NZ618168B2 - Tamper-resistant tablet providing immediate drug release - Google Patents
Tamper-resistant tablet providing immediate drug release Download PDFInfo
- Publication number
- NZ618168B2 NZ618168B2 NZ618168A NZ61816812A NZ618168B2 NZ 618168 B2 NZ618168 B2 NZ 618168B2 NZ 618168 A NZ618168 A NZ 618168A NZ 61816812 A NZ61816812 A NZ 61816812A NZ 618168 B2 NZ618168 B2 NZ 618168B2
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- New Zealand
- Prior art keywords
- tablet
- particulates
- matrix material
- active compound
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- 229960002419 flupentixol Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 229920000578 graft polymer Polymers 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009478 high shear granulation Methods 0.000 description 1
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- 238000006703 hydration reaction Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 229960005208 ipecacuanha Drugs 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229950009272 isomethadone Drugs 0.000 description 1
- 229960003029 ketobemidone Drugs 0.000 description 1
- 229960000272 levacetylmethadol Drugs 0.000 description 1
- 229960004615 levomepromazine Drugs 0.000 description 1
- 229960002710 levomethadone Drugs 0.000 description 1
- 229950006661 levomethadyl acetate Drugs 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 229960001451 lisdexamfetamine Drugs 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229960000299 mazindol Drugs 0.000 description 1
- 229960002225 medazepam Drugs 0.000 description 1
- 229960001468 mefenorex Drugs 0.000 description 1
- 229960001861 melperone Drugs 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
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- 229960000365 meptazinol Drugs 0.000 description 1
- JLICHNCFTLFZJN-HNNXBMFYSA-N meptazinol Chemical compound C=1C=CC(O)=CC=1[C@@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-HNNXBMFYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
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- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- IWVKTOUOPHGZRX-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.COC(=O)C(C)=C IWVKTOUOPHGZRX-UHFFFAOYSA-N 0.000 description 1
- 229960001703 methylphenobarbital Drugs 0.000 description 1
- 229960000316 methyprylon Drugs 0.000 description 1
- 229950006080 metopon Drugs 0.000 description 1
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- 229960001165 modafinil Drugs 0.000 description 1
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- 238000006011 modification reaction Methods 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 229950007471 myrophine Drugs 0.000 description 1
- 229960002967 nabilone Drugs 0.000 description 1
- 229960005297 nalmefene Drugs 0.000 description 1
- 230000000701 neuroleptic Effects 0.000 description 1
- 229960004300 nicomorphine Drugs 0.000 description 1
- 229950001981 nimetazepam Drugs 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 229960004013 normethadone Drugs 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 229940051807 opiod analgesics Morphinan derivatives Drugs 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000008385 outer phase Substances 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 201000008125 pain agnosia Diseases 0.000 description 1
- 229960003294 papaveretum Drugs 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- MBWXNTAXLNYFJB-LKUDQCMESA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCCC(C)CCCC(C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-LKUDQCMESA-N 0.000 description 1
- 229960002034 pinazepam Drugs 0.000 description 1
- 229960002776 pipamperone Drugs 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229960000753 pipradrol Drugs 0.000 description 1
- 229960001286 piritramide Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001707 polybutylene terephthalate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920005606 polypropylene copolymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960000957 prothipendyl Drugs 0.000 description 1
- 239000001327 prunus amygdalus amara l. extract Substances 0.000 description 1
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- 238000000518 rheometry Methods 0.000 description 1
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- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 1
- NWZBFJYXRGSRGD-UHFFFAOYSA-M sodium;octadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOS([O-])(=O)=O NWZBFJYXRGSRGD-UHFFFAOYSA-M 0.000 description 1
- QGLITUFXHVRMGV-UHFFFAOYSA-M sodium;tetratriacontyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCOS([O-])(=O)=O QGLITUFXHVRMGV-UHFFFAOYSA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000000152 swallowing Effects 0.000 description 1
- 229960005214 tetrazepam Drugs 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 229960001402 tilidine Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000002936 tranquilizing Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 229960005392 vinylbital Drugs 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 150000003700 vitamin C derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229960004496 zotepine Drugs 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N α-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical group OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Abstract
Provided is a tamper-resistant tablet comprising: i) a matrix material in an amount of more than one third of the total weight of the tablet ii) a plurality of coated particulates in an amount of less than two thirds of the total weight of the tablet, wherein said particulates comprise a pharmacologically active compound and a physiologically acceptable polymer, preferably a polyalkylene oxide, have a coating comprising a water-soluble polymer, and form a discontinuous phase within the matrix material; wherein under physiological conditions the tablet has released after 30 minutes at least 70% of the pharmacologically active compound originally contained in the tablet. ogically active compound and a physiologically acceptable polymer, preferably a polyalkylene oxide, have a coating comprising a water-soluble polymer, and form a discontinuous phase within the matrix material; wherein under physiological conditions the tablet has released after 30 minutes at least 70% of the pharmacologically active compound originally contained in the tablet.
Description
ation] kza
1 GRA3573-WO/JBdg
Tamper-resistant tablet providing immediate drug release
FIELD OF THE INVENTION
The invention relates to tamper-resistant tablets comprising a matrix material and a plurality
of coated particulates which comprise a pharmacologically active compound and form a
discontinuous phase within the matrix material, ably providing under in vitro conditions
ate release of the pharmacologically active compound.
BACKGROUND OF THE INVENTION
A large number of pharmacologically active substances have a potential for being abused or
misused, i.e. they can be used to e effects which are not consistent with their intended
use. Thus, e.g. opioids which exhibit an excellent efficacy in lling severe to extremely
severe pain, are frequently abused to induce euphoric states r to being intoxicated. In
particular, active substances which have a psychotropic effect are abused accordingly.
To enable abuse, the corresponding dosage forms, such as tablets or capsules are crushed,
for example ground by the abuser, the active substance is extracted from the thus obtained
powder using a ably aqueous liquid and after being optionally filtered through cotton
wool or cellulose wadding, the resultant solution is administered erally, in particular
intravenously. This type of dosage results in an even faster diffusion of the active substance
compared to the oral abuse, with the result desired by the abuser, namely the kick. This kick
or these intoxication-like, euphoric states are also reached if the powdered dosage form is
administered y, i.e. is sniffed.
Various concepts for the avoidance of drug abuse have been developed.
It has been proposed to incorporate in dosage forms aversive agents and/or antagonists in a
manner so that they only produce their aversive and/or antagonizing effects when the
dosage forms are tampered with. r, the presence of such aversive agents is
principally not ble and there is a need to provide sufficient tamper-resistance without
relying on aversive agents and/or antagonists.
2 GRA3573-WO/JBdg
Another concept to prevent abuse relies on the ical properties of the pharmaceutical
dosage forms, particularly an increased breaking strength (resistance to crushing). The major
advantage of such pharmaceutical dosage forms is that comminuting, particularly pulveri-
zation, by conventional means, such as ng in a mortar or fracturing by means of a
hammer, is impossible or at least substantially impeded. Thus, the pulverization, necessary
for abuse, of the dosage forms by the means usually available to a potential abuser is
prevented or at least complicated.
Such pharmaceutical dosage forms are useful for avoiding drug abuse of the phannacolo-
gically active compound contained therein, as they may not be ed by tional
means and thus, cannot be administered in powdered form, e.g. y. The mechanical
ties, particularly the high breaking strength of these pharmaceutical dosage forms
renders them tamper-resistant. In the context of such tamper-resistant pharmaceutical
dosage forms it can be ed to, e.g., W0 2005/016313, W0 16314, WC 2005/
063214, W0 2005/102286, W0 2006/002883, , W0 2006/002886, W0
2006/082097, W0 2006/082099, and W02009/092601.
These dosage forms secured t abuse are distinguished by a controlled, preferably
retarded release of the active substance which has abuse potential. However, a rapid
e of the active substance is necessary for numerous therapeutic applications, for
example pain relief using active substances with abuse potential.
W0 2010/140007 discloses dosage forms comprising melt-extruded uncoated particulates
sing a drug, wherein said melt-extruded particulates are present as a discontinuous
phase in a matrix. The dosage forms e prolonged release of the drug.
W0 2008/107149 discloses multiparticulate dosage forms with impeded abuse containing,
one or more active substances having abuse potential, at least one synthetic or l
polymer, and at least one disintegrant, with the individual particles of the tablet having a
breaking strength of at least 500 N and a release of the active substance of at least 75%
after 45 minutes. The exemplified capsules provide rapid release of the pharmacologically
active compound.
US 2010/0092553 and US 2007/224129 A1 disclose solid multiparticulate oral
pharmaceutical forms whose composition and structure make it possible to avoid misuse.
The microparticles have an extremely thick coating layer which assures the modified release
3 GRA3573-WO/JBdg
of the drug and simultaneously imparts crushing ance to the coated microparticles so
as to avoid misuse.
ses a pharmaceutical composition that may include a granulate
which may at least include one active pharmaceutical ingredient susceptible to abuse. The
particle contains both an alcohol soluble and alcohol insoluble and at leasts partially water
soluble material. Both materials are granulated in the presence of alcohol and water. The
granulate may also include a coating on the granulate exhibiting crush resistance. Material
deposition on the granule is performed using an alcohol based solvent.
The properties of capsules, however, are not satisfactory in every respect, e.g. with respect
to disintegration time, t compliance (e.g. swallowability) and ease of manufacture.
Further, capsules frequently contain ne thus causing the risk of bovine spongifonn
encephalopathy (BSE, or TSE). As far as -resistant dosage forms are concerned,
capsules are antageous as they can typically be opened easily thereby releasing the
ingredients in powdery or ulate form without requiring any ical impact. If
components of different type are contained in a capsule, e.g. drug—containing particles
besides ree particles, a potential abuser might be able to visually distinguish the intact,
undisrupted components of different type (e.g. according to their color, size or other
macroscopic properties) allowing for manual separation.
The properties of these tamper-resistant dosage forms, r, are not satisfactory in
every respect. There is a need for tamper-resistant dosage forms that possess crush
resistance and release the pharmacologically active compound as quick as possible
(immediate release), i.e. should show a gradual increase reaching 85% to 100% at about 30
to 45 minutes or earlier. The dosage form should advantageously be of a shape, size and
weight that can be taken orally with ease. Of course, the dosage form should also be easy to
make in a cost effective manner. When trying to tamper the dosage form in order to prepare
a formulation suitable for abuse by intravenous administration, the liquid part of the
ation that can be separated from the remainder by means of a syringe should be as
less as le, e.g. should contain not more than 20 wt.-% of the pharmacologically active
compound originally contained in the dosage form.
The manufacturing of functionally coated microparticles or granules, however, is not
satisfactory with respect to the excessive manufacturing effort by applying the film-coating in
an c spraying procedure, which needs extensive measure to prevent vapor explosions.
From an environmental and logical perspective the use of organic solvents is further
undesirable. Furthermore, applying a functional film coat in general requires high efforts
to assure the integrity of the functional barrier and is therefore a tion step
ting high manufacturing cost.
It is an object according to the invention to provide tamper-resistant pharmaceutical
dosage forms that provide rapid release of the cologically active compound and
that have ages compared to the -resistant pharmaceutical dosage forms of
the prior art.
This object has been achieved by the patent claims.
Y OF THE INVENTION
A first aspect of the invention es for a tamper-resistant tablet comprising
(i) a matrix material in an amount of more than one third of the total weight of the
tablet; and
(ii) a plurality of coated ulates in an amount of less than two thirds of the total
weight of the tablet; wherein said particulates comprise a pharmacologically active
compound and a physiologically acceptable polymer; and form a discontinuous phase
within the matrix material;
wherein
the physiologically acceptable polymer is a kylene oxide having a
molecular weight of more than 20,000 g/mol;
the matrix material comprises binder/filler, disintegrant and lubricant;
wherein
the filler/binder is selected from the group consisting of silicon dioxide;
microcrystalline cellulose; cellulose ether; mannitol; dextrines; dextrose; calcium
hydrogen phosphate; maltodextrin; lactose; polyvinylpyrrolidone; saccharose; magnesium
salts; starches and pretreated starches;
the disintegrant is selected from the group consisting of crosslinked sodium
carboxymethylcellulose; crosslinked casein; polysaccharide mixtures obtained from
soybeans; pretreated maize starch; sodium alginate; polyvinylpyrrolidone; crosslinked
polyvinylpyrrolidone; starch and pretreated starch such as sodium carboxymethyl
starch; and
(10972217_1):KZA
the lubricant is selected from the group consisting of calcium stearate;
magnesium stearate; glycerol monobehenate; sodium stearylfumarate; and talcum;
under physiological conditions the tablet has released after 30 minutes at least
70% of the pharmacologically active compound originally contained in the tablet; and
the particulates are coated with a coating material comprising a water-soluble
polymer selected from the group consistingcelluloseof esters, cellulose ethers,
poly(meth)acrylates, vinyl polymers, and natural film formers.
The invention relates to a tamper- resistant tablet, preferably for oral administration,
comprising
(i) a matrix al in an amount of more than one third of the total weight of the
tablet; and
(ii) a plurality of coated ulates in an amount of less than two thirds of the total
weight of the tablet; wherein said particulates comprise a pharmacologically active
compound and a physiologically acceptable polymer, preferably a polyalkylene oxide;
and form a discontinuous phase within the matrix material;
which ably es n vitro ions immediate release of the pharmacologically
active compound in accordance with Ph. Eur.
It has been singly found that thein vitro release profile of -resistant dosage
forms can be accelerated by embedding particulates containing the pharmacologically
active compound in a matrix material and increasing the relative weight ratio of the
matrix material to the coated particulates.
Further, it has been surprisingly found that mixtures of matrix material, optionally in pre -
compacted or pre-granulated form, can be mixed with the coated particulates and
subsequently be compacted to tablets which in turn exhibit excellent, i.e. accelerated
disintegration times and in vitro release characteristics.
Still further, it has been surpris ingly found that oral dosage forms can be designed that
provide the best compromise between tamper- resistance, disintegration time and drug
release, drug load, processability (especially tablettability) and patient compliance.
(10799087_1):KZA
GRA3573-WO/JBdg
In particular, it has been surprisingly found that disintegration and drug release can be
accelerated when providing the particulates with a coating, preferably with a coating material
comprising a water-soluble polymer. It has been unexpectedly found that the dissolution of
said coating does not additionally impede egration and drug release, respectively, but
causes a significant ration thereof.
DETAILED DESCRIPTION OF THE INVENTION
Figure 1 schematically illustrates a red embodiment of the tablets according to the
invention.
Figure 2 schematically illustrates another preferred embodiment of the tablets according to
the invention.
Figure 3 shows in vitro release profiles of different tablets according to the invention having
ent compositions and particulate sizes.
Figure 4 shows in vitro e profiles of different tablets according to the invention having
different compositions.
Figure 5 illustrates the behavior of the particulates contained in the tablets according to the
invention when being subjected to a breaking th test, in particular their deformability.
Figure 6 rates the behavior of conventional ulates when being subjected to a
breaking strength test.
Figure 7 shows the distance-force-diagram obtained by ing the mechanical properties
of conventional particulates.
Figure 8 shows the distance-force—diagram obtained by measuring the mechanical properties
of particulates according to the invention.
Figure 9 shows the distance-force-diagram obtained by measuring the mechanical properties
of particulates according to the invention.
6 GRA3573—WO/JBdg
As used herein, the term "tablet" refers to a ceutical entity that is sed of a
pharmacologically active compound and which is actually administered to, or taken by, a
patient. It may be compressed or molded in its manufacture, and it may be of almost any
size, shape, , and color. Most tablets are intended to be swallowed whole and
accordingly, red tablets according to the invention are designed for oral administration.
However, alternatively s may be dissolved in the mouth, chewed, or dissolved in liquid
before swallowing, and some may be placed in a body . Thus, the tablet ing to
the invention may alternatively be adapted for buccal, lingual, rectal or vaginal administration.
lmplants are also possible.
The tablet according to the invention preferably can be regarded as a MUPS formulation
(multiple unit pellet system). In a preferred embodiment, the tablet according to the invention
is monolithic. In another preferred embodiment, the tablet according to the invention is not
monolithic. In this regard, monolithic preferably means that the tablet is formed or composed
of material without joints or seams or consists of or constitutes a single unit.
Preferably, the tablet according to the invention contains all ingredients in a dense compact
unit which in comparison to capsules has a comparatively high density.
The tablets according to the ion comprise subunits having different morphology and
properties, namely drug-containing particulates and matrix material, wherein the coated
ulates form a discontinuous phase within the matrix material. The coated particulates
typically have mechanical properties that differ from the mechanical properties of the matrix
material. Preferably, the coated particulates have a higher mechanical strength than the
matrix material. The coated particulates within the tablets according to the invention can be
visualized by conventional means such as solid state nuclear magnetic resonance
spectroscopy, raster electron microscopy, terahertz spectroscopy and the like.
An advantage of the tablets according to the invention is that the same particulates may be
mixed with matrix material in ent s to thereby e tablets of different
strengths.
The tablet according to the invention has ably a total weight in the range of 0.01 to 1.5
g, more preferably in the range of 0.05 to 1.2 g, still more preferably in the range of 0.1 g to
1.0 9, yet more preferably in the range of 0.2 g to 0.9 g, and most preferably in the range of
0.3 g to 0.8 g. In a preferred embodiment, the total tablet weight is within the range of
7 GRA3573-WO/JBdg
500:450 mg, more preferably 500:300 mg, still more preferably 500i200 mg, yet more
preferably 5001150 mg, most preferably 0 mg, and in particular 500t50 mg.
It has been surprisingly found that the total tablet weight, which is a function of the total size
of the tablet, can be optimized in order to provide the best mise between tamper-
resistance, disintegration time and drug release, drug load, processability (especially
tablettability) and patient compliance.
In a preferred embodiment, the tablet according to the invention is a round tablet. s of
this embodiment preferably have a diameter in the range of about 1 mm to about 30 mm, in
particular in the range of about 2 mm to about 25 mm, more in particular about 5 mm to
about 23 mm, even more in particular about 7 mm to about 13 mm; and a thickness in the
range of about 1.0 mm to about 12 mm, in particular in the range of about 2.0 mm to about
mm, even more in particular from 3.0 mm to about 9.0 mm, even further in particular from
about 4.0 mm to about 8.0 mm.
In another preferred embodiment, the tablet according to the invention is an oblong tablet.
Tablets of this embodiment preferably have a lengthwise extension (longitudinal extension)
of about 1 mm to about 30 mm, in particular in the range of about 2 mm to about 25 mm,
more in particular about 5 mm to about 23 mm, even more in particular about 7 mm to about
mm; a width in the range of about 1 mm to about 30 mm, in particular in the range of
about 2 mm to about 25 mm, more in particular about 5 mm to about 23 mm, even more in
ular about 7 mm to about 13 mm; and a ess in the range of about 1.0 mm to
about 12 mm, in particular in the range of about 2.0 mm to about 10 mm, even more in
particular from 3.0 mm to about 9.0 mm, even further in particular from about 4.0 mm to
about 8.0 mm.
The tablets according to the invention can optionally be provided, partially or completely, with
a conventional coating. The tablets according to the invention are ably film coated with
tional film coating compositions. Suitable coating als are commercially
available, eg. under the arks Opadry® and Eudragit®.
Examples of suitable materials include cellulose esters and cellulose ethers, such as methyl-
cellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), poly(meth)-
tes, such as aminoalkylmethacrylate copolymers, methacrylic acid methylmethacrylate
8 GRA3573-WO/JBdg
copolymers, methacrylic acid methylmethacrylate copolymers; vinyl polymers, such as
polyvinylpyrrolidone, nyl alcohol, polyvinylacetate; and natural film formers.
In a particularly preferred ment, the coating is water-soluble. in a preferred
embodiment, the coating is based on polyvinyl l, such as polyvinyl alcohol-part.
hydrolyzed, and may additionally n polyethylene glycol, such as macrogol 3350, and/or
pigments. In another preferred embodiment, the coating is based on hydroxypropylmethyl-
cellulose, preferably hypromellose type 2910 having a viscosity of 3 to 15 mPas.
The coating can be ant to gastric juices and dissolve as a function of the pH value of
the release environment. By means of this coating, it is possible to ensure that the tablet
ing to the invention passes through the stomach undissolved and the active
compound is only released in the intestines. The coating which is ant to gastric juices
preferably ves at a pH value of between 5 and 7.5.
The coating can also be applied e.g. to improve the aesthetic impression and/or the taste of
the tablets and the ease with which they can be swallowed. Coating the s according to
the invention can also serve other purposes, e.g. improving ity and shelf-life. Suitable
coating formulations comprise a film forming r such as, for example, polyvinyl alcohol
or hydroxypropyl methylcellulose, e.g. ellose, a plasticizer such as, for example, a
glycol, e.g. propylene glycol or polyethylene glycol, an opacifier, such as, for example,
titanium dioxide, and a film smoothener, such as, for example, talc. Suitable coating solvents
are water as well as organic solvents. Examples of organic solvents are alcohols, e.g.
ethanol or isopropanol, s, e.g. e, or halogenated hydrocarbons, e.g. methylene
chloride. Coated tablets according to the invention are preferably prepared by first making
the cores and subsequently coating said cores using conventional techniques, such as
coating in a coating pan.
As used herein, the term "tamper-resistant" refers to tablets that are resistant to conversion
into a form suitable for misuse or abuse, ular for nasal and/or intravenous
administration, by conventional means such as grinding in a mortar or crushing by means of
a hammer. In this regard, the tablets as such may be crushable by conventional means.
However, the coated particulates contained in the tablets according to the invention exhibit
mechanical properties such that they cannot be pulverized by conventional means any
further. As the coated particulates are of macroscopic size and contain the pharmacologically
active compound, they cannot be administered nasally thereby rendering the tablets tamper-
resistant. ably, when trying to tamper the dosage form in order to prepare a formulation
9 GRA3573-WO/JBdg
suitable for abuse by intravenous administration, the liquid part of the formulation that can be
separated from the remainder by means of a syringe is as less as possible, ably it
contains not more than 20 wt.-%, more preferably not more than 15 wt.-%, still more
ably not more than 10 wt.-%, and most preferably not more than 5 wt.-% of the
originally contained pharmacologically active compound. Preferably, this property is tested by
(i) dispensing a tablet that is either intact or has been manually comminuted by means of two
spoons in 5 ml of purified water, (ii) heating the liquid up to its boiling point, (iii) boiling the
liquid in a covered vessel for 5 min without the addition of further purified water, (iv) drawing
up the hot liquid into a syringe (needle 21G ed with a tte filter), (v) determining
the amount of the pharmacologically active compound contained in the liquid within the
syringe.
Further, when trying to disrupt the s by means of a hammer or mortar, the coated
particulates may also, ing on the circumstances, tend to adhere to one another
thereby forming aggregates and agglomerates, respectively, which are larger in size than the
untreated coated particulates.
The ts to which the tablets according to the invention can be administered are not
ularly limited. Preferably, the subjects are animals, more preferably human .
In the tablets according to the invention, the coated particulates are incorporated into a
matrix material. From a macroscopic perspective, the matrix material preferably forms a
continuous phase in which the coated particulates are embedded as tinuous phase.
Preferably, the matrix material is a homogenous coherent mass, preferably a homogeneous
mixture of solid constituents, in which the coated particulates are embedded thereby spatially
separating the coated particulates from one another. While it is possible that the surfaces of
coated particulates are in t or at least in very close proximity with one another, the
plurality of coated particulates preferably cannot be regarded as a single continuous
coherent mass within the tablet.
In other words, the tablet according to the invention comprises the coated particulates as
volume element(s) of a first type in which the pharmacologically active compound and the
physiologically acceptable polymer, preferably the polyalkylene oxide are contained,
ably homogeneously, and the matrix material as volume element of a second type
ing from the material that forms the coated particulates, preferably containing neither
pharmacologically active compound nor physiologically acceptable polymer, preferably no
1O GRA3573—WO/JBdg
polyalkylene oxide, but optionally polyethylene glycol which differs from polyethylene oxide in
its molecular weight.
A purpose of the matrix material in the tablet according to the invention is to ensure rapid
disintegration and uent e of the pharmacologically active compound from the
disintegrated s, i.e. from the coated particulates. Thus, the matrix material preferably
does not contain any excipient that might have a retardant effect on disintegration and drug
release, respectively. Thus, the matrix al preferably does not contain any polymer that
is typically employed as matrix material in prolonged release formulations.
Figure 1 schematically rates a preferred embodiment of the tablet according to the
invention. Tablet (1) contains a plurality of coated particulates (2) having core (2a) and
coating (2b) that form a discontinuous phase within matrix material (3) which in turn forms a
continuous phase.
The tamper-resistant tablet according to the invention ses the matrix material in an
amount of more than one third of the total weight of the tablet.
It has been surprisingly found that the content of the matrix material in the tablet can be
optimized in order to provide the best compromise between tamper-resistance, disintegration
time and drug release, drug load, sability (especially tablettability) and patient
compliance.
Preferably, the content of the matrix material is at least 35 wt.-%, at least 37.5 wt.-% or at
least 40 wt.-%; more preferably at least 42.5 wt.-%, at least 45 wt.-%, at least 47.5 wt.-% or
at least 50 wt.-%; still more preferably at least 52.5 wt.-%, at least 55 wt.-%, at least 57.5 wt.—
% or at least 60 wt.-%; yet more preferably at least 62.5 wt.-%, at least 65 wt.-%, at least
67.5 wt.-% or at least 60 wt.-%; most preferably at least 72.5 wt.-%, at least 75 wt.-%, at
least 77.5 wt.-% or at least 70 wt.-%; and in particular at least 82.5 wt.-%, at least 85 wt.-%,
at least 87.5 wt.-% or at least 90 wt.-%; based on the total weight of the tablet.
Preferably, the content of the matrix material is at most 90 wt.-%, at most 87.5 wt.-%, at most
85 wt.-%, or at most 82.5 wt.-%; more preferably at most 80 wt.-%, at most 77.5 wt.—%, at
most 75 wt.-% or at most 72.5 wt.-%; still more ably at most 70 wt.-%, at most 67.5 wt.-
%, at most 65 wt.-% or at most 62.5 wt.-%; yet more preferably at most 60 wt.-%, at most
57.5 wt.-%, at most 55 wt.-% or at most 52.5 wt.-%; most preferably at most 50 wt.-%, at
11 GRA3573-WO/JBdg
most 47.5 wt.-%, at most 45 wt.-% or at most 42.5 wt.-%; and in particular at most 40 wt.-%,
at most 37.5 wt.-%, or at most 35 wt.—%; based on the total weight of the tablet.
In a preferred embodiment, the content of the matrix material is within the range of 40:5 wt.-
°/o, more preferably 40:2.5 wt.-%, based on the total weight of the tablet. In another preferred
embodiment, the t of the matrix material is within the range of 45:10 wt.-%, more
preferably 45:7.5 wt.-%, still more ably 45:5 wt.-%, and most preferably 45:2.5 wt.-%,
based on the total weight of the tablet. In still another preferred ment, the content of
the matrix material is within the range of 50:10 wt.-%, more preferably 50:7.5 wt.-%, still
more preferably 50:5 wt.-%, and most preferably 50:2.5 wt.-%, based on the total weight of
the tablet. In yet another preferred embodiment, the content of the matrix material is within
the range of 55:10 wt.-%, more ably 55:7.5 wt.-%, still more preferably 55:5 wt.—%,
and most preferably 55:2.5 wt.-%, based on the total weight of the tablet.
Preferably, the matrix material is a mixture, preferably a homogeneous mixture of at least two
different constituents, more preferably of at least three different tuents. In a red
embodiment, all constituents of the matrix material are homogeneously distributed in the
continuous phase that is formed by the matrix material.
In a preferred embodiment, the mixture of all constituents of the matrix material is blended
and employed as a , i.e. in non-pre-compacted form, subsequently mixed with the
particulates that contain the pharmacologically active compound and the kylene oxide,
and then ssed into tablets. Tablets having acceptance values between about 5 and 6
according to Ph. Eur. 2.9.40 "Uniformity of Dosage Units" (UDU) can be obtained when
properly adjusting the tablet press. Vibrations should be avoided to a l extent (eg. by
decoupling of hopper and tablet press) and nce of equipment parts should be as small
as possible. For example, on a rotary tablet press IMA 8250 plus with 26 stations, the
following parameters are suitable: round punches 10 mm diameter, radius of curvature 8mm
without debossing; fill curve 13 mm; tablet weight 500 mg; speed: 13700 - 13800 tablets per
hour; pre compression force 4.7 kN; main compression force 6.7 kN and 8.7 kN; fill depth
14.5 mm and 15 mm; height of tablet bar (pre compression): 3.5 mm; height of tablet bar
(main compression): 3.3 mm and 3.1 mm; revolution speed of feeder (Filomat): 40 rmp.
In another red embodiment, the matrix material is also provided in particulate form, i.e.
in the course of the manufacture of the tablets according to the invention, the constituents of
the matrix material are preferably processed into particulates, subsequently mixed with the
coated particulates that contain the pharmacologically active compound and the
12 GRA3573-WO/JBdg
physiologically acceptable polymer, preferably the polyalkylene oxide, and then compressed
into the tablets.
ably, the average size of the particulates of the matrix material is within the range of
iSOO/o, more preferably 150%, still more preferably 140%, yet more preferably 130%, most
preferably 120%, and in particular i10% of the average size of the coated particulates that
contain the phannacologically active compound and the physiologically able polymer,
preferably the polyalkylene oxide.
It has been surprisingly found that when proceeding this way, segregation ena upon
blending the coated ulates with the matrix material in particulate form can be d
or even completely suppressed, thereby substantially improving the content uniformity of the
tablets according to the invention.
This is particularly surprising, as the larger the particulates are which are to be mixed and
compressed to tablets, the more difficult it typically is to satisfy content uniformity
requirements. Compared to conventional tablets, the tablets according to the invention are
manufactured from comparatively large coated particulates and optionally, also from
comparatively large pre-compacted particulates of matrix material. ably, the AV
(acceptance value) concerning the content uniformity of the tablets ing to the invention
is at most 15, more preferably at most 14, still more preferably at most 13, yet more
ably at most 12, even more preferably at most 11, most preferably at most 10 and in
particular at most 9. Methods to ine the AV are known to the skilled artisan.
ably, the AV is determined in ance with Eur. Ph.
This preferred embodiment of the tablets according to the invention is schematically
illustrated in Figure 2. Tablet (1) contains a plurality of coated particulates (2) having core
(2a) and coating (2b) that form a tinuous phase within matrix material (3) which in turn
forms a continuous phase and is also provided in particulate form, the individual particulates
being in intimate contact with one another at boundaries (4). As the particulates of the matrix
material typically have a mechanical th lower than that of the coated particulates (2),
the particulates of the matrix material are deformed in the course of the manufacture of the
tablets by compression.
The particulates of the matrix material can principally also be coated, optionally with the
same coating material of the coated particulates according to the invention or with another
coating material. ably, however, the particulates of the matrix material are uncoated.
13 GRA3573-WO/JBdg
The ulates of the matrix material can be manufactured by conventional methods for the
preparation of aggregates and agglomerates from powder mixtures such as granulating and
compacting.
In a preferred embodiment, the mixture of all constituents of the matrix al is blended
and pre—compacted thereby yielding a pre-compacted matrix material.
Suitable s for the manufacture of such a mpacted matrix material are known to
the skilled person. Preferably, mpaction proceeds by dry granulation, preferably
slugging or roller compaction. When proceeding this way, the process parameters are
typically to be adjusted in order to achieve the desired properties (see below). Typical
process parameters are compaction force (preferably adjusted within the range of 2 to 12
kN), roller displacement (preferably adjusted within the range of 2 to 5 mm) and granule
sieve rably adjusted within the range of 1.0 to 2.0 mm). The desired properties of the
pre-compacted material include primarily the le size and the content of fine particles.
The density may also play a role. The particle size is preferably within the range for the size
of the particulates (preferably at least 60% > 700 pm for particulates having dimensions of
0.8 x 0.8 mm). The content of fine particles (i.e. particles having a size of less than 600 pm)
is preferably at most 40%, more preferably at most 30%, most preferably at most 20%. The
effect of said process parameters on said desired properties can be easily determined by a
skilled person by routine experimentation.
In another preferred embodiment, the mixture of all constituents of the matrix material is dry
granulated thereby yielding a granulated matrix material. In still another preferred
embodiment, the mixture of all constituents of the matrix material is wet granulated by means
of a non-aqueous solvent e.g. ethanol y yielding another granulated matrix al.
Aqueous granulation, however, is preferably avoided, as this typically has a detrimental
influence on disintegration of the tablet. In yet another preferred embodiment, the mixture of
all constituents of the matrix material is melt ated, eg. by means of an extruder, a
heatable high-shear mixer or a granulator.
As already mentioned above, the matrix material in the tablet according to the invention
should ensure rapid disintegration and subsequent release of the pharrnacologically active
compound from the egrated tablets, i.e. from the coated particulates. Thus, the matrix
al preferably does not contain any excipient that might have a retardant effect on
14 GRA3573-WO/JBdg
disintegration and drug release, respectively. Further, the matrix material preferably does not
n any pharmacologically active compound.
Preferably, the matrix material comprises a disintegrant. Suitable egrants are known to
the skilled person and are ably selected from the group consisting of crosslinked
sodium carboxymethylcellulose (Na-CMC) (e.g. Crosscarrnellose, Ac-Di-Sol®); crosslinked
casein (e.g. Esma—Spreng®); polysaccharide mixtures obtained from soybeans (e.g.
Emcosoy®); pretreated maize starch (e.g. Amijel®); sodium alginate; polyvinylpyrrolidone
(PVP) (e.g. KolIidone®, PolypIasdone®, Polydone®); crosslinked polyvinylpyrrolidone (PVP CI)
(e.g. Polyplasdone® XL); starch and pretreated starch such as sodium carboxymethyl starch
(e.g. Explotab®, Prejel®, Primotab® ET, Starch® 1500, UImatryI®). Crosslinked polymers are
particularly preferred disintegrants, especially crosslinked sodium carboxymethylcellulose
(Na-CMC) or crosslinked nylpyrrolidone (PVP CI).
ably, the disintegrant is contained in the matrix material but not in the coated
particulates of the tablet according to the invention.
In a preferred embodiment, the content of the disintegrant in the matrix material is within the
range of 5:4 wt.-°/o, more preferably 5:3 wt.-%, still more preferably 5:2.5 wt.-%, yet more
preferably 5:2 wt.-%, most preferably 5:1.5 wt.-%, and in particular 5:1 wt.-%, based on the
total weight of matrix al. In another preferred embodiment, the content of the
disintegrant in the matrix material is within the range of 7.5:4 wt.-%, more preferably 7.5:3
wt.-%, still more preferably 5 wt.-%, yet more preferably 7.5:2 wt.-%, most preferably
7.5:1.5 wt.-%, and in particular 7.5:1 wt.-%, based on the total weight of matrix material. In
still another red embodiment, the t of the disintegrant in the matrix material is
within the range of 10:4 wt.-%, more preferably 10:3 wt.-%, still more preferably 10:2.5 wt.-
%, yet more preferably 10:2 wt.-%, most preferably 10:1.5 wt.-%, and in particular 10:1 wt.-
%, based on the total weight of matrix al. In another red embodiment, the content
of the disintegrant in the matrix material is within the range of 12.5:4 wt.-%, more preferably
12.5:3 wt.-%, still more preferably 12.5:2.5 wt.-%, yet more preferably 12.5:2 wt.-%, most
preferably 12.5:1.5 wt.-%, and in particular 12.5:1 wt.-%, based on the total weight of matrix
material.
In a preferred embodiment, the content of the disintegrant in the tablet is within the range of
2:1.8 wt.-%, more preferably 2:1.5 wt.-%, still more preferably 2:1.3 wt.-%, yet more
preferably 2:1.0 wt.-%, most preferably 2:0.8 wt.-%, and in particular 2:0.5 wt.-%. based on
the total weight of . In another preferred embodiment, the content of the disintegrant in
GRA3573-WO/JBdg
the tablet is within the range of 4:1.8 wt.-%, more preferably 4:1.5 wt.-%, still more
preferably 4:1.3 wt.-%, yet more preferably 4:1.0 wt.-%, most ably 4:0.8 wt.-%, and in
ular 4:0.5 wt.-%, based on the total weight of tablet. In still another preferred
embodiment, the content of the egrant in the tablet is within the range of 6:1.8 wt.—%,
more preferably 6:1.5 wt.-%, still more preferably 6:1.3 wt.-%, yet more preferably 6:1.0 wt.-
%, most preferably 6:0.8 wt.-%, and in particular 6:0.5 wt.-%, based on the total weight of
tablet. In another preferred embodiment, the content of the disintegrant in the tablet is within
the range of 8:1.8 wt.-%, more preferably 8:1.5 wt.-%, still more preferably 8:1.3 wt.-%, yet
more preferably 8:1.0 wt.-%, most preferably 8:0.8 wt.-%, and in particular 8:0.5 wt.-%,
based on the total weight of tablet.
Preferably, the matrix material comprises a disintegrant in combination with one or more
water ble pharmaceutical excipients, preferably fillers/binders and/or lubricants.
Preferably, the matrix al comprises a filler or a binder. As many fillers can be regarded
as binders and vice versa, for the purpose of cation "filler/binder" refers to any
ent that is le as filler, binder or both. Thus, the matrix material preferably
comprises a filler/binder.
Preferred fillers (=filler/binders) are selected from the group consisting of silicium dioxide
(e.g. Aerosil®), microcrystalline cellulose (e.g. ®, Elcema®, Emocel®, ExCel®, Vitacell®);
cellulose ether (e.g. Natrosol®, Kluce|®, Methoce|®, Blanose®, Pharmacoat®, Viscontran®);
ol; dextrines; dextrose; calciumhydrogen phosphate (e.g. Emcompress®);
maltodextrine (e.g. Emdex®); lactose (e.g. Fast-Flow Lactose®; Ludipress®' Tablettose®,
Zeparox®); polyvinylpyrrolidone (PVP) (e.g. Kollidone®, Polyplasdone®, Polydone®);
saccharose (e.g. Nu-Tab®, Sugar Tab®); magnesium salts (e.g. MgC03, MgO, MgSi03);
starches and pretreated starches (e.g. Prejel®, Primotab® ET, Starch® 1500). Preferred
binders are ed from the group ting of alginates; chitosanes; and any of the fillers
mentioned above (= fillers/binders).
Some fillers/binders may also serve other purposes. It is known, for example, that silicium
dioxide exhibits excellent function as a t. Thus, preferably, the matrix material
comprises a glidant such as silicium dioxide.
In a preferred embodiment, the content of the filler/binder or mixture of fillers/binders in the
matrix material is within the range of 50:25 wt.-%, more preferably 50:20 wt.-%, still more
preferably 50:15 wt.-°/o, yet more preferably 50:10 wt.-%, most preferably 50:7.5 wt.-%, and
16 GRA3573-WO/JBdg
in particular 50:5 wt.-%, based on the total weight of matrix material. In another preferred
embodiment, the content of the filler/binder or mixture of fillers/binders in the matrix material
is within the range of 65:25 wt.-%, more preferably 65:20 wt.-%, still more preferably 65:15
wt.-%, yet more preferably 65:10 wt.-%, most preferably 65:7.5 wt.-%, and in particular 65:5
wt.-%, based on the total weight of matrix material. In still another preferred embodiment, the
content of the filler/binder or mixture of fillers/binders in the matrix material is within the range
of 80:19 wt.-%, more preferably 80:17.5 wt.-°/o. still more preferably 80:15 wt.-%, yet more
preferably 80:10 wt.-%, most preferably 80:7.5 wt.-%, and in particular 80:5 wt.-%, based
on the total weight of matrix material. In r preferred embodiment, the t of the
filler/binder or mixture of fillers/binders in the matrix material is within the range of 90:9 wt.-
%, more preferably 90:8 wt.-%, still more preferably 90:7 wt.-%, yet more ably 90:6
wt.-%, most preferably 90:5 wt.-%, and in particular 90:4 wt.-%, based on the total weight of
matrix material.
In a preferred embodiment, the content of the binder or mixture of fillers/binders in the
tablet is within the range of 25:24 wt.-%, more ably 25:20 wt.-%, still more preferably
:16 wt.-%, yet more preferably 25:12 wt.-%, most preferably 25:8 wt.-%, and in particular
:4 wt.-%, based on the total weight of tablet. In another preferred embodiment, the content
of the filler/binder or mixture of fillers/binders in the tablet is within the range of 30:29 wt.-°/o,
more preferably 30:25 wt.-%, still more preferably 30:20 wt.-%, yet more preferably 30:15
wt.-%, most preferably 30:10 wt.-%, and in particular 30:5 wt.-%, based on the total weight
of . In still another preferred embodiment, the content of the filler/binder or mixture of
s/binders in the tablet is within the range of 35:34 wt.-%, more preferably 35:28 wt.-%,
still more preferably 35:22 wt.-%, yet more preferably 35:16 wt.-%, most preferably 35:10
wt.-%, and in particular 35:4 wt.-%, based on the total weight of tablet. In another preferred
embodiment, the content of the filler/binder or mixture of fillers/binders in the tablet is within
the range of 40:39 wt.-%, more preferably 40:32 wt.-%, still more preferably 40:25 wt.-%,
yet more ably 40:18 wt.-°/o, most preferably 40:11 wt.-%, and in particular 40:4 wt.-%,
based on the total weight of tablet.
Preferably, the filler/binder is ned in the matrix material but not in the coated
particulates of the tablet according to the invention.
In a preferred embodiment, a portion (e.g. 10% of the total tablet mass) of the matrix is
granulated on the coated particulates (preferably by ueous wet granulation, e.g. with
isopropylic alcohol) and the remaining matrix material is added to the thus granulated coated
particulates and d prior to ssion / processing to tablets. Thus, according to this
17 GRA3573-WO/JBdg
embodiment, the particulates are coated by a coating that in turn is overcoated a n of
the matrix material, whereas the remainder of the matrix material is preferably employed in
non-granulated form.
ably, the matrix material comprises a diluent or lubricant, preferably selected from the
group consisting of calcium stearate; magnesium stearate; glycerol monobehenate (e.g.
Compritol®); x®; Precirol®; Precirol® At05; sodium stearylfumarate (e.g. Pruv®); and
talcum. Magnesium stearate is particularly preferred. Preferably, the content of the ant
in the matrix material is at most 10.0 wt.-%, more preferably at most 7.5 wt.-%, still more
preferably at most 5.0 wt.-%, yet more preferably at most 2.0 wt.-%, even more preferably at
most 1.0 wt.-%, and most preferably at most 0.5 wt.-%, based on the total weight of the
matrix material and based on the total weight of tablet.
In particularly preferred embodiment, the matrix material ses a combination of
disintegrant, filler/binder and lubricant.
Particularly preferred contents of disintegrant, filler/binder and lubricant of the matrix
material, relative to the total weight of the matrix material, are summarized as embodiments
A1 to A6 in the table here below:
wherein the disintegrant is ably crosslinked sodium carboxymethyl cellulose (Na-CMC)
or crosslinked nylpyrrolidone (PVP Cl); the filler binder is preferably microcrystalline
cellulose or a combination of microcrystalline cellulose with colloidal n dioxide; and the
lubricant is ably magnesium stearate.
The matrix material of the tablets according to the invention may additionally contain other
excipients that are conventional in the art, e.g. diluents, binders, granulating aids, colourants,
flavourants, pore formers, surfactants, glidants, wet-regulating agents and disintegrants. The
skilled person will readily be able to ine appropriate quantities of each of these
excipients.
Preferred pore formers include, but are not limited to glucose, fructose, ol, mannose,
galactose, sorbitol, pullulan, dextran, water-soluble hydrophilic polymers, hydroxyalkyl-
celluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic
13 GRA3573-WO/JBdg
, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, hylene oxide,
carbowaxes. carbopol, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene
glycols, polypropylene glycols or block polymers thereof, polyglycols, po|y(a-m)alkylenediols;
inorganic compounds; alkali metal salts; ne earth metal salts, or combinations thereof.
Preferred tants are nonionic, c, cationic or amphoteric surfactants.
In a preferred embodiment, the matrix material contains an ionic surfactant, in particular an
anionic surfactant.
Suitable anionic surfactants include but are not limited to sulfuric acid esters such as sodium
lauryl sulfate (sodium dodecyl sulfate, e.g. Texapon® K12), sodium cetyl e (e.g. Lanette
E®), sodium cetylstearyl sulfate, sodium stearyl sulfate, sodium dioctylsulfosuccinate
(docusate sodium); and the corresponding potassium or calcium salts thereof.
Preferably, the c surfactant has the general formula (ll-a)
CnH2n+1O-803' M‘ (ll-a),
wherein n is an integer of from 8 to 30, preferably 10 to 24, more preferably 12 to 18;
and M is ed from Li‘, Na’, K’, NH4“ 1/2 Mg” and 1/2 Ca2+.
Further suitable anionic surfactants include salts of cholic acid including sodium glycocholate
(e.g. Konakion® MM, Cernevit®), sodium holate and the corresponding potassium or
ammonium salts.
In another red embodiment, the matrix material contains a non-ionic surfactant.
Suitable non-ionic surfactants include but are not limited to
- fatty ls that may be linear or branched, such as cetylalcohol, stearylalcohol,
cetylstearyl alcohol, ldodecane-1—ol and 2-hexyldecaneol;
- s, such as cholesterole;
- partial fatty acid esters of sorbitan such as sorbitanmonolaurate, sorbitanmonopalmitate,
sorbitanmonostearate, sorbitantristearate, sorbitanmonooleate, sorbitansesquioleate and
sorbitantrioleate;
- partial fatty acid esters of polyoxyethylene sorbitan (polyoxyethylene-sorbitan-fatty acid
esters), preferably a fatty acid monoester of polyoxyethylene sorbitan, a fatty acid diester
of polyoxyethylene sorbitan, or a fatty acid triester of polyoxyethylene sorbitan; e.g. mono-
19 GRA3573-WO/JBdg
and tri- lauryl, palmityl, l and oleyl esters, such as the type known under the name
"polysorbat" and commercially ble under the trade name "Tween" including Tween®
[polyoxyethylene(20)sorbitan monolaurate], Tween® 21 [polyoxyethylene(4)sorbitan
monolaurate]. Tween® 40 [polyoxyethylene(20)sorbitan monopalmitate], Tween® 60
[polyoxyethylene(20)sorbitan monostearate], Tween® 65 [polyoxyethylene(20)sorbitan
tristearate]. Tween® 80 [polyoxyethylene(20)sorbitan monooleate], Tween 81
[polyoxyethylene(5)sorbitan monooleate], and Tween® 85 [polyoxyethylene(20)sorbitan
ate]; preferably a fatty acid monoester of yethylenesorbitan according to
general formula (ll-b)
HO(C2H4O)W (OC2H4)XOH
CH—(OC2H4)yOH
H2C—(OC2H4)zO—C—Aikyiene—CH3
(ll-b)
wherein (w+x+y+z) is within the range of from 15 to 100, preferably 16 to 80, more
ably 17 to 60, still more preferably 18 to 40 and most preferably 19 to 21;
and alkylene is an optionally unsaturated alkylene group comprising 6 to 30 carbon
atoms, more preferably 8 to 24 carbon atoms and most ably 10 to 16 carbon
atoms;
polyoxyethyleneglycerole fatty acid esters such as mixtures of mono-, di- and triesters of
glycerol and di- and monoesters of macrogols having molecular weights within the range
of from 200 to 4000 g/mol, e.g., olglycerolcaprylocaprate, macrogolglycerollaurate,
macrogolglycerolococoate, macrogolglycerollinoleate, macrogolglycerolmonostearate,
macrogoI-6—glycerolcaprylocaprate, macrogolglycerololeate; macrogolglycerolstearate,
macrogolglycerolhydroxystearate (e.g. Cremophor® RH 40), and
macrogolglycerolrizinoleate (e.g. Cremophor® EL);
yethylene fatty acid esters, the fatty acid preferably having from about 8 to about 18
carbon atoms, e.g. macrogololeate, macrogolstearate, macrogolhydroxystearate.
polyoxyethylene esters of 12-hydroxystearic acid, such as the type known and
commercially available under the trade name "Solutol HS 15"; preferably according to
general formula (ll-c)
CH3CH2-(OCH2CH3)n-O-CO-(CH2)mCH3 (ll-c)
GRA3573-WO/JBdg
wherein n is an integer of from 6 to 500, preferably 7 to 250, more preferably 8 to 100,
still more ably 9 to 75, yet more preferably 10 to 50, even more preferably 11 to
, most preferably 12 to 25, and in particular 13 to 20; and
wherein m is an integer of from 6 to 28; more preferably 6 to 26, still more preferably 8
to 24, yet more preferably 10 to 22, even more preferably 12 to 20. most preferably 14
to 18 and in particular 16;
- polyoxyethylene fatty alcohol ethers, e.g. macrogolcetylstearylether, macrogollarylether,
macrogololeylether, macrogolstearylether;
- polyoxypropylene—polyoxyethylene block copolymers (poloxamers);
- fatty acid esters of saccharose; e.g. saccharose distearate, saccharose dioleate,
saccharose dipalmitate, saccharose monostearate, saccharose monooleate, saccharose
monopalmitate, saccharose monomyristate and saccharose monolaurate;
- fatty acid esters of ycerol, e.g. ycerololeate;
- polyoxyethylene esters of alpha-tocopheryl succinate, e.g. D-alpha-tocopheryI-PEG-1000—
succinate (TPGS);
- polyglycolyzed glycerides, such as the types known and cially available under the
trade names "Gelucire 44/14", "Gelucire 50/13 and "Labrasol";
- reaction ts of a natural or hydrogenated castor oil and ethylene oxide such as the
various liquid surfactants known and commercially available under the trade name
"Cremophor"; and
— partial fatty acid esters of multifunctional alcohols, such as glycerol fatty acid esters, e.g.
mono- and tri-lauryl, palmityl, stearyl and oleyl esters, for example glycerol monostearate,
ol monooleate, e.g. glyceryl monooleate 40, known and commercially available
under the trade name "Peceol"; glycerole dibehenate, glycerole distearate, ole
monolinoleate; ethyleneglycol monostearate, ethyleneglycol lmitostearate,
pentaerythritol monostearate.
In a preferred embodiment, the matrix material according to the invention comprises a
surfactant or mixture of different surfactants obtainable by
(i) esterifying ted or unsaturated C12-C18-fatty acids, ally bearing a hydroxyl
group, with a polyethylene glycol and optionally, ol; wherein the hylene
glycol preferably comprises 10 to 40 ethylene oxide units (-CH2CH20-); and/or
21 GRA3573-WO/JBdg
(ii) etherifying triglycerides of saturated or unsaturated C12-C18-fatty acids bearing a hydroxyl
group with ethylene oxide so that a polyethylene glycol moiety is linked to the hydroxyl
group of the C12-C13-fatty acids via an ether bond; wherein the hylene glycol
moiety preferably comprises 30 to 50 ethylene oxide units (-CH2CH20-).
In a preferred ment, the content of the surfactant is at least 0.001 wt.-% or at least
0.005 wt.-%, more preferably at least 0.01 wt.-% or at least 0.05 wt.-%, still more preferably
at least 0.1 wt.-%, at least 0.2 wt.-%, or at least 0.3 wt.-%, yet more ably at least 0.4
wt.-%, at least 0.5 wt.-%, or at least 0.6 wt.-%, and in particular at least 0.7 wt.-%, at least 0.8
wt.-%, at least 0.9 wt.-%. or at least 1.0 wt.-%, based on the total weight of the tablet.
in a preferred embodiment, however, the matrix material of the tablet according to the
invention consists of one or more disintegrants, one or more filler/bindel’s and one or more
lubricants, but does not n any other constituents.
In a particularly preferred embodiment, the matrix material of the tablet according to the
invention does not contain one or more gel-forming agents and/or a silicone.
As used herein the term "gel-forming agent" is used to refer to a compound that, upon
t with a solvent (e.g. water), absorbs the solvent and swells, thereby forming a viscous
or semi-viscous substance. Preferred gel-forming agents are not cross-linked. This
substance may moderate cologically active compound release from the embedded
particulates in both aqueous and aqueous alcoholic media. Upon full hydration, a thick
viscous solution or dispersion is typically produced that significantly reduces and/or
minimizes the amount of free solvent which can n an amount of solubilized
cologically active compound, and which can be drawn into a syringe. The gel that is
formed may also reduce the overall amount of pharmacologically active compound
extractable with the solvent by entrapping the pharmacologically active compound within a
gel structure. Thus the gel-forming agent may play an important role in ring tamper-
resistance to the tablets according to the invention.
Gel-forming agents that preferably are not contained in the matrix material include
pharmaceutically acceptable polymers, typically hydrophilic polymers, such as els.
Representative examples of rming agent include polyethylene oxide. polyvinyl alcohol,
ypropylmethyl ose, carbomers, poly(uronic) acids and mixtures thereof.
22 3-WO/JBdg
Thus, the physiologically acceptable polymer, preferably the polyalkylene oxide that is
contained in the coated particulates of the tablets ing to the invention is preferably not
also contained in the matrix material.
Preferably, the pharmacologically active nd which is contained in the coated
particulates of the tablet according to the invention is preferably not also contained in the
matrix material.
Thus, in a preferred embodiment, the total amount of pharmacologically active nd
contained in the tablet according to the invention is present in the coated particulates which
form a discontinuous phase within the matrix material; and the matrix material forming a
continuous phase does not contain any pharmacologically active compound.
The tablet according to the invention contains a plurality of coated ulates. The coated
particulates comprise a pharmacologically active compound and a physiologically able
polymer, preferably a polyalkylene oxide. Preferably, the cologically active compound
is dispersed in the physiologically acceptable polymer, ably the polyalkylene oxide.
For the purpose of specification, the term "particulate" refers to a discrete mass of material
that is solid, e.g. at 20 °C or at room temperature or ambient temperature. Preferably a
particulate is solid at 20 °C. Preferably, the coated particulates are monoliths. ably, the
pharmacologically active compound and the logically acceptable polymer, preferably
the polyalkylene oxide are intimately homogeneously distributed in the coated particulates so
that the coated particulates do not contain any segments where either pharmacologically
active compound is present in the absence of physiologically acceptable polymer, preferably
polyalkylene oxide or where physiologically acceptable polymer, ably polyalkylene
oxide is present in the absence of pharmacologically active compound.
The particulates are film coated and the physiologically able polymer, preferably the
polyalkylene oxide is preferably homogeneously distributed in the core of the pharmaceutical
dosage form (tablet), i.e. the film coating preferably does not contain physiologically
able polymer, preferably polyalkylene oxide, but optionally polyalkylene glycol that
differs from polyalkylene oxide in its lower molecular weight. Nonetheless, the film coating as
such may of course contain one or more rs, which however, preferably differ from the
polyalkylene oxide contained in the core.
23 GRA3573-WO/J8dg
The coated particulates are of macroscopic size, typically the average diameter is within the
range of from 100 pm to 1500 um, preferably 200 pm to 1500 pm, more preferably 300 pm to
1500 um, still more preferably 400 pm to 1500 um, most preferably 500 pm to 1500 pm, and
in particular 600 pm to 1500 pm. The tablets according to the invention comprise particulates
as a discontinuous phase, i.e. the coated ulates form a discontinuous phase in the
matrix material which in turn preferably forms a continuous phase. In this regard,
discontinuous means that not each and every particulate is in intimate contact with another
particulate but that the coated particulates are at least partially separated from one another
by the matrix material in which the coated particulates are embedded. In other words, the
coated ulates preferably do not form a single coherent mass within the tablets
according to the invention.
The tablet according to the invention comprises ulates in an amount of less than two
thirds of the total weight of the .
It has been surprisingly found that the content of particulates in the tablet can be optimized in
order to provide the best compromise between tamper-resistance, disintegration time and
drug e, drug load, processability (especially tablettability) and patient compliance.
Preferably, the content of the coated particulates in the tablets according to the invention is
at most 65 wt.-%, more preferably at most 62.5 wt.-%, still more preferably at most 60 wt.-%,
yet more preferably at most 57.5 wt.-%, most preferably at most 55 wt.-% and in particular at
most 52.5 wt.-%, based on the total weight of the tablets.
Preferably, the content of the coated particulates in the tablets according to the invention is
at least 10 wt.-%, at least 12.5 wt.-%, at least 15 wt.-% or at least 17.5 wt.-%; more
preferably at least 20 wt.-%, at least 22.5 wt.-%, at least 25 wt.-% or at least 27.5 wt.-%;
most preferably at least 30 wt.-%. at least 32.5 wt.-%, at least 35 wt.-% or at least 37.5 wt.-
%; and in particular at least 40 wt.-%, at least 42.5 wt.-%, at least 45 wt.-% or at least 47.5
wt.-%; based on the total weight of the .
In a preferred embodiment, the t of the coated particulates in the tablets according to
the invention is within the range of 35130 wt.-%, more preferably 35:25 wt.-%, still more
preferably 35120 wt.-%, yet more ably 35115 wt.—°/o, most preferably 35:10 wt.-%, and
in particular 3515 wt.-%, based on the total weight of the tablet. In another preferred
embodiment, the t of the coated particulates in the s according to the invention is
within the range of 40:30 wt.-%, more preferably 40i25 wt.-%, still more preferably 40i20
24 GRA3573-WO/JBdg
wt.-%, yet more preferably 40¢15 wt.-%, most preferably 40i10 wt.-%, and in particular 40i5
wt.-%, based on the total weight of the tablet. In still another preferred embodiment. the
content of the coated particulates in the tablets according to the invention is within the range
of 45:30 wt.-%, more preferably 45125 wt.-%, still more preferably 45120 wt.-°/o. yet more
preferably 45115 wt.-°/o, most preferably 45¢10 wt.-%, and in particular 45i5 wt.-%, based on
the total weight of the tablet. In yet another preferred embodiment, the content of the coated
particulates in the tablets according to the invention is within the range of 50130 wt.—%, more
preferably 50125 wt.-%, still more preferably 50120 wt.-%, yet more preferably 50115 wt.-%,
most preferably 501-10 wt.-%, and in particular 50:5 wt.-%, based on the total weight of the
tablet. In another preferred embodiment, the content of the coated particulates in the tablets
according to the invention is within the range of 55130 wt.-%, more preferably 55125 wt.-%,
still more preferably 55120 wt.-%, yet more preferably 55:t15 wt.-%, most preferably 551-10
wt.-%, and in particular 55:5 wt.-%, based on the total weight of the . In still another
preferred embodiment, the t of the coated particulates in the tablets according to the
invention is within the range of 60130 wt.-%, more preferably 60i25 wt.-%, still more
preferably 60120 wt.-%, yet more preferably 60115 wt.-%, most preferably 60110 wt.-%, and
in particular 6015 wt.-%, based on the total weight of the tablet.
The shape of the coated particulates is not ularly d. As the coated particulates are
preferably manufactured by hot-melt extrusion, red coated particulates t in the
tablets according to the invention are generally cylindrical in shape. The diameter of such
coated particulates is therefore the diameter of their circular cross section. The cylindrical
shape is caused by the extrusion process according to which the er of the circular
cross section is a function of the extrusion die and the length of the cylinders is a function of
the cutting length according to which the extruded strand of material is cut into pieces of
preferably more or less predetermined length.
The suitability of cylindrical, Le. a cal particulates for the manufacture of the tablets
according to the invention is cted. Typically, the aspect ratio is ed as an
important measure of the spherical shape. The aspect ratio is defined as the ratio of the
maximal diameter (dmax) and its orthogonal Feret-diameter. For aspherical ulates, the
aspect ratio has values above 1. The smaller the value the more spherical is the particulate.
Aspect ratios below 1.1 are typically ered actory, aspect ratios above 1.2,
however, are typically considered not le for the manufacture of conventional tablets.
The inventors have surprisingly found that when manufacturing the tablets according to the
invention, even particulates having aspect ratios above 1.2 can be processed t
difficulties and that it is not necessary to provide spherical particulates. In a preferred
GRA3573-WO/JBdg
embodiment, the aspect ratio of the coated particulates is at most 1.40, more preferably at
most 1.35, still more preferably at most 1.30, yet more preferably at most 1.25, even more
preferably at most 1.20, most preferably at most 1.15 and in particular at most 1.10. In
another preferred ment, the aspect ratio of the coated particulates is at least 1.10,
more preferably at least 1.15, still more preferably at least 1.20, yet more preferably at least
1.25, even more preferably at least 1.30, most preferably at least 1.35 and in particular at
least 1.40.
The coated particulates in the tablets according to the invention are of macroscopic size, i.e.
typically have an average particle size of at least 50 pm, more preferably at least 100 um, still
more preferably at least 150 pm or at least 200 um, yet more preferably at least 250 pm or at
least 300 um, most preferably at least 400 pm or at least 500 um, and in particular at least
550 pm or at least 600 um.
Preferred coated particulates have an e length and average diameter of about 1000
pm or less. When the coated ulates are manufactured by ion technology, the
"length" of coated particulates is the ion of the coated particulates that is parallel to
the direction of extrusion. The "diameter" of coated particulates is the t dimension that
is dicular to the direction of extrusion.
Particularly preferred coated particulates have an average diameter of less than about 1000
pm, more preferably less than about 800 um, still more preferably of less than about 650 um.
Especially preferred coated particulates have an average diameter of less than 700 um,
ularly less than 600 um, still more ularly less than 500 um, e.g. less than 400 um.
Particularly preferred particulates have an average diameter in the range 00 pm, more
preferably 400-800 um, still more preferably 450-700 um, yet more preferably 500—650 um,
e.g. about 500-600 um. Further preferred particulates have an average diameter of between
about 300 um and about 400 pm, of between about 400 um and 500 pm, or of between
about 500 um and 600 pm, or of between 600 um and 700 pm or of between 700 um and
800 um.
Preferred particulates that are present in the tablets according to the invention have an
average length of less than about 1000 um, preferably an average length of less than about
800 um, still more preferably an average length of less than about 650 um, e.g. a length of
about 800 um, about 700 um about 600 um, about 500 um, about 400 pm or about 300 um.
Especially red particulates have an average length of less than 700 um, particularly
less than 650 um, still more particularly less than 550 um, e.g. less than 450 um. Particularly
26 GRA3573-WO/JBdg
preferred particulates therefore have an average length in the range 200-1000 pm, more
preferably 400-800 um, still more preferably 450-700 pm, yet more ably 500-650 um,
e.g. about 500—600 pm. The minimum average length of the microparticulates is determined
by the cutting step and may be, e.g. 500 pm, 400 pm, 300 pm or 200 pm.
In a preferred embodiment, the coated particulates have (i) an average diameter of about
10001300 pm, more preferably 10001250 um, still more preferably 10001200 pm, yet more
preferably 1001150 pm, most preferably 10001100 um, and in particular 1000150 pm; and/or
(ii) an average length of about 7501300 pm, more preferably 7501250 um, still more
preferably 7501200 pm, yet more preferably 7501150 pm, most preferably 7501100 um, and
in particular 750150 pm.
In another preferred embodiment, the coated particulates have (i) an average diameter of
about 7501300 pm, more preferably 7501250 um, still more preferably 7501200 pm, yet
more preferably 7501150 um, most preferably 7501100 pm, and in particular 750150 um;
and/or (ii) an average length of about 7501300 pm, more preferably 7501250 um, still more
preferably 7501200 pm, yet more preferably 0 um, most preferably 7501100 um, and
in particular 750150 pm.
It has been surprisingly found that the size of the coated ulates in the tablet can be
optimized in order to provide the best mise n tamper—resistance, disintegration
time and drug release, drug load, processability (especially tability) and patient
compliance.
The size of particulates may be determined by any conventional procedure known in the art,
e.g. laser light scattering, sieve analysis, light microscopy or image analysis.
Preferably, the plurality of coated particulates that is ned in the tablet according to the
ion has an arithmetic average weight, in the following referred to as "aaw", wherein at
least 70%, more ably at least 75%, still more preferably at least 80%, yet more
preferably at least 85%, most preferably at least 90% and in particular at least 95% of the
individual particles contained in said plurality of coated particulates has an individual weight
within the range of aaw130%, more ably aaw125%, still more preferably aaw120%, yet
more preferably aaw115%, most preferably aaw110%, and in particular . For
e, if the tablet according to the invention contains a plurality of 100 particulates and
aaw of said plurality of coated particulates is 1.00 mg, at least 75 individual particles (Le.
75%) have an individual weight within the range of from 0.70 to 1.30 mg (1.00 mg 130%).
27 GRA3573-WO/JBdg
The particulates are coated, preferably film coated. it has been surprisingly found that when
the particulates are film coated, the disintegration time and/or the drug release from the
s can be further accelerated, which is particularly significant for tablets with ate
drug release.
ably, the plurality of coated particulates contained in the dosage form according to the
invention encompasses the total quantity of particulates which contain the pharmacologically
active compound, i.e. ably all active compound containing particulates are coated.
Preferably, the coating material does not contain a disintegrant.
The particulates according to the invention are provided, partially or preferably completely,
with a coating. The particulates according to the invention are preferably film coated with film
coating compositions. Suitable coating als are commercially available, e.g. under the
trademarks Opadry® and Eudragit®.
Preferably, the coating al comprises a water-soluble polymer. For the purpose of
specification, a water-soluble polymer is preferably a non-enteric polymer that rapidly
ves when being exposed to an acidic medium such as gastric juice. Preferably, the
solubility of the polymer in 100 g artificial gastric juice (HCI aq.) at pH 1.2 and 21 °C is
at least 1.0 9, more preferably at least 2.0 9, still more preferably at least 3.0 9, yet more
preferably at least 4.0 g, most preferably at least 5.0 g, and in particular at least 6.0 9.
Examples of suitable coating materials include cellulose esters and cellulose ethers, such as
methylcellulose (MC), hydroxypropylmethylcellulose , hydroxypropylcellulose (HPC),
hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), ethylcellulose (EC),
ose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP);
poly(meth)acrylates, such as lkylmethacrylate copolymers, ethylacrylate methyl-
methacrylate copolymers, methacrylic acid methylmethacrylate copolymers, methacrylic acid
methylmethacrylate copolymers; vinyl polymers, such as polyvinylpyrrolidone, polyvinyl—
acetatephthalate, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymers,
polyvinylacetate; and natural film formers.
The coating material may n excipients such as izers (e.g. surfactants such as
macrogol cetostearylether, sodium dodecylsulfate, and the like). Suitable excipients of film
coating materials are known to the skilled person.
28 GRA3573-WO/JBdg
In a particularly preferred embodiment. the g is water-soluble. In a preferred
embodiment, the g is based on polyvinyl alcohol, such as polyvinyl alcohol-part.
hydrolyzed, and may additionally contain polyethylene glycol, such as macrogol 3350, and/or
pigments. In another preferred embodiment, the coating is based on hydroxypropylmethyl-
cellulose, preferably hypromellose type 2910 having a ity of 3 to 15 mPas.
A particularly preferred coating contains polyvinyl alcohol and optionally, further excipients
such as n gum and/or talcum.
The particulates are film coated and the content of the dried film coating is preferably at most
wt.-%, more preferably at most 4 wt.-%, still more preferably at most 3.5 wt.-%, yet more
preferably at most 3 wt.-%, most preferably at most 2.5 wt.-%, and in ular at most 2 wt.-
%, based on the total weight of the coated particulates. In a particularly preferred
embodiment, the weight increase relative to the total weight of the particulates (uncoated
starting material) is within the range of from 3.0 to 4.7 wt.-%, more preferably 3.1 to 4.6 wt.-
%, still more preferably 3.2 to 4.5 wt.—%, yet more preferably 3.3 to 4.4 wt.-%, most
preferably 3.4 to 4.3 wt.-%, and in ular 3.5 to 4.2 wt.-%.
It has been surprisingly found that the relative weight ratio of matrix material : particulates in
the tablet can be optimized in order to provide the best compromise between -
ance, disintegration time and drug e, drug load, processability (especially
tablettability) and patient compliance.
Preferably, said relative weight ratio is within the range of 1 : 1.00:0.75. more preferably 1 :
1.00:l:0.50, still more preferably 1 : 1.001040, yet more preferably 1 : 1.001030, most
preferably 1 : 1001020, and in particular 1 : 1001010.
The coated particulates contain at least a pharmacologically active compound and a
physiologically acceptable polymer, preferably a polyalkylene oxide. Preferably, however, the
coated particulates contain additional pharmaceutical excipients such as antioxidants and
plasticizers.
The cologically active nd is not particularly limited. Preferably, the
pharmacologically active compound is an opioid.
29 GRA3573-WO/JBdg
In a preferred embodiment. the coated particulates and the tablet, respectively, contain only
a single pharmacologically active compound. In another preferred embodiment, the coated
particulates and the tablet, respectively, contain a combination of two or more
pharmacologically active compounds.
Preferably, pharmacologically active compound is an active ingredient with potential for being
abused. Active ients with potential for being abused are known to the person skilled in
the art and comprise e.g. tranquillizers, stimulants, barbiturates, narcotics, opioids or opioid
derivatives.
Preferably, the pharmacologically active compound exhibits psychotropic action.
Preferably, the cologically active compound is selected from the group consisting of
opiates, opioids, stimulants, tranquilizers, and other narcotics.
Particularly preferably, the cologically active compound is an opioid. ing to the
ATC index, opioids are divided into natural opium alkaloids, piperidine derivatives,
diphenylpropylamine derivatives, benzomorphan derivatives, oripavine derivatives,
morphinan derivatives and others.
The following opiates, opioids, tranquillizers or other narcotics are substances with a
psychotropic action, i.e. have a potential of abuse, and hence are preferably contained in the
tablet and the coated ulates, respectively: alfentanil, allobarbital, allylprodine,
alphaprodine, alprazolam, amfepramone, amphetamine, amphetaminil, amobarbital, anileri-
dine, apocodeine, axomadol, barbital, bemidone, morphine, bezitramide, bromaze-
pam, olam, buprenorphine, butobarbital, butorphanol, camazepam, carfentanil,
cathine/D-norpseudoephedrine, chlordiazepoxide, clobazam clofedanol, clonazepam, clonita-
zene, clorazepate, clotiazepam, cloxazolam, ***e, codeine, cyclobarbital, cyclorphan,
cyprenorphine, delorazepam, rphine, dextromoramide, dextropropoxyphene,
dezocine, diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine, o-
morphone, dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetylbutyrate, dipipa-
none, dronabinol, eptazocine, estazolam, ethoheptazine, ethylthiambutene, ethyl
loflazepate, ethylmorphine, azene, etorphine, faxeladol, fencamfamine, fenethylline,
fenpipramide, fenproporex, fentanyl, epam, azepam, flurazepam, halazepam,
haloxazolam, heroin, hydrocodone, orphone, hydroxypethidine, isomethadone,
hydroxymethylmorphinan, ketazolam, ketobemidone, levacetylmethadol (LAAM), levo-
methadone, levorphanol, levophenacylmorphane, levoxemacin, lisdexamfetamine
GRA3573-WO/JBdg
dimesylate, lofentanil, Ioprazolam, lorazepam, azepam, mazindol. medazepam,
mefenorex, meperidine, meprobamate, metapon, meptazinol, metazocine, methylmorphine,
metamphetamine, methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl,
methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil,
morphine, myrophine, nabilone, nalbuphene, nalorphine, narceine, nicomorphine,
nimetazepam, nitrazepam, epam, norlevorphanol, normethadone, normorphine,
anone, opium, oxazepam, oxazolam, oxycodone, oxymorphone, Papaver somniferum,
papaveretum, pernoline, pentazocine, pentobarbital, pethidine, phenadoxone,
phenomorphane, phenazocine, phenoperidine, piminodine, deine, phenmetrazine,
arbital, phenterrnine, pinazepam, pipradrol, piritramide, prazepam, profadol,
proheptazine, promedol, idine, yphene, remifentanil, secbutabarbital,
secobarbital, sufentanil, adol, temazepam, tetrazepam, tilidine (cis and trans),
tramadol, triazolam, vinylbital, N-(1-methyl—2—piperidinoethyl)—N-(2-pyridy|)propionamide,
(1 3-(3-dimethylaminoethy|-2—methyl-propyl)phenol, (1 R,2R,4S)—2—(dimethylamino)—
methyl(p-fluorobenzyloxy)(m—methoxypheny|)cyclohexanol, (1 R,2R)—3-(2—dimethylaminomethyl-cyclohexyl
)phenol, (1S,28)—3-(3-dimethylamino—1-ethylmethyl-propyl)phenol,
)—1-dimethylamino-3(3-methoxypheny|)methyl-pentano|, (1RS,3RS,6RS)di-
methylaminomethyl—1-(3-methoxypheny|)-cyclohexane-1,3-diol, preferably as racemate, 3-(2—
dimethylaminomethylhydroxy-cyc|ohexy|)phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-
ylaminomethylhydroxy-cyclohexyl)phenyl ethoxy-naphthalenyl)propionate,
3-(2-dimethylaminomethyl-cyclohexenyl)—pheny| 2-(4—isobutyl-phenyl)propionate, 3—(2-
dimethylaminomethyI-cyclohexenyl)—phenyl 2-(6-methoxy-naphthalen-2—yl)propionate,
)—2—acetoxytrifluoromethyl-benzoic acid 3-(2-dimethylaminomethylhydroxycyclohexy
|)-pheny| ester, (RR-SS)—2-hydroxytrifluoromethyl-benzoic acid 3-(2-
dimethylaminomethylhydroxy-cyclohexy|)-phenyl ester, (RR-SS)—4—chlorohydroxy-
benzoic acid 3—(2-dimethylaminomethylhydroxy-cyclohexy|)—phenyl ester, (RR-SS)—2-
hydroxymethyI-benzoic acid 3-(2-dimethylaminomethylhydroxy-cyclohexyl)—pheny|
ester, (RR-SS)hydroxymethoxy-benzoic acid 3-(2—dimethylaminomethyl-1~hydroxy-
cyclohexy|)-pheny| ester, (RR-SS)—2—hydroxynitro-benzoic acid 3-(2-dimethylaminomethyl-
1-hydroxy-cyclohexy|)-pheny| ester, (RR-SS)—2',4'-difluorohydroxy-biphenyIcarboxylic
acid 3-(2-dimethylaminomethylhydroxy-cyclohexyl)-pheny| ester, and corresponding
stereoisomeric compounds, in each case the corresponding derivatives thereof,
physiologically acceptable enantiomers, stereoisomers, diastereomers and racemates and
the logically acceptable derivatives thereof, e.g. ethers, esters or amides, and in each
case the physiologically acceptable compounds thereof, in particular the acid or base
addition salts thereof and solvates, e.g. hydrochlorides.
31 GRA3573-WO/JBdg
in a preferred embodiment, the cologically active compound is selected from the
group consisting of 5, M6G (CE-04—410), AOL-5859, CR-665, NRP290 and sebacoyl
dinalbuphine ester.
In a preferred ment, the pharmacologically active compound is selected from the
group consisting of oxymorphone, hydromorphone and morphine.
In r preferred embodiment, the pharmacologically active compound is selected from
the group consisting of tapentadol, faxeladol and axomadol.
In still another red embodiment, the pharmacologically active compound is selected
from the group consisting of -dimethylaminophenylpentamethylene)—6—fluoro-1,3,4,9—
tetrahydropyrano[3,4—b]indole, particularly its hemicitrate; 1,1-[3-dimethylamino(2-thienyl)-
pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]indole, particularly its citrate; and -
dimethylamino(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4—b]fluoroindo|e,
particularly its hemicitrate. These compounds are known from, e.g., , WO
2005/066183.
The pharmacologically active compound may be present in form of a physiologically
acceptable salt, e.g. physiologically acceptable acid addition salt.
Physiologically acceptable acid addition salts comprise the acid addition salt forms which can
conveniently be obtained by treating the base form of the active ingredient with appropriate
organic and inorganic acids. Active ingredients containing an acidic proton may be ted
into their non-toxic metal or amine addition salt forms by ent with appropriate organic
and inorganic bases. The term addition salt also comprises the hydrates and solvent addition
forms which the active ingredients are able to form. Examples of such forms are e.g.
hydrates, alcoholates and the like.
It has been surprisingly found that the content of the pharmacologically active compound in
the tablet and in the coated particulates, respectively, can be optimized in order to provide
the best compromise between tamper-resistance, disintegration time and drug release, drug
load, processability (especially tablettability) and patient compliance.
The pharmacologically active compound is present in the tablet in a therapeutically effective
amount. The amount that constitutes a therapeutically ive amount varies according to
32 GRA3573-WO/JBdg
the active ingredients being used, the condition being treated, the severity of said condition,
the patient being treated, and the frequency of administration.
The content of the pharmacologically active compound in the tablet is not limited. The dose
of the pharrnacologlcally active compound which is adapted for administration preferably is in
the range of 0.1 mg to 500 mg, more preferably in the range of 1.0 mg to 400 mg, even more
preferably in the range of 5.0 mg to 300 mg, and most preferably in the range of 10 mg to
250 mg. In a preferred embodiment, the total amount of the pharmacologically active
compound that is contained in the tablet is within the range of from 0.01 to 200 mg, more
preferably 0.1 to 190 mg, still more preferably 1.0 to 180 mg, yet more preferably 1.5 to 160
mg, most preferably 2.0 to 100 mg and in particular 2.5 to 80 mg.
Preferably, the content of the pharmacologically active compound is within the range of from
0.01 to 80 wt.-%, more preferably 0.1 to 50 wt.-%, still more preferably 1 to 25 wt.-%, based
on the total weight of the tablet.
In a preferred embodiment, the content of pharmacologically active compound is within the
range of from 50:45 wt.-%, or 75:70 wt.-%, or 10:9.0 wt.-%, or 2.0 wt.-%, or 15:14
wt.-%, or 17.5:17.0 wt.-%, or 20:19 wt.-%, or 2.0 wt.-%, or 25:24 wt.—%; more
preferably 5.0:4.0 wt.-%, or 75:60 wt.-%, or 10:80 wt.-%, or 12.5:12.0 wt.—%, or 15:12
wt.-%, or 17.5:15.0 wt.-%, or 20:19 wt.-%, or 22.5:22.0 wt.-%, or 25:24 wt.-%; still more
preferably 5.0:3.5 wt.-%, or 75:50 wt.-%, or 10:7.0 wt.-%, or 12.5:10.0 wt.-%, or 15:10
wt.-%, or 17.5:13.0 wt.-%, or 20:17 wt.-%, or 22.5:19.0 wt.-%, or 25:21 wt.-%; yet more
ably 0 wt.-%, or 75:40 wt.-%, or 10:6.0 wt.-%, or .0 wt.-%, or 15:80
wt.-%, or 17.5:11.0 wt.-%, or 20:15 wt.-%, or 22.5:16.0 wt.-%, or 25:18 wt.-%; even more
ably 5.0:2.5 wt.-%, or 75:30 wt.—%, or 10:5.0 wt.-%, or 12.5:6.0 wt.-%, or 15:60
wt.-%, or 17.5:9.0 wt.-%, or 20:13 wt.-%, or 22.5:13.0 wt.—%, or 25:15 wt.—°/o; most
preferably 5.0:2.0 wt.-%, or 75:20 wt.—%, or 10:4.0 wt.-%, or 12.5:4.0 wt.-%, or 15:4.0
wt.-%, or 17.5:7.0 wt.-%, or 20:11 wt.-%, or 22.5:10.0 wt.-%, or 25:12 wt.-%; and in
ular 5.0:1.5 wt.-%, or 75:10 wt.-%, or 10:30 wt.-%, or 12.5:2.0 wt.-%, or 15:2.0 wt.-
%, or 17.5:5.0 wt.-%, or 20:9 wt.-%, or .0 wt.-%, or 25:9 wt.-%; in each case based
on the total weight of the tablet.
In a further preferred embodiment, the content of pharmacologically active compound is
within the range of from 20:6 wt.~%, more preferably 20:5 wt.-%, still more preferably 20:4
wt.—%, most preferably 20:3 wt.-%, and in particular 20:2 wt.-%, based on the total weight of
the tablet. In another preferred embodiment, the content of pharmacologically active
33 GRA3573-WO/JBdg
compound is within the range of from 25:6 wt.-%, more preferably 25:5 wt.-%, still more
preferably 25:4 wt.-%, most preferably 25:3 wt.-%, and in ular 25:2 wt.-%. based on
the total weight of the tablet.
The skilled person may readily determine an appropriate amount of pharmacologically active
compound to include in a tablet. For instance, in the case of analgesics, the total amount of
cologically active compound present in the tablet is that sufficient to provide
analgesia. The total amount of pharmacologically active compound administered to a patient
in a dose will vary ing on numerous factors ing the nature of the
pharmacologically active compound, the weight of the patient, the severity of the pain, the
nature of other therapeutic agents being administered etc.
In a preferred ment, the pharmacologically active compound is contained in the tablet
in an amount of 7.5:5 mg, 10:5 mg, 20:5 mg, 30:5 mg, 40:5 mg, 50:5 mg, 60:5 mg, 70:5
mg, 80:5 mg, 90:5 mg, 100:5 mg, 110:5 mg, 120:5 mg, 130:5, 140:5 mg, 150:5 mg,
160:5 mg, 170:5 mg, 180:5 mg, 190:5 mg, 200:5 mg, 210:5 mg, 220:5 mg, 230:5 mg,
240:5 mg, 250:5 mg, 260:5 mg, 270:5 mg, 280:5 mg, 290:5 mg, or 300:5 mg. In another
preferred embodiment, the pharmacologically active compound is contained in the tablet in
an amount of 5:2.5 mg, 7.5:2.5 mg, 10:2.5 mg, 15:2.5 mg, 20:2.5 mg, 25:2.5 mg, 30:2.5
mg, 35:2.5 mg, 40:2.5 mg, 45:2.5 mg, 50:2.5 mg, 55:2.5 mg, 60:2.5 mg, 65:2.5 mg,
70:2.5 mg, 75:2.5 mg, 80:2.5 mg, 85:2.5 mg, 90:2.5 mg, 95:2.5 mg, 100:2.5 mg, 105:2.5
mg, 110:2.5 mg, 115:2.5 mg, 120:2.5 mg, 125:2.5 mg, 130:2.5 mg, 135:2.5 mg, 5
mg, 145:2.5 mg, 150:2.5 mg, 155:2.5 mg, 160:2.5 mg, 165:2.5 mg, 170:2.5 mg, 175:2.5
mg, 180:2.5 mg, 185:2.5 mg, 190:2.5 mg, 195:2.5 mg, 200:2.5 mg, 205:2.5 mg, 210:2.5
mg, 215:2.5 mg, 220:2.5 mg, 225:2.5 mg, 230:2.5 mg, 235:2.5 mg, 5 mg, 245:2.5
mg, 250:2.5 mg, 255:2.5 mg, 260:2.5 mg, or 265:2.5 mg.
In a particularly red embodiment, the pharmacologically active compound is tapentadol,
preferably its HCI salt, and the tablet is adapted for administration once daily, twice daily,
thrice daily or more frequently. In this embodiment, pharmacologically active compound is
preferably contained in the tablet in an amount of from 25 to 100 mg.
In a particularly preferred embodiment, the pharmacologically active nd is
oxymorphone, preferably its HCI salt, and the tablet is adapted for administration once daily,
twice daily, thrice daily or more frequently. In this embodiment, the pharmacologically active
compound is preferably ned in the tablet in an amount of from 5 to 40 mg. In r
particularly red embodiment, the pharmacologically active compound is oxymorphone,
34 GRA3573-WO/JBdg
preferably its HCI salt, and the tablet is adapted for administration once daily. In this
embodiment, the pharmacologically active nd is preferably contained in the tablet in
an amount of from 10 to 80 mg.
In another particularly preferred ment, the pharmacologically active compound is
oxycodone, preferably its HCI salt, and the tablet is adapted for administration once daily,
twice daily, thrice daily or more ntly. In this embodiment, the pharmacologically active
compound is ably contained in the tablet in an amount of from 5 to 80 mg.
In still another particularly preferred embodiment, the pharmacologically active compound is
hydromorphone, preferably its HCI, and the tablet is adapted for administration once daily,
twice daily, thrice daily or more frequently. In this embodiment, the pharmacologically active
compound is preferably contained in the tablet in an amount of from 2 to 52 mg. In another
particularly preferred embodiment, the pharmacologically active compound is hydro-
morphone, preferably its HCI, and the tablet is adapted for administration once daily, twice
daily, thrice daily or more frequently. in this embodiment, the pharmacologically active
compound is preferably ned in the tablet in an amount of from 4 to 104 mg.
The coated particulates present in the tablets according to the invention preferably comprise
3 to 75 wt.-% of pharmacologically active compound, more preferably 5 to 70 wt.-% of
pharmacologically active compound, still more ably 7.5 to 65 wt.-% of
cologically active compound, based on the total weight of a particulate.
Preferably, the content of the pharmacologically active compound is at least 25 wt.-%, more
preferably at least 30 wt.-%, still more ably at least 35 wt.-%, yet more preferably at
least 40 wt.-%, most preferably at least 45 wt.-%, based on the total weight of a particulate.
Preferably, the content of the pharmacologically active compound is at most 70 wt.-%, more
preferably at most 65 wt.-%, still more preferably at most 60 wt.-%, yet more preferably at
most 55 wt.-%, most ably at most 50 wt.-%, based on the total weight of a particulate.
In a preferred embodiment, the t of the pharmacologically active compound is within
the range of 35:30 wt.-%, more preferably 35:25 wt.-%, still more preferably 35:20 wt.-%.
yet more preferably 35:15 wt.-%, most preferably 35:10 wt.-%, and in particular 35:5 wt.-%,
based on the total weight of a particulate. In another preferred embodiment, the content of
the cologically active compound is within the range of 45:30 wt.-%, more preferably
45:25 wt.-%, still more preferably 45:20 wt.-%, yet more preferably 45:15 wt.-%, most
3-WO/JBdg
preferably 45:10 wt.-%, and in particular 45:5 wt.-%, based on the total weight of a
particulate. In still another red embodiment, the content of the cologically active
compound is within the range of 55:30 wt.-%, more preferably 55:25 wt.-%, still more
preferably 55:20 wt.—%, yet more preferably 55:15 wt.-%, most preferably 55:10 wt.-%, and
in particular 55:5 wt.-%, based on the total weight of a particulate.
The pharmacologically active compound that is included in the preparation of the tablets
according to the invention ably has an average particle size of less than 500 microns,
still more preferably less than 300 microns, yet more preferably less than 200 or 100
microns. There is no lower limit on the average particle size and it may be, for example, 50
microns. The particle size of pharmacologically active nds may be determined by any
technique conventional in the art, e.g. laser light scattering, sieve analysis, light microscopy
or image is. Generally speaking it is preferable that the largest dimension of the
pharmacologically active compound particle be less than the size of the coated particulates
(e.g. less than the smallest dimension of the coated particulates).
A d person knows how to determine pharmacokinetic parameters such as t1/2, Tmax,
Cmax, AUC and bioavailability. For the purposes of the description, the pharmacokinetic
parameters, which may be determined from the blood plasma concentrations of 3-(2-
dimethylaminomethylcyclohexyl)phenol, are defined as follows:
-administration (5 average peak plasma level)Cmax maximum measured plasma concentration of the active ingredient after single
_AUCtotal area of the plasma concentration/time curve including the subarea from
The above parameters are in each case stated as mean values of the individual values for all
investigated patients/test ts.
A person skilled in the art knows how the pharmacokinetic parameters of the active
ingredient may be calculated from the measured concentrations of the active ingredient in
the blood plasma. In this connection, reference may be made, for example, to Willi o
(ed.) Parameters for Compartment-free cokinetics, Shaker Verlag Aachen (1999).
in a preferred embodiment, the pharmacologically active compound is tapentadol or a
physiologically acceptable salt thereof, e.g. the hloride. Preferably, the tablet
36 GRA3573—WO/JBdg
according to the invention provides a mean absolute bioavailability of of tapentadol at least
22%, more preferably at least 24%. still more preferably at least 26%, yet more preferably at
least 28%, most preferably at least 30%. and in particular at least 32%. Tmax of tapentadol is
preferably within the range of 1251120 h, more preferably 1.2511.00 h, still more preferably
1.2510.80 h, yet more preferably .60 h, most preferably 1.2510.40 h, and in particular
1.2510.20 h. t1/2 of tapentadol is ably within the range of 4.0128 h, more preferably
4.012.4 h, still more ably 4.012.0 h. yet more preferably 4.011.6 h, most preferably
4.011.2 h, and in particular 4.010.8 h. ably, when normalized to a dose of 100 mg
tapentadol, Cmax of tapentadol is preferably within the range of 90185 ng/mL, more preferably
90175 ng/mL, still more preferably 90165 ng/mL, yet more preferably 90155 ng/mL, most
preferably 90145 ng/mL, and in ular 90135 ng/mL; and/or AUC of tapentadol is
preferably within the range of 4201400 ng/mL-h, more preferably 4201350 ng/mL-h, still more
preferably 4201300 ng/mL-h, yet more preferably 4201250 ng/mL-h, most preferably
4201200 ng/mL-h, and in particular 4201150 ng/mL-h.
In another preferred embodiment, the pharmacologically active compound is oxymorphone or
a physiologically acceptable salt thereof, 6.9. the hydrochloride. Preferably, the tablet
according to the invention provides a mean absolute ilability of oxymorphone of at
least 1%, more preferably at least 2%, still more preferably at least 4%, yet more preferably
at least 6%, most preferably at least 8%, and in particular at least 10%. Tmax of oxymorphone
is preferably within the range of 0.510.45 h, more preferably 0.510.40 h, still more preferably
0.510.35 h, yet more preferably 0.510.30 h, most preferably 0.510.25 h, and in particular
0.510.20 h. t1,2 of oxymorphone is preferably within the range of 9518.0 h, more preferably
0 h, still more preferably 9.516.0 h, yet more preferably 9.515.0 h, most preferably
9.514.0 h, and in ular 9.513.0 h. Preferably, when ized to a dose of 20 mg
oxymorphone, Cmax of oxymorphone is preferably within the range of 4.4135 ng/mL, more
preferably 4.413.0 ng/mL, still more preferably 4.412.5 ng/mL, yet more preferably 4.412.0
ng/mL, most preferably 4.411.5 ng/mL, and in particular 4.411.0 ng/mL; and/or AUC of
oxymorphone is preferably within the range of 20.0115.0 ng/mL-h, more preferably 20.0112.5
ng/mL-h, still more preferably 20.0110.0 ng/mL-h, yet more preferably .5 ng/mL-h,
most preferably 20016.0 ng/mL-h, and in ular 0 ng/mL-h.
In another preferred embodiment, the pharmacologically active compound is oxycodone or a
physiologically able salt f, 6.9. the hydrochloride. Preferably, the tablet
according to the invention provides a mean absolute bioavailability of oxycodone of at least
40%, more ably at least 45%, still more preferably at least 50%, yet more ably at
least 55%, most preferably at least 60%, and in ular at least 70%. Tmax of oxycodone is
37 GRA3573~WOIJBdg
preferably within the range of 2.6125 h, more preferably 2.6120 h, still more preferably
2611.8 h, yet more preferably 2610.1.6 h, most preferably 2611.4 h, and in particular
h. t1,2 of oxycodone is preferably within the range of 3.8135 h, more preferably
3813.0 h, still more preferably 3.8125 h, yet more preferably 3.8120 h, most preferably
3.8115 h, and in particular 3811.0 h. Preferably, when normalized to a dose of 30 mg
oxycodone, Cmax of oxycodone is preferably within the range of 40135 ng/mL, more
preferably 40130 ng/mL, still more preferably 40125 ng/mL, yet more ably 40120
ng/mL, most preferably 40115 ng/mL, and in particular 40110 ng/mL; and/or AUC of
oxycodone is ably within the range of 2701250 ng/mL-h, more preferably 2701200
ng/mL-h, still more preferably 2701150 ng/mL-h, yet more preferably 2701100 ng/mL-h, most
preferably 270175 ng/mL-h, and in particular 270150 ng/mL-h.
In still another preferred embodiment, the pharmacologically active compound is morphine or
a physiologically acceptable salt thereof, e.g. the sulfate. Preferably, the tablet according to
the invention provides a mean absolute bioavailability of morphine of at least 15%, more
preferably at least 20%, still more preferably at least 25%, yet more preferably at least 30%,
most ably at least 35%, and in particular at least 40%. Tmx of morphine is ably
within the range of 06251060 h, more preferably 062510.50 h, still more preferably
062510.40 h, yet more preferably .30 h, most preferably 062510.20 h, and in
particular 062510.15 h. ably, when normalized to a dose of 30 mg morphine sulfate,
Cmax of morphine is preferably within the range of 25120 ng/mL, more preferably 25115
ng/mL, still more preferably 25110 ng/mL, yet more preferably 2515 ng/mL; and/or AUC of
morphine is preferably within the range of 50145 ng/mL-h, more preferably 50140 ng/mL-h,
still more preferably 50135 ng/mL-h, yet more preferably 50130 ng/mL-h, most preferably
50125 ng/mL-h, and in particular 50120 ng/mL-h.
The tablets according to the invention may also comprise one or more additional
cologically active compounds. The additional cologically active compound
may be susceptible to abuse or another pharmaceutical. Additional pharmacologically active
nds may be present within the coated particulates agranular") or within the
matrix (e.g. "extragranular", or when the matrix material is also provided in form of
particulates, also "intragranular"). Where an additional pharmacologically active compound is
present intragranularly, it may be present either in combination with one or more
cologically active compounds within the same particulates or in a discrete population
of particulates alone and separate from any other pharmacologically active compounds
present in the tablet.
38 GRA3573-WO/JBdg
In a preferred embodiment, the tablet according to the invention, preferably the coated
particulates se an opioid (agonist) as well as an opioid nist.
Any conventional opioid antagonist may be present, e.g. naltrexone or naloxone or their
pharmaceutically acceptable salts. ne, including its salts, is particularly red. The
opioid antagonist may be present within the coated particulates or within the matrix.
Alternatively, opioid antagonist may be provided in separate particulates to the
pharmacologically active compounds. The preferred composition of such particulates is the
same as that described for cologically active compound-containing particulates.
The ratio of opioid agonist to opioid antagonist in the s according to the invention is
preferably 1 :1 to 3:1 by weight, for example, about 2:1 by weight.
In another preferred embodiment, neither the coated particulates nor the tablet comprise any
opioid antagonist.
The coated particulates according to the invention contain a physiologically acceptable
polymer, preferably a polyalkylene oxide.
Preferably, the physiologically acceptable polymer is selected from the group consisting of
polyalkylene oxide, preferably thylene oxide, polyethylene oxide, polypropylene oxide;
polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyvinyl-
pyrrolidone, poly(alk)acry|ate, ydroxy fatty acids), such as for example poly(3-hydroxybutyrate
—cohydroxyvalerate) (Biopo|®), ydroxyvaleric acid); polycaprolactone,
polyvinyl alcohol, polyesteramide, polyethylene succinate, ctone, polyglycolide,
polyurethane, polyamide, polylactide, polyacetal (for example polysaccharides ally with
modified side chains), polylactide/glycolide, polylactone, polyglycolide, polyorthoester,
polyanhydride, block rs of polyethylene glycol and polybutylene terephthalate
(Polyactive®), polyanhydride (Polifeprosan), copolymers thereof, copolymers thereof
(e.g., Poloxamer®), and mixtures of at least two of the stated rs, or other polymers
with the above characteristics. Polyalkylene oxide is particularly preferred.
Preferably, the physiologically acceptable polymer is a polyalkylene oxide, more preferably
selected from polymethylene oxide, polyethylene oxide and polypropylene oxide, or
copolymers thereof. Polyethylene oxide is preferred.
39 GRA3573-WO/JBdg
In a preferred embodiment, the physiologically acceptable polymer, preferably. the
polyalkylene oxide has a weight average molecular weight (MW) or viscosity average
molecular weight (Mn) of at least 0 or at least 500,000 g/mol, preferably at least
1,000,000 g/mol or at least 2,500,000 g/mol, more preferably in the range of about 000
g/mol to about 15,000,000 g/mol, and most preferably in the range of about 5,000,000 g/mol
to about 10,000,000 g/mol. Suitable s to determine Mw and Mn are known to a person
skilled in the art. Mn is preferably determined by rheological measurements, whereas MW can
be determined by gel permeation chromatography (GPC).
The physiologically acceptable polymer, preferably the polyalkylene oxide may comprise a
single polymer having a particular average molecular weight, or a mixture ) of different
polymers, such as two, three, four or five polymers, e.g., polymers of the same chemical
nature but ent average molecular weight, polymers of different chemical nature but
same average molecular weight, or polymers of different al nature as well as different
molecular weight.
For the purpose of specification, a polyalkylene glycol has a molecular weight of up to 20,000
g/mol whereas a polyalkylene oxide has a molecular weight of more than 20,000 g/mol. In a
preferred embodiment, the weight average over all molecular weights of all polyalkylene
oxides that are contained in the tablet is at least 200,000 g/mol. Thus, polyalkylene glycols, if
any, are preferably not taken into consideration when determining the weight average
molecular weight of kylene oxide.
In a preferred embodiment, the physiologically acceptable r, preferably the
polyalkylene oxide is homogeneously distributed in the coated particulates according to the
invention. Preferably, the pharmacologically active compound and the physiologically
acceptable polymer, preferably the polyalkylene oxide are tely homogeneously
distributed in the coated particulates so that the coated particulates do not contain any
segments where either pharmacologically active compound is present in the absence of
physiologically acceptable polymer, preferably kylene oxide or where physiologically
acceptable polymer, preferably polyalkylene oxide is t in the absence of
pharmacologically active compound.
The particulates are film coated and the physiologically acceptable polymer, preferably the
polyalkylene oxide is preferably homogeneously distributed in the core of the coated
particulates, i.e. the film coating ably does not contain logically acceptable
r, preferably polyalkylene oxide. Nonetheless, the film coating as such may of course
40 GRA3573-WO/JBdg
contain one or more polymers, which however, preferably differ from the physiologically
acceptable polymer, preferably the polyalkylene oxide contained in the core.
The physiologically acceptable polymer, preferably the polyalkylene oxide may be combined
with one or more different rs selected from the group consisting of kylene oxide,
ably polymethylene oxide, polyethylene oxide, polypropylene oxide; hylene,
polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyvinylpyrrolidone,
poly(alk)acrylate, poly(hydroxy fatty acids), such as for example po|y(3-hydroxybutyrate-co
hydroxyvalerate) (Biopol®), poly(hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol,
polyesteramide, polyethylene succinate, ctone, ycolide, polyurethane, polyamide,
polylactide, polyacetal (for example polysaccharides optionally with d side chains),
polylactide/glycolide, polylactone, polyglycolide, polyorthoester, polyanhydride, block
polymers of hylene glycol and polybutylene thalate (Polyactive®), polyanhydride
(Polifeprosan), copolymers thereof, block-copolymers thereof (e.g., Poloxamer®), and
mixtures of at least two of the stated polymers, or other polymers with the above
characteristics.
Preferably, the molecular weight dispersity MWJMn of the physiologically acceptable polymer,
preferably the polyalkylene oxide is within the range of 25120, more preferably 2511.5, still
more preferably 2511.0, yet more preferably 2510.8, most preferably 2510.6, and in
particular 2510.4.
The physiologically acceptable polymer, preferably the polyalkylene oxide preferably has a
viscosity at 25°C of 30 to 17,600 cP, more preferably 55 to 17,600 cP, still more preferably
600 to 17,600 cP and most preferably 4,500 to 17,600 cP, measured in a 5 wt.-% aqueous
solution using a model RVF Brookfield imeter (spindle no. 2 / rotational speed 2 rpm);
of 400 to 4,000 cP, more preferably 400 to 800 GP or 2,000 to 4,000 cP, ed on a 2
wt.-% aqueous solution using the stated viscosimeter (spindle no. 1 or 3 / rotational speed 10
rpm); or of 1,650 to 10,000 cP, more preferably 1,650 to 5,500 cP, 5,500 to 7,500 cP or
7,500 to 10,000 cP, measured on a 1 wt.-% aqueous solution using the stated viscosimeter
le no. 2 / rotational speed 2 rpm).
hylene oxide that is suitable for use in the tablets according to the invention is
commercially available from Dow. For example, Polyox WSR N-12K, Polyox N-60K, Polyox
WSR 301 NF or Polyox WSR 303NF may be used in the tablets according to the invention.
For details concerning the properties of these products, it can be referred to e.g. the product
specification.
41 GRA3573-WO/JBdg
Preferably, the content of the physiologically acceptable polymer, ably the polyalkylene
oxide is within the range of from 1 to 60 wt.-%, more preferably 3 to 55 wt.—%, still more
preferably 5 to 50 wt.—%, yet more preferably 7 to 45 wt.-%, most preferably 10 to 40 wt.—%
and in particular 15 to 35 wt.-%, based on the total weight of the tablet. In a preferred
embodiment, the content of the physiologically acceptable polymer, preferably the
polyalkylene oxide is at least 2 wt.-%. more preferably at least 5 wt.-%, still more preferably
at least 10 wt.-%, yet more preferably at least 15 wt.-% and in particular at least 20 wt.-%,
based on the total weight of the tablet.
In a preferred ment, the overall content of logically acceptable polymer,
preferably polyalkylene oxide is within the range of 10:8 wt.-%, more preferably 10:6 o,
most preferably 10:4 wt.-%, and in particular 10:2 wt.—%, based on the total weight of the
tablet. In another preferred embodiment, the overall content of physiologically acceptable
polymer, preferably kylene oxide is within the range of 15:12 wt.-%, more preferably
:10 wt.—°/o, most ably 15:7 wt.-%, and in ular 15:3 wt.-%, based on the total
weight of the tablet. In still another preferred embodiment, the overall content of
physiologically acceptable polymer, preferably polyalkylene oxide is within the range of
:16 wt.-%, more ably 20:12 wt.-°/o, most preferably 20:8 wt.-%, and in particular
:4 wt.-%, based on the total weight of the tablet. In yet another preferred embodiment, the
overall content of physiologically acceptable polymer, preferably polyalkylene oxide is within
the range of 25:20 wt.-%, more preferably 25:15 wt.-%, most preferably 25:10 wt.-%, and in
particular 25:5 wt.-%, based on the total weight of the tablet. In a further preferred
embodiment, the overall t of physiologically acceptable polymer, preferably
polyalkylene oxide is within the range of 30:20 wt.-°/o, more preferably 30:15 wt.-%, most
preferably 30:10 wt.-%, and in particular 30:5 wt.-%, based on the total weight of the tablet.
In still a r a preferred embodiment, the l content of physiologically acceptable
r, preferably polyalkylene oxide is within the range of 35:20 wt.-%, more preferably
:15 wt.-%, most preferably 35:10 wt.-%, and in particular 35:5 wt.-%. In a still further a
preferred embodiment, the overall content of physiologically acceptable polymer, preferably
polyalkylene oxide is within the range of 40:20 wt.-%, more preferably 40:15 wt.-%, and
most preferably 40:10 wt.-%, and in particular 40:5 wt.-%. based on the total weight of the
tablet.
Preferably. the content of the physiologically acceptable polymer, ably the polyalkylene
oxide is within the range of from 1 to 99 wt.-%, more preferably 5 to 95 wt.-%, still more
preferably 10 to 90 wt.-%, yet more preferably 15 to 85 wt.-%, most preferably 20 to 80 wt.-%
42 GRA3573-WO/JBdg
and in particular 25 to 75 wt.-%, based on the total weight of the coated particulates. In a
preferred embodiment, the content of the physiologically able polymer, preferably the
polyalkylene oxide is at least 10 wt.-%, more ably at least 15 wt.-%, still more
preferably at least 20 wt.-%, yet more preferably at least 25 wt.-% and in particular at least
wt.—%. based on the total weight of the coated ulates.
In a preferred embodiment, the overall content of physiologically acceptable polymer,
preferably polyalkylene oxide is within the range of 30:20 wt.-%, more preferably 30:15 wt.-
%, most preferably 30:10 wt.-%, and in particular 30:5 wt.—%, based on the total weight of
the coated ulates. In another preferred embodiment, the overall content of
physiologically acceptable r, preferably polyalkylene oxide is within the range of
:20 wt.—%, more preferably 35:15 wt.-%, most preferably 35:10 wt.-%, and in particular
:5 wt.-%, based on the total weight of the coated particulates. In still another preferred
embodiment, the overall content of physiologically acceptable polymer, preferably
polyalkylene oxide is within the range of 40:20 wt.-%, more preferably 40:15 wt.-%, most
preferably 40:10 wt.—%, and in particular 40:5 wt.-%, based on the total weight of the coated
particulates. In yet another preferred ment, the overall content of physiologically
acceptable polymer, preferably kylene oxide is within the range of 45:20 wt.-%, more
preferably 45:15 wt.-%, most preferably 45:10 wt.-%, and in particular 45:5 wt.-%, based on
the total weight of the coated particulates. In a further preferred ment, the overall
content of physiologically acceptable polymer, preferably polyalkylene oxide is within the
range of 50:20 wt.-%, more preferably 50:15 wt.-%, most preferably 50:10 wt.-%, and in
particular 50:5 wt.-%, based on the total weight of the coated particulates. In still a further a
preferred embodiment, the overall content of physiologically acceptable polymer, preferably
polyalkylene oxide is within the range of 55:20 wt.—%, more preferably 55:15 wt.-%, most
preferably 55:10 wt.-%, and in particular 55:5 wt.-%. In a still further a preferred
embodiment, the overall content of physiologically acceptable polymer, preferably
polyalkylene oxide is within the range of 60:15 wt.-%, more preferably 60:10 wt.-%, most
preferably 60:5 wt.-%, and in particular 60:5 wt.-%, based on the total weight of the coated
ulates.
Preferably, the relative weight ratio of the physiologically acceptable r, preferably the
polyalkylene oxide to the pharmacologically active nd is within the range of 1 :
1.00:0.75, more ably 1 : 1.00:0.50, still more preferably 1 : 1.00:0.40, yet more
preferably 1 : 1.00:0.30, most preferably 1 : 1.00:0.20, and in particular 1 : 1.00:0.10.
43 GRA3573-WO/JBdg
The coated particulates according to the invention may contain additional pharmaceutical
excipients conventionally ned in tablets in conventional amounts, such as antioxidants.
vatives, lubricants, plasticizer, fillers, binders, and the like.
The skilled person will readily be able to determine riate further excipients as well as
the quantities of each of these excipients. Specific examples of pharmaceutically acceptable
carriers and excipients that may be used to formulate the tablets according to the invention
are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical
Association (1986).
In a preferred ment, the coated particulates do not n a disintegrant.
Preferably, the coated particulates further comprise an antioxidant. Suitable antioxidants
include ic acid, butylated yanisole (BHA), butylated hydroxytoluene (BHT), salts
of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and the
derivatives thereof, coniferyl benzoate, nordihydroguajaretic acid, gallus acid esters, sodium
te, particularly ably butylhydroxy‘toluene or butylhydroxyanisole and d-tocopherol.
The antioxidant is preferably present in quantities of 0.01 wt.-% to 10 wt.-%, more preferably
of 0.03 wt.-% to 5 wt.-%, most preferably of 0.05 wt.-% to 2.5 wt.-%, based on the total
weight of the coated particulates.
In a preferred embodiment, the coated particulates further comprise an acid, ably citric
acid. The amount of acid is preferably in the range of 0.01 wt.-% to about 20 wt.-%, more
preferably in the range of 0.02 wt.-% to about 10 wt.-%, and still more preferably in the range
of 0.05 wt.-% to about 5 wt.-%, and most preferably in the range of 0.1 wt.-% to about 1.0
wt.-%, based on the total weight of the coated particulates.
In a preferred embodiment, the coated particulates further comprise another polymer which
is preferably selected from cellulose esters and ose ethers, in particular hydroxypropyl
methylcellulose (HPMC).
Other preferred polymers are polyvinyl caprolactam-polyvinyl e-polyethylene glycol
graft co-polymers, such as the one commercially available under the trade name Soluplus®.
The amount of the r polymer, preferably hydroxypropyl methylcellulose, preferably
ranges from 0.1 wt.-% to about 30 wt.-%, more preferably in the range of 1.0 wt.-% to about
44 GRA3573-WO/JBdg
wt.-%, most preferably in the range of 2.0 wt.-% to about 15 wt.-%, and in particular in the
range of 3.5 wt.-% to about 10.5 wt.-%, based on the total weight of the coated particulates.
In a preferred embodiment, the relative weight ratio of the physiologically able
polymer, preferably the polyalkylene oxide to the further polymer is within the range of 4.5:2 :
1, more preferably 45:1.5 : 1, still more preferably 4.5:1 : 1, yet more preferably 45:0.5 : 1,
most preferably 45:0.2 : 1, and in particular 45:0.1 : 1. In another preferred embodiment,
the relative weight ratio of the physiologically acceptable polymer, ably the polyalkylene
oxide to the further polymer is within the range of 8:7 : 1, more ably 8:6 2 1, still more
preferably 8:5 : 1, yet more preferably 8:4 : 1, most preferably 8:3 : 1, and in particular 8:2 :
1. In still r preferred embodiment, the relative weight ratio of the physiologically
acceptable polymer, ably the polyalkylene oxide to the further polymer is within the
range of 11:8 : 1, more preferably 11:7 : 1, still more ably 11:6 : 1, yet more
preferably 11:5 : 1, most preferably 11:4 : 1, and in particular 11:3 : 1.
In another preferred ment, the coated particulates ing to the invention do not
contain any further polymer besides the physiologically acceptable polymer, preferably the
polyalkylene oxide and optionally, polyethylene glycol.
In a preferred embodiment, the coated particulates contain at least one lubricant. In another
red embodiment, the coated particulates contain no lubricant. Especially preferred
lubricants are selected from
- magnesium stearate and stearic acid;
- glycerides of fatty acids, including monoglycerides, diglycerides, triglycerides, and
mixtures thereof; preferably of C5 to C22 fatty acids; especially red are partial
glycerides of the C15 to C22 fatty acids such as ol behenat, glycerol palmitostearate
and glycerol monostearate;
- polyoxyethylene glycerol fatty acid esters, such as mixtures of mono-, di~ and ers of
glycerol and di- and monoesters of macrogols having molecular weights within the range
of from 200 to 4000 g/mol, e.g., macrogolglycerolcaprylocaprate, macrogolglycerollaurate,
macrogolglycerolococoate, macrogolglycerollinoleate, macrogolgcherolmonostearate,
macrogol-6—gcherolcaprylocaprate, olglycerololeate; macrogolgcherolstearate,
macrogolglycerolhydroxystearate, and macrogolglycerolrizinoleate;
- polyglycolyzed glycerides, such as the one known and commercially available under the
trade name "Labrasol";
45 GRA3573-WO/JBdg
- fatty ls that may be linear or branched, such as cetylalcohol, stearylalcohol,
cetylstearyl alcohol, ldodecane-1—ol and 2-hexyldecaneol;
- polyethylene glycols having a molecular weight n 10.000 and 60.000 g/mol; and
- natural semi-synthetic or tic waxes, preferably waxes with a softening point of at
least 50 °C, more preferably 60 °C, and in ular carnauba wax and bees wax.
ably, the amount of the lubricant ranges from 0.01 wt.-% to about 10 wt.-%, more
preferably in the range of 0.05 wt.-% to about 7.5 wt.-%, most preferably in the range of 0.1
wt.-% to about 5 wt.-%, and in particular in the range of 0.1 wt.-% to about 1 wt.-%, based on
the total weight of the coated particulates.
Preferably, the coated particulates further comprise a plasticizer. The plasticizer improves
the processability of the physiologically acceptable polymer, preferably the kylene
oxide. A preferred plasticizer is polyalkylene glycol, like polyethylene glycol, triacetin, fatty
acids, fatty acid esters, waxes and/or microcrystalline waxes. Particularly preferred
plasticizers are polyethylene glycols, such as PEG 6000.
Preferably, the content of the plasticizer is within the range of from 0.5 to 30 wt.-%, more
preferably 1.0 to 25 wt.-%, still more preferably 2.5 wt.-% to 22.5 wt.-%, yet more preferably
.0 wt.-% to 20 wt.-%, most preferably 6 to 20 wt.—% and in particular 7 wt.-% to 17.5 wt.-%,
based on the total weight of the coated particulates.
In a preferred embodiment, the plasticizer is a polyalkylene glycol having a content within the
range of 7:6 wt.-%, more preferably 7:5 wt.-%, still more preferably 7:4 wt.-%, yet more
preferably 7:3 wt.-%, most preferably 7:2 wt.-%, and in particular 7:1 wt.-%, based on the
total weight of the coated particulates.
In another preferred embodiment, the plasticizer is a polyalkylene glycol having a content
within the range of 10:8 wt.-%, more preferably 10:6 wt.-%, still more preferably 10:5 wt.-%,
yet more preferably 10:4 wt.-%, most preferably 10:3 wt.—%, and in particular 10:2 wt.-%,
based on the total weight of the coated particulates.
In a red embodiment, the relative weight ratio of the physiologically acceptable
polymer, preferably the polyalkylene oxide to the polyalkylene glycol is within the range of
.4:2 : 1, more preferably 5.4:1.5 : 1, still more preferably 5.4:1 : 1, yet more preferably
.4:0.5 : 1, most preferably 5.4:0.2 : 1, and in particular 5.4:0.1 : 1. This ratio es the
requirements of relative high polymer content and good extrudability.
46 GRA3573-WO/JBdg
Plasticizers can sometimes act as a lubricant, and lubricants can sometimes act as a
plasticizer.
The coated particulates and the matrix material of the tablets according to the invention
preferably do not contain any polymers selected from the group consisting of
o acrylates (such as acrylic and methacrylic polymers including c acid and methacrylic
acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl
methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide
copolymer, poly(methyl rylate), polymethacrylate, poly(methyl methacrylate)
copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid
anhydride), and glycidyl methacrylate copolymers; e.g., Eudragit® NE, NM, R8 or RL).
- alkylcelluloses and hydroxy alkyl celluloses (such as methylcellulose, ellulose,
y propyl cellulose and hydroxylpropyl methylcellulose); and
- g agents which hydrate to form gels to l the movement of water, such as high
molecular weight grade (high viscosity) hydroxypropylmethyl cellulose (HPMC), pectin,
locust bean gum and xanthan gum.
In a red embodiment, the tablet according to the invention ns no substances
which irritate the nasal passages and/or x, i.e. substances which, when administered
via the nasal es and/or pharynx, bring about a physical reaction which is either so
unpleasant for the patient that he/she does not wish to or cannot ue administration, for
example burning, or physiologically racts taking of the corresponding active
compound, for example due to increased nasal secretion or sneezing. Further examples of
substances which irritate the nasal passages and/or pharynx are those which cause burning,
itching, urge to sneeze. increased formation of secretions or a combination of at least two of
these stimuli. Corresponding substances and the quantities thereof which are conventionally
to be used are known to the person d in the art. Some of the substances which irritate
the nasal passages and/or pharynx are ingly based on one or more constituents or
one or more plant parts of a hot substance drug. Corresponding hot substance drugs are
known per se to the person skilled in the art and are described, for example, in
"Pharmazeutische Biologie - Drogen und ihre lnhaltsstoffe" by Prof. Dr. Hildebert Wagner,
2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq..
The corresponding description is hereby introduced as a reference and is deemed to be part
of the disclosure.
47 GRA3573-WO/JBdg
The tablet according to the invention furthermore preferably contains no antagonists for the
pharmacologically active compound, preferably no antagonists against tropic
substances, in particular no antagonists against opioids. Antagonists suitable for a given
cologically active compound are known to the person skilled in the art and may be
present as such or in the form of corresponding derivatives, in particular esters or , or
in each case in the form of corresponding physiologically acceptable compounds, in
particular in the form of the salts or solvates thereof. The tablet according to the invention
preferably contains no antagonists selected from among the group sing naloxone,
naltrexone, nalmefene, nalide, nalmexone, nalorphine or naluphine, in each case optionally
in the form of a corresponding physiologically acceptable compound, in particular in the form
of a base, a salt or solvate; and no neuroleptics, for example a compound selected from
among the group comprising haloperidol, promethacine, fluphenazine, perphenazine,
levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopenthixol,
flupentixol, prothipendyl, zotepine, idol, pipamperone, melperone and bromperidol.
The tablet according to the invention furthermore preferably contains no emetic. Emetics are
known to the person skilled in the art and may be present as such or in the form of
corresponding derivatives, in particular esters or ethers, or in each case in the form of
corresponding physiologically acceptable compounds, in particular in the form of the salts or
solvates thereof. The tablet according to the invention preferably contains no emetic based
on one or more constituents of ipecacuanha (ipecac) root, for example based on the
tuent emetine, as are, for example, bed in "Pharmazeutische Biologie - Drogen
und ihre sstoffe" by Prof. Dr. ert Wagner, 2nd, revised edition, Gustav r
Verlag, Stuttgart, New York, 1982. The corresponding literature ption is hereby
introduced as a reference and is deemed to be part of the disclosure. The tablet according to
the invention ably also contains no apomorphine as an emetic.
Finally, the tablet according to the invention preferably also contains no bitter substance.
Bitter substances and the quantities effective for use may be found in US-2003/0064099 A1,
the corresponding disclosure of which should be deemed to be the disclosure of the present
application and is hereby introduced as a reference. Examples of bitter substances are
ic oils, such as peppermint oil, ptus oil, bitter almond oil, menthol, fruit aroma
substances, aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof,
and/or denatonium benzoate.
48 GRA3573-WO/JBdg
The tablet according to the invention accordingly preferably contains neither substances
which irritate the nasal es and/or pharynx, nor antagonists for the pharmacologically
active nd, nor emetics, nor bitter substances.
Particularly preferred contents of pharmacologically active compound, physiologically
acceptable polymer, preferably polyalkylene oxide, plasticizer and antioxidant of the coated
particulates, ve to the total weight of the coated ulates, are summarized as
embodiments B1 to 86 in the table here below:
Wt.-%
wherein the pharmacologically active compound is preferably an opioid, particularly
preferably tapentadol or a physiologically acceptable salt thereof; the polymer is preferably a
polyalkylene oxide, more preferably a polyethylene oxide having a weight average molecular
weight of at least 500,000 g/mol; the cizer preferably is a poylethylene glycol; and the
antioxidant preferably is a-tocopherol.
Besides the coated particulates and the preferably pre-compacted or granulated matrix
material, the tablet according to the invention may se one or more pharmaceutical
excipients such as binders, fillers, lubricants and the like.
In a preferred embodiment, the table additionally comprises a lubricant. Magnesium stearate
is preferred. Further preferred lubricants are described above and therefore are not repeated
hereinafter.
If the tablet contains an additional lubricant outside the preferably pre-compacted or pre-
granulated matrix material, its content is preferably not more than 1 wt.—%, more preferably
not more than 0.5 wt.-%, based on the total weight of the tablet.
While the coated particulates that are contained in the tablet ing to the invention
ably exhibit increased mechanical strength, the tablet as such preferably has
conventional mechanical ties. Typically, the tablet according to the invention can be
d e.g. by means of a hammer thereby yielding a fractured composition containing the
matrix material. the coated particulates and any other ients contained in the tablet.
49 GRA3573-WO/JBdg
However, the coated particulates thereby ed in more or less isolated form preferably
cannot be further crushed and fractured by means of a hammer.
Preferably, the coated particulates are hot melt-extruded and/or have a breaking strength of
at least 300 N.
The tablet according to the invention is -resistant. Preferably, tamper-resistance is
achieved based on the mechanical properties of the coated particulates so that comminution
is avoided or at least substantially impeded. According to the invention, the term
comminution means the pulverization of the coated particulates using conventional means
usually available to an abuser, for example a pestle and mortar, a hammer, a mallet or other
conventional means for pulverizing under the action of force. Thus, tamper-resistance
preferably means that pulverization of the coated particulates using conventional means is
avoided or at least substantially impeded.
Preferably, the mechanical ties of the coated particulates according to the invention,
particularly their breaking strength and deformability, substantially rely on the presence and
spatial distribution of logically able polymer, preferably polyalkylene oxide,
gh their mere presence does typically not suffice in order to achieve said properties.
The ageous mechanical properties of the coated particulates according to the
invention may not automatically be achieved by simply processing pharmacologically active
compound, physiologically able polymer, preferably polyalkylene oxide, and optionally
further excipients by means of conventional methods for the preparation of tablets. In fact,
usually suitable apparatuses must be selected for the preparation and al processing
parameters must be adjusted, particularly pressure/force, temperature and time. Thus, even
if tional apparatuses are used, the process protocols usually must be adapted in order
to meet the ed criteria.
In general, the coated particulates exhibiting the desired properties may be obtained only if.
during preparation of the particulates,
- suitable components
- in suitable amounts
are exposed to
- a sufficient pressure
- at a ient ature
- for a sufficient period of time.
regarded as being broken if the force decreases by 50% (threshold value) of the highest force
measured during the measurement (see .
AH26(8067809_1):RTK
51 GRA3573-WO/JBdg
The coated particulates ing to the invention are distinguished from conventional
ulates that can be contained in tablets in that, due to their breaking strength, they
cannot be pulverized by the application of force with conventional means, such as for
example a pestle and mortar, a hammer, a mallet or other usual means for pulverization, in
ular devices developed for this purpose (tablet crushers). in this regard "pulverization"
means crumbling into small particles. Avoidance of pulverization virtually rules out oral or
parenteral, in particular intravenous or nasal abuse.
Conventional particulates typically have a breaking th well below 200 N.
The breaking strength of conventional round tablets/particulates may be estimated ing
to the following empirical a: Breaking Strength [in N] = 10 x Diameter Of The
Tablet/Particulate [in mm]. Thus, according to said empirical formula, a round
tablet/particulate having a breaking strength of at least 300 N would require a diameter of at
least 30 mm). Such a particulate, however, could not be swallowed, let alone a tablet
ning a plurality of such particulates. The above empirical formula preferably does not
apply to the coated particulates according to the invention, which are not conventional but
rather special.
Further, the actual mean chewing force is about 220 N (cf., e.g., P.A. Proeschel et al., J Dent
Res, 2002, 81(7), 464—468). This means that tional particulates having a breaking
strength well below 200 N may be crushed upon spontaneous chewing, whereas the coated
particulates ing to the invention may preferably not.
Still further, when applying a ational acceleration of about 9.81 m/sz, 300 N correspond
to a gravitational force of more than 30 kg, i.e. the coated ulates according to the
invention can preferably withstand a weight of more than 30 kg without being pulverized.
Methods for measuring the breaking strength of a tablet are known to the skilled artisan.
Suitable devices are commercially available.
For example, the breaking strength (resistance to ng) can be measured in accordance
with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08 "Resistance to ng of Tablets". The test is
intended to determine, under defined conditions, the resistance to crushing of tablets and
particulates, respectively, measured by the force needed to disrupt them by crushing. The
apparatus consists of 2 jaws facing each other, one of which moves towards the other. The
flat surfaces of the jaws are perpendicular to the direction of movement. The crushing
52 GRA3573-WO/JBdg
surfaces of the jaws are flat and larger than the zone of contact with the tablet and
particulate, respectively. The apparatus is calibrated using a system with a precision of 1
Newton. The tablet and particulate, respectively, is placed n the jaws, taking into
account, where applicable, the shape, the break-mark and the inscription; for each
measurement the tablet and ulate, respectively, is oriented in the same way with
respect to the direction of application of the force (and the direction of ion in which the
breaking strength is to be measured). The measurement is carried out on 10 tablets and
particulates, respectively, taking care that all fragments have been removed before each
determination. The result is expressed as the mean, minimum and maximum values of the
forces measured, all expressed in .
A similar description of the breaking strength (breaking force) can be found in the USP. The
breaking strength can alternatively be ed in accordance with the method described
therein where it is stated that the breaking strength is the force required to cause a tablet and
particulate, respectively, to fail (i.e., break) in a specific plane. The tablets and particulates,
respectively, are generally placed between two platens, one of which moves to apply
sufficient force to the tablet and particulate, respectively, to cause fracture. For conventional,
round (circular cross-section) tablets and particulates, respectively, loading occurs across
their diameter (sometimes referred to as diametral loading), and fracture occurs in the plane.
The ng force of tablets and ulates, respectively, is commonly called hardness in
the ceutical literature; however, the use of this term is misleading. ln al
science, the term hardness refers to the resistance of a surface to penetration or indentation
by a small probe. The term crushing strength is also frequently used to describe the
resistance of tablets and particulate, respectively, to the application of a compressive load.
Although this term describes the true nature of the test more accurately than does hardness,
it implies that tablets and particulate, respectively, are actually crushed during the test, which
is often not the case.
Alternatively, the breaking strength (resistance to crushing) can be measured in accordance
with , which can be regarded as a modification of the method described in
the Eur. Ph. The apparatus used for the measurement is preferably a "Zwick 2 2.5" materials
tester, Fmax = 2.5 kN with a maximum draw of 1150 mm, which should be set up with one
column and one spindle, a nce behind of 100 mm and a test speed adjustable between
0.1 and 800 mm/min together with testControl re. A skilled person knows how to
properly adjust the test speed, e.g. to 10 mm/min, 20 mm/min, or 40 mm/min, for example.
Measurement is med using a pressure piston with screw-in inserts and a er
(diameter 10 mm), a force transducer, Fmax. 1 kN, diameter = 8 mm, class 0.5 from 10 N,
53 GRA3573-WO/JBdg
class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M according to DIN
55350-18 (Zwick gross force Fmax = 1.45 kN) (all apparatus from Zwick GmbH & Co. KG,
Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 for the tester, Order No BTC-LC 0050N.
P01 for the force transducer, Order No BO 70000 806 for the ng device.
When using the testControl re (testXpert ), the following ified settings
and parameters have revealed to be useful: LE-position: clamping length 150 mm. ed:
500 mm/min, clamping length after pre-travel: 195 mm, pre-travel speed: 500 mm/min, no
pre-force l — pre-force: pre-force 1N, pre-force speed 10 mm/min — sample data: no
sample form, measuring length traverse distance 10 mm, no input required prior to testing —
testing / end of test; test speed: position-controlled 10 mm/min, delay speed shift: 1, force
shut down threshold 50% Fmax, no force threshold for break-tests, no max length variation,
upper force limit: 600N — expansion compensation: no correction of measuring length —
actions after g: LE to be set after test, no unload of sample — TRS: data memory: TRS
distance interval until break 1 pm, TRS time interval 0.15, TRS force interval 1N - machine;
traverse distance controller: upper soft end 358 mm, lower soft end 192 mm — lower test
space. Parallel arrangement of the upper plate and the ambos should be ensured - these
parts must not touch during or after testing. After testing, a small gap (e.g. 0.1 or 0.2 mm)
should still be present between the two brackets in intimated contact with the tested
particulate, representing the remaining thickness of the deformed particulate.
In a red embodiment, the particulate is regarded as being broken if it is fractured into at
least two separate pieces of comparable morphology. Separated matter having a
morphology ent from that of the deformed particulate, e.g. dust, is not considered as
pieces qualifying for the definition of breaking.
The coated particulates according to the ion preferably exhibit mechanical strength
over a wide temperature range, in addition to the breaking strength (resistance to crushing)
optionally also sufficient hardness, yield strength, fatigue strength, impact resistance, impact
elasticity, e strength, compressive strength and/or s of elasticity, optionally also
at low temperatures (e.g. below -24 °C, below -40 °C or possibly even in liquid nitrogen), for
it to be virtually impossible to ize by spontaneous chewing, gn‘nding in a mortar,
pounding, etc. Thus, preferably, the comparatively high breaking strength of the particulate
according to the invention is maintained even at low or very low temperatures, e.g., when the
tablet is initially chilled to increase its brittleness, for example to temperatures below -25°C,
below -40 °C or even in liquid nitrogen.
displacement-diagram when being subjected to a breaking th test as described above.
This mechanical property, i.e. the deformability of the individual particulates, is illustrated in
Figures 5 and 6.
Figure 5 schematically illustrates the measurement and the corresponding force- cementdiagram.
In ular, Figure 5A shows the initial situation at the beginning of the
measurement. The sample particulate (9) is placed between upper jaw (8a) and lower jaw (8b)
which each are in intimate contact with the surface of the particulate (9). The initial
displacement d0 between upper jaw (8a) and lower jaw (8b) corresponds to the
AH26(8067809_1):RTK
extension of the particulate orthogonal to the surfaces of upper jaw (8a) and lower jaw (8b). At
this time, no force is exerted at all and thus, no graph is displayed in the force- displacementdiagram
below. When the measurement is commenced, the upper jaw is moved in direction of
lower jaw (8b), preferably at a constant speed. Figure 5B shows a situation where due to the
movement of upper jaw (8a) towards lower jaw (8b) a force is exerted on particulate (9).
Because of its deformability, the particulate (9) is flattened without being fractured. The isplacement-diagram
indicates that after a reduction of the displacement d0 of upper jaw (8a)
and lower jaw (8b) by ce x1, i.e. at a displacement of d1 = d0 - x1, a force F1 is measured.
Figure 5C shows a situation where due to the continuous movement of upper jaw (8a) towards
lower jaw (8b), the force that is exerted on particulate (9) causes r deformation, gh
the particulate (9) does not fracture. The force- displacement-diagram indicates that after a
reduction of the cement d0 of upper jaw (8a) and lower jaw (8b) by ce x2, i.e. at a
displacement of d2 = d0 - x2, a force F2 is measured. Under these circumstances, the ulate
(9) has not been broken (fractured) and a substantially steady increase of the force in the forcedisplacement-diagram
is measured.
In contrast, Figure 6 tically illustrates the measurement and the corresponding forcedisplacement-diagram
of a conventional comparative particulate not having the degree of
deformability as the particulates according to the invention. Figure 6A shows the initial
ion at the beginning of the measurement. The comparative sample particulate (9) is placed
between upper jaw (8a) and lower jaw (8b) which each are in intimate contact with the surface
of the comparative particulate (9). The initial displacement d0 between upper jaw (8a) and
lower jaw (8b) corresponds to the extension of the ative particulate orthogonal to the
surfaces of upper jaw (8a) and lower jaw (8b). At this time, no force is exerted at all and thus,
no graph is displayed in the force- displacement-diagram below. When the measurement is
commenced, the upper jaw is moved in ion of lower jaw (8b), preferably at a constant
speed. Figure 6B shows a situation where due to the movement of upper jaw (8a) towards lower
jaw (8b) a force is exerted on comparative particulate (9). Because of some deformability, the
comparative ulate (9) is slightly flattened without being red. The forcedisplacement-diagram
indicates that after a reduction of the cement d0 of upper jaw (8a)
and lower jaw (8b) by distance x1, i.e. at a displacement of d1 = d0 - x1, a force F1 is measured.
Figure 6C shows a situation where due to the continuous movement of upper jaw (8a) towards
lower jaw (8b), the force that is exerted on particulate (9) causes sudden fracture of the
comparative particulate (9). The force- displacement-diagram indicates that after a reduction of
the displacement d0 of upper jaw (8a) and lower jaw (8b) by distance x2, i.e. at a displacement of
d2 = d0 - x2, a force F2 is measured that suddenly drops when the particulate fractures. Under
these circumstances, the particulate (9) has been broken (fractured) and no steady increase of the
force in the force- displacement-diagram is measured. The sudden drop (decrease) of the force
can easily be recognized and does not need to be quantified for the measurement. The steady
AH26(8067809_1):RTK
increase in the force- displacement-diagram ends at displacement d2 = d0 - x2 when the
particulate .
In a preferred embodiment, the particulates contained in the tablet according to the invention
have a deformability such that they show an increase, preferably a substantially steady increase
of the force at a corresponding decrease of the displacement in the force- displacement-diagram
when being subjected to a breaking strength test as
displacement-diagram when being ted to a breaking strength test as
AH26(8067809_1):RTK
displacement-diagram when being ted to a breaking strength test as
AH26(8067809_1):RTK
58 GRA3573—WO/JBdg
(i.e. d S 0.15 ' do), at most 10% of the original displacement do (i.e. d S 0.1 - do), or at most
% of the original displacement do (i.e. d S 0.05 - do).
Preferably, the particulates contained in the tablet according to the invention have a
deformability such that they are deformed without being fractured when subjected to a
constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking
strength test as described above k 2 2.5" materials tester, constant force), until the
displacement d of upper jaw (8a) and lower jaw (8b) is reduced so that no further
deformation takes place at said constant force, whereas at this equilibrated state the
displacement d of upper jaw (8a) and lower jaw (8b) is at most 0.80 mm or at most 0.75 mm,
preferably at most 0.70 mm or at most 0.65 mm, more preferably at most 0.60 mm or at most
0.55 mm, still more preferably at most 0.50 mm or at most 0.45 mm, yet more preferably at
most 0.40 mm or at most 0.35 mm, even more preferably at most 0.30 mm or at most 0.25
mm, most preferably at most 0.20 mm or at most 0.15 mm and in ular at most 0.10 or at
most 0.05 mm.
In another ment, the particulates contained in the tablet ing to the invention
have a deformability such that they are ed without being fractured when subjected to
a constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breaking
strength test as described above ("Zwick 2 2.5" materials tester, constant , until the
displacement d of upper jaw (8a) and lower jaw (8b) is reduced so that no further
ation takes place at said constant force, whereas at this equilibrated state the
displacement d of upper jaw (8a) and lower jaw (8b) is at least 5% of the original
displacement do (i.e. d 2 0.05 - do), preferably at least 10% of the original cement do
(i.e. d 2 0.1 - do), more preferably at least 15% of the original displacement do (i.e. d 2 0.15 -
do), still more preferably at least 20% of the original displacement do (i.e. d 2 0.2 - do), yet
more preferably at least 30% of the original cement do (i.e. d 2 0.3 - do), even more
preferably at least 40% of the original displacement do (i.e. d 2 0.4 - do), most preferably at
least 50% of the al displacement do (i.e. d 2 0.5 - do), and in particular at least 60% of
the original displacement do (i.e. d 2 0.6 - do), or at least 70% of the original displacement do
(i.e. d 2 0.7 - do), at least 80% of the original displacement do (i.e. d 2 0.8 - do), or at least
90% of the original displacement do (i.e. d 2 0.9 - do).
Preferably, the particulates contained in the tablet according to the invention have a
deformability such that they are deformed without being fractured when subjected to a
constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a ng
strength test as described above ("Zwick 2 2.5" materials tester, constant force), until the
59 GRA3573-WO/JBdg
displacement d of upper jaw (8a) and lower jaw (8b) is d so that no further
ation takes place at said constant force, whereas at this equilibrated state the
displacement d of upper jaw (8a) and lowerjaw (8b) is at least 0.05 mm or at least 0.10 mm,
preferably at least 0.15 mm or at least 0.20 mm, more preferably at least 0.25 mm or at least
0.30 mm, still more preferably at least 0.35 mm or at least 0.40 mm, yet more preferably at
least 0.45 mm or at least 0.50 mm, even more ably at least 0.55 mm or at least 0.60
mm, most preferably at least 0.65 mm or at least 0.70 mm and in particular at least 0.75 or at
least 0.80 mm.
Preferably, the tablet according to the invention provides under in vitro conditions immediate
release of the pharmacologically active compound in accordance with Ph. Eur.
The term "immediate release" as applied to tablets is understood by persons skilled in the art
which has structural implications for the respective tablets. The term is defined, for example,
in the current issue of the US Pharmacopoeia (USP), l Chapter 1092, "THE
DISSOLUTION PROCEDURE: DEVELOPMENT AND VALIDATION", heading "STUDY
DESIGN", "Time Points". For immediate-release dosage forms, the on of the procedure
is typically 30 to 60 s; in most cases, a single time point specification is adequate for
Pharmacopeia purposes. Industrial and regulatory concepts of product comparability and
performance may require additional time points, which may also be required for product
registration or approval. A sufficient number of time points should be selected to tely
characterize the ascending and plateau phases of the dissolution curve. According to the
Biopharmaceutics Classification System referred to in several FDA ces, highly
e, highly permeable drugs formulated with rapidly dissolving products need not be
ted to a profile comparison if they can be shown to release 85% or more of the active
drug substance within 15 minutes. For these types of products a int test will suffice.
However, most products do not fall into this category. Dissolution profiles of immediate-
release products typically show a gradual increase ng 85% to 100% at about 30 to 45
minutes. Thus, dissolution time points in the range of 15, 20, 30, 45, and 60 minutes are
usual for most immediate-release products.
Preferably, under physiological conditions the tablet according to the invention has released
after 30 minutes at least 70%, more preferably at least 75%, still more preferably at least
80%, yet more preferably at least 82%, most preferably at least 84% and in ular at east
86% of the pharmacologically active compound originally contained in the tablet.
60 GRA3573-WO/JBdg
Preferably, under physiological conditions the tablet according to the invention has released
after 10 minutes at least 70%. more preferably at least 73%, still more preferably at least
76%, yet more preferably at least 78%, most preferably at least 80% and in particular at east
82% of the cologically active compound originally contained in the tablet.
r preferred release profiles C1 to C10 are summarized in the table here below [all data
in wt.-% of released pharmacologically active compound]:
iIiiiEiIEI
mi IV (A)0 IV (A) 01 IV A0 IV A01 IV 010 IV 0')0 IV V0 IV 0)0 IV 0)0 IV 0)O
mi IV 010 IV 01 01 IV 0')0 IV 0') 01 IV V0 IV V 01 IV on0 IV oo01 IV (D0 IV (O 01
mi IV 0101 IV 0')0 IV 0) 01 IV V0 IV V 01 IV on 01 IV (00 IV (001 IV (001 IV (O 01
IV 0)0 IV 0') 01 IV \I0 IV ooC IV on 01 IV (O0 IV (0 0'! IV (0 01 IV (O01 IV (O 01
IV 0) U1 IV \IO IV onO IV oo 01 IV oo (I) IV (DN IV (D U1 IV (DU1 IV (0 01 IV (D 01
IV V 01 IV (I)0 IV O) 01 IV (D0 IV (DN IV (DA IV (O01 IV (001 IV (001 IV (O 01
Preferably, the release , the drug and the pharmaceutical excipients of the tablet
according to the invention are stable upon e, preferably upon e at elevated
temperature, e.g. 40°C, for 3 months in sealed containers.
In connection with the release profile "stable" means that when comparing the initial e
profile with the e profile after storage, at any given time point the release profiles
deviate from one another by not more than 20%, more preferably not more than 15%, still
more preferably not more than 10%, yet more preferably not more than 7.5%, most
preferably not more than 5.0% and in particular not more than 2.5%.
in tion with the drug and the pharmaceutical excipients "stable" means that the tablets
satisfy the requirements of EMEA concerning shelf-life of pharmaceutical products.
Suitable in vitro ions are known to the skilled artisan. In this regard it can be referred
to, e.g., the Eur. Ph. Preferably, the release profile is measured under the following
conditions: Paddle apparatus equipped without sinker, 50 rpm, 3715 °C, 900 mL simulated
intestinal fluid pH 6.8 hate buffer) or pH 4.5. In a preferred embodiment, the rotational
speed of the paddle is increased to 75 rpm.
In a preferred embodiment, the tablet according to the invention is adapted for administration
once daily. In another preferred embodiment, the tablet according to the invention is adapted
for administration twice daily. In still another preferred embodiment, the tablet according to
the invention is adapted for stration thrice daily. In yet another preferred embodiment,
61 3-WO/JBdg
the tablet according to the invention is adapted for stration more frequently than thrice
daily, for example 4 times daily, 5 times daily, 6 times daily, 7 times daily or 8 times daily.
For the purpose of specification, "twice daily" means equal or nearly equal time intervals, i.e.,
about every 12 hours, or different time intervals, e.g., 8 and 16 hours or 10 and 14 hours,
between the individual administrations.
For the purpose of specification, "thrice daily" means equal or nearly equal time intervals, i.e.,
about every 8 hours, or different time intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours,
n the individual administrations.
Preferably, the tablet according to the invention has under in vitro conditions a disintegration
time measured in accordance with Ph. Eur. of at most 5 minutes, more preferably at most 4
minutes, still more ably at most 3 minutes, yet more preferably at most 2.5 minutes,
most preferably at most 2 minutes and in particular at most 1.5 minutes.
It has been surprisingly found that oral dosage forms can be designed that e the best
compromise between tamper-resistance, disintegration time and drug release, drug load,
sability (especially tablettability) and patient compliance.
It has been found that the disintegration time of the tablets according to the invention can be
influenced by the relative weight ratio of matrix material: particulates. In general, it was
observed that the higher this ratio the faster disintegration. However, this ratio cannot be
increased ad ultimo, as further tablet properties need to be taken into account, particularly
drug load and total tablet size and weight. As a certain dosage of pharmacologically active
compound needs to be administered, the content of particulates should still be ently
high and the total tablet weight should not exceed a certain limit, as this would deteriorate
patient compliance, e.g. swallowability.
The situation is more complicated by trends in opposite ion. In particular, it has been
found that the tability of the tablets according to the invention can also be influenced by
the relative weight ratio of matrix material : particulates. In general, it was observed that the
lower this ratio the better the tablettability. This trend parallels the trend of the drug load.
Thus, disintegration time on the one hand and tability/drug load on the other hand can
be optimized by finding the best compromise.
62 GRA3573-WO/JBdg
Similarly, tamper-resistance and drug release also antagonize each other. While smaller
ulates should typically show a faster release of the pharmacologically active compound,
-resistance requires some minimal size of the coated particulates in order to
effectively prevent abuse, e.g. i.v. administration. The larger the coated particulates are the
less they are suitable for being abused nasally. The smaller the coated particulates are the
faster gel formation occurs.
Thus, drug release on the one hand and tamper-resistance on the other hand can be
optimized by finding the best compromise.
Preferred embodiments D1 to D4 of the tablets according to the ion are summarized in
the table here below:
wt.-%, relative to weioht of tablet I_I_I_I_
coated articulates
50i7-5
800i100
23:5
22i6
— content of elasticizer wt.-% 4:2
-contentoffurtherexcioients wt.-% 0.05:0.02
2-0zt1-2
49i6
43i4
5i2-5
0-15i0-12
The coated particulates according to the invention are preferably prepared by melt-extrusion,
although also other methods of thermoforming may be used in order to manufacture the
coated particulates according to the invention such as press-molding at elevated ature
or heating of particulates that were manufactured by conventional ssion in a first step
and then heated above the softening temperature of the logically acceptable polymer,
preferably the polyalkylene oxide in the coated particulates in a second step to form hard
tablets. In this regards, thermoforming means the g, or molding of a mass after the
application of heat. In a preferred embodiment, the coated particulates are therrnoformed by
hot-melt extrusion.
ln a preferred embodiment, the coated particulates are prepared by hot melt-extrusion.
preferably by means of a twin-screw-extruder. Melt extrusion ably provides a melt-
63 GRA3573-WO/JBdg
extruded strand that is preferably cut into monoliths, which are then optionally ssed
and formed into ulates. Preferably, compression is achieved by means of a die and a
punch, preferably from a monolithic mass ed by melt extrusion. If obtained via melt
extrusion, the compressing step is ably carried out with a monolithic mass exhibiting
ambient temperature, that is, a temperature in the range from 20 to 25° C. The strands
obtained by way of extrusion can either be subjected to the compression step as such or can
be out prior to the compression step. This cutting can be performed by usual ques, for
example using rotating knives or compressed air, at elevated temperature, eg. when the
extruded stand is still warm due to hot-melt extrusion, or at ambient temperature, i.e. after
the extruded strand has been allowed to cool down. When the extruded strand is still warm,
singulation of the extruded strand into extruded particulates is preferably performed by
cutting the extruded strand immediately after it has exited the extrusion die. However, when
the extruded strand is cut in the cooled state, subsequent singulation of the extruded strand
into extruded particulates is preferably performed by optionally transporting the still hot
extruded strand by means of or belts, allowing it to cool down and to congeal, and
subsequently cutting it into extruded particulates. Alternatively, the shaping can take place as
described in EP-A 240 906 by the extrudate being passed between two counter-rotating
calender rolls and being shaped directly to ulates. It is of course also possible to
subject the extruded strands to the compression step or to the g step when still warm,
that is more or less immediately after the extrusion step. The extrusion is preferably carried
out by means of a twin-screw extruder.
The coated particulates according to the ion may be produced by different processes,
the particularly preferred of which are explained in greater detail below. Several suitable
processes have already been described in the prior art. In this regard it can be referred to,
e.g., WC 2005/ 016313, , , , WO
2006/002883, WO 02884, WO 2006/002886, WO 2006/082097, and WO
2006/082099.
In general, the process for the production of the coated particulates according to the
ion preferably comprises the following steps:
(a) mixing all ingredients;
(b) optionally pre-forming the mixture obtained from step (a), preferably by applying heat
and/or force to the mixture obtained from step (a), the quantity of heat supplied
preferably not being sufficient to heat the physiologically acceptable r, preferably
the polyalkylene oxide up to its softening point;
64 GRA3573-WO/JBdg
(c) hardening the mixture by applying heat and force, it being possible to supply the heat
during and/or before the application of force and the quantity of heat supplied being
sufficient to heat the physiologically acceptable polymer, preferably the polyalkylene
oxide at least up to its softening point; and thereafter allowing the material to cool and
removing the force
(d) optionally singulating the hardened mixture;
(e) optionally shaping the particulates; and
(f) ing a coating, preferably a film coating.
Heat may be supplied directly, e.g. by t or by means of hot gas such as hot air, or with
the assistance of ultrasound; or is indirectly supplied by friction and/or shear. Force may be
applied and/or the ulates may be shaped for example by direct tabletting or with the
assistance of a suitable extruder, particularly by means of a screw extruder equipped with
one or two screws (single-screw-extruder and twin-screw-extruder, respectively) or by means
of a planetary gear extruder.
The final shape of the particulates may either be provided during the hardening of the
mixture by ng heat and force (step (c)) or in a subsequent step (step (e)). In both
cases, the e of all components is preferably in the plastified state, i.e. preferably,
shaping is performed at a ature at least above the ing point of the
physiologically acceptable polymer, ably the polyalkylene oxide. However, extrusion at
lower atures, e.g. ambient temperature, is also possible and may be preferred.
Shaping can be performed, e.g., by means of a tabletting press comprising die and punches
of appropriate shape.
Suitable methods for providing particulates with a g, preferably with a film coating, are
known to the skilled person such as ed bed coating, pan-coating, coazervation, , dry
powder coating, extrusion coating, and phoqus technology (copy—coating). Preferably, the
particulates are coated by spraying (top-spray or bottom-spray) e.g. in a fluidized bed spray
dry granulator.
A particularly preferred process for the cture of the coated particulates according to
the invention involves hot-melt extrusion. In this process, the coated particulates according to
the invention are produced by thermoforrning with the assistance of an er, preferably
without there being any observable consequent discoloration of the extrudate.
65 GRA3573-WO/JBdg
This process is characterized in that
a) all components are mixed,
b) the resultant mixture is heated in the extruder at least up to the softening point of the
physiologically acceptable polymer, preferably the polyalkylene oxide and extruded
through the outlet orifice of the er by application of force,
c) the still plastic extrudate is singulated and formed into the particulates or
d) the cooled and ally reheated singulated extrudate is formed into the particulates.
Mixing of the components according to process step a) may also proceed in the extruder.
The components may also be mixed in a mixer known to the person skilled in the art. The
mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer.
The, preferably molten, e which has been heated in the extruder at least up to the
softening point of physiologically acceptable polymer, ably polyalkylene oxide is
extruded from the extruder through a die with at least one bore.
The process according to the invention requires the use of suitable extruders, preferably
screw extruders. Screw extruders which are equipped with two screws (twin-screw-extruders)
are particularly preferred.
Preferably, extrusion is performed in the absence of water, i.e., no water is added. r,
traces of water (e.g., caused by atmospheric ty) may be present.
The extruder preferably comprises at least two temperature zones, with heating of the
mixture at least up to the ing point of the physiologically able polymer, preferably
the polyalkylene oxide proceeding in the first zone, which is downstream from a feed zone
and optionally mixing zone. The throughput of the mixture is preferably from 1.0 kg to 15
kg/hour. In a preferred embodiment, the throughput is from 0.5 r to 3.5 kg/hour. In
another red embodiment, the throughput is from 4 to 15 kg/hour.
In a preferred embodiment, the die head pressure is within the range of from 25 to 200 bar.
The die head pressure can be adjusted inter alia by die geometry, temperature profile,
ion speed, number of bores in the dies, screw configuration, first feeding steps in the
extruder, and the like.
66 GRA3573-WO/JBdg
The die geometry or the geometry of the bores is freely selectable. The die or the bores may
accordingly exhibit a round, oblong or oval cross-section, wherein the round cross-section
preferably has a er of 0.1 mm to 2 mm. Preferably, the die or the bores have a round
cross-section. The casing of the er used according to the ion may be heated or
cooled. The corresponding temperature control, i.e. heating or cooling, is so arranged that
the mixture to be extruded exhibits at least an average temperature (product temperature)
corresponding to the softening temperature of the physiologically acceptable polymer,
preferably the polyalkylene oxide and does not rise above a temperature at which the
pharmacologically active compound to be processed may be d. Preferably, the
temperature of the mixture to be extruded is adjusted to below 180 °C, preferably below 150
°C. but at least to the softening temperature of the physiologically acceptable polymer,
preferably the polyalkylene oxide. Typical extrusion temperatures are 120 °C and 150 °C.
In a preferred embodiment, the extruder torque is within the range of from 30 to 95%.
er torque can be adjusted inter alia by die geometry, temperature profile, extrusion
speed, number of bores in the dies, screw configuration, first feeding steps in the extruder,
and the like.
After extrusion of the molten mixture and optional cooling of the extruded strand or extruded
strands, the ates are preferably singulated. This singulation may preferably be
performed by cutting up the extrudates by means of revolving or rotating knives, wires,
blades or with the ance of laser cutters.
ably, intermediate or final storage of the optionally singulated extrudate or the final
shape of the particulates according to the invention is med under oxygen-free
atmosphere which may be achieved, e.g., by means of oxygen—scavengers.
The singulated extrudate may be press-formed into particulates in order to impart the final
shape to the particulates.
The application of force in the er onto the at least plasticized mixture is adjusted by
controlling the rotational speed of the conveying device in the extruder and the geometry
thereof and by dimensioning the outlet orifice in such a manner that the re necessary
for extruding the cized mixture is built up in the extruder, preferably immediately prior to
extrusion. The extrusion ters which, for each particular composition, are necessary to
67 GRA3573-WO/JBdg
give rise to a tablet with desired mechanical properties, may be established by simple
preliminary testing.
For example but not limiting, extrusion may be performed by means of a twin-screw-extruder
type ZSE 18 or ZSE27 (Leistritz, NiJrnberg, Germany), screw diameters of 18 or 27 mm.
Screws having eccentric or blunt ends may be used. A heatable die with a round bore or with
a multitude of bores each having a diameter of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 mm
may be used. The ion ters may be adjusted e.g. to the following values:
rotational speed of the screws: 120 Upm; delivery rate 2 kg/h for a ZSE 18 or 3 kg/h, 8 kg/h,
or even 10 kg/h and more for a ZSE27; product temperature: in front of die 125 °C and
behind die 135 °C; and jacket temperature: 110 °C. The throughput can generally be
increased by increasing the number of dies at the extruder outlet.
Preferably, extrusion is performed by means of twin-screw-extruders or ary-gear-
extruders, crew extruders (co-rotating or contra-rotating) being particularly preferred.
The particulates according to the invention are preferably produced by thermoforming with
the assistance of an extruder without any observable consequent discoloration of the
extrudates.
The s for the preparation of the coated particulates according to the invention is
preferably performed continuously. Preferably, the process involves the extrusion of a
homogeneous mixture of all components. It is particularly advantageous if the thus obtained
intermediate, e.g. the strand obtained by ion, exhibits uniform properties. Particularly
desirable are uniform density, uniform distribution of the active compound, uniform
mechanical properties, uniform porosity, uniform ance of the surface, etc. Only under
these circumstances the uniformity of the pharmacological properties, such as the stability of
the release profile, may be ensured and the amount of rejects can be kept low.
Preferably, the coated particulates according to the invention can be regarded as ded
pellets". The term “extruded pellets" has ural implications which are understood by
persons d in the art. A person skilled in the art knows that pelletized dosage forms can
be prepared by a number of techniques, ing:
0 drug layering on nonpareil sugar or rystalline cellulose beads,
o spray ,
0 spray congealing,
. rotogranulation,
68 GRA3573-WO/JBdg
. hot-melt extrusion,
. spheronization of low melting materials, or
. extrusion—spheronization of a wet mass.
Accordingly, "extruded pellets" can be obtained either by hot-melt ion or by extrusionspheronization.
ded pellets" can be distinguished from other types of pellets, as extruded pellets
typically have a different shape. The shape of the extruded pellets is typically more cut-rod-
like than tly globated round.
"Extruded pellets" can be distinguished from other types of pellets because they are
structurally different. For example, drug layering on nonpareils yields multilayered pellets
having a core, whereas extrusion lly yields a thic mass comprising a
homogeneous mixture of all ingredients. Similarly, spray drying and spray congealing
lly yield spheres, whereas extrusion typically yields cylindrical extrudates which can be
subsequently spheronized.
The structural differences between “extruded s" and “agglomerated pellets" are
significant because they may affect the release of active substances from the s and
consequently result in different pharmacological profiles. Therefore, a person skilled in the
pharmaceutical formulation art would not consider “extruded s" to be equivalent to
“agglomerated pellets".
The tablets according to the invention may be prepared by any conventional method.
Preferably, r, the tablets are prepared by compression. Thus, coated ulates as
hereinbefore defined are preferably mixed, e.g. blended and/or granulated (e.g. wet
granulated), with matrix material and the resulting mix (e.g. blend or granulate) is then
compressed, preferably in moulds, to form tablets. It is also ged that the coated
particulates herein described may be incorporated into a matrix using other processes, such
as by melt granulation (e.g. using fatty alcohols and/or water-soluble waxes and/or water-
insoluble waxes) or high shear granulation, followed by compression.
When the tablets according to the invention are manufactured by means of an eccentric
press, the compression force is preferably within the range of from 5 to 15 kN. When the
tablets according to the invention are ctured by means of a rotating press, the
69 GRA3573-WO/JBdg
compression force is preferably within the range of from 5 to 40 kN, in certain embodiments
>25 kN, in other embodiments about 13 kN.
The tablets ing to the invention may optionally comprise a coating, e.g. a cosmetic
coating. The g is preferably applied after formation of the tablet. The coating may be
applied prior to or after the curing s. Preferred coatings are ® coatings available
from Colorcon. Other preferred coating are Opaglos® gs, also commercially available
from Colorcon.
The tablet according to the invention is terized by excellent storage stability.
Preferably, after storage for 4 weeks at 40°C and 75% rel. humidity, the content of
pharmacologically active compound amounts to at least 98.0%, more preferably at least
98.5%, still more preferably at least 99.0%, yet more preferably at least 99.2%, most
preferably at least 99.4% and in particular at least 99.6%, of its original content before
storage. Suitable methods for measuring the content of the pharmacologically active
compound in the tablet are known to the skilled artisan. In this regard it is referred to the Eur.
Ph. or the USP, especially to ed phase HPLC analysis. Preferably, the tablet is stored
in closed, preferably sealed containers.
Further aspects according to the invention - basis for additional claim ries
The coated particulates and tablets according to the invention may be used in medicine, e.g.
as an analgesic. The coated ulates and tablets are therefore particularly suitable for the
treatment or management of pain. In such tablets, the pharmacologically active compound is
ably an analgesic.
A further aspect according to the invention relates to the tablet as described above for use in
the treatment of pain.
A r aspect according to the invention relates to the use of a tablet as described above
for avoiding or hindering the abuse of the pharmacologically active compound contained
therein.
A further aspect according to the invention relates to the use of a tablet as described above
for avoiding or hindering the unintentional overdose of the pharmacologically active
compound contained therein.
70 GRA3573-WO/JBdg
In this regard, the invention also relates to the use of a pharmacologically active compound
as bed above and/or a physiologically able polymer, preferably a polyalkylene
oxide as described above for the manufacture of the tablet according to the invention for the
laxis and/or the treatment of a disorder, thereby preventing an overdose of the
pharmacologically active compound, particularly due to comminution of the tablet by
mechanical action.
The following es further illustrate the invention but are not to be construed as limiting
its scope.
Example 1:
The relevance of the ulate size on tamper resistance was investigated.
It was found that comparatively small particulates, e.g. particulates having a diameter and
length of 0.5 mm x 0.5 mm already provide a certain degree of tamper resistance: when
administered nasally they cause an unpleasant feeling and furthermore, due to the lack of
water on the mucous membrane, do not release the cologically active compound as
quick as when being administered orally. Therefore, a kick or rush can unlikely be achieved
by nasal administration of such particulates. Thus, even when being administered nasally,
such atively small particulates already e tamper resistance, i.e. avoid drug
abuse or at least make drug abuse ntially more difficult. Furthermore, such
comparatively small particulates have excellent swelling properties thereby effectively
preventing conversion into a liquid formulation for intravenous administration.
It was found that tamper-resistance can even further be improved by increasing the
particulate size, e.g. to a diameter and length of 1.0 mm x 1.0 mm. Such ulates even
e a more unpleasant feeling when being administered y and in the absence of
sufficient water, rather slowly release the pharmacologically active compound. Further, they
cannot be easily converted into a liquid formulation for intravenous administration either.
As such a more pronounced retardant effect, however, is detrimental for the desired
immediate release upon prescribed oral administration of the tablets, a compromise must be
found between tamper resistance on the one hand and immediate drug release upon
prescribed oral administration on the other hand, particularly with respect to disintegration
71 GRA3573-WO/JBdg
time and drug release kinetics. Furthermore, drug load, processability (especially
tablettability) and t compliance are also important requirements to be satisfied with.
A predetermined particulate size of 800 pm x 800 pm was considered most appropriate, i.e. it
was considered most appropriate to adjust the diameter of the ion die as well as
cutting length of the extruded stand to 800 pm taking into consideration that die swelling may
occur during the extrusion process, particularly when the strand exits the die, so that the
diameter of the extruded strand in fact is expanded, ing upon the composition and the
extrusion parameters to a diameter of about 1000 pm. Thus, when proceedings this way, it
was ered most appropriate to manufacture extruded particulates having a diameter of
about 1000 um (after die swelling, diameter of extrusion die 800 pm) and a length of about
800 pm.
Example 2:
Different particulate compositions were investigated and particulates of different sizes were
ctured thereform.
The particulate compositions are summarized in the table here below:
TramadolHCl 46.59 46.59 46.59
PEG 6000 5.31 6.32 8.31
”mm-
a-tocopherol
Lutrol 127
PVP CL
total weight
film coating
AMB varnish
All als were weighed, sieved (manual sieve, 1 mm), blended (Bohle LM40 with MC5 or
MC10, depending on size of bath) for 15 minutes at 14 rpm, and hot-melt extruded (Leistritz
er Type ZSE18 with different configuration of screws).
The compositions 1 to 9 were extruded under the following extrusion conditions:
72 GRA3573-WO/JBdg
_—_3
C 20
100°C 100 100
C C 120
C 120
1 20
1 20
1 30
1 00
Throughput 10.00-16.66 16.66-28.04 16.66 16.66 16.66
/min
Screw low shear low shear low shear extreme
confi uration shear
For larger scales, screw configuration can be adopted and temperatures can be raised (e.g.,
H28 and 10: 130°C, HZ11: 145°C; or HZ11: 150°C and extreme shear ration,
throughput 25 g/min).
The in vitro release characteristics were monitored in 900mL 0.1N HCl at 37°C, using a
paddle apparatus 50 rpm. The results are depicted in Figure 3.
Example 3:
The influence of the content of particulates in the tablet was investigated.
The following compositions were tested:
300 mg particulates in tablets having a total weight of 600 mg
250 mg particulates in tablets having a total weight of 600 mg
200 mg particulates in tablets having a total weight of 600 mg
The most promising mise between tability and size ed to be 250 mg
particulates in tablets having a total weight of 500 mg. Tablets having a total weight of 600
mg were considered too large with respect to patient compliance, although the relative
weight ratio of particulates to matrix material of about 1:1 appeared advantageous with
respect to disintegration time and dissolution time.
73 GRA3573-WO/JBdg
Example 4-1:
The influence of the matrix material was investigated - wet granulation.
Granules having the following composition were prepared for manufacturing of pellet-tablets.
Granules for outer the phase, i.e. the matrix material, were manufactured by wet granulation.
Granules and s were blended. Segregation (optically) and disintegration of s after
compression were evaluated. Tablets were manufactured “manually" (components were
separately weighed for each tablet and mixed directly prior to tabletting) using a single
station press (Korsch EKO):
Galen lQ, Na no segregation in mixture disintegration test: no
carboxymethylstarch (5%) able, detectable
aqueous granulation in Diosna disintegration after 3
min.
I Galen IQ, Kollidon CL (5%) no segregation in mixture disintegration test:
aqueous granulation in Diosna detectable slightly dissolved
mixture showed substantial surface after 3 min.
punch deposit upon
compression of 3 tablets
alread
c Avicel with PVP-solution significant ation in disintegration test:
granulated mixture able partial disintegration
after 3 min.
MCC+lactose(20:80) with PVP- no segregation in mixture disintegration test: no
solution granulated detectable detectable
disintegration after 3
min.
MCC+lactose (50:50) with PVP- slight segregation in mixture disintegration test:
solution granulated detectable partial disintegration
after 3 min.
Gelcarin + lactose (20%+80%) no segregation in mixture egration test: no
+ water (57% + 43%) detectable detectable
disintegration after 3
min.
sugar ester 8-1570 + cium- cant segregation in egration test: no
phosphate + Acivel + in mixture detectable detectable
disintegration after 3
min.
incrustation granulate from the granulate could not be no tablets
saccharose sed or only with manufactured
difficulties
blending with particulates is
not possible -> thus. no
tablets were manufactured
74 GRA3573-WO/JBdg
It was not possible to manufacture rapidly disintegrating tablets from the above compositions,
probably because the disintegrants lose the egrating capacity in the course of the wet
granulation process.
Example 4—2:
The influence of the matrix material was igated - dry granulation - roller compaction.
The following compositions were processed by slugging involving the steps of:
o weighing I sing of components
0 sieving I blending
o manufacture of bi—planar tablets of 20 mm diameter using a single station press
(Korsch EKO), 25 kN compression force
0 breaking the tablets into parts (manually) and sieving using a Frewitt Sieving machine
(1.5 mm mesh size)
0 ing granules as outer phase I matrix material for pellet-tablets
The experimental results are ized in the following table:
2 a EE 9 2 9 2 2 2 N. N.
253. 95 .Az._ 2x EE 5% 2x 2 mcozo ti 3 28m EE 8:5 28m EE 52.5 958. EE 5.3 253. EE 5:5 28m EE 5.5 253. EE 335 253. EE 5.5 28”. EE
-Bsms cofia
89:3
659 coaweanov 2x38.2
“.9838 8 $2856
$565 SummaESV .8 2
was 22% 2222: 85:3 28
:83 game :8 88358 5;)
émméo 0202 38m -
-mEmw 82% -- .m-
a>a .6 $03 $23
.92 993% $8.0 .xbmd
2 $28.. £2“
$23. 2: 33% 38.3 fig $8.3 $oqmv $8.3 $83 $oo.§ I
sumac; 226a 38.8 $8
on n$.83 $8.8 .«98.3 °58.8 n$.83 $8.8 $8.0m
E2398 .- $3 888.. 05:2 28 35%ng 289a
.ooxmz $3 261025
$829 onSun :_E 23 H I!I!l!- :-
9 9 9 9 9 2 2 9 NF NF
88”. EE 5.5 5.55 EE 5.5 5.53. EE 5.5 5.55 EE 5.5 5.55 EE 5.5 5.58 EE 5.5 5.58 EE 5.5 953. EE 52.5 950m EE :mEn 950m
«.228 28:3 gas
mum20>>énmm<mo
55$ 55mm 55.5
an 5.3.8 5 mm E $5.5m
IllgII '553 5.5 55mm .5.
S. 5.8.
mm 5 mm E R iomdv
58.8 $8.0m 558.8 $8.8 $8.0m $8 $8 588 I588 588 58
on on 58.8 I 588 8
5255 .mimN mtm 855855 85:85.0, 582;
58 558 “2an 282m 59.3. 282m 58 282m 855855 I
Q2 2 2 2 2 2 2 2 2
950m SE 89.5 950m SE 82.3 950m EE 22.5 950m 95.5 950m 82.5 950m 82.5 950m 83.3 950m 82.3 950m 838
EE SE EE EE EE EE 8:5
In)U)>~ Imm» mm» 8» 8» m2m.:o_tma .Cs
+ m5 3
B ”.>
9:88 .m>
9: .m>
85 :
A..:_E .m>
x0 ”.c
0 O on
mumzoiémméo .w>
$mms 5% c
$8.\. $mmN 8322.. a
.m new
S563 .0
233885 o
239 r:
m>onm .c
-- .w>
m5 c
k €20ch 5 ”.E
$$. $8.~v $8. - .5
3. 2. 8255
Emu 38.2
$88 $88 $88 $88 $88 $8.8 -gas. $88 $88 639308
c 9%
am am 6
$8 $8 038222 $8 2255 axm
*8 $8 $8 2255 .bowoflmzmm 9:
+ E0: 88.288
Q8 . . .uoom
- - ++ 520
- m_
= fizcflmnzw
78 GRA3573-WO/JBdg
The release characteristics of tablets containing the thus compacted matrix material were
investigated. The s are depicted in Figure 4 (900 mL HCI, 50 rpm, paddle apparatus
without sinker).
Example 4-3:
Since the slugging method is not state of the art for dry granulation, corresponding tests
concerning dry granulation were conducted by means of a roller compactor. This has the
advantage that all relevant parameters (roller displacement, compression force, granulator
size) can be adjusted such that a granulate having the desired properties is obtained (particle
size, ss, compressibility, density).
Parameters (Gerteis MiniPactor):
roller displacement: 2 to 3 mm
tion velocity: 2 to 5 rpm
tion force: 3 to 15 kN/cm
screen size: 1.0 to 1.25 to 1.5 to 2.0 mm
The thus prepared ts (dry granulates) were blended with particulates and
compressed to tablets. Upon blending, lubricant (magnesium stearate and sodium
stearylfumarate, respectively) was added as an external excipient neither contained in the
compacts nor in the ulates.
#1 m
—--—-
—----
Na-CMC -5.00% --
Lactose Monohydrate 230----
Prosolv b ---- 100.00%
The experiments revealed that tablets made from compacts and made from slugging-
granulates show a similarly fast release.
Confirming experiments:
Mime-n
GRA3573-WO/JBdg
-- -
- -
_- -
PVP CL - -
Na-stearylfumarate -
Example 4-4:
Tablets (500 mg) were prepared from the particulates according to Example 2-5 (250 mg)
and the matrix material ing to Example 4-3 #12 (250 mg).
The in vitro e was determined according to Ph. Eur.:
-time % released (n=6)
-_35 101.4
The in vitro release of the tablets was compared to a non-tamper resistant commercial
t containing Tapentadol HCI (film coated tablets). After 30 minutes (according to Ph.
Eur. 2.9.3), both formulations released the entire amount of the pharmacologically active
ingredient (100%).
80 GRA3573-WO/JBdg
Example 5:
The mechanical properties of conventional, commercial neutral pellets were investigated
under the following conditions:
product pellets neutral (Hans tramadol TRF IR tramadol TRF IR
G. Werner GmbH & pellets pellets
Tramadol HCI — 46.59 wt.-% 4.17 wt.—%
PEG 6000 — 8.31 wt.-% 8.33 wt.-%
_ 45.00 wt.-% 87.30 wt.-%
testXpert V10.11
The reduction of the displacement between plate and ambos x in mm (= “compression [c]")
and the ponding force f in N were measured. The maximum force fmax ed during
the measurement and the corresponding reduction of displacement xmax are summarized in
the table here below:
I mmm5-1 (Figure 7) 5-2 (Figure 8) 5-3 (Figure 9)
fmax [N]
I'm-mm
-V“mm.
”mm-
mmax
It s clear from the above data that the comparative particulates of e 5-1 break
at very low forces of only about 5 N and can be deformed by less than 0.1 mm. In contrast,
81 GRA3573-WO/JBdg
the inventive particulates of examples 5-2 and 5-3 do not break at all, and can be deformed
(flattened) by more than 0.8 mm.
The corresponding displacement-diagrams are shown in Figures 7. 8 and 9,
respectively.
We
Claims (11)
1. A tamper-resistant tablet comprising (i) a matrix material in an amount of more than one third of the total weight of the tablet; and 5 (ii) a plurality of coated particulates in an amount of less than two thirds of the total weight of the tablet; wherein said particulates comprise a pharmacologically active compound and a physiologically acceptable polymer; and form a tinuous phase within the matrix material; wherein 10 the logically acceptable polymer is a polyalkylene oxide having a lar weight of more than 20,000 g/mol; the matrix material comprises binder/filler, disintegrant and lubricant; 15 the filler/binder is selected from the group consisting of silicon dioxide; microcrystalline cellulose; cellulose ether; mannitol; dextrines; dextrose; calcium hydrogen phosphate; maltodextrin; lactose; polyvinylpyrrolidone; saccharose; magnesium salts; starches and pretreated starches; the disintegrant is ed from the group consisting of crosslinked sodium 20 carboxymethylcellulose; crosslinked casein; ccharide mixtures obtained from soybeans; pretreated maize starch; sodium alginate; nylpyrroli done; crosslinked polyvinylpyrrolidone; starch and pretreated starch such as sodium ymethyl starch; and the lubricant is selected from the group consisting of calcium stearate; 25 magnesium stearate; glycerol monobehenate; sodium stearylfumarate; and talcum; under physiological conditions the tablet has released after 30 minutes at least 70% of the pharmacologically active compound ally contained in the ; and the particulates are coated with a coating material comprising a water-soluble polymer ed from the group consistingcelluloseof esters, cellulose ethers, 30 poly(meth)acrylates, vinyl polymers, and natural film formers.
2. The tablet according to claim 1, which has inundervitro conditions a disintegration time measured in accordance with Ph. Eur.(Edition 6.0) of at most 3 minutes. (10799087_1):KZA
3. The tablet according to anyone of the preceding claims, wherein the content of the matrix material is at least 40 wt.-%, based on the total weight of the tablet.
4. The tablet according to anyone of the preceding claims, wherein the cologically active compound is an opioid.
5 5. The tablet according to any one of the preceding claims, wherein the particulates have an average diameter of about 1000±250 μm and/or an average length of about 750±250 μm.
6. The tablet according to anyone of the preceding , wherein the content of the polymer is at least 25 wt.-%, based on the total weight of a particulate. 10
7. The tablet according to anyone of the preceding claims, wherein the content of the pharmacologically active compound is at least 25 wt.-%, based on the total weight of a particulate.
8. The tablet according to claim 1, which has a total weight of 0 mg and contains 15 (i) 50±15 wt.-% coated particulates having an average particle size of 800±400 µm, wherein the coated particulates comprise • 23±20 wt.-% cologically active compound, • 22±12 wt.-% physiologically acceptable r, • optionally, 4.0±3.5 wt.-% plasticizer, and 20 • optionally, 0.05±0.05 wt.-% further excipients; and (ii) 49±15 wt.-% matrix material, n the matrix material comprises • 43±10 wt.-% filler and/or binder, • optionally, 5±4 wt.-% egrant and • optionally, .15 wt.-% lubricant; 25 all wt.-% being expressed relative to the total weight of the tablet.
9. The tablet according to any one of the preceding claims, wherein the particulates are hot melt-extruded. (10799087_1):KZA
10. The tablet ing to anyone of the preceding claims, wherein the matrix material is also present in particulate form. Grünenthal GmbH By the Attorneys for the Applicant 5 SPRUSON & FERGUSON Per: (10799087_1):KZA 3-WO/JBdg 23 2b ’3: ,.V 1” / tax, A / , , /1- xx», / >a$m<mo 8 EEmd x 5&3me mm . EEmd EEmd x [ill . md TN 396+ .m-m om 96 96 lxl
II. EEFxEEF.m-Naxm+ EEmd . EEmd 8 x x EEF eemoxeer EEF ._.-N . .m-m mm 96 96 m $2.3 ho IT 396+ ll EEFxEE_._w-NmeIII yv‘l‘lillf‘ij Es; 9N 2:9“. 8 cozmuEzao 2:; EEF EEIEEF EEF mm x x EEF EEF .TN . om .m-m 96 em. le vial? I EEFxEE_._~-Nme+ 2 TI S omr OE. oor om om ov on om 9. mumzoiémméo 2%: N M. x .8 .: :0 .Q __u L .3 _> em naxw em 1wa wa axm wa oaxw em wa em me em wa 93..- 32.11! 22. 3 93+ DE. 98. £le 38. 98. 92. DE. .::.. IT 5!: .IT 38.1.1 | .o... 10' :6... I-nl ham-rial 923 35am 923 9553 5% N a u E c __: .o a a L 3 > $03 em em me :5 1wa em wa me wa wa em em me me 33 98 Hum-pl] El! DE.-.X.: 38. nmqul. 32. nag-Incl nmklll 38. 38. 22. 398 . ---.:+ IT Hum-rial. .IT :.:.u o 239". om 335.5%... 3 3033.53; am cotzfimma E 7 xuuuuunmumnnmmmnm Immunuuumummnmwnuimmuuuumnuuuuuummn ¢ Illllllilllllulu!"III“llllllllllIlillllllflllflInlfllllllllflllnflml"ammmmmmmmmmu am— 8— C CD a 5; on [yo] escalau émméo 9v 959". mm V\\\\\\\\\\\\\\\\\\\\\\\\\\\k < mum20>>énmm<m0 \\\\\\\\ \\\\\\\\\\\\\\\ \\\\\\\\\\\\\\\\\\\\\\\\\ \\\\\\\\- ............. «x §Zwow ........ Qm 959". \\\\\\\\\\\\\\\\\\\\\\\\\\\\\_x/////%_ aw flfi V\\\\\\\\\\\\\\\\\\\\\\\\\\\k \ .mnmm<m0 ,.~_-...—n..~_m.~_w~~M:M_My...”__Mimm
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11006254 | 2011-07-29 | ||
EP11006254.4 | 2011-07-29 | ||
PCT/EP2012/003188 WO2013017234A1 (en) | 2011-07-29 | 2012-07-27 | Tamper-resistant tablet providing immediate drug release |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ618168A NZ618168A (en) | 2016-03-31 |
NZ618168B2 true NZ618168B2 (en) | 2016-07-01 |
Family
ID=
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