DELAYED RELEASE PHARMACEUTICAL FORMULATIONS COMPRISING VALPROIC ACID, AND USES THEREOF

Abstract

There is provided herein a pharmaceutical formulation having one or more component comprising valproic acid (VPA) and/or a pharmaceutically acceptable salt thereof; and one or more secondary acid, and optionally comprising one or more pharmaceutically acceptable excipient. There is also provided uses of such formulations.

Claims

1-13. (canceled)

14. A method for treating or reducing the risk of a pathological condition associated with excess fibrin deposition and/or thrombus formation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a delayed release pharmaceutical formulation having two or more components comprising: (a) valproic acid (VPA) and/or a pharmaceutically acceptable salt thereof; and (b) one or more secondary acids, and optionally comprising one or more pharmaceutically acceptable excipient.

15. The method of claim 14, wherein the pharmaceutical formulation is administered to the subject during a time period that is from about 20:00 hours to about 00:00 hours.

16. The method of claim 14, wherein the pharmaceutical formulation is administered to the subject: as a single dose per 24 hour period; and/or (ii) with a dose of valproic acid and/or a pharmaceutically acceptable salt thereof sufficient to achieve a reduction in PAI-1 plasma levels of at least about 20%.

17. The method of claim 14, wherein the pathological condition associated with excess fibrin deposition and/or thrombus formation is selected from the group consisting of atherosclerosis, myocardial infarction, ischemic stroke, deep vein thrombosis, pulmonary embolism, disseminated intravascular coagulation, renal vascular disease and intermittent claudication.

18. The method of claim 17, wherein the pathological condition associated with excess fibrin deposition and/or thrombus formation is: (a) ischemic stroke, such as a major ischemic stroke and minor ischemic stroke; and/or (b) myocardial infarction.

19. The method of claim 14, wherein the subject is a human.

20-21. (canceled)

22. The method of claim 14, wherein the delayed release pharmaceutical formulation has two or more components comprising: (a) valproic acid (VPA) and/or a pharmaceutically acceptable salt thereof; and (b) one or more secondary acids selected from fumaric acid and/or succinic acid, and optionally comprising one or more pharmaceutically acceptable excipients, wherein the amount of secondary acid is from about 0.1% to about 5% of the weight of the VPA and/or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical formulation comprises an enteric coating, and wherein upon oral administration to a subject: release of the VPA and/or pharmaceutically acceptable salt thereof from the pharmaceutical formulation is delayed for about four hours, and at least 60% of the VPA and/or pharmaceutically acceptable salt thereof is released during a period from about four to about eight hours after administration.

23. The method of claim 22, wherein the one or more secondary acids is fumaric acid.

24. The method of claim 22, wherein the amount of secondary acid is from about 0.1% to about 3% of the weight of the VPA and/or a pharmaceutically acceptable salt thereof.

25. The method of claim 22, wherein the formulation comprises one or more components having a solid core comprising component (a), wherein component (a) is present in an amount that is at least 50% by weight thereof, and optionally wherein said solid core further comprises component (b).

26. The method of claim 25, wherein the solid core comprising components (a) and (b) is first coated with a sustained release coating and then an enteric coating.

27. The method of claim 25, wherein the solid core comprising components (a) and (b) is first coated with an enteric coating and then a sustained release coating.

28. The method of claim 22, wherein the composition is in the form of a tablet or capsule for oral administration and is formulated such that at least 70% of the VPA and/or pharmaceutically acceptable salt thereof is released during a period from about four to about eight hours after administration.

29. The method of claim 22, wherein at least 60% of the VPA and/or pharmaceutically acceptable salt thereof is released during a period from about six to about eight hours after administration.

30. The method of claim 14, wherein the delayed release pharmaceutical formulation has two or more components comprising: (a) valproic acid (VPA) and/or a pharmaceutically acceptable salt thereof; and (b) one or more secondary acids selected from fumaric acid and/or succinic acid, and optionally comprising one or more pharmaceutically acceptable excipients, wherein the amount of secondary acid is from about 0.1% to about 5% of the weight of the VPA and/or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical formulation comprises an enteric coating, and wherein upon oral administration to a subject: release of the VPA and/or pharmaceutically acceptable salt thereof from the pharmaceutical formulation is delayed for about four hours to about six hours, and at least 60% of the VPA and/or pharmaceutically acceptable salt thereof is released during a period from about eight to about ten hours after administration.

31. The method of claim 30, wherein the one or more secondary acids is fumaric acid.

32. The method of claim 30, wherein the amount of secondary acid is from about 0.1% to about 3% of the weight of the VPA and/or a pharmaceutically acceptable salt thereof.

33. The method of claim 30, wherein the formulation comprises one or more components having a solid core comprising component (a), wherein component (a) is present in an amount that is at least 50% by weight thereof, and optionally wherein said solid core further comprises component (b).

34. The method of claim 33, wherein the solid core comprising components (a) and (b) is first coated with a sustained release coating and then an enteric coating.

35. The method of claim 33, wherein the solid core comprising components (a) and (b) is first coated with an enteric coating and then a sustained release coating.

Description

FIGURES

[0487] FIG. 1 shows a schematic representation of the circadian rhythm (i.e. variation) of PAI-1 levels in an adult human during a typical 24 hour period. The lower curve represents the variation of PAI-1 levels in a normal (i.e. healthy) patient. The upper curve represents the variation in PAI-1 levels in a patient having increased levels of PAI-1 (e.g. patients with obesity and/or the metabolic syndrome). The y-axis represents arbitrary plasma levels and is abbreviated to illustrate the positively skewed distribution toward high plasma levels in obesity/metabolic syndrome. The x-axis represents clock time.

[0488] FIG. 2 shows the results of the in vitro release profile analysis as described in Example herein below.

[0489] FIG. 3 provides an example of a release profile as may be provided by pharmaceutical formulations as described in the eighth aspect of the invention, compared to release profiles as may be provided by corresponding immediate release (IR) and extended release (ER) formulations.

[0490] FIG. 4 shows the results of the in vitro release profile analysis as described in Example herein below.

[0491] FIG. 5 shows the results of the in vitro release profile analysis of tablets (mini tablets) coated with Eudragit FS 30 D as described in Example 12 herein below.

[0492] FIG. 6 shows the results of the in vitro release profile analysis of tablets (mini tablets) coated with Eudragit L 30 D-55 and Kollicoat SR 30 D/Kollicoat IR using different tablet cores and the same coating amount for the top coating as described in Example herein below.

[0493] FIG. 7 shows the results of the in vitro release profile analysis of tablets (mini tablets) coated with Eudragit L 30 D-55 and Kollicoat SR 30 D/Kollicoat® IR using the same tablet cores and varying coating amounts of the top coating as described in Example 12 herein below.

EXAMPLES

[0494] The following examples are included to further illustrate the invention, although the skilled person will understand that the invention is in no way restricted to the specific aspects described therein.

Example 1—VPA and PAI-1

[0495] The effects of VPA on PAI-1 were analysed in two different proof-of-concept studies in healthy subjects as well as in patients with manifest atherosclerotic disease. The studies had a randomized cross-over design and PAI-1 levels were investigated before and after treatment with valproic acid. PAI-1 plasma levels were measured in the morning at the first day of the study as well as at the end of the treatment period with VPA (see example for details on the PAI-1 analysis).

[0496] In the first study, 10 healthy non-smoking white male subjects (with mean BMI of approximately 26), aged 50-70 years were included and treated with valproic acid 500 mg (Ergenyl Retard. Sanofi) twice daily during 14 days. Unexpectedly we detected a more than 50% reduction (from 22.2 to 10.8 ng/ml, p<0.05) in circulating plasma PAI-1 levels during mid-morning in comparison to the midmorning levels found before treatment with VPA.

[0497] In the second study, 16 non-smoking white male patients, aged 50-80 years with a history of a myocardial infarction were included. On top of their ordinary prescription (beta-blocker, ACE-inhibitor, statin, aspirin) they were treated with valproic acid 500 mg (Ergenyl Retard, Sanofi), twice daily during 28 days. In this study we detected a 45% reduction in circulating plasma PAI-1 levels (from 19.6 ng/ml to 11 ng/ml (p=0.01)), during midmorning.

Example 2—Intermediate Endpoint Study: Effects of Valproic Acid on In Vivo PAI-1 in Man

[0498] An intermediate endpoint proof-of-concept study is performed in patients with TIA/minor stroke investigated before and after treatment with Valproic acid. Valproic acid is administrated as an enteric-coated tablet with delayed absorption.

[0499] The study comprises 20 patients with TIA/minor stroke. Patients are investigated before and after oral treatment with 400 mg valproic acid once time daily at 11 pm for 2 weeks. Plasma PAI-1 levels and plasma concentrations of valproic acid is followed daily during the study period at the following time-points: 3 am, 6 am, 10 am, 16 pm, 22 pm PAI-1 levels are measured by commercially available ELISA-kits (Coaliza PA-1, Chromogenix AB) and the plasma concentration of valproic acid an metabolites thereof is analyzed according to clinical routine at the Sahlgrenska University laboratory, Gothenburg, Sweden.

[0500] The plasma concentration of valproic acid is found to peak between 3 am and 6 am and thereafter declines to very low levels during the trough in PAI-1 concentrations. The peak in plasma valproic acid coincides with the peak level of plasma PAI-1 between 3 am and am. The plasma concentration of valproic acid and plasma PA-1 levels follow each other with a pronounced circadian elevation with its peak during the early morning hours. The plasma PA-1 levels are lowered by approximately 30% after the treatment.

Example 3—Clinical Outcome Study in High-Risk Patients for Prevention of Recurrent Thromboembolic Events Using Valproic Acid

[0501] A clinical outcome study is performed in high-risk patients who have experienced a recent major atherothrombotic cardiovascular event (myocardial infarction or TIA/ischemic stroke) to investigate the preventive effect of valproic acid treatment on the risk for recurrent events. The annual risk for a recurrent atherothrombotic event in the investigated population is estimated to approximately 7%.

[0502] Patients are randomized in a parallel study design to receive double-blind oral treatment with 400 mg valproic acid (as in Example 2) or placebo once time daily at 11 pm, in addition to optimal conventional treatment. The event rate is monitored by Kaplan-Meyer statistics. The primary efficacy endpoint is the composite measure of either mortality, or non-fatal myocardial infarction or ischemic stroke. The study is event-driven to a total of events.

[0503] The study is expected to show that long-term valproic acid treatment reduces this risk by approximately 30% in addition to that of conventional therapy, i.e. lowers the annual absolute event rate to approximately 5%. Thus, the study is expected to confirm the clinical efficacy and feasibility of using valproic acid for secondary prevention of cardiovascular disease.

Example 4

[0504] Core tablets with a composition according to Table 1 were manufactured at a batch size of 200 g.

TABLE-US-00002 TABLE 1 Core tablet formulation. Component Amount, % w/w Sodium valproate 23.06 MCC 64.94 Copovidone 5 Croscarmeliose sodium 5 Silica, colloidal anhydrous 1 Magnesium stearate 1

[0505] Sodium valproate was crushed in a mortar and sieved through a 0.50 mm screen. 46.1 g of the screened material was charged in a 1 L-vessel of Turbula T2F together with 129.9 g MCC, 10 g copovidone, 10 g croscarmellose sodium and 2 g silica. After mixing for 4 min at 32 rpm the mixture was sieved through a 0.50 mm screen and mixed for 4 min further. Magnesium stearate 2 g was roughly pre-mixed with a similar volume of the powder mixture in a steel vessel with a spoon and sieved through a 0.50 mm screen, added to the 1 L-vessel and mixed with the powder mixture for 2 min at 22 rpm. Tablets were compressed in 5 mm circular punch/die sets with normal cup depth in a rotary press (Fette 52i) at a main compression force of 2 kN. Tablet weight was approx. 65 mg and resistance to crushing approx. 5 kp.

Example 5

[0506] Core tablets with a composition according to Table 2 were manufactured at a batch size of 300 g.

TABLE-US-00003 TABLE 2 Core tablet formulation. Component Amount, % w/w Sodium valproate 23.06 MCC 47.94 Fumaric acid 16 Copovidone 5 Croscarmellose sodium 5 Silica, colloidal anhydrous 1 Magnesium stearate 2

[0507] Sodium valproate was crushed in a mortar and sieved through a 0.50 mm screen. 69.2 g of the screened material was charged in a 21-vessel of Turbula T2F together with 133.8 g MCC. Fumaric acid 48 g, sieved through a 0.50 mm screen, was added to the mixer vessel, too, together with 15 g copovidone and 15 g croscarmellose sodium. Silica 3 g and MCC 10 g were roughly mixed in a steel vessel with a spoon and sieved through a 0.50 mm screen and added to the 21-vessel. The powders were nixed for 8 min at 32 rpm. Magnesium stearate 6 g was roughly pre-mixed with a similar volume of the powder mixture in a steel vessel with a spoon and sieved through a 0.50 mm screen, added to the 21-vessel and mixed with the powder mixture for 2 min at 22 rpm. Tablets were compressed in 5 mm circular punch/die sets with normal cup depth in a rotary press (Fette 52i) at a main compression force of 2 kN. Tablet weight was approx. 75 mg and resistance to crushing approx. 5 kp.

Example 6

[0508] Core tablets according to Example 4 were coated with Eudragit® FS30D (aqueous dispersion 30%)/PlasACRYL™ T20 according to Table 3 using a Hüttlin Kugelcoater HKC005. The batch size was 50 g. The coating was performed with an air inlet temperature of 47° C., resulting in a product temperature of 28-29° C. The air flow was adjusted to achieve an appropriate fluidization of the tablets during the coating. The coating layer was applied to the core tablets so as to obtain a weight gain of 20%. After the coating, the tablets were cured at 40° C. for 2 hours.

TABLE-US-00004 TABLE 3 Coating spray suspension for Example 6 Ingredient Quantity, % w/w Eudragit ® FS30D 60.61 PlasACRYL ™ T20 9.09 Water 30.3

Example 7

[0509] Core tablets according to Example 5 were coated with Eudragit® FS30D (aqueous dispersion 30%)/PlasACRYL™ T20 according to Table 3 using a Hüttlin Kugelcoater HKC005. The batch size was 50 g. The coating was performed with an air inlet temperature of 47° C., resulting in a product temperature of 28-29° C. The air flow was adjusted to achieve an appropriate fluidization of the tablets during the coating. The coating layer was applied to the core tablets so as to obtain a weight gain of 9%. After the coating, the tablets were cured at 40° C. for 2 hours.

TABLE-US-00005 TABLE 3 Coating spray suspension for Example 7 Ingredient Quantity, % w/w Eudragit ® FS30D 60.61 PlasACRYL ™ T20 9.09 Water 30.3

Example 8—In Vitro Release

[0510] The in vitro release profile of the composition as prepared in Example 7 was analysed using USP dissolution Apparatus 2 (paddle) Ph. Eur. 2.9.3 (as described herein). The following conditions were used: temperature 37.0±20.5° C.; paddle speed 75 rpm. The samples were analyzed for valproic acid by HPLC using a Phenomenex Luna C18 column, 150×4.6 mm, particle size 5 μm, column temperature 40° C., mobile phase acetonitrile/phosphate buffer (pH 3.0) 1:1, flow rate 1 mL/min.

[0511] The level of release at particular time points and pH of solution was analysed. pH adjustments and sample pulls are described below. pH adjustments were performed immediately after sample pulls. Time points refer to total running time.

Stomach, pH 1

[0512] One tablet was added to a vessel containing 250 mL 0.1 M hydrochloric acid solution and the content was stirred for 1 hour and samples were pulled.

Small Intestine, pH 6.4

[0513] 181 mL of a solution of potassium phosphate buffer and potassium hydroxide was added to the vessel to give pH 6.4. Samples were pulled after 1.5 and 2.5 hours.

Ilium, pH 6.8

[0514] 69 mL of a solution of potassium phosphate buffer and potassium hydroxide was added to the vessel to give pH 6.8. Samples were pulled after 3 and 4 hours.

Terminal Ilium, pH 7.3

[0515] 253 mL of an aqueous potassium hydroxide solution was added to the vessel to give pH 7.3. Samples were pulled after 4.25, 4.5, 4.75, 5, 5.5 and 6 hours.

[0516] The release profile observed for the composition of Example 7 is shown in FIG. 2 as provided herein.

Example 9—Manufacturing of Tablet Cores

[0517] The batch formulas of the granulations and core tablet formulations employed in subsequent coating experiments are displayed in Tables 4 and 5. In Table 5 the actual mean tablet weight (16.1 mg (90% API), 16.5 mg (95% API and 16.3 mg (99% API) was used when calculating the amounts of the components per tablet.

TABLE-US-00006 TABLE 4 Batch formulas of granulations 90% API, 95% API, 99% API, Component 10% acid, 5% acid 1% acid Sodium 1350 1425 1485 valproate, g Fumaric acid, g 150 75 15 Silica, colloidal 150 150 150 anhydrous, g Hydroxypropyl 28.5 28.5 28.5 cellulose*, g Ethanol, 660 660 660 anhydrous** Silica, colloidal 8.4 8.4 8.4 anhydrous***, g Magnesium 16.8 16.8 16.8 stearate, g *Klucel LF **Evaporated during the process ***Added at the final mixing

TABLE-US-00007 TABLE 5 Core tablet formulations. Component 90% API 95% API 99% API Sodium valproate, 12.75 (79.24) 13.80 (83.64) 14.21 (87.16) mg/tabl (and %) Fumaric acid, mg/tabl 1.42 (8.80) 0.73 (4.40)  0.14 (0.088) (and %) Silica, colloidal 1.50 (9.30) 1.53 (9.30) 1.52 (9.30) anhydrous, mg/tabl (and %) Hydroxypropyl 0.27 (1.67) 0.28 (1.67) 0.27 (1.67) cellulose*, mg/tabl (and %) Magnesium stearate, 0.16 (0.99) 0.16 (0.99) 0.16 (0.99) mg/tabl (and %)

[0518] Granulation was performed with two sub batches of each formulation. These two sub batches were mixed with glidant and lubricant and compressed in a rotary press. Sodium valproate (API) and fumaric acid were sieved through a 1.00 mm screen. A pre-mixture was made of fumaric acid and a part of API in a mortar with pestle for the formulations with 95 and 99% API.

[0519] Aerosil (silica colloidal) was roughly mixed with the pre-mixture and remaining API (95 and 99% API) and sieved through a 1.00 mm sieve. For 90% API, Aerosil and API were roughly mixed and sieved through a 1.00 mm screen, i.e. no pre-mixture.

[0520] The roughly mixed powders were then mixed in a tumbling mixer—6 L vessel, 8 min, at rpm. This mixture was granulated with an ethanolic solution of hydroxypropyl cellulose in a planetary mixer. The granulation was spread on Al-foil in a tray and left on the bench to evaporate the solvent during the night. On the following day the granulation was dried for 4-6 h at 60° C. The dried granulation was then milled in a Quadro Comil. Silica was mixed with dried, milled granulation—i.e. two sub batches—for 8 min at 32 rpm in a 17 L vessel. Magnesium stearate and a similar volume of the silica-granulation-mixture were roughly mixed and sieved through a 1.00 mm screen and added to the vessel with the remaining silica-granulation-mixture. Mixing for 2 min at 23 rpm was performed. Tablets were compressed in 3 mm 5-tip punch/die sets—10 sets, i.e. complete filling of the turret—at a compression pressure of approx. 200 MPa. Tablet weight was approx. 16 mg.

Example 10—Coatings

Kollicoat® IR Coating

[0521] Core tablets according to Example 9 were coated with Kollicoat® IR/talc aqueous dispersion (protective coating) according to the table below using a Hüttlin Kugelcoater HKC005. The batch size was 150 g. The coating was performed with an air inlet temperature of 49° C. resulting in a product temperature of 41-43° C. The airflow was adjusted to achieve an appropriate fluidization of the tablets during the coating. The coating layer was applied to the core tablets so as to obtain a weight gain of 7.9 or 8.5% (4 or 5 mg/cm.sup.2, the former for L 30 D-55 and the latter for FS 30 D). After the coating, the tablets were cured and dried to constant weight in the coating equipment at 60° C. These coated cores were used for all coating processes below.

TABLE-US-00008 Ingredient Quantity, % w/w Kollicoat ® IR 12.00 Talc 4.29 Water 83.71

FS 30 D Coating

[0522] Core tablets according to Example 9 were coated with Eudragit® FS30D (aqueous dispersion 30%)/PlasACRYL™ T20 according to the table below using a Hüttlin Kugelcoater HKC005. The batch size was 80 g. The coating was performed with an air inlet temperature of 48° C., resulting in a product temperature of 37-39° C. The airflow was adjusted to achieve an appropriate fluidization of the tablets during the coating. The coating layer was applied to the core tablets so as to obtain a weight gain of 15, 20 or 29% (9, 12 or 17 mg/cm.sup.2). After the coating, the tablets were cured and dried to constant weight in the coating equipment at 48° C.

TABLE-US-00009 Ingredient Quantity, % w/w Eudragit ® FS30D 60.61 PlasACRYL ™ T20 9.09 Water 30.3

Eudragit L 30 D-55 Coating

[0523] Core tablets according to Example 9 were coated with Eudragit® L 30 D-55 (aqueous dispersion 30%)/PlasACRYL™ HTP20 according to the table below using a Hüttlin Kugelcoater HKC005. The batch size was 150 g. The coating was performed with an air inlet temperature of 52° C., resulting in a product temperature of 42-43° C. The airflow was adjusted to achieve an appropriate fluidization of the tablets during the coating. The coating layer was applied to the core tablets so as to obtain a weight gain of 15% (9 mg/cm.sup.2). After the coating, the tablets were cured and dried to constant weight in the coating equipment at 52° C.

TABLE-US-00010 Ingredient Quantity, % w/w Eudragit ® L 30 D-55 (30% aq. disp) 57.00 PlasACRYL ™ HTP20 14.60 Water 28.40

Kollicoat SR 30 D/Kollicoat IR Coating

[0524] Core tablets according to Example 9 (with Eudragit L 30 D-55 as described above) were coated with Kollicoat® SR 30 D (aqueous dispersion 30%)/Kollicoat® IR/triethyl citrate/talc according to the table below using a Hüttlin Kugelcoater HKC005 (resulting in a Kollicoat® SR 30 D/Kollicoat® IR ratio of 9:1 based on dry weight). The batch size was 80 g. The coating was performed with an air inlet temperature of 49-50° C., resulting in a product temperature of 40-42° C. The airflow was adjusted to achieve an appropriate fluidization of the tablets during the coating. The coating layer was applied to the core tablets so as to obtain a weight gain of 6, 9 or 13% (4, 6 or 9 mg/cm.sup.2). After the coating, the tablets were cured and dried to constant weight in the coating equipment at 50° C.

TABLE-US-00011 Ingredient Quantity, % w/w Kollicoat ® SR 30 D (30% aq. disp) 48.00 Koilcoat ® IR 1.60 Triethyl citrate 0.80 Talc 4.80 Water 44.80

Example 11—In Vitro Release Dissolution Model

[0525] The in vitro release profile of a composition as prepared the examples was analysed using USP dissolution Apparatus 2 (paddle) Ph. Eur. 2.9.3 (as described herein). The following conditions were used: temperature 37.0±0.5° C.; paddle speed 75 rpm. The samples were analyzed for valproic acid by HPLC using a Phenomenex Luna C18 column, 150×4.6 mm, particle size 5 μm, column temperature 40° C., mobile phase acetonitrile/phosphate buffer (pH 3.0) 1:1, flow rate 1 mL/min.

[0526] The level of release was measured after 2 hours in acidic media (750 mL 0.1 M hydrochloric acid solution, pH 1); pH is then raised to 7.0 by adding 250 mL 0.2 M trisodium phosphate buffer. The level of release was generally measured at time points 30, 60, 120, 180, 240, 360 and 480 minutes in the buffer stage.

Example 12—Effect of Coating on Dissolution

[0527] The coated tablets from Example 10 were analysed using the method described in Example 11. The results for the tablets coated with Eudragit FS 30 D are found in FIG. and the results for the tablets coated with Eudragit L 30 D-55 and Kollicoat SR 30 D/Kollicoat IR are found in FIG. 6 (different cores, same coating amount) and FIG. 7 (same tablet cores, varying coating amounts).

Example 13—Effect of Core on Dissolution

[0528] Tablet cores with different combinations of sodium valproate and fumaric acid were produced according to the method described in Example 9, as described in the table below.

TABLE-US-00012 Core type (%) 50 75 95 99 100 Sodium 46.08% 66.03% 83.64% 87.16% 88.04% valproate Fumaric acid 46.08% 22.01% 4.40% 0.88% 0.00% Aerosil 200 5.10% 9.30% 9.30% 9.30% 9.30% Klucel LF 1.75% 1.67% 1.67% 1.67% 1.67% Magnesium 0.99% 0.99% 0.99% 0.99% 0.99% stearate Total 100.00% 100.00% 100.00% 100.00% 100.00%

[0529] Tablet dissolution was measured in accordance with the procedure described in Example 9. Samples were pulled at 5, 10, 15, 20, 30 and 40 minutes and analysed according to the method described in Example 11 without the acidic pH stage (pH about 7.0 throughout the experiment). Results are shown in FIG. 4.