DOSAGE FORM THAT IS SAFEGUARDED FROM ABUSE
The invention relates to a dosage form that is thermoshaped without being extruded and that is safeguarded from abuse, comprising at least one synthetic or natural polymer having a breaking strength of at least 500 N in addition to one or more active substances that could be subject to abuse and optionally physiologically acceptable adjuvants. The invention also relates to a corresponding method for producing said dosage form.
1 . An abuse-proofed dosage form thermoformed by extrusion without discoloration, characterised in that, in addition to one or more active ingredients with abuse potential (A) optionally together with physiologically acceptable auxiliary substances (B), it contains at least one synthetic or natural polymer (C) and optionally at least one wax (D), wherein component (C) and the optionally present component (D) exhibit a breaking strength of at least 500 N.
2 . A dosage form according to claim 1 , characterised in that it is in the form of a tablet.
3 . A dosage form according to claim 1 , characterised in that it is in multiparticulate form, preferably in the form of microtablets, micropellets, granules, spheroids, beads or pellets, optionally pressed into tablets or packaged in capsules.
4 . A dosage form according to claim 1 , characterised in that it contains as polymer (C) at least one polymer selected from the group comprising polyethylene oxide, polymethylene oxide, polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers and the mixtures thereof, preferably polyethylene oxide.
5 . A dosage form according to claim 1 , characterised in that the polyethylene oxide (C) has a molecular weight of at least 0.5 million.
6 . A dosage according to claim 5 , characterised in that the molecular weight of the polyethylene oxide (C) is at least 1 million.
7 . A dosage form according to claim 6 , characterised in that the molecular weight of the polyethylene oxide (C) is 1-15 million.
8 . A dosage form according to claim 1 , characterised in that it contains as the wax (D) at least one natural, semi-synthetic or synthetic wax with a softening point of at least 60° C.
9 . A dosage form according to claim 8 , characterised in that the wax (D) is carnauba wax or beeswax.
10 . A dosage form according to claim 1 , characterised in that the component(s) (C) and optionally (D) is/are present in quantities such that the dosage form has a breaking strength of at least 500 N.
11 . A dosage form according to claim 1 , characterised in that the active ingredient (A) is at least one active ingredient selected from the group comprising opioids, tranquillisers, stimulants, barbiturates and further narcotics.
12 . A dosage form according to claim 1 characterised in that it 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 preferably 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.
13 . A dosage form according to claim 12 , characterised in that 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.
14 . A dosage form according to claim 12 , characterised in that the component (a) irritant substance is based on one or more constituents of at least one hot substance drug.
15 . A dosage form according to claim 14 , characterised in that the hot substance drug is at least one drug selected from the group comprising 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 (white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root), particularly preferably at least one drug selected from the group comprising Capsici fructus ( capsicum ), Capsici fructus acer (cayenne pepper) and Piperis nigri fructus (pepper).
16 . A dosage form according to claim 14 , characterised in that 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.
17 . A dosage form according to claim 14 , characterised in that the constituent of the hot substance drug is at least one constituent selected from the group comprising myristicin, elemicin, isoeugenol, β-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids, preferably capsaicin, piperine, preferably trans-piperine, glucosinolates, preferably based on non-volatile mustard oils, particularly preferably based on p-hydroxybenzyl mustard oil, methylmercapto mustard oil or methylsulfonyl mustard oil, and a compound derived from these constituents.
18 . A dosage form according to claim 12 , characterised in that component (b) is at least one viscosity-increasing agent selected from the group comprising 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), pectins from citrus fruit or apples (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®), apple pectin, sodium hyaluronate, tragacanth, tara gum (Vidogum SP 200®), fermented polysaccharide welan gum (K1A96), xanthan gum (Xantural 180®).
19 . A dosage form according to claim 12 , characterised in that component (c) is at least one opioid antagonist selected from the group comprising naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphine, naluphine and a corresponding physiologically acceptable compound, in particular a base, a salt or solvate.
20 . A dosage form according to claim 12 , characterised in that the component (c) used is at least one neuroleptic as a stimulant antagonist, preferably selected from the group comprising haloperidol, promethazine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopentixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone and bromperidol.
21 . A dosage form according to claim 12 , characterised in that the component (d) emetic is based on one or more constituents of ipecacuanha (ipecac) root, preferably on the constituent emetine, and/or is apomorphine.
22 . A dosage form according to claim 12 , characterised in that component (e) is at least one physiologically acceptable dye.
23 . A dosage form according to claim 12 , characterised in that component (f) is at least one bitter substance selected from the group comprising aromatic oils, preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol and mixtures thereof, fruit aroma substances, preferably from lemons, oranges, limes, grapefruit and mixtures thereof comprising at least 2 components, denatonium benzoate and mixtures thereof comprising at least 2 components.
24 . A dosage form according to claim 12 , characterised in that the active ingredient or active ingredients (A) is/are spatially separated from component (c) and/or (d) and/or (f), preferably without direct contact, wherein the active ingredient or active ingredients (A) is/are preferably 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.
25 . A dosage form according to claim 1 , characterised in that it contains at least one active ingredient at least partially in controlled release form.
26 . A dosage form according to claim 25 , characterised in that each of the active ingredients with abuse potential (A) is present in a controlled release matrix.
27 . A dosage form according to claim 26 , characterised in that component (C) and/or the optionally present component (D) also serve as a controlled release matrix material.
28 . A process for the production of a dosage form according to claim 1 , characterised in that,
z) components (A), (B), (C) and the optionally present component (D) are mixed and the optionally present components a) to f) are co-mixed or, if necessary, are mixed separately with the addition of component (C) and optionally (D),
y) the resultant mixture or the resultant mixtures is/are heated in the extruder at least up to the softening point of component (C) and extruded through the outlet orifice of the extruder by application of force,
x) the still plastic extrudate is singulated and formed into the dosage form or
w) the cooled and optionally reheated singulated extrudate is formed into the dosage form,
wherein process steps y) and x) and optionally process steps z) and w) are performed under an inert gas atmosphere.
29 . A process according to claim 28 , characterised in that mixing of the components according z) also proceeds in the extruder under an inert gas atmosphere.
30 . A process according to claim 28 , characterised in that the mixtures according to z) are coextruded or separately extruded.
31 . A process according to claim 28 , characterised in that the mixture or the mixtures according to z) are extruded through a die with at least one bore.
32 . A process according to claim 28 , characterised in that the extrudate is singulated by chopping.
33 . A process according to claim 28 , characterised in that the extrudate is in the form of a strand and is shaped and singulated with the assistance of contrarotating calender rolls comprising opposing recesses in their outer sleeve.
34 . A process according to claim 28 , characterised in that the singulatable extrudate is pelletised or pressed into tablets.
35 . A process according to claim 28 , characterised in that nitrogen is used as the inert gas atmosphere.
36 . A dosage form according to claim 1 obtainable by a process according to claim 28.