Process for the production of an abuse-proofed dosage form

Abstract

The present invention relates to a process for the production of an abuse-proofed dosage form containing, apart from one or more active ingredients with potential for abuse and optionally physiologically acceptable auxiliary substances, at least one synthetic or natural polymer (C) with a breaking strength of at least 500 N, wherein the formulation mixture is combined with a solvent for the polymer (C) at least in quantities such that the formulation mixture is at least uniformly moistened, the at least moistened composition is optionally divided into sub-portions, dried and shaped to yield the dosage form.

Claims

1. A process for the production of a solid dosage form, said process comprising: a) producing a formulation mixture by homogeneously mixing (i) at least one active ingredient with potential for abuse selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, tramadol, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, and physiologically acceptable salts thereof, and (ii) at least 40 wt. %, based on the weight of the solid dosage form, of at least one polyalkylene oxide (C) having a molecular weight of at least 1,000,000 g/mol and exhibiting a breaking strength of at least 500 N; b) producing a uniformly moistened formulation mixture by combining the formulation mixture produced in a) with (iii) a solvent for the polyalkylene oxide (C), wherein said solvent is in the form of a foam, the form is stabilized by foam stabilizers, and the solvent is in a quantity sufficient to provide uniform moistening of the formulation mixture; c) optionally dividing the uniformly moistened formulation mixture into sub-portions; d) drying the uniformly moistened formulation mixture or the sub-portions to granules; and e) shaping the granules to produce a solid dosage form that exhibits a breaking strength of at least 500 N and cannot be comminuted using a hammer or with the assistance of a mortar and pestle.

2. The process according to claim 1, where the dried sub-portions in each case correspond to the mass of a unit of the dosage form.

3. The process according to claim 1, which further comprises dispersing the formulation mixture in a liquid dispersant in which the polymer component (C) is not soluble before addition of the solvent.

4. The process according to claim 3, which further comprises dividing the formulation mixture into sub-portions in each case corresponding to the mass of a unit of the dosage form either before or after the formulation mixture is dispersed.

5. The process according to claim 3, where the solvent and the dispersant are miscible with one another.

6. The process according to claim 1, which further comprises drying the uniformly moistened formulation mixture to granules, and then dividing the granules into sub-portions, which sub-portions in each case correspond to the mass of a unit of the dosage form, and shaping to yield the dosage form.

7. The process according to claim 1, which further comprises adding solvent to the formulation mixture in an amount such that a shapeable paste is obtained.

8. The process according to claim 7, which further comprises drying the paste and, before or after it is dried, the paste is divided into sub-portions and shaping or converting into the dosage form the dried portions, optionally after further dividing each case into a portion corresponding to the mass of a unit of the dosage form.

9. The process according to claim 8, where the sub-portions have the form of strands.

10. The process according to claim 9, which further comprises producing the strands with the assistance of a screen or strand former.

11. The process according to claim 9, which further comprises singulating and shaping dried strands to yield the dosage form.

12. The process according to claim 11, where shaping proceeds with the assistance of a tablet press.

13. The process according to claim 9, which further comprises shaping dried strands with the assistance of shaping rollers or shaping belts equipped with rollers to yield the dosage form.

14. The process according to claim 8, which further comprises converting the paste into a planar structure, from which the dosage form is stamped.

15. The process according to claim 7, where the process is performed with the assistance of an extruder.

16. The process according to claim 1, which further comprises adding a quantity of solvent sufficient to dissolve at least the polymer component (C) to the formulation mixture.

17. The process according to claim 16, which further comprises converting the solution into a planar structure.

18. The process according to claim 17, which further comprises producing the planar structure with the assistance of an extruder with a flat die or by casting the solution onto a level planar support.

19. The process according to claim 16, which further comprises shaping the dosage form by stamping from the dried planar structure or by calendaring.

20. The process according to claim 16, where the mixture is divided into portions such that, after drying, the portions correspond in each case to the mass of a unit of the dosage form.

21. The process according to claim 20, which further comprises placing the portions in molds corresponding to the shape of a unit of the dosage form.

22. The process according to claim 16, which further comprises dividing the mixture into any desired portions, and, after drying, optionally recombining the portions, and shaping to yield the dosage form.

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) FIG. 1 shows the measurement of the breaking strength of a tablet, in particular the tablet (4) adjustment device (6) used for this purpose before and during the measurement. To this end, the tablet (4) is held between the upper pressure plate (1) and the lower pressure plate (3) of the force application apparatus (not shown) with the assistance of two 2-part clamping devices, which are in each case firmly fastened (not shown) with the upper and lower pressure plate once the spacing (5) necessary for accommodating and centring the tablet to be measured has been established. The spacing (5) may be established by moving the 2-part clamping devices horizontally outwards or inwards in each case on the pressure plate on which they are mounted.

(2) The tablets deemed to be resistant to breaking under a specific load include not only those which have not broken but also those which may have suffered plastic deformation under the action of the force.

(3) The breaking strength of the dosage forms obtained according to the invention is determined by the stated measurement method for determining breaking strength, with dosage forms other than tablets also being tested.

(4) The invention is explained below with reference to Examples. These explanations are given merely by way of example and do not restrict the general concept of the invention.

EXAMPLES

Example 1

(5) TABLE-US-00001 Per tablet Complete batch Tramadol HCl 100.0 mg 1495.0 g Polyethylene oxide, 167.8 mg 2508.6 g MW 7 000 000 Hydroxypropylmethylcellulose 33.5 mg 500.8 g (Hypromellose 100 000 mPa) Butyihydroxytoluene (BHT) 0.2 mg 3.0 g Total mass 300.5 mg 4507.4 g

(6) The stated quantity of BHT was dissolved in ethanol (96%), such that a 7.7% (mass/mass) ethanolic solution was obtained. This was mixed initially with 150 g of polyethylene oxide in a high speed mixer for 30 minutes and then the remaining quantity of polyethylene oxide was added and stirring continued for a further 30 minutes. The composition was dried for 12 h at 40 C.

(7) All the further components were added and mixed for 15 min in a free-fall mixer. The powder mixture was divided between moulds, each having a diameter of 13 mm and a depth of 6 mm. Using a syringe with cannula, the mixture was suspended in each case in 0.5 ml of 96% ethanol and then in each case combined with 0.5 ml of distilled water After 24 hours swelling time, the swollen composition was dried for 24 h at 40 C.

(8) The divided up, dried portions were each press-moulded into tablets using a model EK 0 eccentric press. The tabletting tool had a diameter of 10 mm and a radius of curvature of 8 mm.

(9) The breaking strength of the tablets was determined using the above-described method. No breakage occurred when a force of 500 N was applied. The tablets could not be comminuted using a hammer, nor with the assistance of a pestle and mortar.

(10) In vitro release of the active ingredient from the tablets was determined in a paddle stirrer apparatus with sinker 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. The release medium used was 600 ml of intestinal juice, pH 6.8. The quantity of active ingredient released in each case into the dissolution medium at any one time was determined by spectrophotometry.

(11) TABLE-US-00002 Time Quantity of active ingredient released 30 min 20% 240 min 43% 480 min 83% 720 min 90%

Example 2

(12) TABLE-US-00003 Powder mixture Complete batch Per tablet Tramadol HCl 100.1 g 100 mg Polyethylene oxide 300.0 g 299.7 mg MW 5000 000 (Polyox WSR Coagulant, Hydroxypropylmethylcellulose 50.05 g 50.0 mg (Hypromellose 100 000 mPa) Butylhydroxytoluene (BHT) 0.25 g 0.25 mg Foam 0.250 g 0.25 mg Hydroxypropylmethylcellulose (Hypromellose 100 000 mPa) Dist. water 49.8 g

(13) The powder mixture was first produced as stated in Example 1.

(14) The foam was produced by dissolving the stated quantity of Hypromellose in distilled water. A foam was then produced using a high performance homogeniser (IKA Ultraturrax 25 Basic) by stirring initially for 2 minutes at level 1, then for 2 minutes with a mixer/granulator at level 2 and finally for 3 minutes at level 3. The powder mixture was slowly added to the foam with constant stirring in a mixer (Kenwood Major Classic 25 Basic).

(15) The granulated mixture was then dried for 24 hoursat 40 C. and, after being passed through a screen (from Frewitt, model GLA-A-ORV) with 1 mm orifices, was press-moulded into tablets with a weight of 450.2 mg. A model EK 0 eccentric press with a round tabletting tool having a diameter of 10 mm and a radius of curvature of 8 mm was used for this purpose. These tablets were dried for 1 hour at 70 C.

(16) The breaking strength of the tablets was determined using the above-stated method. No breakage occurred when a force of 500 N was applied. The tablet could not be comminuted using a hammer, nor with the assistance of a pestle and mortar.

(17) In vitro release of the active ingredient from the tablets was determined in a paddle stirrer apparatus with sinker 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. The release medium used was 600 ml of intestinal juice, pH 6.8. The quantity of active ingredient released in each case into the dissolution medium at any one time was determined by spectrophotometry.

(18) TABLE-US-00004 Time Quantity-of active ingredient released 30 min 12% 240 min 47% 480 min 71% 720 min 84%