NZ601713B - Solid pharmaceutical composition for buccal administration of agomelatine - Google Patents
Solid pharmaceutical composition for buccal administration of agomelatine Download PDFInfo
- Publication number
- NZ601713B NZ601713B NZ601713A NZ60171312A NZ601713B NZ 601713 B NZ601713 B NZ 601713B NZ 601713 A NZ601713 A NZ 601713A NZ 60171312 A NZ60171312 A NZ 60171312A NZ 601713 B NZ601713 B NZ 601713B
- Authority
- NZ
- New Zealand
- Prior art keywords
- pharmaceutical composition
- agomelatine
- composition according
- sucked
- tablet
- Prior art date
Links
- YJYPHIXNFHFHND-UHFFFAOYSA-N Agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 59
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
- 239000007787 solid Substances 0.000 title claims abstract description 26
- 239000003826 tablet Substances 0.000 claims abstract description 50
- 239000000203 mixture Substances 0.000 claims abstract description 41
- 239000004480 active ingredient Substances 0.000 claims abstract description 25
- 239000003085 diluting agent Substances 0.000 claims abstract description 12
- 239000002085 irritant Substances 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000011780 sodium chloride Substances 0.000 claims abstract description 9
- 230000035493 absolute bioavailability Effects 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 8
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 8
- 238000001746 injection moulding Methods 0.000 claims abstract description 8
- 235000010603 pastilles Nutrition 0.000 claims abstract description 8
- 239000004014 plasticizer Substances 0.000 claims abstract description 8
- 239000003765 sweetening agent Substances 0.000 claims abstract description 8
- 238000007792 addition Methods 0.000 claims abstract description 7
- 239000011248 coating agent Substances 0.000 claims abstract description 7
- 239000000796 flavoring agent Substances 0.000 claims abstract description 7
- 150000004677 hydrates Chemical class 0.000 claims abstract description 7
- 239000007937 lozenge Substances 0.000 claims abstract description 7
- 238000009474 hot melt extrusion Methods 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims description 14
- 230000036912 Bioavailability Effects 0.000 claims description 13
- 230000035514 bioavailability Effects 0.000 claims description 13
- 238000007906 compression Methods 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 229920005862 polyol Polymers 0.000 claims description 4
- 150000003077 polyols Chemical group 0.000 claims description 4
- 230000035489 relative bioavailability Effects 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 241000257303 Hymenoptera Species 0.000 claims 1
- 150000002500 ions Chemical class 0.000 claims 1
- 239000011230 binding agent Substances 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 6
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- 230000003628 erosive Effects 0.000 abstract 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 22
- 230000035492 administration Effects 0.000 description 21
- 238000009472 formulation Methods 0.000 description 20
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 235000019359 magnesium stearate Nutrition 0.000 description 11
- 229960004998 Acesulfame potassium Drugs 0.000 description 8
- WBZFUFAFFUEMEI-UHFFFAOYSA-N Acesulfame potassium Chemical compound [K+].CC1=CC(=O)NS(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-N 0.000 description 8
- IAOZJIPTCAWIRG-QWRGUYRKSA-N Aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 8
- 229960003438 Aspartame Drugs 0.000 description 8
- 108010011485 Aspartame Proteins 0.000 description 8
- 210000000214 Mouth Anatomy 0.000 description 8
- 235000010358 acesulfame potassium Nutrition 0.000 description 8
- 239000000619 acesulfame-K Substances 0.000 description 8
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- 235000010357 aspartame Nutrition 0.000 description 8
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- 150000001875 compounds Chemical class 0.000 description 7
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- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 6
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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- BAQAVOSOZGMPRM-JVFSCRHWSA-N (2R,3R,4R,5R,6R)-2-[(2S,3R,4R,5R)-2,5-bis(chloromethyl)-3,4-dihydroxyoxolan-2-yl]oxy-5-chloro-6-(hydroxymethyl)oxane-3,4-diol Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@]1(CCl)[C@H](O)[C@@H](O)[C@H](CCl)O1 BAQAVOSOZGMPRM-JVFSCRHWSA-N 0.000 description 2
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- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 2
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- 210000002381 Plasma Anatomy 0.000 description 2
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
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- 230000036528 appetite Effects 0.000 description 2
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- -1 for example Chemical class 0.000 description 2
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- 239000000546 pharmaceutic aid Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
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- 238000007493 shaping process Methods 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000006190 sub-lingual tablet Substances 0.000 description 2
- 235000019408 sucralose Nutrition 0.000 description 2
- 235000019640 taste Nutrition 0.000 description 2
- 229920001169 thermoplastic Polymers 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229940096516 Dextrates Drugs 0.000 description 1
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- 239000004375 Dextrin Substances 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N Glyceryl behenate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- SERLAGPUMNYUCK-DCUALPFSSA-N Isomalt Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N Maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 241001182492 Nes Species 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene (PE) Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- URAYPUMNDPQOKB-UHFFFAOYSA-N Triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
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- PYGXAGIECVVIOZ-UHFFFAOYSA-N dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
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- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
ABSTRACT - 601713 The disclosure relates to a solid buccal pharmaceutical composition intended for systemic action, which is a tablet to be sucked, a pastille to be sucked, a lozenge to be sucked, or a solid obtained by hot-melt extrusion or injection-moulding, comprising agomelatine or one of its hydrates, complexes, co-crystals, crystalline forms, addition salts with a pharmaceutically acceptable acid or base, and one or more excipients selected from diluents, binders, flow agents, lubricants, coating agents, plasticisers, flavourings, counter-irritants and sweeteners, characterised in that it makes it possible to obtain a release time of the active ingredient comprised between 3 and 30 minutes and an absolute bioavailability greater than 25%. These compositions have a slow erosion release of agomelatine and are suitable for the treatment of major depression, seasonal affective disorder, generalized anxiety disorder, obsessional compulsive disorder, bipolar disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet-lag, appetite disorders and obesity, and any pathology associated with deregulation of circadian rhythms. s hydrates, complexes, co-crystals, crystalline forms, addition salts with a pharmaceutically acceptable acid or base, and one or more excipients selected from diluents, binders, flow agents, lubricants, coating agents, plasticisers, flavourings, counter-irritants and sweeteners, characterised in that it makes it possible to obtain a release time of the active ingredient comprised between 3 and 30 minutes and an absolute bioavailability greater than 25%. These compositions have a slow erosion release of agomelatine and are suitable for the treatment of major depression, seasonal affective disorder, generalized anxiety disorder, obsessional compulsive disorder, bipolar disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet-lag, appetite disorders and obesity, and any pathology associated with deregulation of circadian rhythms.
Description
NEW ZEALAND
PATENTS ACT, 1953
COMPLETE SPECIFICATION
SOLID PHARMACEUTICAL ITION FOR BUCCAL ADMINISTRATION OF
AGOMELATINE
We, LES LABORATOIRES SERVIER, a French y of 35, rue de Verdun 92284,
Suresnes Cedex, France, do hereby declare the invention for which we pray that a patent
may be granted to us, and the method by which it is to be performed, to be particularly
described in and by the following statement:
The present invention relates to a new solid pharmaceutical form for administration of
agomelatine by the buccal route.
Agomelatine, or N-[2-(7-methoxynaphthyl)ethyl]acetamide of formula (I):
NHCOMe
(I),
and its hydrates, crystalline forms, complexes, co-cristals, and on salts with a
pharmaceutically acceptable acid or base has le cological properties: it is a
selective agonist of ors of the melatoninergic system and, on the other hand, an
antagonist of the 5-HT2C receptor. These properties provide it with activity in the central
nervous system and, more especially, in the ent of major depression, seasonal
affective disorder, generalized anxiety disorder, obsessional compulsive disorder, bipolar
ers, sleep ers, cardiovascular pathologies, pathologies of the digestive system,
insomnia and fatigue due to jet-lag, appetite ers and obesity.
In one aspect, the invention provides a solid buccal pharmaceutical composition intended
for systemic action, which is a tablet to be sucked, a pastille to be sucked, a e to be
sucked, or a solid ed by hot-melt extrusion or injection-moulding, sing
agomelatine or one of its hydrates, complexes, co-crystals, crystalline forms, addition salts
with a pharmaceutically acceptable acid or base, and one or more excipients selected from
diluents, binders, flow agents, lubricants, coating , plasticisers, flavourings, counterirritants
and sweeteners, characterised in that it makes it possible to obtain a release time of
the active ingredient comprised between 3 and 30 minutes and an absolute bioavailability
greater than 25%.
The invention also provides a use of agomelatine or one of its hydrates, complexes, cocrystals
, crystalline forms, addition salts with a pharmaceutically acceptable acid or base,
and one or more excipients selected from diluents, binders, flow agents, lubricants, coating
agents, plasticisers, flavourings, counter-irritants and sweeteners in the manufacture of a
solid buccal pharmaceutical composition intended for systemic action, which is a tablet to
be sucked, a pastille to be sucked, a lozenge to be sucked, or a solid obtained by hot-melt
extrusion or injection-moulding, wherein the composition has a e time of the active
ingredient comprised between 3 and 30 s and an absolute bioavailability r
than 25%, n the pharmaceutical composition is for use in the treatment of major
depression, seasonal affective disorder, generalized anxiety disorder, obsessional
compulsive disorder, bipolar disorders, sleep disorders, cardiovascular pathologies,
pathologies of the digestive system, insomnia and fatigue due to jet-lag, appetite disorders
and obesity, and any pathology associated with deregulation of circadian rhythms.
Agomelatine, its crystalline forms, its complexes, its co-crystals, its addition salts with a
pharmaceutically acceptable acid or base, its preparation and its use in therapeutics have
been described, among others, in the patent applications EP0447285, WO2005/077887,
WO2007/015003, WO2007/015002, WO2007/015004, WO2010/097052,
WO2010/102554, 55440, WO2011/050742, CN102050756, WO2011/006387,
WO2011/075943, CN101774937, CN101870662, CN102030673, WO2012/046253,
/113362, WO2011/113363, CN102206864, 03886, and CN102432490.
In all that s hereinbelow, "agomelatine" is understood to mean agomelatine, its
hydrates, its complexes, its co-crystals, its crystalline forms and its addition salts with a
pharmaceutically acceptable acid or base.
The agomelatine may especially be in crystalline form II.
Agomelatine can be administered by the oral route or, more specifically, by the enteral
route in the form of immediate-release tablets to be swallowed with half a glass of water.
These agomelatine tablets are , ally in treating major depression, seasonal
affective disorder, generalized anxiety disorder, obsessional compulsive disorder, bipolar
disorders, sleep ers, cardiovascular pathologies, pathologies of the digestive system,
insomnia and fatigue due to jet-lag, appetite ers and obesity, and any ogy
associated with deregulation of circadian rhythms.
Pharmacokinetic studies in humans have shown that the bioavailability of agomelatine by
the oral route is low compared to the parenteral route and varies for one and the same
individual and from one individual to another.
The low bioavailability of agomelatine and the variations in inter- and individual
concentrations have therefore ed in the search for a new formulation allowing those
drawbacks to be overcome. A solid orodispersible pharmaceutical composition of
agomelatine, described in Patent ation EP1427724, was therefore developed,
containing agomelatine and granules consisting of lactose and starch dried by isation
and marketed under the name C. This pharmaceutical composition
makes it possible to obtain tablets having a very good capacity for disintegrating in the oral
cavity and, more specifically, in the sublingual cavity, meeting the ia for
persibility. The orodispersible tablets make it possible to deliver the active ingredient
into the oral cavity and, more specifically, into the sublingual cavity in less than three
minutes. Dissolution of the active ient in the saliva and then absorption via the
mucous membranes of the oral cavity and, more specifically, the sublingual mucous
membrane, and rapid passage into the blood make it possible to avoid presystemic
degradation and the c first-pass effect. Accordingly, bioavailability is very clearly
improved with much lower variability and rapid appearance of the active ingredient in the
blood.
However, it quickly became apparent that this formulation had a drawback due to the
active ingredient used - agomelatine - which causes a pronounced sensation of irritation in
the mucous nes of the oral cavity.
When the sublingual route is ically targeted, this stinging effect is exacerbated
because of the high local concentrations of agomelatine, the end result of which is very
poor patient ability. In this context, a formulation of the sublingual tablet type was
developed and described in Patent Application WO2007/068829, meeting the requirements
for orodispersibility and patient acceptability. The favoured strategy was to obtain a solid
pharmaceutical composition composed of a central core or central layer containing
agomelatine and excipients ng an orodispersible formulation to be obtained, and an
orodispersible coating optionally containing a counter-irritant. These orodispersible tablets
make it possible to obtain rapid egration in less than 3 minutes and have shown an
excellent ability to limit the stinging character of the active ingredient.
The Applicant has now followed a new strategy consisting of ping a pharmaceutical
ation ng gradual release of agomelatine in the buccal cavity. The important
point of this new formulation is to maintain, throughout release of the active ingredient,
local trations which are sufficiently low to limit the stinging sensation and to obtain
a form able to the patient.
Accordingly, a new pharmaceutical formulation was developed, making it possible to
remedy the problem of irritation by the agomelatine whilst favouring delivery of the active
ient into the buccal cavity for the purpose of systemic action, that effect being
sought in order to improve the problems of bioavailability and intra- and inter-individual
variability with tablets administered by the oral route. In surprising and completely
unexpected manner, this new formulation has resulted in an increase in the bioavailability
of the active ingredient not only compared to the oral (enteral) tablet but also compared to
the orodispersible oromucosal formulations ped in the prior art for the purpose of
systemic , for ations having the same dosage in active principle and wherein
the active principle has the same form. By “same form” it is understood, here and every
time it will be used hereinafter, that the active principle has the same crystalline form, or is
under the same hydrate, complexe, salt or co-crystal form, and that particle sizes of active
principle are the same.
The present invention accordingly relates to a solid buccal preparation intended for
systemic action, which makes possible lled release of the active ingredient in the oral
cavity so as to obtain good acceptability in terms of taste and better absolute bioavailability
compared to the orodispersible tablets having an oromucosal absorption described in the
prior art, for formulations having the same dosage in active principle and wherein the
active principle is under the same form.
The buccal preparation according to the invention relates more especially to es,
pastilles to be sucked, s to be sucked, sublingual tablets, gingival tablets, solids
obtained by hot-melt extrusion or injection-moulding or also medicament-containing
spheres intended to dissolve in the oral cavity, which contain agomelatine.
The buccal preparation according to the invention may contain diluents, binders, flow
agents, lubricants, coating agents, plasticisers, flavourings, counter-irritants and
sweeteners.
The buccal preparation according to the invention is characterised by the absence of a
disintegrant, which, combined with a high compression strength, makes it possible to
provide a tablet which does not disintegrate but erodes slowly by dissolution of the
constituents on the surface.
The systemic-action buccal preparation according to the invention has an active ingredient
release time less than 30 s, and more preferably less than 15 minutes. The active
ingredient release time will be for example between 3 minutes and 30 minutes, and more
ably n 3 minutes and 15 minutes.
Lozenges and pastilles to be sucked are solid unit-dose preparations ed to be sucked
and to dissolve or disintegrate slowly in the mouth. Lozenges to be sucked are hard
preparations obtained by moulding. They n the active ingredient y in a
flavoured and sugary excipient. They may optionally contain counter-irritants. les to
be sucked are soft and malleable preparations obtained by ng mixtures containing
gums or natural or synthetic polymers and sweeteners. They may optionally contain
rings and counter-irritants.
Lozenges and pastilles to be sucked, in ance with the invention, will comprise, for
e, agomelatine, gum arabic, mono- or di-saccharides such as glucose or sucrose,
polysaccharides, isomalt, maltodextrin or polyols such as maltitol.
Tablets to be sucked are solid unit-dose preparations intended to be sucked in order to
exert a local or systemic action. They are obtained by direct compression or by granulation
followed by compression.
The ceutical composition according to the invention will be, for example, a tablet to
be sucked which may be prepared by a direct compression process. The tablet to be
sucked, in accordance with the invention, comprises agomelatine, a diluent and, optionally,
a binding agent, a lubricating agent and/or a flow agent and/or one or more sweetening,
flavouring or counter-irritation agents. It is characterised by slow n in the oral cavity.
The diluent that may be used in accordance with the invention is so selected that it allows
use in direct compression and provides the pharmaceutical form with high resistance to
crushing and able organoleptic properties for a buccal preparation to be sucked. The
diluent used is ably a polyol or a saccharide (mono-, oligo- or poly-saccharide) or a
combination of those various compounds such as, for example, glucose, sucrose, mannitol,
dextrates or dextrin.
Among the binding agents that may be used in accordance with the invention there may be
mentioned cellulose compounds and starch compounds, crospovidone and maltodextrin.
The counter-irritant optionally used is a compound acting on the vanilloid receptors or the
ASIC (acid-sensitising ion channel) receptors responsible for sensations of irritation and
pain. Preference is given to the counter-irritant used being citric acid.
The other ents used are excipients customarily described for each of the categories in
reference works such as, for e, the Handbook of Pharmaceutical Excipients (Rowe,
Sheskey and Owen, ceutical Press).
Among the ating agents that may be used in accordance with the invention there may
be mentioned magnesium stearate, stearic acid, glycerol behenate, sters and sodium
stearyl fumarate, more preferably magnesium stearate or sodium stearyl fumarate.
Among the sweeteners optionally envisaged according to the invention there may be
mentioned aspartame, acesulfame potassium, sucralose and saccharin.
The flavourings optionally envisaged according to the invention may comprise any
compound intended to have an effect relating to the taste descriptors (saltiness, sweetness,
bitterness, sourness, .
Sublingual and gingival tablets are solid unit-dose preparations intended for ation
h the tongue and in the gingivo-buccal space, respectively, for the purpose of
systemic action. They are produced by compression of mixtures of s or granules so
as to obtain s having a shape matched to their intended use.
Sublingual and gingival tablets according to the invention will comprise the same
ingredients as tablets to be sucked. They have similar release es. They differ from
tablets to be sucked only in their administration route. Tablets to be sucked are intended for
administration via the oromucosal route, that is to say absorption of the active ingredient
occurs via the entirety of the mucous membranes of the buccal cavity, whereas sublingual
s are d specifically by the gual route, that is to say beneath the tongue,
and gingival tablets specifically by the gingival route, that is to say via the gums.
The solids obtained by hot-melt extrusion or injection-moulding are prepared using the
same ingredients as tablets to be sucked, but thermoplastic polymers are specifically added
in order to provide the mixture of ingredients with flow properties in the hot state. Shaping
of the solid is ed by extrusion through a die and then calendering and cooling or by
injection of the material into a cooled mould. The thermoplastic polymers used in
accordance with the invention are compounds customarily described in reference works
such as, for example, the Polymer Handbook (Brandrup, Immergut and Grulke, Wiley-
Interscience). There may be mentioned, for example, cellulose compounds,
ethylenes, polyvinylpyrrolidones or polymethacrylates. Plasticising nds may
optionally be used in order to facilitate flow and shaping of the material. Plasticisers used
in accordance with the invention are plasticisers customarily described in reference works
such as, for example, the Handbook of Pharmaceutical Excipients (Rowe, Sheskey and
Owen, Pharmaceutical Press). There may be mentioned, for example, dibutyl sebacate,
triacetin, glycerol, sorbitol and polyethylene s.
The solid buccal preparation intended for systemic action in accordance with the invention,
after administration, has shown excellent active ingredient acceptability to the t. The
formulation developed in ance with the invention does indeed allow gradual
dissolution of the agomelatine, and therefore slow and controlled release, avoiding the
introduction of an especially irritating very large amount of the active substance.
The Applicant has moreover carried out pharmacokinetic studies in humans and has been
able to demonstrate, in entirely unexpected and surprising manner, much better
bioavailability for a solid pharmaceutical ition for buccal administration according
to the invention compared to the persible s described in the prior art, for
ations having the same dosage in active ple, and wherein the active principle
has the same form.
The pharmaceutical composition according to the invention has therefore made it possible
to increase the bioavailability of the active ingredient very icantly and, as a
consequence, to reduce intra- and inter-individual variability, whilst offering the patient a
highly acceptable formulation.
The invention accordingly relates to a solid buccal ceutical ition comprising
agomelatine, intended for systemic action, resulting in an increase in the bioavailability of
the active ingredient compared especially to an orodispersible form administered by the
sublingual or oromucosal route. More especially, the pharmaceutical composition
according to the invention makes it possible to attain absolute bioavailability of the active
ingredient of more than 25 %, and more preferably of more than 30 %, corresponding to an
increase by a factor of close to 1.5 to 2 compared to the gual or oromucosal
orodispersible formulations of the prior art, when formulations having the same dosage in
active principle and wherein the active principle has the same form are compared.
The pharmaceutical compositions according to the invention are ably terised in
that they contain, in relation to the total weight of the composition, from 0.01 % to 20 %
agomelatine by weight, more especially from 0.01 % to 10 %, and even more preferably
from 0.01 % to 5 %.
The pharmaceutical compositions according to the invention preferably comprise a t
having a very good compression capability, whilst providing the formulation with an
erodable character. Among the diluents according to the invention there may be mentioned
rides and polyols, more preferably sucrose.
The useful dosage can be varied according to the nature and ty of the disorder, the
administration route and the age and weight of the patient. The dosage varies from 0.1 mg
to 25 mg of agomelatine per day in one or more administrations, and preferably from
0.1 mg to 10 mg of agomelatine per day in one or more administrations, and even more
preferably from 0.1 mg to 5 mg of agomelatine per day in one or more administrations.
In this specification where reference has been made to patent specifications, other external
documents, or other sources of information, this is generally for the purpose of ing a
context for discussing the features of the invention. Unless specifically stated otherwise,
nce to such external nts is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of
the common general knowledge in the art.
In the description in this specification reference may be made to t matter that is not
within the scope of the claims of the current application. That subject matter should be
readily identifiable by a person skilled in the art and may assist in putting into practice the
invention as d in the claims of this ation.
The Examples that follow illustrate the invention but do not limit it in any way:
EXAMPLE 11
Formulation :: TTaabblleett ttoo bbee ssuucckkeedd,, hhaavviinngg aa wweeiigghhtt ooff 550000 mmgg
Constituents Amount (mg)
Agomelatine 2
Sucrose for direct ssion 434.25
Pregelatinised maize starch 50
Aspartame 5
Acesulfame potassium 5
Magnesium stearate 3.75
The tablet to be sucked is prepared by mixing the constituents (with four premixing steps)
followed by direct compression with a compression force of 30 kN and at a speed of
,000 tablets per hour. The tablets obtained have a hardness of 50 N.
Examples 2 and 3 are obtained in accordance with the same process:
EXAMPLE 22
Formulation :: TTaabblleett ttoo bbee ssuucckkeedd,, iinngg aa wweeiigghhtt ooff 550000 mmgg
Constituents Amount (mg)
Agomelatine 0.5
Sucrose for direct compression 435.75
Pregelatinised maize starch 50
Aspartame 5
Acesulfame potassium 5
Magnesium stearate 3.75
EXAMPLE 33
Formulation :: TTaabblleett ttoo bbee ssuucckkeedd,, hhaavviinngg aa wweeiigghhtt ooff 550000 mmgg
Constituents Amount (mg)
Agomelatine 1
Sucrose for direct ssion 435.25
atinised maize starch 50
Aspartame 5
Acesulfame potassium 5
Magnesium stearate 3.75
EXAMPLE 44
Formulation :: iidd oobbttaaiinneedd bbyy iinnjjeeccttiioonn--mmoouullddiinngg
Constituents Amount (mg)
Agomelatine 2
Hydroxypropylcellulose 333
Mannitol 150
Aspartame 7.5
Acesulfame potassium 7.5
The solid is prepared by mixing the constituents. The mixture is then poured into a feed
hopper for an Arburg S250 type injection-moulding press. The mixture is heated to 140°C
by the five heating zones of the plasticising unit regulated incrementally from 95°C to
140°C and is injected at 1500 bar into a multi-cavity mould.
EXAMPLE 55
A single-administration pharmacokinetic test was d out in 12 y male
volunteers. Three formulations - two orodispersible tablets and one tablet to be sucked -
were tested. As the orodispersible ceutical formulations can be administered
oromucosally (on top of the tongue) or gually, these two modes of administration
were also considered and assessed. Accordingly, the 12 volunteers were alternatively
given:
- an orodispersible tablet having a central core co ntaining 2 mg of agomelatine,
administered by sublingual application (central core containing 2 mg of
agomelatine, 0.35 mg of magnesium stearate, 67.65 mg of Starlac; outer
layer containing 236.25 mg of Starlac, 2.5 mg of acesulfame potassium,
2.5 mg of aspartame, 7.5 mg of citric acid and 1.25 mg of magnesium
te);
- a layer orodispersible tablet containing 2 mg of atine,
administered by sublingual application (central core containing 2 mg of
agomelatine, 0.35 mg of magnesium stearate, 67.65 mg of Starlac; 2 outer
layers, each of 125 mg, containing 238.75 mg of Starlac, 2.5 mg of
sucralose, 7.5 mg of citric acid and 1.25 mg of magnesium stearate);
- a three-layer orodispersible tablet containing 2 mg of agomelatine,
administered by oromucosal application;
- a tablet to be sucked, according to the invention , containing 2 mg of
agomelatine, administered in the buccal cavity t of Example 1).
Samples of plasma were taken immediately prior to treatment and then regularly from
2 minutes to 24 hours after administration of the tablet, and the following pharmacokinetic
parameters were measured: Cmax (maximum concentration observed following
administration) and AUC (absorption-elimination result for the active ingredient
administered). The following results were obtained:
Absolute
Formulation Cmax (ng/ml) AUC (ng.h/ml) bioavailability
Central core, orodispersible, 8.3 + 4.6 5.7 + 2.7
2 mg of agomelatine (7.8) (5.4) 19 % + 8.6
Sublingual administration
Three-layer, orodispersible, 7.8 + 3.4 5.1 + 2.1
Prior 2 mg of agomelatine (7.5) (5.2) 17 % + 6.6
art gual administration
Three-layer, orodispersible, 8.7 + 2.5 6.1 + 1.6
2 mg of agomelatine (8.7) (6.1) 20 % + 4.9
Oromucosal administration
Example 1 Tablet to be sucked, 2 mg 16 + 4.9 11 + 2.8
of agomelatine (16.0) (11.0) 38 % + 8.9
Buccal administration
The results obtained show that the formulation developed according to the present
invention makes it possible to double the pharmacokinetic parameters obtained using the
persible formulations previously described. The AUC, in direct correlation to the
bioavailability, shows that this new formulation makes it possible to double the
bioavailability obtained, compared to the orodispersible tablet.
EXAMPLE 66
A second single-administration pharmacokinetic test was d out in 12 y male
volunteers. Four formulations - two orodispersible s and two s to be sucked -
were tested. The orodispersible pharmaceutical formulations were administered
sublingually. Accordingly, the 12 volunteers were alternatively given:
- a tablet to be sucked, containing 0.5 mg of agome , administered in the
buccal cavity t of Example 2);
- a tablet to be sucked, containing 1 mg of agomela tine, stered in the
buccal cavity (tablet of Example 3);
- an orodispersible tablet having a central core co ntaining 0.5 mg of
atine, stered by sublingual application (central core containing
0.5 mg of agomelatine, 0.35 mg of ium stearate, 69.15 mg of
Starlac; outer layer containing 236.25 mg of Starlac , 2.5 mg of
acesulfame potassium, 2.5 mg of aspartame, 7.5 mg of citric acid and 1.25 mg
of magnesium stearate);
- an orodispersible tablet having a central core co ntaining 1 mg of agomelatine,
administered by sublingual application (central core containing 1 mg of
agomelatine, 0.35 mg of magnesium stearate, 68.65 mg of Starlac; outer
layer containing 236.25 mg of Starlac, 2.5 mg of acesulfame potassium,
2.5 mg of aspartame, 7.5 mg of citric acid and 1.25 mg of magnesium
stearate).
Samples of plasma were taken immediately prior to treatment and then regularly from
2 minutes to 24 hours after stration of the tablet, and the following pharmacokinetic
parameters were measured: Cmax (maximum concentration observed following
stration) and AUC (absorption-elimination result for the active ingredient
administered). The relative bioavailability blet ing to the invention / AUCorodispersible tablet
from the prior art) was calculated for each individual and the s obtained were averaged. All
the results obtained are set out in the following Table:
Relative
Formulation Cmax (ng/ml) AUC (ng.h/ml) bioavailability
(Ftablet to be sucked /
Forodispersible tablet)
Prior Central core, orodispersible, 3.6 + 1.5 2.7 + 0.97
0.5 mg of agomelatine (3.2) (2.6) -
art Sublingual administration
Example 2 Tablet to be sucked, 0.5 mg 5.3 + 1.2 3.8 + 0.93 1.55 + 0.65
of agomelatine (5.1) (4.0) (1.38)
Buccal administration
Prior Central core, orodispersible, 6.1 + 2.6 4.3 + 1.9
1 mg of atine (5.9) (3.7) -
art Sublingual administration
Example 3 Tablet to be sucked, 1 mg 9.4 + 3.0 7.3 + 2.2 1.86 + 0.75
of agomelatine (9.0) (7.0) (1.54)
Buccal administration
The results ed show that the formulation developed ing to the present
invention, at different dosages (0.5 and 1 mg of active ingredient), makes it possible to
significantly increase the pharmacokinetic parameters compared to those obtained with the
orodispersible formulations bed in the prior art at the same dosages, and wherein the
active principle is under the same form. Accordingly, the relative bioavailability of the new
formulation according to the invention, compared to the orodispersible formulation in the
prior art, shows an improvement by a factor ranging from 1.5 to 1.8.
Claims (15)
1. Solid buccal pharmaceutical composition intended for systemic action, which is a tablet to be sucked, a pastille to be sucked, a lozenge to be sucked, or a solid obtained by 5 hot-melt extrusion or injection-moulding, comprising agomelatine or one of its hydrates, complexes, co-crystals, crystalline forms, addition salts with a pharmaceutically able acid or base, and one or more excipients selected from diluents, s, flow agents, ants, coating agents, plasticisers, flavourings, counter-irritants and sweeteners, characterised in that it makes it le to obtain a release time of the active ingredient 10 comprised between 3 and 30 minutes and an absolute bioavailability greater than 25%.
2. Solid buccal ceutical composition according to claim 1 characterised in that it makes it possible to obtain a release time of the active ingredient comprised between 3 and 30 minutes and a bioavailability greater than that obtained for an orodispersible tablet 15 with an oromucosal absorption ning the active principle agomelatine under the same form and at the same dosage.
3. Pharmaceutical composition according to claim 1 or 2, characterised in that it comprises a diluent having a very good compression lity and providing an erodable 20 character.
4. Pharmaceutical composition according to claim 3, characterised in that the diluent is a polyol or a saccharide. 25
5. Pharmaceutical composition according to one of claims 1 to 4, which is a tablet to be sucked.
6. Pharmaceutical composition according to one of claims 1 to 4, which is a lozenge to be .
7. Pharmaceutical composition according to one of claims 1 to 4, which is a solid obtained by hot-melt ion or injection-moulding.
8. Pharmaceutical composition according to one of claims 1 to 4, which is a pastille to be sucked.
9. Pharmaceutical composition according to one of claims 1 to8 , characterised in that 5 the active ingredient used in its preparation is ed in crystalline form II.
10. Pharmaceutical composition according to one of claims 1 to9 , characterised in that it comprises from 0.1 to 25 mg of agomelatine. 10
11. Pharmaceutical composition according to claim 1 to9 , characterised in that it comprises from 0.1 to 10 mg of agomelatine.
12. Pharmaceutical composition according to claim 1 to9 , characterised in that it comprises from 0.1 to 5 mg of agomelatine.
13. Pharmaceutical composition according to claim 1 to9 , characterised in that it comprises from 0.1 to 3 mg of agomelatine.
14. Pharmaceutical composition according to any one of claims 1 to13 , terised 20 in that it makes it possible to obtain an absolute bioavailability greater than 30 %.
15. Pharmaceutical composition according to any one of claims 1 to13 , characterised in that the relative bioavailability of the tablet to be sucked compared to an orodispersible tablet with an osal tion as defined in WO
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1102500A FR2978916B1 (en) | 2011-08-10 | 2011-08-10 | SOLID PHARMACEUTICAL COMPOSITION FOR BUCCAL ADMINISTRATION OF AGOMELATIN |
FR11/02500 | 2011-08-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ601713A NZ601713A (en) | 2014-01-31 |
NZ601713B true NZ601713B (en) | 2014-05-01 |
Family
ID=
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