Tamper resistant dosage form comprising a matrix and melt-extruded particulates comprising a drug

Abstract

The present invention provides a dosage form, particularly a tamper resistant dosage form, comprising: melt-extruded particulates comprising a drug; and a matrix; wherein said melt-extruded particulates are present as a discontinuous phase in said matrix.

Claims

1. A dosage form comprising: melt-extruded particulates comprising a drug which is an opioid agonist and a copolymer of acrylic acid alkyl esters and methacrylic acid alkyl esters or mixtures thereof; and a matrix; wherein said melt-extruded particulates have an average diameter of 200-800 μm and are present as a discontinuous phase in said matrix; wherein said matrix is a continuous phase comprising a gel-forming agent selected from polyethylene oxide which has an average molecular weight of at least 1,000,000, polyvinyl alcohol, hydroxypropyl methyl cellulose, carbomers, poly(uronic) acids, or mixtures thereof; wherein said dosage form comprises 30-55% wt of said melt-extruded particulates and 45-70% wt of said matrix, based on the total weight of the dosage form.

2. The dosage form as claimed in claim 1, wherein said melt-extruded particulates are stretched melt-extruded particulates.

3. The dosage form as claimed in claim 1, in the form of a tablet.

4. The dosage form as claimed in claim 1, wherein said dosage form is tamper resistant.

5. The dosage form as claimed in claim 1, wherein the amount of drug released from the dosage form at 0.5 hour when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) with 40% ethanol at 37° C., is within ±20% of the amount of drug released from the dosage form at 0.5 hour when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) with 0% ethanol at 37° C.

6. The dosage form as claimed in claim 1, wherein said melt-extruded particulates have a breaking strength of at least 350 Newtons.

7. The dosage form as claimed in claim 1, wherein said melt-extruded particulates are microparticulates.

8. The dosage form as claimed in claim 1, wherein said melt-extruded particulates have a length of less than 1000 μm.

9. The dosage form as claimed in claim 1, wherein said opioid agonist is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, codeine, buprenorphine, fentanyl, tramadol, tapentadol and pharmaceutically acceptable salts thereof.

10. The dosage form as claimed in claim 1, wherein said melt-extruded particulates comprise 3 to 50% wt of drug, based on the total weight of a melt-extruded particulate.

11. The dosage form as claimed in claim 1, further comprising one or more additional active ingredients.

12. The dosage form as claimed in claim 1, wherein said melt-extruded particulates comprise 10 to 50% wt of said copolymer based on the total weight of a melt-extruded particulate.

13. The dosage form as claimed in claim 1, wherein said melt-extruded particulates further comprise a rate controlling or modifying agent.

14. The dosage form as claimed in claim 13, wherein said melt-extruded particulates comprise 20 to 50% wt of rate controlling or modifying agent, based on the total weight of the melt-extruded particulate.

15. The dosage form as claimed in claim 13, wherein said rate controlling or modifying agent is an alkyl cellulose.

16. The dosage form as claimed in claim 15, wherein said alkyl cellulose is ethylcellulose.

17. The dosage form as claimed in claim 1, wherein said melt-extruded particulates further comprise a lubricant.

18. The dosage form as claimed in claim 1, wherein said melt-extruded particulates further comprise a plasticiser.

19. The dosage form as claimed in claim 1, wherein said melt-extruded particulates comprise oxycodone or hydromorphone, an ethyl acrylate and methyl methacrylate copolymer, ethyl cellulose as rate controlling or modifying agent, stearyl alcohol and/or triethyl citrate as plasticiser, glyceryl dibehenate as lubricant and optionally an opioid antagonist.

20. The dosage form as claimed in claim 19, wherein said oxycodone or hydromorphone is present as its hydrochloride salt.

21. The dosage form as claimed in claim 1, wherein said melt-extruded particulates comprise an opioid agonist and further comprise an opioid antagonist.

22. The dosage form as claimed in claim 1, wherein said gel-forming agent is curable.

23. The dosage form as claimed in claim 1, wherein said dosage form can be flattened without breaking to a thickness of less than 60% of the thickness of the dosage form before flattening.

24. A process for preparing a dosage form as claimed in claim 1, comprising: mixing melt-extruded particulates comprising a drug which is an opioid agonist with a matrix material so that said melt-extruded particulates form a discontinuous phase in said matrix and said matrix forms a continuous phase, and forming said mixture into a dosage form comprising 30-55% wt of said melt-extruded particulates and 45-70% wt of said matrix, based on the total weight of the dosage form.

25. The process as claimed in claim 24, wherein said particulates are melt extruded at a temperature of 100° C. or less.

26. The process as claimed in claim 24, further comprising curing said matrix.

27. A process for preparing a dosage form as claimed in claim 1, comprising: mixing melt-extruded particulates with a matrix material to obtain a mixture so that said melt-extruded particulates form a discontinuous phase in said matrix and said matrix forms a continuous phase, and forming said mixture into a dosage form comprising 30-55% wt of said melt extruded particulates and 45-70% wt of said matrix, based on the total weight of the dosage form, wherein said melt-extruded particulates are optionally prepared by stretching and cutting a melt extrudate comprising a drug.

28. A process for preparing a dosage form as claimed in claim 1, comprising: i) melt extruding a composition comprising said drug which is an opioid agonist to than a melt extrudate; ii) optionally stretching said melt extrudate to form an optionally stretched extrudate; iii) cutting said optionally stretched extrudate to form particulates; iv) mixing said particulates with a matrix material to obtain a mixture so that said particulates form a discontinuous phase in said matrix and said matrix forms a continuous phase; and forming said mixture into a dosage form comprising 30-55% wt of said melt-extruded particulates and 45-70% wt of said matrix, based on the total weight of the dosage form.

29. A method of treating or managing pain, comprising treating or managing the pain with the dosage form of claim 1.

30. A method of treating a subject in need of pain relief, comprising administering to said subject in need of pain relief the dosage fonts as claimed in claim 1.

31. The dosage form as claimed in claim 1, wherein said copolymer is selected from the group consisting of poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, and poly(ethyl acrylate-co-methyl methacrylate) 2:1.

32. The dosage form as claimed in claim 1, comprising 35-45% wt of said melt-extruded particulates, based on the total weight of the dosage form.

33. The dosage form as claimed in claim 1, wherein said melt-extruded particulates are blended or granulated, or both blended and granulated, with the matrix material and the resulting mix is compressed to form a plurality of tablets.

34. The dosage form as claimed in claim 1, wherein said melt-extruded particulates are blended or granulated, or both blended and granulated, with the matrix material in the form of a curable matrix material and the resulting mix is compressed to form a plurality of tablets, and said curable matrix material is then cured at a temperature of at least about 60° C.

35. The dosage form as claimed in claim 1, comprising 45-65% wt of said matrix, based on the total weight of the dosage form.

36. The dosage form as claimed in claim 1, comprising 50-60% wt of said matrix, based on the total weight of the dosage form.

37. The dosage form as claimed in claim 1 in the form of a tablet, wherein said melt-extruded particulates are blended or granulated, or both blended and granulated, with the matrix material and the resulting mix is compressed to form said tablet.

38. The dosage form as claimed in claim 1 in the form of a tablet, wherein said melt-extruded particulates are blended or granulated, or both blended and granulated, with the matrix material in the form of a curable matrix material and the resulting mix is compressed to form said tablet and said curable matrix material is then cured at a temperature of at least about 60° C.

39. The dosage form of claim 37, wherein said melt-extruded particulates and the matrix material are granulated by wet granulation.

40. The dosage form of claim 38, wherein said melt-extruded particulates and the matrix material are granulated by wet granulation.

41. The dosage form as claimed in claim 1, wherein said melt-extruded particulates have an average length of 200-800 μm.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention will now be described by the following non-limiting examples, wherein

(2) FIG. 1 shows a hypothetical dissolution rate for the particulates present in the dosage forms of the invention as well as for a dosage form per se;

(3) FIGS. 2-7 show the in vitro dissolution rate for the particulates present in the dosage forms of the invention as well as for a dosage form per se.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

(4) Testing Procedures

(5) In Vitro Dissolution Rate

(6) The tablets are tested in vitro using standard procedures, e.g. USP Apparatus 1 (basket) or USP Apparatus 2 (paddle) at e.g. 50 rpm in e.g. 900 ml simulated gastric fluid without enzymes (SGF) at 37° C., using a Perkin Elmer UVVIS Spectrometer Lambda 20, UV at an appropriate wavelength for detection of the drug present therein. Particulates, uncured tablets, cured tablets and tampered, i.e. flattened particulates or tablets may be tested. Tampered tablets/particulates are flattened with a hammer using 7 manually conducted hammer strikes to impart physical tampering. The tablet/particulate dimensions before and after the flattening and the dissolution profiles are evaluated on separate samples.

(7) The dissolution rate for the particulates present in the dosage form of the invention as well as for a dosage form per se is shown in FIG. 1. FIG. 1 shows that the release rate of drug from the particulates is higher than that from the dosage form. However the release rate of drug from the particulates is not sufficiently high for an abuser to achieve a euphorigenic effect. Thus even if an abuser crushes a dosage form of the present invention, the release rate of drug would not be significantly increased. This reduces the motivation of an abuser to try to tamper with a dosage form.

(8) Tamper Resistance Test

(9) (i) Crushability

(10) Cured tablets are subjected to a breaking strength test applying a force of a maximum of 196 Newtons using a Schleuniger 2E/106 Apparatus to evaluate the resistance to breaking. The particulates may be subjected to the same or a similar breaking strength test.

(11) (ii) Resistance to Ethanol Extraction

(12) Tablets are tested in vitro using ethanol/SGF media at ethanol concentrations of 0%, 20% and 40% to evaluate alcohol extractability. Testing is performed using standard procedures, e.g. USP Apparatus 1 (basket) or USP Apparatus 2 (paddle) at e.g. 50 rpm in e.g. 500 ml of media at 37° C., using a Perkin Elmer UV/VIS Spectrometer Lambda 20, UV at an appropriate wavelength for detection of the drug present therein. Sample time points include 0.5 and 1 hour.

Example 1

(13) Particulates having the compositions summarised in Table 1 below are prepared as follows:

(14) TABLE-US-00003 Particulates A Particulates B % w/w % w/w Hydromorphone HCl 10 10 Naloxone HCl 20 20 Ethylcellulose 29 27 Triethyl citrate 2.9* 5.4** Stearyl alcohol 10 10 Glyceryl dibehenate 3.0 3.0 Eudragit NE 40D 25.1 24.6 *10% based on ethyl cellulose **20% based on ethyl cellulose

(15) An ethylcellulose/triethyl citrate preparation is initially prepared by placing ethylcellulose in a blender and gradually adding, e.g. by spraying, triethyl citrate. Mixing is continued until a uniform blend is obtained then the mixture is allowed to stand overnight so that the triethyl citrate can penetrate through the ethylcellulose.

(16) Hydromorphone HCl, naloxone HCl, stearyl alcohol, glyceryl dibehenate and the above-prepared ethylcellulose/triethyl citrate preparation are then added to a blender and mixed. The resulting mixture is granulated with an aqueous dispersion of Eudragit® NE 40D. The granulate is then dried to constant weight.

(17) The dried granulate is then extruded. The melt extruder is set to predetermined extrusion conditions and extrusion is carried out. The extrudate obtained has an average diameter of 1 mm. The extrudate is then stretched by the conveyor belt and nip rollers during its transfer to the pelletiser. The stretched extrudate has an average diameter of about 500 μm. The stretched extrudate is then cut into particulates having an average length of about 500 μm.

(18) Tablets having the compositions summarised in Table 2 below are prepared as follows:

(19) TABLE-US-00004 TABLE 2 Tablet 1 Tablet 2 Tablet 3 Tablet 4 Particulates (mg) 40 80 160 240 Matrix material (mg) 58 116 232 348 Lubricant (mg) 2 4 8 12 Total weight (mg) 100 200 400 600

(20) The particulates are blended with the matrix material and optionally other excipients. The lubricant is then added and the mixture is blended to form a uniform blend. The blend is then compressed in a suitable tool to the predetermined weight and thickness of tablet.

(21) Coating and curing may subsequently be carried out in a single piece of equipment. If coating is required before curing, the tablet is heated to a predetermined temperature, spray coated and dried, before increasing the temperature to that required for curing. If curing is required prior to coating, the tablet is heated to the required temperature for a predetermined time then cooled. Spray coating may then optionally be carried out to a predetermined weight gain.

Example 2

(22) Melt-extruded particulates with the composition as summarised in Table 3 below were produced by firstly preparing (by fluid bed granulation) placebo granules with the composition as summarised in Table 4 below, secondly milling the placebo granules (using a Retsch mill with a 0.5 mm screen), thirdly blending the milled placebo granules with hydromorphone hydrochloride, naloxone hydrochloride and magnesium stearate in a suitably sized cone blender to produce blended granules, and lastly melt extruding the blended granules in a Leistritz Micro 27 melt extruder to obtain an extrudate that is stretched and finally cut with a pelletiser to obtain the melt-extruded particulates.

(23) The particulates obtained had an average diameter of 0.80 mm and an average length of 0.84 mm.

(24) TABLE-US-00005 TABLE 3 Example 2 (melt- extruded particulates) mg/unit Hydromorphone HCl 4 Naloxone HCl 8 Eudragit NE 40 D 40 (S) Ethylcellulose (N10) 25.8 Hydroxypropyl methylcellulose 0.15 (Methocel E5) Glycerly monostearate 2 Talc 20 Lactose (anhydrous) 4 Stearyl alcohol 5 Glycerol dibehenate 3 Magnesium stearate 1 Total 113 (S) = Solid content

(25) TABLE-US-00006 TABLE 4 Example 2 (placebo granules) mg/unit Eudragit NE 40 D 40 (S) Ethylcellulose (N10) 25.8 Hydroxypropyl methylcellulose 0.15 (Methocel E5) Glycerly monostearate 2 Talc 20 Lactose (anhydrous) 4 Stearyl alcohol 5 Glycerol dibehenate 3 Total 100 (S) = Solid content

(26) Tablets with the composition as summarised in Table 5 below were manufactured by blending the particulates with hydroxypropyl methylcellulose (Methocel K4M) and magnesium stearate, followed by direct compression (using a Manesty F3 Betapress) of the resulting blend.

(27) TABLE-US-00007 TABLE 5 Example 2 (Tablets) (mg/unit) Hydromophone/Naloxone 113 particulates (4 mg/8 mg per unit) Hydroxypropyl methylcellulose 56.5 (Methocel K4M) Magnesium stearate 1.7 Total 171

Example 3

(28) A lab scale batch of tablets with the composition as summarised in Table 6 below was manufactured by wet granulating the particulates of Example 2 (see Table 3) with the various excipients (water was used as a liquid binder and hydroxypropyl methylcellulose (Methocel K4M) as a binder) in a Kenwood processor, followed by compression of the resulting granulate using a Manesty F3 Betapress.

(29) TABLE-US-00008 TABLE 6 Example 3 (mg/unit) Hydromophone/Naloxone 113 particulates (4 mg/8 mg) Hydroxypropyl methylcellulose 113 (Methocel K4M) Lactose 57 Magnesium stearate 2.26 Purified water q.s. Total 285

(30) The particulates and tablets were tested for dissolution using Ph.Eur paddle dissolution apparatus at 37° C., 75 rpm separately in 500 ml of simulated gastric fluid without enzyme (SGF) at pH 1.2 and in 500 ml of 40% ethanol. Standard HPLC procedures were used for assay to measure the in vitro release rates, and the results obtained are plotted in accompanying FIG. 2.

Example 4

(31) Tablets with the composition as summarised in Table 7 below were manufactured by the following process: 1. The particulates of Example 2 and lactose were loaded into the bowl of a Kenwood mixer and dry mixed. 2. Water was added dropwise to granulate the mixture until large granules were obtained. 3. HPMC (Methocel K100M) was added to the wet granules with continuous mixing. 4. Additional water was added as the mix was powdery. 5. The granules were dried in Gallenkamp oven for 2 hours at 50-55° C. 6. The dried granules were blended with magnesium stearate in a Pharmatech blender. 7. The blend was compressed into tablets using a Manesty F3 Betapress.

(32) TABLE-US-00009 TABLE 7 Example 4 (mg/unit) Hydromophone/Naloxone 113 particulates (4 mg/8 mg) Hydroxypropyl methylcellulose 113 (Methocel K100M) Lactose 57 Magnesium stearate 2.26 Purified water q.s. Total 285

(33) The particulates and tablets were tested for dissolution using Ph.Eur paddle dissolution apparatus at 37° C., 75 rpm in 500 ml of SGF at pH 1.2. Standard HPLC procedures were used for assay to measure the in vitro release rates, and the results obtained are plotted in accompanying FIG. 3.

Example 5

(34) Tablets with the composition as summarised in Table 8 below were manufactured by the following process: 1. The particulates of Example 2 and lactose were loaded into a bowl and dry mixed. 2. Water was added dropwise to over-wet the mixture until large granules were obtained. 3. PEO was added to the wet granules with continuous mixing. 4. The granules were dried in a Gallenkamp oven for 2 hours at 50-55° C. 5. The dried granules were blended with magnesium stearate in a Pharmatech blender. 6. The blend was compressed into tablets using a Manesty F3 Betapress. 7. The resulting tablets were cured at 72° C. for 1 hour in an oven.

(35) TABLE-US-00010 TABLE 8 Example 5 (mg/unit) Hydromophone/Naloxone 113 particulates (4 mg/8 mg) Polyethylene oxide 113 (Polyox WSR-301) Lactose 57 Magnesium stearate 2.26 Purified water q.s. Total 285

(36) The particulates and tablets were tested for dissolution in SGF as for Example 4. The tablets were additionally tested for dissolution in 40% ethanol as for Example 3. Standard HPLC procedures were used for assay to measure the in vitro release rates, and the results obtained are plotted in accompanying FIGS. 4 and 5.

Example 6

(37) Melt-extruded particulates with the composition as summarised in Table 9 below were produced by firstly preparing (by fluid bed granulation) placebo granules with the composition as summarised in Table 10 below, secondly milling the placebo granules (using a Retsch mill with a 0.5 mm screen), thirdly blending the milled placebo granules with hydromorphone hydrochloride, naloxone hydrochloride and magnesium stearate and sodium lauryl sulphate (2 mg/unit) in a suitably sized cone blender to produce blended granules, and lastly melt extruding the blended granules in a Leistritz Micro 27 melt extruder to obtain an extrudate that is stretched and finally cut with a pelletiser to obtain the melt-extruded particulates.

(38) The particulates obtained had an average diameter of 0.82 mm and an average length of 0.81 mm.

(39) TABLE-US-00011 TABLE 9 Example 6 (melt- extruded particulates) mg/unit Hydromorphone HCl 4 Naloxone HCl 8 Eudragit NE 40 D 30 (S) Ethylcellulose (N10) 47.3 Hydroxypropyl methylcellulose 0.23 (Methocel E5) Glycerly monostearate 4.5 Talc 5 Lactose (anhydrous) 4 Stearyl alcohol 5 Glycerol dibehenate 2 Sodium lauryl sulphate 4 Magnesium stearate 1 Total 115 (S) = Solid content

(40) TABLE-US-00012 TABLE 10 Example 6 (placebo granules) mg/unit Eudragit NE 40 D 30 (S) Ethylcellulose (N10) 47.3 Hydroxypropyl methylcellulose 0.23 (Methocel E5) Glycerly monostearate 4.5 Talc 5 Lactose (anhydrous) 4 Stearyl alcohol 5 Glycerol dibehenate 2 Sodium lauryl sulphate 2 Total 100 (S) = Solid content

(41) Tablets with the composition as summarised in Table 11 below were manufactured by the process of Example 5 but without step 7 (tablet curing), and except that in step 1 the particulates of this example, instead of Example 2, were dry mixed with lactose and trisodium citrate, and in step 3 sodium alginate, instead of PEO, was added to the wet granules with continuous mixing.

(42) TABLE-US-00013 TABLE 11 Example 6 (mg/unit) Hydromophone/Naloxone 115 particulates (4 mg/8 mg) Sodium alginate 113 Lactose 28.5 Trisodium citrate 28.5 Magnesium stearate 2.26 Purified water q.s. Total 287

Example 7

(43) Tablets with the composition as summarised in Table 12 below were manufactured by the process of Example 5 but without step 7 (tablet curing), and except that in step 1 the particulates of Example 6, instead of Example 2, were dry mixed with lactose and magnesium stearate, and in step 3 xanthan gum, instead of PEO, was added to the wet granules with continuous mixing.

(44) TABLE-US-00014 TABLE 12 Example 7 (mg/unit) Hydromophone/Naloxone 115 particulates (4 mg/8 mg) Xanthan gum 113 Lactose 57 Magnesium stearate 2.26 Purified water q.s. Total 287

(45) The particulates and tablets were tested for dissolution in SGF as for Examples 4 and 5. The tablets were additionally tested for dissolution in 40% ethanol as for Examples 3 and 5. Standard HPLC procedures were used for assay to measure the in vitro release rates, and the results obtained are plotted in accompanying FIGS. 6 and 7.