Pharmaceutical processing

Abstract

A method for making a controlled release material, comprising the steps of: — (a) forming granules comprising one or more wax and one or more disintegrant; (b) spheronisation of the granules and (c) compaction of the spheronised granules of step so as to form the controlled release material. The invention also relates to a tablet and delayed and sustained release material made according to the method.

Claims

1. A method for making an erodible controlled release tablet, comprising: (a) forming granules comprising 20 to 80% by weight of one or more waxes and 12-50% by weight of one or more disintegrants, wherein the one or more waxes are insoluble in water, and wherein the granules are formed by mixing the one or more disintegrants and the one or more waxes, in molten form, to form a mixture, whilst retaining the one or more waxes in molten form, and solidifying the mixture by cooling below melting point whilst mixing to form the granules; (b) spheronising the granules; and (c) compacting the spheronised granules around a core tablet comprising an Active Pharmaceutical Ingredient to form a controlled release barrier layer.

2. The method of claim 1, further comprising milling of granules formed in step (a) prior to spheronisation in step (b).

3. The method of claim 1, wherein the one or more waxes are selected from the group consisting of carnauba wax, paraffin wax, castor wax, hydrogenated castor oil, beeswax, glycerol behenate, a glycowax or any combination thereof.

4. The method of claim 1, wherein the one or more disintegrants are selected from the group consisting of LH-11, LH-21, LH-22, LH-32, NBD-021, NBD-020, LH-B1, sodium carboxymethylcellulose, cross-linked starch, hydroxylpropylmethyl cellulose, ion exchange resins or any combination thereof.

5. The method of claim 1, wherein the controlled release barrier layer further comprises a therapeutic agent.

6. A tablet comprising a core and a first layer encapsulating the core, wherein the first layer is an erodible controlled release barrier layer comprising compacted spheronized granules comprising 20 to 80% by weight of one or more waxes and 12-50% by weight of one or more disintegrants; wherein the one or more waxes is insoluble in water; wherein the tablet is formed via the steps comprising: (a) forming granules comprising 20 to 80% by weight of one or more waxes and 12-50% by weight of one or more disintegrants, wherein the one or more waxes is are insoluble in water, and wherein the granules are formed by mixing the one or more disintegrants and the one or more waxes, in molten form, to form a mixture, whilst retaining the one or more waxes in molten form, and solidifying the mixture by cooling below melting point whilst mixing to form the granules; (b) spheronising the granules; and (c) compacting the spheronised granules around a core tablet comprising an Active Pharmaceutical Ingredient to form a controlled release barrier layer.

7. The tablet of claim 6, further comprising a second layer encapsulating the first layer.

8. The tablet of claim 7, wherein the second layer comprises one or more therapeutic agents, one or more disintegrants and one or more waxes.

9. The tablet of claim 7, wherein the second layer includes no therapeutic agent.

10. The tablet of claim 7, wherein the second layer is a functional layer.

11. The tablet of claim 6, further comprising one or more therapeutic agents.

Description

(1) The present invention will now be described by way of example and with reference to the FIGURE, in which: —

(2) FIG. 1 shows a magnified image of granules prepared according to the present invention.

1. PRODUCTION OF A DELAYED RELEASE MATERIAL ACCORDING TO THE PRESENT INVENTION

(3) Wax Granules were prepared by melt granulation of the wax glycerol behenate with a disintegrant (i.e. Low-substituted hydroxypropyl cellulose), using one of the methods described below.

(4) 1) Laboratory Scale Method <100 g

(5) Glyceryl behenate (i.e. the wax) was melted by heating to 90° C. in a heated water jacketed vessel. Once melted, L-HPC (LH 21 and LH 32) was then gradually added to the molten wax, and resultant mixture combined thoroughly by hand using a spatula. To aid mixing, heat was maintained in the jacketed vessel until a homogenous 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 if necessary.

(6) The resultant granules were then milled while warm through a 1.00 mm sieve by hand.

(7) 2) Large Scale Hot Melt Extruder Method >5 Kg Scale

(8) Glyceryl behenate and the L-HPC (LH 21 and LH 32) were pre blended using a tumbling motion for a sufficent time to ensure a homogenous mix was obtained. This powder blend was then run through a heated twin screw extruder with temperature raising up to 140° C. with no die plate fitted. The extrudate fell directly into an oscillating granulator running at 120 RPM fitted with a 1.00m mesh screen.

(9) These milled granules from 1 and 2 were then added directly to a heated Caleva spheroniser while the spheronising plate was spinning. The granules were left in the operating spheroniser for the required temperature (typically 60-74° C.), time (typically 0-5 minutes) and speed for small scale spheronisation before being removed and allowed to cool.

(10) The cooled spheronised granules were compressed onto a core tablet to form the delayed release material and so provide a delayed release tablet.

(11) 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.

(12) 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

(13) Weight of water used in granulation process is approximately 72% w/w of final blend weight (or 81% w/w of intragranular blend weight). 100 mg 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.

(14) The delayed release layer was put in place using the following protocol. A 10 mm concave punch and die were used to compress the cooled spheronised granules around the core tablet. The required quantity of delayed release spheronised granules were placed onto the lower punch, the core tablet carefully placed on the granule bed and centralised, before placing the remaining granules on top. The contents of the die was then compressed using a single station tablet press.

2, THE EFFECT ON ANGLE OF REPOSE OF WAX GRANULES BEFORE AND AFTER THE SPHERONISATION TECHNIQUE

(15) The milled pre-spheronised granules discussed above in 1. were cooled and their angle of repose determined. The granules were then spheronised and cooled as described above in 1. and under the conditions provided in table 1 belowtheir angle of repose determined.

(16) 50 g of the test material was allowed to flow through the orifice of a funnel which was fixed at 5 cm above a flat surface. The magnitude of the angle of the powder heap formed relative to the flat surface was measured and recorded as the angle of repose.

(17) TABLE-US-00002 TABLE 1 Spheronisation Time (mins) Temperature (° C.) Speed Angle of Repose None None None 39.8°  3 72 Maximum 30.3° 10 74 40% 29.4°

(18) These results clearly show that the warm spheronisation of the wax granules does significantly improve the flow properties of the granules.

3. EFFECT OF SPHERONISATION ON DELAY TIME BEFORE RELEASE OF ACTIVE

(19) Delayed release tablets formed with the delayed release material processed according to the present invention as a delayed release layer encapsulating a therapeutic core, in accordance with that described in 1. were made. Prior to compression around the core, the granules were spheronised at 72° C. for 3 minutes. A second set of delayed release tablets were prepared in a manner identical to that of the first, but no spheronisation step was carried out.

(20) The period for the delay in the release for both sets of tablets was studied. Dissolution studies were carried out on tablets prepared according to the present invention using an automated ADT8 USP dissolution type II apparatus (TDT08L 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 the absorbance of the core therapeutic agent was measured by UV analysis using an SP700 High Performance UV Visibility Spectrometer (T70+18-1815-1-0054, PG Instruments Ltd., Wibtoft, U.K.) and compared with a standard prepared to the appropriate concentration. Onset of release was defined as the time at which the absorbance recorded for the therapeutic agent was more than 3%.

(21) Results of the study are shown in Table 2.

(22) TABLE-US-00003 Spheronised Non-Spheronised (n = 6 tablets) (n = 6 tablets) Delay Time (hr:min) 03:51 02:14 Standard Deviation 00:21 00:12 RSD (%) 9.3 8.9

(23) Spheronisation has been demonstrated to have a significant impact on prolongation of release delay, which is thought to be because of its ability to prolong erosion and swelling rate of wax based granules. The methods of the present invention are shown to prolong delay when compacted into tablets.