Immediate/delayed drug delivery

Abstract

In one aspect, the present invention is concerned with a treatment where it is desired that an active agent is designed to be released immediately following administration and again at a time point some time after administration of the active agent. The present invention is particularly suited to administering an agent which may be released before sleep and while a subject is sleeping. As well as treating certain conditions by a particular regime, the invention also provides novel formulations for an immediate, followed by a delayed release of drug.

Claims

1. A press-coated tablet formulation for an immediate, followed by a delayed release of an active agent, the tablet comprising: (a) a core comprising an active agent together with an excipient(s); and (b) a delayed release layer surrounding the core and comprising a wax and a low substituted hydroxypropyl cellulose in a ratio of 40:60 to 60:40 w/w; wherein the delayed release layer substantially delays release of the active agent within the core for between 3-8 hours after administration of the tablet to a subject and thereafter a pulsed release of the active agent from the core occurs, such that at least 70% of the active agent in the core is released within 5-45 minutes and wherein the low substituted hydroxypropyl cellulose is micronized with a mean particle diameter of 20 mm and has a molecular weight of 115,000 and a hydroxypropyl cellulose content of 8%; and (c) a top-coating layer comprising a portion of an active agent together with one or more excipients wherein a substantially immediate pulsed release of the active agent occurs following administration to the subject of the tablet; wherein the active agent in the core and on the top-coating layer is an NSAID.

2. The press-coated tablet according to claim 1 further comprising an amount of an active agent, which is the same or different to the active agent in the core and/or top-coating layer, in the delayed release layer.

3. The press-coated tablet according to claim 1 wherein the wax is selected from the group consisting of beeswax, carnuba wax, microcrystalline wax, hydrogenated castor oil, and a glyceryl ester.

4. The press-coated tablet according to claim 3 wherein the glyceryl ester is glycerol behenate.

5. The press-coated tablet according to claim 1 wherein the wax and the low substituted hydroxypropyl cellulose are present in a ratio of 45:55 to 55:45 w/w.

6. The press-coated tablet according to claim 5 wherein the wax and the low substituted hydroxypropyl cellulose are present in a ratio of 50:50 w/w ratio and wherein the wax is glycerol behenate.

7. A method of alleviating pain and/or inflammation, the method comprising administering a press-coated tablet according to claim 1.

8. The method according to claim 7 wherein the NSAID is diclofenac.

9. The method according to claim 7 wherein delayed release of the NSAID is achieved by providing a press-coated tablet comprising a delayed release layer surrounding a core comprising the NSAID agent.

10. The method according to claim 9 wherein the delayed release layer comprises a wax and a low substituted hydroxypropyl cellulose, wherein the low substituted hydroxpropyl cellulose is micronized with a mean particle diameter of 20 mm and has a molecular weight of 115,000 and a hydroxypropyl cellulose content of 8%.

11. The press-coated tablet according to claim 1, wherein the active agent is diclofenac.

12. A press-coated tablet formulation for an immediate, followed by a delayed release of an NSAID active agent, the tablet comprising: (a) a core comprising an active agent together with an excipient(s); and (b) a delayed release layer surrounding the core and comprising a wax and a low substituted hydroxypropyl cellulose in a ratio of 40:60 to 60:40 w/w; wherein the delayed release layer substantially delays release of the active agent within the core for between 3-8 hours, and thereafter a pulsed release of the active agent from the core occurs, such that at least 70% of the active agent in the core is released within 5-45 minutes; wherein the low substituted hydroxypropyl cellulose is micronized with a mean particle diameter of 20 mm and has a molecular weight of 115,000 and a hydroxypropyl cellulose content of 8%; and (c) a top-coating layer comprising a portion of an active agent together with one or more excipients wherein a substantially immediate pulsed release of the active agent occurs following administration to the subject of the tablet; wherein said release is measured in 900 ml of 0.01M sodium phosphate buffer at pH 7, at 37? C. as determined by UV analysis at 248 nm; wherein the active agent in the core and on the top-coating layer is an NSAID.

13. The press-coated tablet according to claim 12 further comprising an amount of an active agent, which is the same or different to the active agent in the core and/or top-coating layer, in the delayed release layer.

Description

DETAILED DESCRIPTION

(1) The present invention will now be further described by way of example and with reference to the figures which show:

(2) FIG. 1 shows the release profile of a tablet formulation comprising an immediate release top-coating and a delayed release layer of 50:50 w/w glycerol behenate: LH-32;

(3) FIG. 2 shows the release profile of a tablet formulation comprising an immediate release top-coating and a delayed release layer of 50:50 w/w glycerol behenate: LH-21;

(4) FIG. 3 shows Gamma Scintigraphy imaging of In-vivo release of controlled release Diclofenac formulation. Radiolabel was incorporated in the delayed release layer only and so only the delayed release is being visualised; and

(5) FIG. 4 shows the analysis of blood plasma levels of Diclofenac following administration of a controlled release formulation of Diclofenac, there is a period of time between drug release and detection in blood plasma as the drug is solubilised and absorbed by the body.

CLINICAL NEED

(6) This formulation is designed to relieve night-time pain (e.g. in arthritic patients) by releasing an immediate burst of diclofenac and then another after six hours.

(7) Methods

(8) Core Tablet Blend and Core Tablet Compression

(9) (MW Diclofenac=296.2 and MW Diclofenac sodium=318.1)

(10) (i) Diclofenac and excipients weighed into tared weigh boats and all except the magnesium stearate placed into an amber screw-top glass jar of sufficient volume (e.g. 125 ml) according to Table 1.

(11) TABLE-US-00001 TABLE 1 API/Excipient Weight (g) Diclofenac sodium 5.4 Ac-di-sol 1.3 Lactose 1.7 Magnesium stearate 0.6
(ii) These API/excipients blended (in the glass jar) using the Turbula mixer for 1 minute.
(iii) Magnesium stearate added and all blended for further 5 minutes 90 mg of this blend comprises each core tablet. 90 mg weighed into a tared weigh boat.
(iv) The 6.9 mm punch and die set used to compress 90 mg powder for 10 seconds at 1 ton using the IR press.
(v) Tablets stored in an amber glass screw-top jar until use.
Granules (to Surround Core Tablet)
(i) Glycerol behenate and LH-32 weighed into tared weigh boats according to Table 2:

(12) TABLE-US-00002 TABLE 2 Excipient Weight (g) GB 10 LH-32 10
(ii) GB placed in a glass beaker on a hot plate set at 100? C. Once the GB melted, LH-32 added gradually whilst stirring until a uniform mix is achieved.
(iii) The mix stirred continuously until cooled to room temperature. The granules are left for at least 30 min at room temperature before the next step.
(iv) The cooled granules forced through a 1 mm sieve (using a spatula and a brush) and collected on a 500?? sieve so that the granules used are in the size range 500???-1 mm.
(v) Granules stored in amber glass screw-top jar until use.
Top Layer Blend

(13) Diclofenac and excipients are weighed into tared weigh boats and all placed into an amber screw-top glass jar of sufficient volume (eg 125 ml) according to Table 3.

(14) TABLE-US-00003 TABLE 3 API/Excipient Weight (g) Diclofenac sodium 10.8 Lactose 8.6 LH-21 8.6

(15) The API/excipients blended (in the glass jar) using the Turbula mixer for 15 minutes.

(16) Formulation Compression

(17) (i) A 13 mm die and matching flat-faced punches were used to compress the formulation. For 6 tablets, 12?250 mg granules (to surround core tablet) are weighed into tared weigh boats.

(18) (ii) 250 mg granules placed onto the lower punch, core tablet dropped on and centralised (centralising tool) before placing the other 250 mg granules on top.

(19) (iii) For 6 tablets, 6?140 mg top layer blend weighed into tared weigh boats.

(20) (iv) 140 mg of the top layer blend added to the top granule layer.

(21) (v) The formulation compressed at 5 ton for 3 minutes in a 13 mm die/punch set.

(22) Dissolution

(23) Dissolution (n=3) performed in 900 ml sodium phosphate buffer (0.01 M, pH 7) at 37? C., with UV analysis at 248 nm.

(24) Results

(25) As can be seen in FIG. 1, a tablet is provided which provides an initial release of diclofenac, over about 10 minutes, followed by a delay of about 5.5. hours and a further release of diclofenac over about 30-40 mins.

(26) Supporting Data

(27) This profile in FIG. 2 shows a dramatically shortened time between pulses of diclofenac e.g. with LH-21 instead, as compared to that with LH-32, thus rendering it inappropriate for the desired clinical application.

(28) Clinical Trial Protocol

(29) Diclofenac 50 mg immediate-release with diclofenac 50 mg delayed-release (6 hour time-delay)

(30) Diclofenac Extraction from Plasma Calibration and Calculation of % Recovery

(31) Preliminary Preparation:

(32) 1. Preparation of 100 ml stock solution of 3M Orthophosphoric acid (H3PO4. 98 g/mol) (i) Using an 85% solution (VWR). (ii) 3M=294 g/L, therefore 29.4 g in 100 ml. (iii) Take 34.6 ml of the 85% VWR solution and make up to 100 ml with water in a volumetric flask. 2. Preparation of 1 L stock solution of Hexane:IPA, 90:10. (i) Add 900 ml hexane and 100 ml IPA to a 1 L duran bottle. Wrap the top with parafilm for storage.
3. Ketoprofen (internal standard) stock solution (1 mg/ml) (i) Weigh 100 mg into a weigh boat and transfer to a 100 ml volumetric flask. Add 60 ml mobile phase and dissolve. Make up to the 100 ml mark with mobile phase. 4. Diclofenac stock solutions (i) Solution A: Weigh 100 mg diclofenac and make up to 100 ml with water in a volumetric flask (1 mg/ml). (ii) Solution B: Take 10 ml from Solution A and make up to 100 ml with water in a volumetric flask (100 ?g/ml). (iii) Solution C: Take 10 ?I of Solution A and make up to 1 ml with water (1 pg/ml).
Preparing the Standard Series of Diclofenac Solutions:

(33) Add the required volume of either stock solution B or C to a small vial and make up to 1 ml with water as shown in the following table.

(34) TABLE-US-00004 Required Conc. Vol stock Vol H.sub.2O In 100 ?l Standard (?g/ml) sol. (?l) (?l) (ng) 1 0.25 250 (C) 750 25 2 0.5 500 (C) 500 50 3 1.0 10 (B) 990 100 4 2.5 25 (B) 975 250 5 5.0 50 (B) 950 500 6 10 100 (B) 900 1000 7 20 200 (B) 800 2000 8 30 300 (B) 700 3000
Extraction Procedure: (i) Add 1 ml blank plasma to each of 8 plastic 15 ml centrifuge tubes (ii) Add 100 ?I of the diclofenac stock solutions to each (iii) Vortex for 1 min (iv) Add 1 ml of 3M Orthophosphoric acid to each (v) Add 5 ml of hexane:isopropyl alcohol, 90:10 (vi) Vortex for 3 min (vii) Centrifuge at 2000 rpm for 3 min (viii) Extract the top (solvent) layer and transfer to a clean centrifuge tube (ix) Evaporate the solvent to dryness under nitrogen (x) Reconstitute residue in 100 ?I mobile phase (xi) Add 10 ?I internal standard stock solution to each (xii) Vortex (xiii) Inject 50

(35) The on column mass for each sample is as follows:

(36) TABLE-US-00005 On column mass Sample (ng) 1 12.5 2 25 3 50 4 125 5 250 6 500 7 1000 8 1500

(37) Clinical studies were carried out in Healthy male volunteers aged between 18-65 years inclusive with a body mass index (BMI) between 18.0 and 29.9 kg/m.sup.2. Subjects received a standard dinner comprising roast chicken with salad, low fat yoghurt and one cup of decaffeinated tea, coffee or juice 2 hours prior to dosing.

(38) Gastrointestinal transit of the delayed-release tablets was characterised by inclusion of a radiolabel marker, technetium-99m (.sup.99mTc), complexed with diethylenetriaminepentaacetic acid (DTPA) which prevents absorption from the gastrointestinal tract. The radiolabel is incorporated into the core tablet. Each tablet was radiolabelled with 4 MBq 99mTc-DTPA and administered with 240 ml of water at bedtime.

(39) Scintigraphic imaging was performed using a Siemens E-Cam gamma camera fitted with a low-energy high-resolution collimator. Subjects were imaged in a standing position except during periods of sleep where the subjects were imaged lying down. Anterior static acquisitions of 25-second duration each were collected immediately after dosing then every 30 minutes until 3 hours post-dose then every 15 minutes until complete release of radiolabel marker.

(40) A 5 mL pre-dose blood sample was taken from each subject 15 minutes before dosing. Following dosing blood samples were taken. Every 15 minutes until 2 hours post-dose then every 30 minutes until burst release observed by scintigraphy then every 15 minutes for 2 hours then every 30 minutes for 1 hour then hourly until end of study day (15 hours post-dose). See FIG. 3.

(41) Blood samples were centrifuged at 2000 g for 10 minutes and the plasma fraction removed and stored at ?20? C. for subsequent analysis. See FIG. 4.