Composition

Abstract

A press coated tablet for delayed release of an active ingredient comprising: (a) a core comprising one or more active ingredients, and; (b) an erodible delayed release barrier surrounding the core and comprising a wax and two or more grades of L-HPC, wherein the wax and L-HPC are provided in a weight ratio of wax to L-HPC of from 30%:70% to 70%:30%. The invention also relates to a method of making the press coated tablet.

Claims

1. A press coated tablet for delayed release of an active ingredient comprising: (a) a core comprising one or more active ingredients, and; (b) an erodible delayed release barrier surrounding the core and comprising a wax and two or more grades of L-HPC, wherein the wax and L-HPC are provided in a weight ratio of wax to L-HPC of from 30%:70% to 70%:30%.

2. The press coated tablet as claimed in claim 1, wherein the two or more grades of L-HPC include coarse and medium particle L-HPCs.

3. The press coated tablet as claimed in claim 2, wherein the two or more grades of L-HPC are selected from any one of the following combinations: LH-11 and LH-21, LH-11 and LH-22, LH-11 and NBD-22, LH-11 and NBD-021, LH-11 and NBD-020, LH-B 1 and LH-21, LH-B 1 and LH-22, LH-B 1 and NBD-22, LH-B 1 and NBD-021, LH-B1 and NBD-020.

4. The press coated tablet as claimed in claim 1, wherein the two or more grades of L-HPC include coarse and micronised particle L-HPCs

5. The press coated tablet as claimed in claim 4, wherein the two or more grades of L-HPC are selected from any one of the following combinations: LH-11 and LH-31, LH-11 and LH-32, LH-B 1 and LH-31, and LH-B 1 and LH-32.

6. The press coated tablet as claimed in claim 1, wherein the two or more grades of L-HPC include medium and micronised particle L-HPCs.

7. The press coated tablet as claimed in claim 6, wherein the two or more grades of L-HPC are selected from any one of the following combinations: LH-21 and LH-31, LH-22 and LH-31, NBD-22 and LH-31, NBD-021 and LH-31, NBD-020 and LH-31, LH-21 and LH-32, LH-22 and LH-32, NBD-22 and LH-32, NBD-021 and LH-32, and NBD-020 and LH-32.

8. The press coated tablet as claimed in claim 1, wherein the two or more grades of L-HPC include a low and a high level hydroxypropoyl content L-HPCs.

9. The press coated tablet as claimed in claim 8, wherein the two or more grades of L-HPC are selected from any one of the following combinations: NBD-021 and NBD-022, NBD-020 and NBD-022, LH-11 and NBD-022, LH-21 and NBD-022, LH-31 and NBD-022, LH-B 1 and NBD-022, NBD-021 and LH-22, NBD-020 and LH-22, LH-11 and LH-22, LH-21 and LH-22, LH-31 and LH-22, LH-B 1 and LH-22, NBD-021 and LH-32, NBD-020 and LH-32, LH-11 and LH-32, LH-21 and LH-32, LH-31 and LH-32, and LH-B1 and LH-32.

10. The press coated tablet as claimed in claim 1, wherein the two or more grades of L-HPC include a low and a high level hydroxypropoyi content L-HPCs that are also a combination of coarse and medium particle L-HPCs.

11. The press coated tablet as claimed in claim 10, wherein the two or more grades of L-HPC are selected from any one of the following combinations: LH-11 and LH-22, LH11 and NBD-022, LH-B1 and LH-22, and LH-B1 and NBD-022.

12. The press coated tablet as claimed in claim 1, wherein the two or more grades of L-HPC include a low and a high level hydroxypropyl content L-HPCs that are also a combination of coarse and micronised particle L-HPC.

13. The press coated tablet as claimed in claim 12, wherein the two or more grades of L-HPC are selected from any one of the following combinations: LH-1 1 and LH-32, and LH-B1 and LH-32.

14. The press coated tablet as claimed in claim 1, wherein the two or more grades of L-HPC include a low and a high level hydroxypropyl content L-HPCs that are also a combination of medium and micronised particle L-HPC.

15. The press coated tablet as claimed in claim 14, wherein the two or more grades of L-HPC are selected from any one of the following combinations: LH-22 and LH-31, NBD-022 and LH-31, LH-21 and LH-32, NBD-021 and LH-32, and NBD-020 and LH 32.

16. The press coated tablet as claimed in claim 1, wherein the core tablet releases at least 70% of the active agent within 5-80 minutes after initiation of release.

17. The press coated tablet as claimed in claim 1, wherein the core tablet releases in a sustained manner over a period of 2-12 hours after initiation of drug active ingredient release.

18. The press coated tablet according to claim 1, wherein the wax is chosen from a group consisting of beeswax, microcrystalline wax, a glyceryl ester, hydrogenated castor oil or carnauba wax or any combination of waxes.

19. The press coated tablet as claimed in claim 18, wherein the wax is glycerol behenate.

20. The press coated tablet according to claim 1, further comprising one or more coatings that can be pH dependent or independent or may be functional or aesthetic.

21. The press coated tablet according to claim 20 where the one or more coating may contain an active ingredient that is the same as or different to the active ingredient or ingredients of the core.

22. The press coated tablet according to claim 1, further comprising a top layer which may contain an optional immediate release layer comprising the same or different drug to that in the core.

23. A method of making a press coated tablet according to claim 1, the method comprising the steps of: a) the active ingredient and pharmaceutically acceptable excipients and/or diluents are mixed or granulated together and compressed to form a core; b) one or more wax and two or more L-HPCs are mixed and melted to form granules and the resulting mixture compressed around the outer surface of the core so as to form a barrier layer.

Description

[0060] The present invention will now be described, by way of example, with reference to the figures, in which:

[0061] FIG. 1 shows a diagram of the delayed release tablet of the present invention comprising a drug-containing core tablet that may be either immediate or sustained release and an outer erodible barrier layer that controls the delay of release. Reference numeral 1 shows the tablet core while reference numeral 2 the erodible barrier layer.

[0062] FIG. 2 shows dissolution profiles obtained for tablets according to the present invention with different ratios of wax:disintegrant in the composition of the barrier layer, a fixed release barrier weight and a fixed LH21:32 ratio

[0063] FIG. 3 shows dissolution profiles obtained for tablets according to the present invention with the wax content in the release barrier being kept constant, as has the ratio of the combined L-HPCs, but the combinations of L-HPCs varied.

[0064] FIG. 4 shows dissolution profiles obtained for tablets according to the present invention wherein the wax content in the release barrier and overall weight of release barrier has been kept constant. The ratio of the L-HPCs used in this study (being LH-21 and LH-32) are however varied.

[0065] FIG. 5 shows dissolution profiles for tablets prepared according to the present invention and that include variations in the active ingredient to be released from the core.

[0066] FIG. 6 shows dissolution profiles obtained for tablets according to the present invention and with varying release barrier thicknesses and a fixed formulation content in the release barrier.

[0067] FIG. 7 shows an image of erosion of tablet made according to the present invention (B) compared to the rupture of a tablet that includes only a single grade of L-HPC (A).

1. TABLET STRUCTURE

[0068] The formulation of the invention provides a treatment for the delayed release of an active ingredient or ingredients. The formulation is a press coated tablet manufactured by simple, well understood pharmaceutical processes. Control of the lag period prior to release is achieved by steady erosion of a barrier layer that is compression coated around a drug-containing core tablet to form a tablet in tablet structure (FIG. 1). Control of erosion over a prolonged period is achieved by combining two or more different grades of Low substituted hydroxypropyl celluloses (L-HPC) preferably with different particle sizes and preferably at least one small particle size and one large particle size.

2. MANUFACTURE OF CORE TABLET

[0069] Any core tablet may be used providing it is of an appropriate size for ingestion, e.g. by a human. In this example the following wet granulation process was used to provide an immediate release core tablet.

TABLE-US-00001 API/Excipient % (w/w) Location Diclofenac potassium 25 Intra-granular Microcrystalline cellulose (Avicel PH 101) 63 Croscarmellose sodium (AC-DI-SOL) 1 Croscarmellose sodium (AC-DI-SOL) 10 Extra-granular Magnesium stearate 1

[0070] Weight of water used in granulation process is approximately 72% w/w of final blend weight (or 81% w/w of intragranular blend weight). 100mg of the core blend is pressed to a hardness of 4-5 kp and a thickness of 3.4 mm±0.17 mm using a 6 mm bi-convex punch and die.

3. MANUFACTURE OF ERODIBLE BARRIER LAYER GRANULES

[0071]

TABLE-US-00002 Excipient % (w/w) Glycerol behenate (GB) 42 Low-substituted hydroxypropyl 36 cellulose (LH-32) Low-substituted hydroxypropyl 22 cellulose (LH-21) [0072] All excipients are blended using a tumbling action for 5 minutes. [0073] The blend is processed by hot melt granulation (although other appropriate melt granulation process are suitable). While still warm, the granules are passed through an oscillating granulator with a 1 mm sieve and collected.

[0074] Formulation compression:

[0075] Erodible barrier layer granules are compressed around the 6 mm core tablet using standard compression coating techniques using a 10 mm biconvex punch and die to a hardness of between 5 and 10 Kiloponds. The core tablet is completely coated with an even layer of the granules.

4. IN VITRO DRUG RELEASE STUDIES

[0076] Dissolution studies were carried out on tablets prepared according to the present invention using an automated ADT8 USP dissolution type II apparatus (TDTO8L Bath 1105230, Electrolab Inc., Cupertino, USA), with paddle operated at 50 rpm, at 37° C.±0.5° C. Dissolution was carried out in 900 ml of pH6.8 phosphate buffer. Samples of dissolution media were withdrawn every 5 minutes and measured by UV analysis using an SP700 High Performance UV Visibility Spectrometer (T70+18-1815-1-0054, PG Instruments Ltd., Wibtoft, U.K.). Appropriate standard samples for the active ingredient per tablet preparations were measured prior to dissolution, using pH 6.8 phosphate buffer as a blank, to provide absorbance for 100% drug release.

5. EFFECT OF CHANGE OF PROPORTION OF L-HPCS IN BLEND ON RELEASE

[0077]

TABLE-US-00003 TABLE 1 Excipient Ratio Lag time achieved Lag time achieved Erosion GB:LH-11:LH-32 4 hr formulation 6 hr formulation observed? 42:14.5:43.5 4 hrs 6 min  6 hrs 5 min  Negligible 42:17.4:40.6 3 hrs 53 min 5 hrs 13 min Yes 42:20.3:37.7 3 hrs 26 min 4 hrs 55 min Good

[0078] Table 1 shows the results of an examination of the release profile (as described in 4. above) of diclofenac potassium from a composition according to the present invention and manufactured according to that described in numbered paragraphs 2 and 3 above, with proportions of wax to L-HPC as shown in table 1. The amount of glycerol behenate (i.e. wax) in each tested tablet was kept constant, whilst the proportion of L-HPC was varied. The results clearly show that mixing the proportion of one grade of L-HPC to another grade in the release barrier can control the erosion of the delayed release layer and subsequently the time of release from the core.

6. EFFECT OF INCREASED WEIGHT OF DELAYED RELEASE BARRIER ON RELEASE OF ACTIVE INGREDIENT

[0079]

TABLE-US-00004 TABLE 2 Thickness of erosion layer for GB:LH-21:LH-32 Time ratio of 42:20.3:37.7 of release 260 mg 3 hrs 26 mins 290 mg 4 hrs 3 mins  300 mg 4 hrs 11 mins 330 mg 4 hrs 40 mins

[0080] Table 2 shows the results of an examination of the release profile (as described in 4. above) of diclofenac potassium from a composition according to the present invention and manufactured according to that described in numbered paragraphs 2 and 3 above, with proportions of wax to L-HPC as shown in table 2. The results demonstrate that an increase in thickness of release barrier corresponds to an increase in the lag time for release of the diclofenac potassium; thereby demonstrating the controllability of release by control of the thickness of the release barrier of the present invention.

6. EFFECT OF VARIATION OF PROPORTION OF WAX TO L-HPC IN RELEASE BARRIER

[0081] An examination of the release profile (as described in 4. above) of diclofenac potassium from a composition according to the present invention and manufactured according to that described in numbered paragraphs 2 and 3 above, with proportions of wax to L-HPC as shown below. Ratios of wax to disintegrant were used from 30:70 to 70:30 (with fixed LH 21:32 ratio and constant release barrier weight): [0082] i. 30:70 (maintain LH21:LH32 ratio of 38:68) [0083] ii. 40:60 (maintain LH21:LH32 ratio of 38:68) [0084] iii. 50:50 (maintain LH21:LH32 ratio of 38:68) [0085] iv. 70:30 (maintain LH21:LH32 ratio of 38:68)

[0086] The results are shown in FIG. 2, and tables 3 and 4. As the wax content of the release barrier increases the lag time before release becomes longer. It was found here that with the LH mix composition used, the 70:30 tablet did not release the active from the core tablet during the time-frame of the study.

TABLE-US-00005 TABLE 3 Wax:L-H PC 30:70 40:60 50:50 70:30 Average release time 02:02 03:30 06:57 No (hh:mm) Release Standard deviation 00:05 00:07 00:15 No Release RSD (%) 4.3 3.4 3.8 No Release

[0087] Dissolution data obtained with different ratios of wax:disintegrant in the composition of the barrier layer, a fixed release barrier release barrier weight and a fixed LH21:32 ratio, showing the effect of total wax content on delay before—release, with diclofenac contained in the immediate release core.

TABLE-US-00006 TABLE 4 Wax:L-HPC 30:70 40:60 50:50 70:30 Excipient % (w/w) % (w/w) % (w/w) % (w/w) Glycerol behenate 30 40 50 70 (GB) Low-substituted 43.4 37.25 31.15 11.35 hydroxypropyl cellulose (LH-32) Low-substituted 26.6 22.75 18.85 18.65 hydroxypropyl cellulose (LH-21)

[0088] Composition of formulations used to obtain above dissolution profiles with different ratios of wax:disintegrant in the composition of the barrier layer, and a fixed LH21:32 ratio.

7. EFFECT OF GRADE COMBINATIONS OF L-HPC ON DISSOLUTION PROFILE

[0089] FIG. 3 shows the results of an examination of the release profile (as described in 4. above) of diclofenac potassium from a composition according to the present invention and manufactured according to that described in numbered paragraphs 2 and 3 above, with proportions of wax and combinations of L-HPC as shown in table 5. The wax content in the release barrier has been kept constant, as has the ratio of the combined L-HPCs.

[0090] The data below shows that combining grades of L-HPCs with different chemistry within the same fixed ratio in the barrier layer can have a significant effect on the lag time to release of active ingredient. Thereby demonstrating that good levels of control of the release profile may be achieved by control over the L-HPC combination.

TABLE-US-00007 TABLE 5 GB: GB: GB: GB: GB:LH11: LH-31: LH-21: NBD022: LH-21: LH32 LH-32 LH-31 LH-32 NBD022 (42:14.5: Composition (42:22:36) (42:22:36) (42:22:36) (42:22:36) 43.5) Average 04:17 02:59 05:07 02:55 04:06 release time (hh:mm) Standard 00:13 00:10 00:19 00:08 00:11 deviation RSD (%) 5.3177 5.9637 6.4837 5.1110 4.6812

[0091] Whilst it can be seen that generally selecting combinations of L-HPCs with high level hydroxypropoxy content provides a shorter delay period (see LH-21 and LH-31 combination), and selecting combinations of L-HPCs with low level hydroxypropyl content provides a longer delay period (see NBD-022 and LH-32), selecting L-HPCs with combinations of hydroxypropoxy content provide intermediate release lag times. Additionally, selecting combinations of L-HPCs with vastly different particles sizes can significantly change the release lag time; compare the results for LH-21 and NBD-022 (both with medium sized particles) with those of LH-11 and LH-32 (that provide course and micronised particles, respectively).

8. EFFECT OF PROPORTION OF L-HPC COMBINATION IN RELEASE BARRIER WITH CONSTANT WEIGHT AND WAX

[0092] FIG. 4 shows the results of an examination of the release profile (according to 4. above) of diclofenac potassium from a composition according to the present invention and manufactured according to that described in numbered paragraphs 2 and 3 above, with proportions of wax and combinations of L-HPC as shown in table 6. The wax content in the release barrier and overall weight of release barrier has been kept constant. The ratio of the L-HPCs used in this study (being LH-21 and LH-32) are as follows:-25:75, 50:50, 75:25 and 90:10.

[0093] As we see from the graph below, increasing the amount of LH32 relative to LH21 results in an increase in the delay time. Previous studies found that LH32 when used on its own (i.e. in a formulation according to the present invention, but for the fact only a single grade of L-HPC is incorporated into the release barrier) provided a longer lag time than LH21 used on its own. A problem with this single L-HPC formulation was found, in that when used on its own, LH32 did not erode, instead the formulation opened up by a rupturing mechanism. Therefore manipulation of the LH ratios allows a more controlled release over longer lag times, while maintaining the key property of erosion.

TABLE-US-00008 TABLE 6 25:75 50:50 75:25 90:10 Composition LH21:LH32 LH21:LH32 LH21:LH32 LH21:LH32 Average 05:33 04:13 03:05 02:30 release time (hh:mm) Standard 00:07 00:02 00:05 00:05 deviation RSD (%) 2.3 1.1 3.1 3.3 (RSD = relative standard deviation)

[0094] 9. EFFECT OF DIFFERENT ACTIVE INGREDIENTS IN TABLET CORE

[0095] FIG. 5 shows that the active ingredient in the tablet core has no effect of the lag period before release of active ingredient. The proportions of wax and combinations of L-HPC are kept constant for each tablet and are as shown in table 7. The tablets in the study however differ from each other by the choice of active ingredient provided in their core. Different active ingredients that are incorporated into the core of the studied tablets are selected from the following: Paracetamol 25 mg, Metformin 25 mg and Diclofenac 25 mg.

[0096] As can be seen from the results (after practicing analysis according to 4. above), the performance of the formulations of the present invention was not affected by the choice of active ingredient to be delivered by the formulations. Consequently, it can be concluded that the tablets of the present invention are a good vehicle for delivery of any active ingredient to be administered orally.

TABLE-US-00009 TABLE 7 Proportions described above of 42:22:36 relate to wax:LH21:LH32. Paracetamol Core Metformin Core Diclofenac Core Composition (42:22:36) (42:22:36) (42:22:36) Average 04:11 04:23 04:13 release time (hh:mm) Standard 00:11 00:10 00:02 deviation RSD (%) 4.38 3.8 0.8

10. EFFECT OF THICKNESS OF RELEASE BARRIER

[0097] FIG. 6 shows the results of an examination of the effect of thickness of release barrier on the release profile (as described in 4. above) of diclofenac potassium from a composition according to the present invention and manufactured according to that described in numbered paragraphs 2 and 3 above, with proportions as provided in table 8. The proportions of wax and combinations of L-HPC are kept constant for each tablet, i.e. 42:22:36 for GB:LH21:LH32.

[0098] As we see from the FIG. 6, increasing the amount of barrier layer we add to the core tablet results in an increase in the delay time before release. Thickness was measured using digital callipers on a tablet that has been broken in half to reveal the layers. The value for the thickness of the core was subtracted from the total thickness of the tablet in order to provide a value for the thickness of the release barrier.

TABLE-US-00010 TABLE 8 1 mm thick 1.4 mm thick 1.9 mm thick release barrier release barrier release barrier Composition layer layer layer Average 03:43 04:58 06:03 release time (hh:mm) Standard 00:02 00:11 00:10 deviation RSD (%) 0.90 3.69 2.75

11. EFFECT OF COMBINATION OF L-HPC COMPARED TO SINGLE L-HPC IN A FORMULATION

[0099] A first tablet was prepared according to the present invention and as described in 2. and 3. above. A second tablet was prepared, differing only by the fact that it contained 58% by weight of the release layer of LH-32 (i.e. as the only L-HPC in the formulation). The erosion of each tablet was studied according to that described in 4. above. Images taken at the point of release of active agent for each tablet is captured in FIG. 7(A), relating to the second tablet, and FIG. 7(B), relating to the first tablet.

[0100] It is clear from these images that the formulation including only a single L-HPC ruptured abruptly into a clam-shell, whereas the tablet formulated according to the present invention showed a more gradual erosion.