TABLET

Abstract

A method of forming an erodible sustained release tablet comprising the steps of:—a. mixing one or more therapeutic agents, one or more disintegrant and one or more molten wax, whilst retaining the wax in molten form; b. solidifying and granulating the mixture; c. forming a tablet by compression of the granules. The invention also relates to a sustained release tablet made according to the method.

Claims

1. A method of forming an erodible sustained release tablet comprising: a. mixing one or more therapeutic agents, one or more disintegrant and one or more molten wax, whilst retaining the wax in molten form to form a mixture; b. solidifying and granulating the mixture; and c. forming the tablet by compression of the granules.

2. The method of claim 1, wherein the compressed granules of step c. entirely form the sustained release tablet.

3. The method of in claim 1, wherein the compressed granules of step c. form an erodible sustained release core of the tablet, and wherein the tablet further comprises one or more functionalised layer encapsulating the core.

4. The method of claim 1, wherein the compressed granules of step c. form an erodible sustained release layer that encapsulates a core of a tablet.

5. The method of claim 1, wherein the wax is carnauba wax, paraffin wax, castor wax, beeswax, glycerol behenate, a glycowax or any combination thereof.

6. The method of claim 1, wherein the wax is present from about 20% to 80% by weight of the compressed granules of step c.

7. The method of claim 1, wherein the disintegrant is a low substituted hydroxypropyl cellulose.

8. The method of claim 7, wherein the disintegrant is LH-11, LH-21, LH-22, LH-32, NBD-021, NBD-020, LH-B1 or any combination thereof.

9. The method of claim 1, wherein the disintegrant is present from about 10-80% by weight of the compressed granules of step c.

10. The method of claim 1, wherein the mixing comprises mixing only a therapeutic agent, a disintegrant and a molten wax in step a.

11. A sustained release tablet comprising a wax, a disintegrant and a therapeutic agent, wherein the wax substantially coats particles or agglomerates of the therapeutic agent and of the disintegrant.

12. (canceled)

13. A sustained release tablet consisting of a wax, a disintegrant and a therapeutic agent, wherein the wax substantially coats particles of the therapeutic agent and of the disintegrant.

14. The sustained release tablet of claim 11, wherein the wax, the disintegrant and the therapeutic agent form a core of the tablet, and the tablet further comprises one or more functionalised layer encapsulating the core.

15. The sustained release tablet of claim 11, wherein the wax, the disintegrant and the therapeutic agent form a layer that encapsulates a core of the tablet.

16. The sustained release tablet of claim 11, wherein the wax is carnauba wax, paraffin wax, castor wax, beeswax, glycerol behenate, a glycowax or any combination thereof.

17. The sustained release tablet of claim 11, wherein the wax is present from about 20% to 80% by weight of a mixture comprising the wax, the disintegrant, and the therapeutic agent.

18. The sustained release tablet of claim 11, wherein the disintegrant is low substituted hydroxypropyl cellulose.

19. The sustained release tablet of claim 18, wherein the dintegrant is LH-11, LH-21, LH-22, LH-32, NBD-021, NBD-020, LH-B1, or any combination thereof.

20. The sustained release tablet of claim 11, wherein the disintegrant is present from about 10-80% by weight of a mixture comprising the wax, the disintegrant, and the therapeutic agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0055] The present invention will now be described, by way of example, with reference to the accompanying figures, in which:—

[0056] FIG. 1 shows mean drug release (n=6) over time from 500 mg tablets prepared according to the present invention and containing a 10 mg or 100 mg dose of metformin, with the remainder of the tablet being 50:50 (w/w) wax to disintegrant in pH 6.8 buffer.

[0057] FIG. 2a shows the release of 100 mg metformin (n=6), from a 500 mg tablet prepared according to the present invention and with a ratio of 50% wax to 50% total powder. The release period is around 4 hours 20 minutes

[0058] FIG. 2b shows the release of 100 mg metformin from a 500 mg tablet (n=6) prepared according to the present invention and, with the ratio of 55% wax to 45% total powder. The release period is around 7 hours 15 minutes.

[0059] FIG. 2c shows the release of 100 mg metformin from a 500 mg tablet (n=6) prepared according to the present invention and, with the ratio of 56% wax to 44% total powder, release occurs over an average period of around 8 hours.

[0060] FIG. 2d shows the release of 100 mg metformin from a 500 mg tablet (n=6) prepared according to the present invention and, with the ratio of 57% wax to 43% total powder, release occurs over an average period of around 9 hours.

[0061] FIG. 2e shows the release of 100 mg metformin from a 500 mg tablet (n=6) prepared according to the present invention and, with the ratio of tablet components altered to 60% wax to 40% total powder. Total drug release was around 48.8%. Full release did not occur within the time frame of the study because of the high wax content of the tablet although it is expected that full release would occur over time.

[0062] FIG. 3 shows sustained release of phenylephrine in the presence of different concentrations of alcohol in tablets prepared according to the present invention.

[0063] FIG. 4 shows release of API from a sustained release matrix in 3 media at 3 different pHs in tablets prepared according to the present invention. N=2

[0064] FIG. 5 shows release of API from sustained release matrix from tablets prepared according to the present invention at varying dissolution paddle speeds. N=2

[0065] FIG. 6a shows triphasic release combining a 4 hour sustained release layer with an immediate release coating and a phenylephrine core tablet prepared according to the present invention.

[0066] FIG. 6b is identical to FIG. 6a but for the fact that the release layer is prepared for a 6 hour sustained release period.

[0067] FIG. 7 shows anterior scintigraphic images of key events in the GI transit of a triphasic release tablet prepared according to the present invention with radiolabel contained in the sustained release portion (carried out on Subject 4 of study discussed below under 7.). Images are taken at various times post-dose: (a) 1 min (tablet located in the stomach); (b) 90 min (onset of radiolabel release in the stomach); (c) 195 min (confirmation of tablet gastric emptying) and (d) 375 min (complete radiolabel release in the ascending colon). Stomach and colon outlines are drawn for visualisation purposes only.

[0068] FIG. 8 shows the comparison of average release (%) of radioactivity from the sustained release component of a triphasic release tablet prepared according to the present invention (n=3) in vitro and in healthy volunteers (n=6) showing good in vitro/in vivo correlation.

1. Preparation of Tablets

[0069] Tablets prepared according to the present invention and tested in studies discussed below include various combinations of the following materials:—Metformin hydrochloride (batch 122110) was obtained from Spruyt Hillen BV (IJsselstein, The Netherlands). Griseofulvin (batch 10I30-B03) was purchased from Fagron (Terressa, Spain). Phenylephrine hydrochloride (batch 031M1736V) was purchased from Sigma-Aldrich (St. Louis, U.S.A.). Glyceryl behenate, also referred to as GB, (batch 134916) was purchased from Gattefosse (St-Priest, France). The L-HPC disintegrants were obtained from Shin Etsu (Tokyo, Japan).

[0070] Granules used to form a wax matrix were produced by melt granulation using glyceryl behenate and disintegrant in different ratios dependent on the target release period.

[0071] Glyceryl behenate (ie the wax) was melted by heating to 90° C. Once melted, the API (ie metformin hydrochloride, griseofulvin or phenylephrine hydrochloride) was added to the molten wax and mixed to form a dispersion. The disintegrant (ie L-HPC) and more of the API was then gradually added to the dispersion, and resultant mixture combined thoroughly using a spatula. To aid mixing, heat was maintained under the beaker until a consistent blend was achieved. Once fully combined the mixture was removed from the heat and granulated by stirring to break up the mixture as it cooled. The resultant granules were then milled while warm through a 1 mm sieve to produce granules of more regular dimension. Granules were compressed into a tablet using a 10 mm biconvex die.

[0072] The final tablets used in the studies below were prepared with varying ratios of API:Low-substituted hydroxypropyl cellulose (L-HPC): glycerol behenate prepared according to the above description in order to deliver sustained release drug delivery over a range of time periods. The ratios in the tablets for each study are provided below. Unless indicated otherwise, all weights are provided in mg.

2. In Vitro Drug Release Studies

[0073] 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 100 mg and 10 mg metformin per tablet preparations were measured prior to dissolution, using pH 6.8 phosphate buffer as a blank, to provide absorbance for 100% drug release.

3. Effect on Release Profile With Varied Amount of API

[0074] An in vitro drug release study was carried out according to 2. above on two sets of 500 mg tablets, both prepared according to the present invention and in accordance with proportions of ingredients presented in Table 1. Both sets of tablets included equal amounts by weight of glyceryl behenate to L-HPC, whilst one set of tablets included almost 10 times the amount by weight of metformin HCL. Results shown are mean results from 6 repeated studies.

TABLE-US-00001 TABLE 1 Ratio of Components API GB disintegrant API  10 mg Metformin•HCl* 48.7 48.7 2.6 100 mg Metformin•HCl* 37.2 37.2 25.6 *dose based on metformin and not metformin•HCl

[0075] Whilst an increase in dose of API in the tablet results an elevated rate of release of API from the tablet, it can be seen that the amount of API does not affected the ability to provide sustained release, ultimately close to total release of the API. The results of this study are provided in FIG. 1.

4. Effect on Release Profile With Varied Ratio of Wax to Disintegrant/API

[0076] An in vitro drug release study was carried out according to 2. above on 5 sets of tablets, all tablets being prepared according to the present invention and in accordance with proportions of ingredients presented in Table 2a to 2e. Results are provided in FIGS. 2a to 2e, corresponding to the tablets of Tables 2a to 2e, respectively.

TABLE-US-00002 TABLE 2a Ratio of Components API GB disintegrant API Metformin•HCl* 50 24.4 25.6

TABLE-US-00003 TABLE 2b Ratio of Components API GB disintegrant API Metformin•HCl* 55 19.4 25.6

TABLE-US-00004 TABLE 2c Ratio of Components API GB disintegrant API Metformin•HCl* 56 18.4 25.6

TABLE-US-00005 TABLE 2d Ratio of Components API GB disintegrant API Metformin•HCl* 57 17.4 25.6

TABLE-US-00006 TABLE 2e Ratio of Components API GB disintegrant API Metformin•HCl* 60 14.4 25.6
* dose based on metformin and not metformin. HCl

[0077] Increasing the wax to powder (ie the combination of API and LHPC) ratio had the effect of extending the period of drug release. The higher the percentage of wax, the longer the period of sustained release (see FIGS. 2a-e). Additionally, it can be seen that the formulations of the present invention provide a good consistent release profile from the fact that that the repeated tests for each table provide almost identical time/release curves in each of the tables 2a-2e.

5. Effect on Release Profile When in Presence of Alcohol

[0078] An in vitro drug release study was carried out according to 2. above, on tablets being prepared according to the present invention and in accordance with proportions of ingredients presented in Table 3. The study was repeated, but on

TABLE-US-00007 Ratio of Components API GB Disintegrant API Phenylephrine 50 46.7 3.3
each repetition with the addition of increasing amounts of alcohol being added to the phosphate buffer in which dissolution occurs. Results are provided in FIG. 3. Table 3.

[0079] One of the potential problems with sustained release formulations is ethanol induced dose dumping, where the controlled release mechanism fails in an ethanol solution causing all or most of the drug to be released over a very short period of time. This can be very hazardous when used for delivery of potent or toxic drugs. The sustained release mechanism of this invention is substantially unaffected by the presence of alcohol even at high concentrations. (see FIG. 3)

6. Effect on Release Profile When in Varied pH Environment

[0080] An in vitro drug release study was carried out according to 2. above, on tablets being prepared according to the present invention and in accordance with proportions of ingredients presented in Table 4. The study was repeated, but on each repetition with the phosphate buffer being controlled so as to present a decreasing pH environment in which dissolution occurs. Results are provided in FIG. 4.

TABLE-US-00008 TABLE 4 Ratio of Components API GB Disintegrant API Phenylephrine 50 46.7 3.3

7. Effect on Release Profile By Agitation

[0081] An in vitro drug release study was carried out according to 2. above, but with the dissolution paddle operating at varying speeds in order to replicate different conditions of agitation that may be experienced by a tablet as it passes through the GI tract. The studies were carried out on tablets being prepared according to the present invention and in accordance with the proportions of ingredients presented in Table 5.

TABLE-US-00009 TABLE 5 Ratio of Components API GB Disintegrant API Phenylephrine 50 46.7 3.3

[0082] Gut motility and degrees of compaction of matter in the gut can vary greatly between individuals and between different states of health of an individual. These changes can vary the amount of agitation that a tablet experiences as it transits through the GI tract. The above studies demonstrates that the present invention works independently of agitation. See FIG. 5.

8. Immediate, Sustained and Pulsed Release

[0083] An in vitro drug release study was carried out according to 2. above, all tablets being prepared with one layer according to formulation described in 1. above and that layer being in accordance with proportions of ingredients presented in Table 6. Each tablet was constructed with a core comprising 10 mg Phenylephrine HCl; 4.5 mg Crosscarmellose sodium; 2.25 mg Kollidon 3; 27.35 mg lactose monohydrate and 0.9 mg Magnesium stearate. The phenylephrine hydrochloride, croscarmellose sodium, Kollidon 30 and lactose monohydrate were mixed by hand in a suitable container for approximately three minutes. Magnesium stearate was then added and the blend mixed for a further three minutes before passing through a 180 sieve. 44 mg of the tablet blend was weighed and mixed with 3 mg of lactose. The tablets were compressed using a tablet press and a 5.9 mm bi-convex punch and die set. The tablets' weights were then measured to confirm that they met the weight specification of between 42.5-47.5 mg. The core being encapsulated in a layer prepared for either 4 or 6 hour sustained release, this encapsulated core itself being coated in a further layer comprising 10 mg of Phenylephrine HCl in a standard Opadry solution. Approximately 1.5 g of Opadry clear was weighed and gradually added to 30 mL of sterile water while mixing on a magnetic stirrer/hotplate.

[0084] Approximately 400 mg of phenylephrine hydrochloride was weighed and added to a 2 mL amber volumetric flask, followed by 1 mL ethanol. A magnetic stirrer was added and the contents of the flask mixed until fully dissolved. The magnetic stirrer was then removed and the flask made to volume with the Opadry clear solution. The solution was then transferred to an amber HPLC vial with a micro magnetic stirrer added and mixed until required for tablet manufacture. 50 μL of the coating was applied to the surface of the tablet.

[0085] The core and outer layer being prepared to facilitate immediate release of API when in contact with aqueous solutions of the GI tract. For the formulations prepared for a 6 hour sustained period, the layer providing sustained release is a larger (400 mg) barrier layer than in the 4 hour sustained period (300 mg).

[0086] Results are provided in FIG. 6a for the tablet prepared for a 4 hour release profile and in FIG. 6b for the tablet prepared for a 6 hour release profile.

TABLE-US-00010 TABLE 6 Ratio of Components API GB disintegrant API T = 4 hours Phenylephrine•HCl 45 50 5 T = 6 hours Phenylephrine•HCl 45 51.2 3.8

[0087] The formulations studied here demonstrate further possibilities for expanding the use of the sustained release technologies of the present invention so as to provide a long acting formulation, or to allow delivery of a combination of drugs if appropriate. One such example, as studied here, is a tri-phasic release tablet that provides an immediate dose-release followed by sustained release and a final burst-release from a tablet core providing a potential for a ‘once a day’ formulation.

9. Clinical Evaluation

[0088] A two-arm clinical study was designed to investigate the in vivo behaviour of a triphasic release formulation which delivers an immediate 10 mg dose of phenylephrine followed by a 15 mg sustained release dose delivered over a 5 hour period and a 10 mg delayed release pulse from a core tablet. Formulated as discussed above in the paragraph numbered 8.

[0089] Qualitative and quantitative scintigraphic methods were used to assess the gastrointestinal transit of the tablets and their disintegration properties.

[0090] In study arm 1 the core tablet was radiolabelled to allow visualisation of release from the tablet core, in the second arm, radiolabel was incorporated into the sustained release layer to demonstrate the consistency of erosion.

[0091] The results for analysis of study arm 1 are provided in Table 7.The mean times for onset of release and complete radiolabel release from the core tablet was 433.5±13.4 min and 562.5±73.5 min respectively post dose (n=5). Identical tablets were also studied in vitro under the procedure outlined in 2. above, providing a slightly longer period of core release observed in vitro and one that occurred at 300 minutes.

[0092] The data in the table below shows the time and location of onset of release from the core tablet showing highly reproducible burst time demonstrating the consistency of erosion of the sustained release layer despite location within the GI tract.

[0093] The above table showstime and location of radiolabel release from core tablets in the triphasic release tablet in healthy volunteers (n=5)

[0094] The mean time for onset of radiolabel release from the sustained release layer (ie arm 2) was 75.0±22.7 min. Results are provided in Table 8. Complete release was from the sustained release layer was observed in the colon for all subjects after a mean time of 425.0±180.7 min.

[0095] The above table shows site and time of radiolabel release from the sustained release portion of the triphasic release tablet in healthy volunteers (n=6). The release are visualised for subject 4 in the second arm study in FIG. 7.

[0096] The utility of the present invention can be clearly seen from the finding of this study that onset of release times for both the sustained release layer and burst release core were highly reproducible, as evidenced by the small standard deviation times of 22.7 min and 13.4 min respectively.

[0097] FIG. 8 shows the mean erosion profile of the tablet in vitro and in vivo, demonstrating close IVIVC (in vitro and in vivo correlation). The Y axis provides percentage released radiolabeled therapeutic agent of the total in the tablet. Data established according to the methods of 2. above.