ABUSE-PROOFED DOSAGE FORM

Abstract

The present invention relates to an abuse-proofed, thermoformed dosage form containing, in addition to one or more active ingredients with abuse potential optionally together with physiologically acceptable auxiliary substances, at least one synthetic or natural polymer with a breaking strength of at least 500 N and to a process for the production thereof.

Claims

1. An abuse-proofed, thermoformed dosage form comprising one or more active ingredients with abuse potential (A) optionally together with physiologically acceptable auxiliary substances (B), at least one synthetic or natural polymer (C) and optionally at least one wax (D), wherein component (C) exhibits a breaking strength of at least 500 N.

2. A dosage form according to claim 1, which is in the form of a tablet.

3. A dosage form according to claim 1, which is in multiparticulate form.

4. A dosage form according to claim 1, wherein the polymer (C) is at least one polymer selected from the group consisting of polyethylene oxide, polymethylene oxide, polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers and mixtures thereof.

5. A dosage form according to claim 1, wherein the polymer (C) has a molecular weight of at least 0.5 million according to rheological measurements.

6. A dosage form according to claim 5, wherein the molecular weight is 1-15 million.

7. A dosage form according to claim 1, which comprises the wax (D) and the wax (D) is at least one natural, semi-synthetic or synthetic wax with a softening point of at least 60 C.

8. A dosage form according to claim 7, wherein the wax (D) is carnauba wax or beeswax.

9. A dosage form according to claim 1, wherein the component(s) (C) is/are present in quantities such that the dosage form has a breaking strength of at least 500 N.

10. A dosage form according to claim 1, wherein the active ingredient (A) is at least one active ingredient selected from the group consisting of opiates, opioids, tranquillisers, stimulants, barbiturates and further narcotics.

11. A dosage form according to claim 1, which additionally comprises at least one of the following components a)-f): (a) at least one substance which irritates the nasal passages and/or pharynx, (b) at least one viscosity-increasing agent, which, with the assistance of a necessary minimum quantity of an aqueous liquid, forms a gel with the extract obtained from the dosage form, which gel optionally remains visually distinguishable when introduced into a further quantity of an aqueous liquid, c) at least one antagonist for the active ingredient or active ingredients with abuse potential, (d) at least one emetic, (e) at least one dye as an aversive agent, (f) at least one bitter substance.

12. A dosage form according to claim 11, wherein the component (a) irritant substance causes burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli.

13. A dosage form according to claim 12, wherein the component (a) irritant substance is based on one or more constituents of at least one hot substance drug.

14. A dosage form according to claim 13, wherein the hot substance drug is at least one drug selected from the group consisting of Allii sativi bulbus (garlic), Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma (calamus root), Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma (Javanese turmeric root), Galangae rhizoma (galangal root), Myristicae semen (nutmeg), Piperis nigri fructus (pepper), Sinapis albae semen (erucae/white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root).

15. A dosage form according to claim 13, wherein the constituent of the hot substance drug is an o-methoxy(methyl)phenol compound, an acid amide compound, a mustard oil or a sulfide compound or is derived from such a compound.

16. A dosage form according to claim 13, wherein the constituent of the hot substance drug is at least one constituent selected from the group consisting of myristicin, elemicin, isoeugenol, -asarone, safrole, gingerols, xanthorrhizol, capsaicinoids, piperine, glucosinolates, and a compound derived from these constituents.

17. A dosage form according to claim 11, wherein component (b) is at least one viscosity-increasing agent selected from the group consisting of microcrystalline cellulose with 11 wt. % carboxymethylcellulose sodium (Avicel RC 591), carboxymethylcellulose sodium (Blanose, CMC-Na C300P, Frimulsion BLC-5, Tylose C300 P), polyacrylic acid (Carbopol 980 NF, Carbopol 981), locust bean flour (Cesagum LA-200, Cesagum LID/150, Cesagum LN-1), citrus pectin (Cesapectin HM Medium Rapid Set), waxy maize starch (C*Gel 04201), sodium alginate (Frimulsion ALG (E401)), guar flour (Frimulsion BM, Polygum 26/1-75), iota carrageen (Frimulsion D021), karaya gum, gellan gum (Kelcogel F, Kelcogel LT100), galactomannan (Meyprogat 150 ), tara bean flour (Polygum 43/1), propylene glycol alginate (Protanal-Ester SD-LB), sodium hyaluronate, apple pectin, pectin from lemon peel, sodium hyaluronate, tragacanth, tara gum (Vidogum SP 200), fermented polysaccharide welan gum (K1A96) and xanthan gum (Xantural 180).

18. A dosage form according to claim 11, wherein component (c) is at least one opiate or opioid antagonist selected from the group consisting of naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphine, naluphine and a corresponding physiologically acceptable compound.

19. A dosage form according to claim 11, wherein the component (c) is at least one neuroleptic stimulant antagonist.

20. A dosage form according to claim 11, wherein the component (d) emetic is based on one or more constituents of radix ipecacuanha (ipecac root) and/or is apomorphine.

21. A dosage form according to claim 11, wherein component (e) is at least one physiologically acceptable dye.

22. A dosage form according to claim 11, wherein component (f) is at least one bitter substance selected from the group consisting of aromatic oils, fruit aroma substances, denatonium benzoate and mixtures thereof.

23. A dosage form according to claim 11, wherein the active ingredient or active ingredients (A) is/are spatially separated from component (c) and/or (d) and/or (f), wherein the active ingredient or active ingredients (A) is/are optionally present in at least one subunit (X) and components (c) and/or (d) and/or (f) is/are present in at least one subunit (Y), and, when the dosage form is correctly administered, components (c) and/or (d) and/or (f) from subunit (Y) do not exert their effect in the body and/or on taking.

24. A dosage form according to claim 1, which comprises at least one active ingredient at least partially in controlled release form.

25. A dosage form according to claim 24, wherein each of the active ingredients with abuse potential (A) is present in a controlled release matrix.

26. A dosage form according to claim 25, wherein component (C) and/or component (D) also serve as a controlled release matrix material.

27. A process for the production of a dosage form according to claim 1, comprising: mixing components (A), (B), (C) and the optionally present component (D) and the optionally present components (a) to (f) to form a resultant mixture, and press-forming the resultant mixture, optionally after granulation, to yield the dosage form with preceding, simultaneous, or subsequent exposure to heat.

28. A process according to claim 27, wherein granulation is performed by means of a melt process.

29. A process according to claim 27, which comprises press-forming the resultant mixture to yield a press-formed product, and exposing the press-formed product to heat to yield the dosage form.

30. A dosage form obtainable by a process according to claim 27.

31. A dosage form obtainable by a process according to claim 29.

32. A method of treating a therapeutic condition in a patient suffering therefrom, said method comprising administering to said patient a dosage form according to claim 1.

33. A method according to claim 32, wherein the therapeutic condition is pain.

34. A method of treating a therapeutic condition in a patient suffering therefrom, said method comprising administering to said patient a dosage form according to claim 30.

35. A method according to claim 34, wherein the therapeutic condition is pain.

36. The dosage form according to claim 1, wherein the content of component (C) is at least 60 wt. %, relative to the total weight of the dosage form.

37. The dosage form according to claim 5, wherein the content of component (C) is at least 60 wt. %, relative to the total weight of the dosage form.

38. The dosage form according to claim 10, which comprises an opioid, wherein the opioid is selected from the group consisting of hydromorphone, morphine, oxycodone, oxymorphone, tramadol, (1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and the physiologically acceptable salts thereof.

39. The dosage form according to claim 1, wherein the one or more active ingredients with abuse potential (A) comprise oxycodone or a physiologically acceptable salt thereof; wherein the at least one synthetic or natural polymer (C) comprises a polyethylene oxide having a molecular weight of 1-15 million according to rheological measurements; and wherein the content of said polyethylene oxide is at least 60 wt. %, relative to the total weight of the dosage form.

40. The dosage form according to claim 1, which additionally comprises at least one physiologically acceptable auxiliary substance (B).

41. The dosage form according to claim 1, which additionally comprises at least one wax (D).

42. The dosage form according to claim 1, which additionally comprises at least one physiologically acceptable auxiliary substance (B) and at least one wax (D).

43. The dosage form according to claim 1, wherein the at least one synthetic or natural polymer (C) comprises a polyethylene oxide having a molecular weight of at least 0.5 million according to rheological measurements.

44. The dosage form according to claim 43, wherein the polyethylene oxide has a molecular weight of 0.5-15 million according to rheological measurements.

45. The dosage form according to claim 44, wherein the polyethylene oxide has a molecular weight of at least 600,000 according to rheological measurements.

46. The dosage form according to claim 45, wherein the polyethylene oxide has a viscosity at 25 C. measured on a 5 wt. % aqueous solution using a model RVF Brookfield viscosimeter (spindle no. 2/rotational speed 2 rpm) of 4500 to 17600 cP.

47. The dosage form according to claim 44, wherein the polyethylene oxide has a molecular weight of at least 1,000,000 according to rheological measurements.

48. The dosage form according to claim 47, wherein the polyethylene oxide has a viscosity at 25 C. measured on a 2 wt. % aqueous solution using a model RVF Brookfield viscosimeter (spindle no. 1 or 3/rotational speed 10 rpm) of 400 to 4000 cP.

49. The dosage form according to claim 44, wherein the polyethylene oxide has a molecular weight of at least 4,000,000 according to rheological measurements.

50. The dosage form according to claim 49, wherein the polyethylene oxide has a viscosity at 25 C. measured on a 1 wt. % aqueous solution using a model RVF Brookfield viscosimeter (spindle no. 2/rotational speed 2 rpm) of 1650 to 10000 cP.

51. A method of reducing the incidence of drug abuse of an active ingredient (A) with abuse potential, said method comprising providing said active ingredient (A) in the form of a dosage form according to claim 1.

Description

EXAMPLES

[0112] Tramadol hydrochloride was used as the active ingredient in a series of Examples. Tramadol hydrochloride was used, despite tramadol not being an active ingredient which conventionally has abuse potential, because it is not governed by German narcotics legislation, so simplifying the experimental work. Tramadol is moreover a member of the opioid class with excellent water solubility.

Example 1

[0113]

TABLE-US-00001 Complete Components Per tablet batch Tramadol hydrochloride 100 mg 100 g Polyethylene oxide, NF, MFI 200 mg 200 g (190 C. at 21.6 kg/10 min) <0.5 g MW 7 000 000 (Polyox WSR 303, Dow Chemicals) Total weight 300 mg 300 g

[0114] Tramadol hydrochloride and polyethylene oxide powder were mixed in a free-fall mixer. A tabletting tool with top punch, bottom punch and die for tablets with a diameter of 10 mm and a radius of curvature of 8 mm was heated to 80 C. in a heating cabinet. 300 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.

[0115] The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N.

[0116] The tablet could not be comminuted using a hammer, nor with the assistance of a mortar and pestle.

[0117] In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus in accordance with Pharm. Eur. The temperature of the release medium was 37 C. and the rotational speed of the stirrer 75 min.sup.1. At the beginning of the investigation, each tablet was placed in a 600 ml portion of artificial gastric juice, pH 1.2. After 30 minutes, the pH value was increased to 2.3 by addition of alkali solution, after a further 90 minutes to pH 6.5 and after a further 60 minutes to pH 7.2. The released quantity of active ingredient present in the dissolution medium at each point in time was determined by spectrophotometry.

TABLE-US-00002 Time Released quantity 30 min 15% 240 min 52% 480 min 80% 720 min 99%

Example 2

[0118] 300 mg portions of the powder mixture from Example 1 were heated to 80 C. and in placed in the die of the tabletting tool. Pressing was then performed. The tablet exhibits the same properties such as the tablet in Example 1.

Example 3

[0119]

TABLE-US-00003 Raw material Per tablet Complete batch Tramadol hydrochloride 50 mg 100 g Polyethylene oxide, NF, 100 mg 200 g MW 7 000 000 (Polyox WSR 303, Dow Chemicals) Total weight 150 mg 300 g

[0120] Tramadol hydrochloride and the above-stated components were mixed in a free-fall mixer. A tabletting tool with top punch, bottom punch and die for tablets with a diameter of 7 mm was heated to 80 C. in a heating cabinet. 150 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.

[0121] The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N.

[0122] In vitro release of the active ingredient was determined as in Example 1 and was:

TABLE-US-00004 Time Released quantity 30 min 15% 240 min 62% 480 min 88% 720 min 99%

Example 4

[0123]

TABLE-US-00005 Raw material Per tablet Complete batch Tramadol hydrochloride 100 mg 100 g Polyethylene oxide, NF, 180 mg 180 g MW 7 000 000 (Polyox WSR 303, Dow Chemicals) Xanthan, NF 20 mg 20 g Total weight 300 mg 300 g

[0124] Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in a free-fall mixer. A tabletting tool with top punch, bottom punch and die for tablets with a diameter of 10 mm and a radius of curvature of 8 mm was heated to 80 C. in a heating cabinet. 300 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.

[0125] The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N. The tablets did suffer a little plastic deformation.

[0126] In vitro release of the active ingredient was determined as in Example 1 and was:

TABLE-US-00006 Time Released quantity 30 min 14% 240 min 54% 480 min 81% 720 min 99%

[0127] The tablets could be cut up with a knife into pieces of an edge length of as small as approx. 2 mm. No further comminution proceeding as far as pulverisation was possible. When the pieces are combined with water, a highly viscous gel is formed. Only with great difficulty could the gel be pressed through a 0.9 mm injection cannula. When the gel was injected into water, the gel did not spontaneously mix with water, but remained visually distinguishable.

Example 5

[0128]

TABLE-US-00007 Raw material Per tablet Complete batch Tramadol hydrochloride 50 mg 100 g Polyethylene oxide, NF, 90 mg 180 g MW 7 000 000 (Polyox WSR 303, Dow Chemicals) Xanthan, NF 10 mg 20 g Total weight 300 mg 300 g

[0129] Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in a free-fall mixer. A tabletting tool with a top punch, bottom punch and die for oblong tablets 10 mm in length and 5 mm in width was heated to 90 C. in a heating cabinet. 150 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.

[0130] The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N. The tablets did suffer a little plastic deformation.

[0131] In vitro release of the active ingredient was determined as in Example 1 and was:

TABLE-US-00008 Time Released quantity 30 min 22% 120 min 50% 240 min 80% 360 min 90% 480 min 99%

[0132] The tablets could be cut up into pieces of an edge length of as small as approx. 2 mm, but could not be pulverised. When the pieces are combined with water, a highly viscous gel is formed. Only with great difficulty could the gel be pressed through a 0.9 mm injection cannula. When the gel was injected into water, the gel did not spontaneously mix with water, but remained visually distinguishable.

Example 6

[0133] A tablet with the following composition was produced as described in Example 1: t,?

[0134] Release of the active ingredient was determined as follows:

[0135] In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus in accordance with Pharm. Eur. The temperature of the release medium was 37 C. and the rotational speed 75 rpm. The phosphate buffer, pH 6.8, described in DSP served as the release medium. The quantity of active ingredient present in the solvent at the particular time of testing was determined by spectrophotometry.

TABLE-US-00009 Time Mean 0 min 0% 30 min 17% 240 min 61% 480 min 90% 720 min 101.1%

[0136] The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N.

[0137] The tablets could be cut up into pieces of an edge length of as small as approx. 2 mm, but could not be pulverised. When the pieces are combined with water, a highly viscous gel is formed. Only with great difficulty could the gel be pressed through a 0.9 mm injection cannula. When the gel was injected into water, the gel did not spontaneously mix with water, but remained visually distinguishable.