month Description White, circular, NCH NCH NCH flat bevelled tablet Assay (% label claim) 101 NT NT 99 Degradation products (% (w/w)): Unspecified <0.05 NT NT <0.05 Total <0.05 NT NT <0.05 Disintegration 60 60 60 60 (seconds) Dissolution (% label claim) Mean 83 78 77 77 Range 81-87 78-79 75-80 75-78 Water content 0.9 0.3 0.6 0.7 (% (w/w)) Tablet Hardness (N) 56 56 53 53 NCH No change NT Not tested

(201) TABLE-US-00050 TABLE 49 Stability data for 25 C./60% RH of ticagrelor orodispersible tablets, 90 mg, Batch 51, stored in Al bags Time (months) Test Initial 3 6 9 12 Description White, round, NCH NCH NCH NCH convex tablet Assay (%) 100 99 100 98 99 Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 <0.05 <0.05 Disintegration 28 48 31 37 23 (seconds) Dissolution (% label claim) Mean 88 89 97 89 89 Range 86-91 85-92 95-101 87-91 85-91 Water content 0.88 0.90 0.90 0.92 0.95 (% (w/w)) Microbial Complies NT NT NT NT quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(202) TABLE-US-00051 TABLE 50 Stability data for 40 C./75% RH of ticagrelor orodispersible tablets, 90 mg, Batch 51, stored in Al bags Time (months) Test Initial 3 6 Description White, round, NCH NCH convex tablet Assay (%) 100 99 100 Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration 28 29 25 (seconds) Dissolution (% label claim) Mean 88 83 92 Range 86-91 81-85 90-95 Water content 0.88 0.86 0.89 (% (w/w)) Microbial Complies NT Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(203) TABLE-US-00052 TABLE 51 Stability data for 25 C./60% RH of ticagrelor orodispersible tablets, 90 mg, Batch 52, stored in Al bags Time (months) Test Initial 3 6 9 12 Description White, round, NCH NCH NCH NCH convex tablet Assay (%) 99 99 99 100 99 Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 <0.05 <0.05 Disintegration 25 35 54 31 26 (seconds) Dissolution (% label claim) Mean 87 82 91 83 83 Range 83-89 80-84 88-93 80-85 81-85 Water content 0.82 0.82 0.85 0.87 0.88 (% (w/w)) Microbial Complies NT NT NT NT quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(204) TABLE-US-00053 TABLE 52 Stability data for 40 C./75% RH of ticagrelor orodispersible tablets, 90 mg, Batch 52, stored in Al bags Time (months) Test Initial 3 6 Description White, round, NCH NCH convex tablet Assay (%) 99 99 100 Degradation products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration 25 29 40 (seconds) Dissolution (% label claim) Mean 87 85 84 Range 83-89 82-87 82-91 Water content 0.82 0.81 0.86 (% (w/w)) Microbial Complies NT Complies quality .sup.a .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(205) TABLE-US-00054 TABLE 53 Stability data for 25 C./60% RH of ticagrelor orodispersible tablets, 90 mg, Batch 53, stored in Al bags Time (months) Test Initial 3 6 9 12 Description White, round, NCH NCH NCH NCH convex tablet Assay (%) 98 101 100 100 99 Degradation products (% (w/w)): Unspecified 0.06.sup.1 0.05.sup.1 0.06.sup.1 0.06.sup.1 0.06.sup.1 Total 0.06 0.05 0.06 0.06 0.06 Disintegration 31 38 31 31 29 (seconds) Dissolution (% label claim) Mean 91 89 97 91 90 Range 90-92 87-91 93-100 89-92 90-92 Water content 0.83 0.88 0.89 0.88 0.94 (% (w/w)) Microbial Complies NT NT NT NT quality .sup.a .sup.1Impurity RRT 1.84 .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(206) TABLE-US-00055 TABLE 54 Stability data for 40 C./75% RH of ticagrelor orodispersible tablets, 90 mg, Batch 53, stored in Al bags Time (months) Test Initial 3 6 Description White, round, NCH NCH convex tablet Assay (%) 98 98 99 Degradation products (% (w/w)): Unspecified 0.06.sup.1 0.06.sup.1 0.07.sup.1 Total 0.06 0.06 0.07 Disintegration 31 37 23 (seconds) Dissolution (% label claim) Mean 91 98 92 Range 90-92 94-102 90-93 Water content 0.83 0.85 0.87 (% (w/w)) Microbial Complies NT Complies quality .sup.a .sup.1Impurity RRT 1.84 .sup.a Total aerobic microbial count (<10.sup.3 cfu/g), total combined yeast and mould count (<10.sup.2 cfu/g) and Escherichia coli (shall be absent) NCH No change NT Not tested

(207) Summary of Results and Discussion

(208) ICH Primary Stability Studies

(209) Stability data for the tablets stored in Al/Al blisters show no significant change in description, assay, degradation products, disintegration or dissolution after 12 months storage at 25 C./60% RH. Storage at the accelerated condition of 40 C./75% RH after 6 months show no significant change in description, assay, degradation products, disintegration or dissolution. Dissolution shows a variation in data over time but no trend can be seen and all results fulfil the specification requirement.

(210) The water content and microbial quality shows no significant changes after 12 months storage at 25 C./60% RH. Storage at the accelerated condition of 40 C./75% RH after 6 months shows no significant changes.

(211) Tablet hardness generally decreases as a result of moisture uptake, which weakens the tablets. Therefore, inhibition of moisture uptake is beneficial for tablet stability. However, the subjective toughness of the tablets is still good even if the hardness has been reduced through moisture uptake.

(212) Photo Stability and Stressed Condition

(213) Stability data for tablets stored in an open dish under photo stability conditions show that light has no significant effect on the stability of the tablets. Formation of one degradation product was seen at very low levels for the tablets that were directly exposed to light. The drug product is fully protected in the Al/Al blister pack since this is impenetrable to light. The stressed condition of 50 C./ambient shows no significant changes in description, assay, degradation products, disintegration, dissolution, water or microbial quality after 3 months storage in Al/Al blisters.

(214) Investigational Stressed Stability Study

(215) The stability data generated during the investigational study demonstrate that storage up to 1 month open, does not appear to have an adverse effect on description, assay, degradation products, disintegration or dissolution. An increase in water content was observed for the tablets stored at humid conditions. This increase in water amount appears to impact on the tablet hardness as it makes the tablets softer. This is an inherent property for orodispersible tablets as they are designed to take up water to readily disintegrate.

Example 15Relative Bioavailability Study (Study A)

(216) A relative bioavailability study (hereafter referred to as clinical study A) compared the orodispersible tablet of Example 7, administered with water (after oral dispersion) and without water, to a film-coated tablet containing 90 mg of ticagrelor. In clinical study A the orodispersible tablet was also suspended in water and administered through a nasogastric tube and compared to the film-coated tablet.

(217) The composition of the orodispersible tablet used in clinical study A was identical to that in Example 7 and was manufactured at a batch size of 256 kg.

(218) The film-coated tablet used in clinical study A was equivalent to the marketed ticagrelor film-coated tablet.

(219) The dissolution profiles for the orodispersible and film-coated tablets used in clinical study A, obtained using the proposed release method (manual sampling used and % ticagrelor dissolved measured by UV) are presented in FIG. 8. As can be seen, the dissolution profiles of the orodispersible and film-coated tablets are similar, which in vivo results in similar exposure.

(220) Study Design and Methodology:

(221) This study was an open-label, randomised, four-period, four-treatment, crossover study in healthy male and female of non-childbearing potential subjects, performed at a single study centre. The study was comprised of: A screening period of maximum 21 days; Four treatment periods during which subjects were resident prior to the evening meal the night before dosing with ticagrelor (Day 1) until at least 48 hours after dosing; discharged on the morning of Day 3; and A final visit within 5 to 10 days after the last administration of ticagrelor.

(222) There was a minimum washout period of 7 days between each dose administration.

(223) Subjects received single doses of ticagrelor in 4 different ways under fasted conditions. Following an overnight fast of at least 10 hours, each subject received a single dose of each treatment on 4 occasions, respectively. The treatment protocol is summarised in Table 55.

(224) TABLE-US-00056 TABLE 55 Treatment protocol Treatment Product Administration Dose Treatment A Test Ticagrelor OD tablets administered 1 90 mg product with 200 mL of water Treatment B Test Ticagrelor OD tablets administered 1 90 mg product without water Treatment C Test Ticagrelor OD tablets suspended in 1 90 mg product water to be administered through a NG tube into the stomach (total of 200 mL of water) Treatment D Reference Ticagrelor IR tablets administered 1 90 mg product with 200 mL of water

(225) Test product: Ticagrelor 90 mg OD tablet according to Example 7

(226) Reference product: Ticagrelor 90 mg IR (immediate release) tablet

(227) Study Subjects

(228) 36 Healthy male and female (non-childbearing potential) subjects were enrolled in the study and 30 subject completed it. All subjects were healthy male or female subjects aged 18 to 55 years, with a body mass index between 18.5 and 29.9 kg/m.sup.2 inclusive weighing at least 50 kg and no more than 100 kg inclusive.

(229) Duration of Treatment:

(230) The duration of study participation for each subject was approximately 7 to 8 weeks consisting of a Screening visit (from Day 21 to 1), admission to the clinical unit (on Day 1 of each treatment period), 4 in-house treatment periods (Days 1 to 3) with a 7-day washout period between administrations of investigational medicinal product (IMP) in each treatment period and a Follow-up visit after Treatment Period 4.

(231) Subjects received a single dose of IMP on Day 1 of each of the 4 in-house treatment periods.

(232) Treatment Compliance:

(233) Dosing took place at the PAREXEL Early Phase Clinical Unit. After IMP administration, a check of the subject's mouth and hands was performed. The exact day and time of IMP administration, as well as the volume of water accompanying the administration were recorded.

(234) Criteria for Evaluation:

(235) Pharmacokinetic Parameters:

(236) The PK parameters were assessed for ticagrelor (parent) and its active metabolite AR-C124910XX based on plasma concentrations.

(237) Primary PK Parameters:

(238) TABLE-US-00057 C.sub.max Maximum observed plasma concentration AUC.sub.(0-t) Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration AUC Area under plasma concentration-time curve from zero to infinity

(239) Secondary PK Parameters:

(240) TABLE-US-00058 t.sub.max Time to reach maximum observed concentration t.sub.1/2z Half-life associated with terminal slope (.sub.z) of a semi-logarithmic concentration-time curve MRC.sub.max Ratio of metabolite C.sub.max to parent C.sub.max, adjusted for differences in molecular weights MRAUC.sub.(0-t) Ratio of metabolite AUC.sub.(0-t) to parent AUC.sub.(0-t), adjusted for differences in molecular weights MRAUC Ratio of metabolite AUC to parent AUC, adjusted for differences in molecular weights

(241) Diagnostic PK parameters were listed.

(242) Safety Variables:

(243) Safety variables included adverse events (AEs), vital signs (blood pressure and pulse), 12-lead electrocardiograms (ECGs) and laboratory assessments (hematology, clinical chemistry and urinalysis).

(244) In addition to the above, physical examination findings, pregnancy testing (females only) and use of concomitant medication were also reported. Viral serology, thyroid-stimulating hormone (TSH) and follicle-stimulating hormone (FSH) (females only), coagulation and urine drugs of abuse, alcohol and cotinine were assessed for eligibility.

(245) Statistical Methods:

(246) Determination of Sample Size

(247) Based on the bioequivalence range of 0.80-1.25 for ticagrelor and its active metabolite AR-C124910XX and a within-subject coefficient of variation (CV) for C.sub.max and AUC of ticagrelor and AR-C124910XX of less than or equal to 24%, 28 evaluable subjects were needed to achieve a power of 90%.

(248) Up to 36 subjects were randomised to a 4 sequence Williams design for 4 periods and 4 treatments: ADBC, BACD, CBDA and DCAB, in order to ensure at least 28 evaluable subjects at the end of the last treatment period.

(249) Pharmacokinetic Analysis:

(250) Pharmacokinetic parameters were summarised for each treatment using descriptive statistics. Where possible, the following descriptive statistics were presented: n, geometric mean, geometric CV, arithmetic mean, arithmetic standard deviation, median, minimum and maximum. For t.sub.max, only n, median, minimum and maximum were presented.

(251) Bioavailability comparison of treatments A, B and C (test product) and D (reference product) were assessed on the ratio of log-transformed C.sub.max, AUC.sub.0-t, and AUC of both ticagrelor and AR-C124910XX using a 2-sided 90% confidence interval (CI) approach based on an analysis of variance (ANOVA) model including fixed effects for treatment, sequence, period and subject within sequence.

(252) All PK parameters were log-transformed prior to analysis. The estimated treatment differences and the 90% CIs on the log scale were back transformed to obtain the geometric mean ratios for each pair of treatments.

(253) For exploratory purposes, the ANOVA as outlined above was repeated with a random effect of subject within sequence.

(254) Safety Analysis:

(255) All AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA), and were listed for each subject. The results of the vital signs measurements, hematology, clinical chemistry and coagulation values were listed by subject and time-point. 12-lead ECG results were listed for each subject and the results of the physical examination were listed by body system for each subject.

(256) Pharmacokinetic Results:

(257) Following 90 mg ticagrelor OD tablets with water, without water, or suspended in water to be administered via NG tube, plasma concentration-time profiles for ticagrelor and metabolite AR-C124910XX were generally similar to those following 90 mg ticagrelor IR tablets. The profiles were characterised as rapid ticagrelor absorption with C.sub.max achieved at median t.sub.max of approximately 2 hours post-dose and rapid formation of metabolite AR-C124910XX with median t.sub.max of 2 to 3 hours post-dose. After reaching C.sub.max, plasma ticagrelor and metabolite AR-C124910XX concentrations declined with terminal mean t.sub.1/2z of 7.99-8.21 hours and 9.35-9.48 hours, respectively. Plasma metabolite AR-C124910XX C.sub.max and AUC was 27.1-30.0% and 38.2-40.5% of plasma ticagrelor C.sub.max and AUC, respectively.

(258) The derived mean PK parameters were similar across the 4 treatments for ticagrelor and metabolite AR-C124910XX, suggesting that the rate of absorption (C.sub.max and t.sub.max) and extent of absorption (AUC) amongst the treatments were similar.

(259) The 90% CIs of the geometric mean ratios for ticagrelor AUC (90.27, 99.89) and metabolite AR-C124910XX AUC (91.36, 98.42) were entirely contained within the acceptance interval of 80-125%. The ticagrelor C.sub.max from OD tablets with water was about 15% (90% CI: 76.77, 93.78) lower than the IR tablets, while the 90% CI for metabolite AR-C124910XX C (82.03, 98.39) was contained within the 80-125% interval.

(260) The 90% CIs of geometric mean ratios for ticagrelor and AR-C124910XX AUC ([89.81, 100.99] and [91.78, 99.82], respectively) and C.sub.max ([88.22, 105.79] and [90.53, 104.90], respectively) after ticagrelor OD tablets without water, and AUC ([90.26, 98.73] and [93.26, 99.87], respectively) and C.sub.max ([85.59, 99.25] and [90.83, 103. 74], respectively) after ticagrelor OD tablets suspended in water to be administered via NG tube, were entirely contained within the acceptance interval of 80-125%.

(261) The between-subject variability was low to moderate and was similar across treatments for both ticagrelor and metabolite AR-C124910XX; the geometric mean CV % in C.sub.max of ticagrelor and metabolite AR-C124910XX was approximately 25-34%, and in AUC of ticagrelor and metabolite AR-C124910XX was approximately 19-44%.

(262) Safety Results

(263) There were no deaths, serious adverse event or AEs leading to permanent discontinuation of IMP during the conduct of this study.

(264) A total of 18 AEs were reported for 9 (25.0%) subjects, all classified as mild in intensity. All AEs resolved by the end of the study.

(265) The most commonly reported AEs were dizziness in the system organ class of Nervous System Disorders and thrombophlebitis in the SOC of Vascular Disorders in 2 (5.6%) subjects, respectively.

(266) No trends were observed in AEs, clinical laboratory values, vital sign measurements, 12 lead ECG readings and physical examination.

(267) This open-label, randomised, four period, four treatment, crossover, single centre, single dose study was designed to assess the bioavailability of ticagrelor OD tablets, compared to ticagrelor IR tablets in healthy subjects.

(268) The extent of absorption (AUC) after ticagrelor OD tablets with water, without water, or suspended in water to be administered via NG tube was equivalent to that after ticagrelor IR tablets, with the 90% CIs of geometric mean ratios for ticagrelor and metabolite AR-C124910XX AUC entirely contained within the acceptance interval of 80-125%. The ticagrelor C.sub.max from ticagrelor OD tablets with water was about 15% (90% CI: 76.77, 93.78) lower than ticagrelor IR tablets, while the 90% CI for metabolite AR-C124910XX C.sub.max as well as the C.sub.max of ticagrelor and metabolite AR-C124910XX from ticagrelor OD tablets without water or suspended in water to be administered via NG tube were entirely contained within the 80-125% interval. (i) The extent of absorption from ticagrelor 90 mg OD tablets administered with water was equivalent to ticagrelor IR, while its C.sub.max was about 15% lower than ticagrelor 90 mg IR tablets. (ii) Ticagrelor 90 mg OD tablets administered without water were bioequivalent to ticagrelor 90 mg IR tablets. (iii) Ticagrelor 90 mg OD tablets suspended in water, administered through NG tube into stomach were bioequivalent to ticagrelor 90 mg IR tablets.

(269) This result demonstrated that ticagrelor OD tablets formulation as well as the ways of administering ticagrelor OD tablets did not greatly affect the pharmacokinetic profiles of ticagrelor and metabolite AR-C124910XX, compared to IR tablets. Overall single 90 mg doses of ticagrelor tablets in healthy male and non-childbearing female subjects were considered safe and well tolerated in this study.

(270) Pharmacokinetic parameters and comparisons according to standard bioequivalence criteria are presented in Table 56.

(271) TABLE-US-00059 TABLE 56 Comparisons of exposures from clinical study A, orodispersible versus film-coated tablet, according to bioequivalence criteria GLS GLS mean 90% Parameter Treatment N mean n Pair ratio (%) CIs AUC A 30 3072 30 A/D 94.96 90.27, (ng .Math. h/mL) D 33 3236 99.89 B 31 3241 31 B/D 95.24 89.81, D 33 3404 100.99 C 33 3220 33 C/D 94.40 90.26, D 33 3411 97.73 C.sub.max A 30 428.3 30 A/D 84.85 76.77, (ng/mL) D 33 504.8 93.78 B 31 500.0 31 B/D 96.61 88.22, D 33 517.5 105.79 C 33 477.9 33 C/D 92.16 85.59, D 33 518.6 99.25 ODTOrodispersible tablet. Treatment A - ODT with water. ODT placed on the tongue, after disintegration subsequently swallowed with 200 mL water; Treatment B - ODT without water. ODT placed on the tongue, after disintegration subsequently swallowed with saliva; Treatment C - ODT suspended in water and given via nasogastric tube (total water volume of 200 mL given); Treatment D - Film-coated tablet given with 200 mL water. AUC - Area under the plasma concentration-time curve from zero to infinity; C.sub.max- Maximum plasma (peak) drug concentration after single dose administration; N - all subjects in the pharmacokinetic analysis set; n - all subjects included in the statistical analysis set; GLSGeometric least squares; CIConfidence interval.

Example 16Assessment of Bioequivalence (Study B)

(272) A bioequivalence study (clinical study B) was also performed in Japanese subjects. The study was an open-label, randomised, three-period, three-treatment, crossover study in healthy Japanese subjects (males and females), performed at a single study center.

(273) The study comprised: (i) A screening period of maximum 28 days; (ii) Three treatment periods during which subjects will be resident prior to the evening meal the night before dosing with ticagrelor (Day 1) until at least 48 hours after dosing; discharged on the morning of Day 3; and (iii) A final visit within 5 to 10 days after the last administration of ticagrelor.

(274) There was a minimum washout period of 7 days between each dose administration. Subjects received single doses of ticagrelor in three different ways under fasted conditions. Following an overnight fast of at least 10 hours, each subject received a single dose of each treatment on three occasions, respectively. The treatment protocol is summarised in Table 57.

(275) TABLE-US-00060 TABLE 57 Treatment protocol Treatment Product Administration Dose Treatment A Test product Ticagrelor OD tablets 1 90 mg (Ticagrelor administered with 90 mg OD 150 mL of water tablets) Treatment B Test product Ticagrelor OD tablets 1 90 mg (Ticagrelor administered 90 mg OD without water tablets) Treatment C Reference Ticagrelor IR tablets 1 90 mg product administered with (Ticagrelor 150 mL of water 90 mg IR tablets)

(276) The route of administration was oral. Patients received a single dose of either the test product or the reference product. Each subject was involved in the study for 7 to 8 weeks.

(277) Blood samples for the determination of plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX were collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). Plasma samples were analysed for ticagrelor and AR-C124910XX using a validated assay.

(278) In the study, the ticagrelor orodispersible tablet (according to Example 7) was administered with water (after oral dispersion) and without water and compared to ticagrelor film-coated tablet 90 mg. The same batches as included in clinical study A were used for the test product and the reference product. The ticagrelor orodispersible tablet administered with and without water was shown to be bioequivalent to ticagrelor film-coated tablet in Japanese subjects. Pharmacokinetic parameters and comparisons according to standard bioequivalence criteria are presented in Table 58.

(279) TABLE-US-00061 TABLE 58 Tablets Compared to Ticagrelor IR Tablets (Pharmacokinetic Analysis Set) Pair Geometric Pairwise (Test/ LS Mean* Comparison Ref- Parameter Ref- 90% erence) (unit) n Test erence Ratio# CI# OD AUC 41 3515 3595 97.75 94.40, 101.21 with (h .Math. ng/mL) water/ AUC.sub.(0-t) 41 3457 3536 97.76 94.46, 101.18 IR (h .Math. ng/mL) C.sub.max 41 529.8 568.7 93.16 85.80, 101.15 (ng/mL) OD AUC 41 3468 3594 96.50 93.31, 99.80 without (h .Math. ng/mL) water/ AUC.sub.(0-t) 41 3406 3534 96.38 93.24, 99.63 IR (h .Math. ng/mL) C.sub.max 41 532.7 568.7 93.67 87.88, 99.84 (ng/mL) ANOVA: analysis of variance; AUC = area under plasma concentration-time curve from zero extrapolated to infinity; AUC.sub.(0-t): area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration; CI: confidence interval; C.sub.max: maximum observed plasma concentration; IR: immediate-release; max: maximum; min: minimum; n: number of subjects included in the statistical comparison analysis; OD: orodispersible; SD: standard deviation. *Based on pairwise balanced comparisons and were back-transformed. #Geometric mean ratio and CI were back-transformed and presented as percentage. Result based on ANOVA of log-transformed pharmacokinetic parameter with treatment, sequence, period and subject within sequence as fixed effects.

Comparative Example 17Assessment of Push-Through Blister Packs

(280) A study was conducted involving 10 test persons (7 female and 3 male, aged 22 to 58) with push-through blister packs.

(281) Each person was provided with 10 blister cards, each blister card containing 10 tablets (100 tablets per person in total). The tablets were identical with the orodispersible tablets of Example 7.

(282) Each person was then asked to push out all of the tablets in the manner in which they normally would.

(283) Result

(284) The number of broken tablets was as follows:

(285) Mean: 2.5 broken tablets per 100 (i.e. per person)

(286) Range: 0-7 broken tablets per 100 (i.e. per person)

Example 18Assessment of Tearable Blister Packs

(287) Tests conducted with standard push through aluminium/aluminium blister packs resulted in approx. 2.5% broken tablets (see Comparative Example 17). A further study was conducted involving 10 test persons (4 female and 6 male, aged 25 to 53) with modified push-through blister packs.

(288) The modified blister packs are shown in FIG. 9. The modification consisted of the excision of a triangular portion of the blister pack material from the outer edge adjacent to each of the blisters. The excision was achieved using a shaped punching tool.

(289) The subjects in this study differed from those in the earlier study using the push-through blister packs (i.e. the study of Comparative Example 17).

(290) Packaging samples were prepared, including samples containing graphic elements, to evaluate breakage of tablets and to see if patients would understand how to open the packaging. The outer dimensions 17288 mm.

(291) Each person was provided with 10 blister cards, each blister card containing 10 tablets (100 tablets per person in total). The tablets were identical with the orodispersible tablets of Example 7.

(292) Test Protocol

(293) Show the blister pack (10 tablets) with a label containing graphics (text and symbols) to the test person and say with approx. wording:

(294) We are doing a packaging test on ten persons to see how this packaging works. We will ask you to take out all tablets from this blister pack. You can start on any tablet of the blister pack. Before you start taking out tablets, please look at this blister pack that contains some text on one side. You will then get an identical blister pack but without any text. From that blister pack you should then take out all ten tablets. The tablets contain active ingredient, Brilinta. When you have emptied one blister pack I will put all tablets in the plastic container and then hand you another blister pack. You will take out in total 100 tablets i.e. 10 blister packs. When all tablets have been taken out I will ask you some questions.

(295) The first blister pack with the label is then handed to the subject. This was taken back when the subject had read it. One blister pack was handed over at time. The approximate time for reading the label was noted. The method by which test persons start to take out tablets was noted (e.g. tearing, pushing or otherwise). The number of broken tablets was noted.

(296) If a test person pushed out all tablets on the first blister pack, he/she was asked to read the label again and tearing was prompted. The test person was then expected to tear open the 9 remaining blister packs.

(297) After the test, the test persons were asked a number of questions for scoring, including: How easy was it to take out the tablets out of the blister pack? Do you think this pack is easier or more difficult to open than a standard push through blister pack?

(298) Result

(299) The number of broken tablets was as follows: 953 tablets were removed using the tear opening methodof these, 1 tablet was broken. 47 tablets were removed using the push through methodof these, 7 tablets were broken.

(300) The data are summarised in Table 59.

(301) TABLE-US-00062 TABLE 59 Results Started No. No. Easy Tear easier with of tablets of tablets to take than tear or pushed tear out by push Gender Age push? out Broken opened Broken tearing out? Man 27 Push 10 3 90 0 5 Tear Woman 38 Tear 7 1 93 0 4 Tear Man 41 Tear 0 100 0 5 Tear Man 39 Push 10 1 90 0 5 Tear Man 53 Push 10 1 90 0 4 Tear Woman 44 Tear 0 100 1 4 Same Woman 46 Tear 0 100 0 4 Tear Man 25 Tear 10 1 90 0 4 Same Man 41 Tear 0 100 0 5 Tear Woman 51 Tear 0 100 0 3 Push