WO2012016708A1 - Forme pharmaceutique orale comportant la diméboline et le donézépil - Google Patents

Forme pharmaceutique orale comportant la diméboline et le donézépil Download PDF

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Publication number
WO2012016708A1
WO2012016708A1 PCT/EP2011/003925 EP2011003925W WO2012016708A1 WO 2012016708 A1 WO2012016708 A1 WO 2012016708A1 EP 2011003925 W EP2011003925 W EP 2011003925W WO 2012016708 A1 WO2012016708 A1 WO 2012016708A1
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Prior art keywords
weight
dosage form
oral dosage
dimebolin
donepezil
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PCT/EP2011/003925
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English (en)
Inventor
Ralph Stefan
Sandra Brueck
Daniela Stumm
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Ratiopharm Gmbh
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Publication of WO2012016708A1 publication Critical patent/WO2012016708A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Oral dosage form comprising dimebolin and donepezil
  • the invention relates to oral dosage forms comprising dimebolin and donepezil and to processes for producing them.
  • Dimebolin (synonyms Dimebon, latrepirdine) is a ⁇ -carboline derivative with antihista- minic and cognition-enhancing effects. Dimebolin appears suitable for the treatment of Huntington's disease, schizophrenia, amyotrophic lateral sclerosis, stroke, chronic and neuropathological pain or also for slowing down the ageing process. In addition, dimebolin appears promising for the treatment of neurodegenerative diseases, such as Alzheimer's disease, as described in EP 0 876 818 Bl .
  • dimebolin 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methyl-3- pyridyl)ethyl)-lH-pyrido(4,3-b)indole.
  • formula (1) The chemical structure of dimebolin is shown in formula (1) below:
  • compositions containing dimebolin are known from WO 2008/069963 Al or WO 2007/087425 Al, for example.
  • Donepezil is a member of the group of reversible cholinesterase inhibitors. The inhibition of that enzyme causes an increase in the concentration of acetylcholine in the synaptic gap, as a result of which acetylcholine receptors are increasingly activated. Donepezil is used for the symptomatic treatment of mild to moderately severe dementia of the Alzheimer's disease type, but is also used, beyond the scope of its approval, for vascular dementia.
  • donepezil (i?S)-l-benzyl-4-[(5,6-dimethoxyindane-l-one-2-yl) methyljpiperidine.
  • formula (2) The chemical structure of donepezil is shown in formula (2) below:
  • compositions containing donepezil are known from WO 2006/045512 Al .
  • dimebolin can act as an NMD A antagonist and can therefore be used in the treatment of neurodegenerative diseases such as Alzheimer's disease.
  • WO 2008/069963 Al also specifically discloses two oral dosage forms of dimebolin, though these are not particularly advantageous with regard to either their release behaviour or their processability.
  • WO 2008/051599 A2 discloses the administration of combinations of active agents. However, no pharmaceutical formulation is disclosed which permits the advantageous joint oral administration of two active agents against Alzheimer's disease.
  • the object of the present invention is therefore to provide dosage forms, preferably oral dosage forms, which contain two active agents together and can be used for the combination therapy of degenerative diseases and in particular Alzheimer's disease.
  • dosage forms in which possible interactions between the two active agents could be ruled out.
  • production processes in which the active agents could be processed simply and without complex procedures.
  • the subject matter of the invention is therefore an oral dosage form comprising dimebolin and donepezil in a weight ratio of between 20: 1 and 1 :5.
  • a further subject matter of the present invention is a process for producing the oral dosage form of the invention, comprising:
  • a further subject matter of the present invention is a process for producing the oral dosage form of the invention, comprising:
  • step d2) converting the mixture resulting from step c2) into a suitable dosage form, preferably compressing the resulting mixture into tablets.
  • the purpose of this process variant is in particular to produce the two-phase oral dosage form described below.
  • steps al) and a2) and dl) and d2) respectively are preferably identical.
  • the term “dimebolin” comprises 2,3,4,5-tetrahydro-2,8- dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-lH-pyrido(4,3-b)indole according to formula (1) above.
  • the term “dimebolin” comprises all the pharmaceutically acceptable salts, hydrates, polymorphous forms and/or solvates thereof.
  • the term “dimebolin” preferably comprises dimebolin dihydrochloride.
  • Dimebolin dihydrochloride exhibits a pronounced polymorphism and, according to WO 2009/1 1 1540 Al, has six different polymorphous forms, namely anhydrous dimebolin dihydrochloride, dimebolin dihydrochloride hemihydrate, dimebolin dihydrochloride monohydrate, dimebolin dihydrochloride dihydrate, dimebolin dihydrochloride trihydrate and amorphous dimebolin dihydrochloride. Dimebolin dihydrochloride dihydrate and dimebolin dihydrochloride trihydrate are preferably used.
  • the term “donepezil” comprises (i?S)-l-benzyl-4-[(5,6- dimethoxyindane- 1 -one-2-yl)methyl]piperidine or DL- 1 -benzyl-4-[(5,6-dimethoxy- indane-l-one-2-yl)methyl]piperidine dione in accordance with formula (2) above.
  • the term “donepezil” comprises all the pharmaceutically acceptable salts, hydrates, polymorphous forms and/or solvates thereof. It is preferable for donepezil hydrochloride, especially donepezil monohydrochloride to be used.
  • the weight ratio between (A) dimebolin and (B) donepezil is usually between 20: 1 and 1 :5, preferably between 15: 1 and 1 :3, more preferably between 10: 1 and 1 :2, particularly preferably between 8 : 1 and 1 : 1 and especially between 7 : 1 and 2 : 1.
  • oral dosage forms are understood to mean capsules, tablets, pellets, granules or powders, for example.
  • the oral dosage form of the invention is a tablet.
  • the oral dosage form of the invention especially the tablet of the invention, has a single-phase structure.
  • a single-phase structure is understood to mean a structure which has a uniform structure within a particular phase.
  • a uniform structure within a particular phase is understood here to mean the substantially uniform spatial distribution of all the components within that phase.
  • a single-phase structure of a tablet is therefore understood to mean the substantially uniform spatial distribution of all the components within that tablet phase, a possible tablet coating not being regarded as part of that tablet phase.
  • the oral dosage form of the invention has a two-phase structure.
  • the dosage form has a first phase and a second phase.
  • the tablet of the invention therefore has a first phase, in which the components of that phase are preferably distributed spatially uniformly within that phase, and a second phase, in which the components of that phase are preferably distributed spatially uniformly within that phase.
  • the arrangement of the first and second phases to one another can take any form desired.
  • the first phase may, for example, form a first tablet core and the second phase the second tablet coating and vice versa. With an arrangement of this kind, one speaks of coated tablets. It is also possible for the two phases to be arranged in such a way that the first phase is arranged as a layer on the second phase and vice versa. With an arrangement of this kind, one speaks of bilayer tablets.
  • the tablet of the invention comprises a first phase (preferably an intragranular phase), which is uniformly distributed in the form of granules in the second phase (preferably an extragranular phase) in the form of a powder mixture.
  • each of the phases preferably contains an active agent, in particular the first phase dimebolin and the second phase donepezil.
  • the second phase may also be granulated. In this case, a first granulated phase and a second granulated phase are subsequently blended and compressed.
  • Dimebolin is generally used in the oral dosage form of the invention in an amount of 2 to 40 % by weight, preferably 3 to 30 % by weight, more preferably 4 to 25 % by weight, especially 5 to 20 % by weight, based on the total weight the oral dosage form.
  • Donepezil is generally used in the oral dosage form of the invention in an amount of 0.5 to 35 % by weight, preferably 1 to 25 % by weight, more preferably 3 to 20 % by weight, especially 5 to 15 % by weight, based on the total weight the oral dosage form.
  • the dimebolin per se or a pharmaceutically acceptable salt thereof used in the dosage form has a water content of 0.1 to 15 % by weight in each case, more preferably 1.0 to 14 % by weight, e.g. 4.0 to 13 % by weight, and particularly preferably 6.0 to 12.5 % by weight.
  • the donepezil per se or a pharmaceutically acceptable salt thereof used in the dosage form has a water content of 0.01 to 10 % by weight in each case, more preferably 0.25 to 8.0 % by weight, e.g. 0.57 to 7.5 % by weight, and particularly preferably 1.0 to 5 % by weight.
  • the water content is preferably determined according to the Karl Fischer method, using a coulometer at 160° C.
  • a Metrohm 831 KF coulome- ter with a titration cell without a diaphragm is preferably used.
  • a 150 mg sample of dimebolin or donepezil is analysed.
  • the oral dosage forms of the invention may contain not only dimebolin and donepezil, but also further pharmaceutical excipients. These are usually the excipients with which the person skilled in the art is familiar, especially those which are described in the European Pharmacopoeia. Examples of excipients used are disintegrants, anti-stick agents, additives to improve the powder flowability, wetting agents and/or lubricants. Where appropriate, further excipients can also be used. These excipients will be explained in more detail below.
  • the oral dosage form of the invention contains a (C) filler in addition to the active agents.
  • a (C) filler in addition to the active agents.
  • mixtures of the fillers described below are possible.
  • fillers are understood to mean substances which are described as pharmaceutical fillers in the state of the art. These fillers are typically substances which are needed in order to form the body of the oral dosage form in the case of dosage forms with small amounts of active agent, so as to obtain a sufficient amount of dosage form mixture for a suitable dosage form size.
  • Si0 2 modified microcrystalline cellulose e.g. Prosolv ® , Rettenmaier & Sonne, Germany
  • Si0 2 modified microcrystalline cellulose e.g. Prosolv ® , Rettenmaier & Sonne, Germany
  • fillers that can be used are sugar alcohols and/or sugars (especially monosaccharides and disaccharides) such as mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof.
  • the fillers are preferably selected from mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, dicalcium hydrogen orthophosphate (preferably as the anhydrate) and starch. Particularly preferred fillers are lactose, microcrystalline cellulose and mixtures thereof.
  • alpha-lactose monohydrate is preferably used.
  • the average particle size (D50) of a-lactose monohydrate is preferably between 60 and 200 ⁇ .
  • fillers are usually employed in amounts of between 15 and 95 % by weight, preferably between 25 and 85 % by weight, more preferably between 35 and 75 % by weight, particularly preferably between 45 and 75 % by weight, based on the total weight of the tablet.
  • the tablet of the invention comprises a first and a second phase
  • fillers are usually employed in the first phase in amounts of between 0 and 40 % by weight, preferably between 5 and 35 % by weight, particularly preferably between 10 and 20 % by weight, based on the total weight the tablet, and in the second phase in amounts of between 0 and 70 % by weight, preferably between 10 and 60 % by weight, particularly preferably between 25 and 55 % by weight, based on the total weight of the tablet.
  • the filler has a yield pressure value of less than 80 MPa. In the following, the meaning of the "yield pressure value" for the purposes of this invention will be explained.
  • Excipients can generally be classified with regard to the change in the shape of the particles under a compressive force (compaction): plastic excipients are characterised by plastic deformation, whereas when compressive force is exerted on brittle excipients, the particles tend to break into smaller particles. Brittle behaviour on the part of the filler can be quantified by the increase in the surface area in a moulding.
  • the values for the "yield pressure” here are low for plastic substances but high in the case of friable substances on the other hand [Duberg, M, Nystrom, C, 1982, Studies on direct compression of tablets VI. Evaluation of methods for the estimation of particle fragmentation during compaction. Acta Pharm. Suec. 19, 421-436; Humbert-Droz P., Mordier D., Doelker E. Methodeless de determination du into a la compression pour des etudes de preformulation. Pharm. Acta Helv., 57, 136-143 (1982)).
  • the "yield pressure value” describes the pressure that has to be reached for the excipient (i.e. preferably the filler) to begin to flow plastically.
  • the “yield pressure value” is preferably calculated using the reciprocal of the gradient of the Heckel plot, as described in York, P., Drug Dev. Ind. Pharm. 18, 677 (1992).
  • the measurement in this case is preferably made at 25° C and a deformation rate of 0.1 mm/s.
  • an excipient (especially a filler) is deemed a non-brittle excipient if it has a "yield pressure value" of no more than 150 MPa, preferably 5 to 80 MPa.
  • An excipient is usually described as a brittle excipient if it has a "yield pressure value" of more than 80 MPa, preferably more than 150 MPa.
  • Brittle excipients may have a yield pressure value of up to 500 MPa.
  • Examples of preferred non-brittle fillers are mannitol or lactose.
  • Examples of preferred brittle fillers are microcrystalline cellulose (MCC), especially with a specific surface area of 0.7 - 3.0 m 2 /g, the specific surface area being determined by means of the gas adsorption method according to Ph. Eur., 6th edition 2.9.26., method 1, dicalcium hydrogen phosphate, tricalcium phosphate and/or calcium carbonate.
  • the filler comprises at least one filler with a yield pressure value of less than 80 MPa and one filler with a yield pressure value of more than 80 MPa.
  • the oral dosage form of the invention also optionally contains (D) disintegrants.
  • Disintegrants for the purposes of the invention are understood to mean substances which accelerate the disintegration of an oral dosage form, especially a tablet, after it is placed in water. Suitable disintegrants are organic disintegrants such as starch, pregelat- inised starch, carrageenan, croscarmellose and/or crospovidone. Alkaline disintegrants are likewise used. The term “alkaline disintegrants” means disintegrants which, when dissolved in water, produce a pH level of more than 7.0. Starch, especially pregelatinis- ed corn starch, is preferred as the disintegrant.
  • disintegrants are usually employed in amounts of 2 to 25 % by weight, preferably 5 to 15 % by weight, particularly preferably 7 to 12 % by weight, based on the total weight of the tablet.
  • disintegrants are usually employed in the first phase in amounts of between 0 and 10 % by weight, preferably between 1 and 7 % by weight, particularly preferably between 1.5 and 5 % by weight, based on the total weight the tablet, and in the second phase in amounts of between 1 and 20 % by weight, preferably between 2 and 15 % by weight, particularly preferably between 3 and 10 % by weight, based on the total weight of the tablet.
  • the oral dosage form of the invention optionally contains (E) lubricants.
  • Lubricants are generally used in order to reduce sliding friction. In particular, the intention is to reduce the sliding friction found during tablet pressing between the punches moving up and down in the die and the die wall, on the one hand, and between the edge of the tablet and the die wall, on the other hand.
  • Suitable lubricants are, for example, stearic acid, adipic acid, sodium stearyl fumarate, (Pruv ® ), magnesium stearate and/or calcium stearate. Magnesium stearate is preferred.
  • lubricants are usually employed in amounts of 0 to 5 % by weight, preferably 0.1 to 4 % by weight, particularly preferably 0.5 to 3 % by weight, based on the total weight of the tablet.
  • lubricants are preferably used only in the second phase in amounts of 0 to 5 % by weight, preferably 0.1 to 4 % by weight, particularly preferably 0.5 to 3 % by weight, based on the total weight the tablet.
  • the oral dosage form of the invention optionally contains (F) binders.
  • binders are understood to mean substances with the aid of which solids, preferably powders, can be adhered together.
  • the binder preferably wets all the solid particles uniformly.
  • the nature of the binder can be used to give the filler new processing and material properties.
  • the binders are preferably dissolved in solvent and added in liquid form to the fillers to be bound.
  • the dosage form of the invention may, for example, comprise the following polymers as binders: polysaccharides, such as hydroxypropyl methyl cellulose (HPMC), carboxy- methyl cellulose (CMC, especially sodium and calcium salts), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC); guar flour, alginic acid and/or alginates; synthetic polymers such as polyvinyl pyrrolidone (povidone), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone/ vinyl acetate copolymers (such as Kollidon ® VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of poly- ethylene glycol, especially
  • Binders particularly preferably used are polyvinyl pyrrolidone, preferably with a weight-average molecular weight of 10,000 to 60,000 g/mol, especially 12,000 to 40,000 g/mol, a copolymer of vinyl pyrrolidone and vinyl acetate, especially with a weight-average molecular weight of 40,000 to 70,000 g/mol and/or polyethylene glycol, especially with a weight-average molecular weight of 2,000 to 10,000 g/mol, and HPMC, especially with a weight-average molecular weight of 20,000 to 90,000 g/mol and/or preferably a content of methyl groups of 10 to 35 % and a content of hydroxy groups of 1 to 35 %.
  • Their weight-average molecular weight is usually determined by means of gel permeation chromatography.
  • Preferred solvents for the binders mentioned are water and ethanol.
  • a solution is preferably employed which contains 1 to 10 % by weight, more preferably 2 to 5 % by weight binder.
  • binders are preferably only used in the first phase in amounts of 0.1 to 5 % by weight, preferably 0.5 to 3 % by weight, particularly preferably 0.8 to 2 % by weight, based on the total weight the tablet.
  • the oral dosage form of the invention may additionally contain a (G) flow- regulating agent.
  • flow-regulating agents are understood to mean substances whose task is to reduce both the interparticulate friction (cohesion) between the individual particles in a tableting mixture and their adherence to the wall surfaces of the press mould (adhesion).
  • an additive to improve the powder flowability is disperse silica (e.g. Aerosil ® ).
  • silica is used with a specific surface area of 50 to 400 m 2 /g, more preferably 100 to 250 m 2 /g, determined by gas adsorption in accordance with Ph. Eur., 6th edition 2.9.26., method 1.
  • flow-regulating agents are usually employed in amounts of 0 to 10 % by weight, preferably 0.1 to 5 % by weight, particularly preferably 1 to 3 % by weight, based on the total weight of the tablet.
  • flow- regulating agents may be employed both in one of the two phases and in both phases, usually in amounts of 0 to 10 % by weight, preferably 0.1 to 5 % by weight, particularly preferably 1 to 3 % by weight, based on the total weight of the tablet.
  • the oral dosage form of the invention is preferably used in the treatment of neurodegenerative diseases, especially Alzheimer's disease.
  • neurodegenerative diseases are understood to mean a group of diseases of the nervous system which usually progress slowly, are hereditary or occur sporadically.
  • Alzheimer's disease is understood to mean the pathological loss of mental (cognitive) faculties, accompanied by a decline in intellectual functions such as thought and memory.
  • the oral dosage form of the invention is preferably used in the treatment of Alzheimer's disease patients in whom a monotherapy with dimebolin is inadequate.
  • a monotherapy is understood to mean the treatment of Alzheimer's disease with a drug that only contains one active agent, preferably dimebolin.
  • an inadequate monotherapy is understood to mean a treatment of Alzheimer's disease patients with an active agent, preferably dimebolin, which does not sufficiently slow the progression of the disease and thus does not sufficiently prevent the entry into an advanced stage of the disease.
  • an active agent preferably dimebolin
  • the oral dosage forms of the invention are preferably suitable for administration once daily, preferably in the evenings.
  • the present invention further relates to a process for producing the oral dosage form of the invention.
  • the process of the invention for producing the oral dosage form of the invention comprises
  • Mating is to be understood for the purposes of the invention as meaning a process of combining substances with the aim of achieving a substantially homogeneous distribution of different substances by the action of mechanical forces.
  • Mixing for the purposes of the invention is performed in conventional mixing devices, such as roll mixers, shaking mixers, free-fall mixers, shear mixers, ploughshare mixers, planetary mixing knead- ers, Z or sigma kneaders or fluid or intensive mixers.
  • a free-fall mixer (Turbula ® ) is preferably used.
  • Dry mixing is preferably performed.
  • “Dry mixing” is intended here to mean mixing as described above without the addition of liquids, such as water, organic solvents etc.
  • the mixing time is usually 1 minute to 2 hours, preferably 5 minutes to 1.5 hours, more preferably 10 minutes to 1 hour.
  • dimebolin and donepezil are used in particulate form, with the particle size distribution of dimebolin and donepezil being matched to one another.
  • the dimebolin used has a D50 value of the particle size distribution of 1 to 150 ⁇ , preferably 5 to 120 ⁇ , more preferably 8 to 80 ⁇ , particularly preferably 10 to 70 ⁇ and especially 15 to 55 ⁇ .
  • the dimebolin used normally has a D10 value of the particle size distribution of between 0.5 and 50 ⁇ , preferably between 2.0 and 20 ⁇ .
  • the dimebolin used normally has a D90 value of the particle size distribution of less than 250 ⁇ , preferably less than 200 ⁇ , more preferably 10 to 160 ⁇ , even more preferably 15 to 120 ⁇ and especially 20 to 105 ⁇ .
  • the donepezil used has a D 50 value of the particle size distribution of 1 to 150 ⁇ , preferably 5 to 120 ⁇ , more preferably 8 to 80 ⁇ , particularly preferably 10 to 70 ⁇ and especially 15 to 55 ⁇ .
  • the donepezil used normally has a Di 0 value of the particle size distribution of between 0.5 and 50 ⁇ , preferably between 2.0 and 20 ⁇ .
  • the donepezil used normally has a D90 value of the particle size distribution of less than 250 ⁇ , preferably less than 200 ⁇ , more preferably 10 to 160 ⁇ , even more preferably 15 to 120 ⁇ and especially 20 to 105 ⁇ .
  • the ratio between the D 50 value and the Dio value of donepezil has a value of between 1.1 and 5.0, preferably between 1.2 and 3.0, particularly preferably between 1.3 and 2.5.
  • the ratio of D 50 (dimebolin) : D 50 (donepezil) is usually 5 : 1 to 1 : 5, preferably 3 : 1 to 1 : 3, more preferably 2 : 1 to 1 : 2, and especially 1.5 : 1 to 1 : 1.5.
  • the ratio of Dio (dimebolin) : Dio (donepezil) is usually 5 : 1 to 1 : 5, preferably 3 : 1 to 1 : 3, more preferably 2 : 1 to 1 : 2, and especially 1.5 : 1 to 1 : 1.5.
  • the ratio of D90 (dimebolin) : D90 (donepezil) is usually 5 : 1 to 1 : 5, preferably 3 : 1 to 1 : 3, more preferably 2 : 1 to 1 : 2, and especially 1.5 : 1 to 1 : 1.5.
  • the "particle size" of a particle to be determined is understood in accordance with the invention to mean the diameter of an equivalent particle which is assumed to be spherical and to have the same light-scattering pattern as the particle to be determined.
  • the particle size is determined by means of laser diffrac- tometry. Specifically, a Malvern Instruments Mastersizer 2000 was used to determine the particle size. It is preferable to perform a wet measurement with particles dispersed in a dispersant, 2,000 r.p.m., ultrasound 60 seconds with shading of 4 to 15 %. The evaluation is carried out for particles with a D 50 value of less than 5.0 ⁇ using the Mie method and for particles with a D 50 value of at least 5.0 ⁇ using the Fraunhofer method.
  • particles of the intermediate and “intermediate particles” are used synonymously herein.
  • Particle size distribution of the intermediate is to be understood in the context of this invention as meaning the statistical distribution of the volume portions based on all the particle sizes of the particles of the intermediate.
  • Volume portion means the volume- based proportion in per cent of all particles of a defined particle size.
  • the D90 value of the particle size distribution of the intermediate describes the particle size at which 90 % by volume of the particles have a smaller particle size than the particle size corresponding to the D90 value.
  • the D 50 value of the particle size distribution is defined as the particle size at which 50 % by volume of the particles have a smaller particle size than the particle size corresponding to the D50 value. Likewise, 50 % by volume of the particles then have a larger particle size than the D 50 value.
  • the D 10 value of the particle size distribution of the intermediate is defined as the particle size at which 10 % by volume of the particles have a smaller particle size than the particle size corresponding to the D10 value.
  • the process of compressing, especially by direct compression, can be carried out, as explained above, without further pre-treatment by compressing the mixture obtained from a).
  • a rotary press or eccentric press is preferably used.
  • a compressive force of 2 to 40 kN, preferably 2.5 to 35 kN is usually applied.
  • a compressive force of 1 to 20 kN, preferably 2.5 to 10 kN is usually applied.
  • the orsch ® EK0 is used.
  • the process of the invention for producing the oral dosage form of the invention comprises producing the first phase by means of granulation.
  • the process preferably comprises the following steps: a2) mixing the active agent with pharmaceutical excipients,
  • step d2) converting the mixture resulting from step c2) into a suitable dosage form, preferably compressing the resulting mixture into tablets.
  • "Granulation” is generally understood to mean the formation of relatively coarse or granular aggregate material as a powder by assembling and/or aggregating finer powder particles (agglomerate formation, or build-up granulation) and/or the formation of finer granules by breaking up coarser aggregates (disintegration, or break-down granulation).
  • Granulation can conventionally mean wet or dry granulation.
  • Granulation is generally carried out in conventional granulating devices, such as extruder, perforated-disk, perforated-roll, or fluidised-bed granulators. Compulsory mixers or spray dryers can likewise be used.
  • Dry granulation is generally carried out using pressure or temperature.
  • Wet granulation is generally carried out using binders and/or solvents as described above.
  • the first phase is preferably produced by means of wet granulation.
  • the granulation time especially in the case of wet granulation is usually 1 minute to 1 hour, preferably 2 minutes to 30 minutes.
  • the wet granulation is carried out in a fluidised bed granulator, such as a Glatt ® GPCG 3 (Glatt GmbH, Germany).
  • the granules are preferably dried.
  • the drying step can be performed after or at the same time as the granulation step.
  • "Drying" for the purposes of this invention is understood to mean the separation of liquids adhering to solids.
  • the adhering liquids are preferably water in the form of contact moisture, capillary water, adsorption water, hydration water and water of constitution. Drying generally takes place in conventional drying equipment, such as cabinet or tray dryers, vacuum dryers, fluidised bed dryers, spray dryers or freeze dryers.
  • the drying and granulation process is preferably performed in a cabinet dryer at 30 to 80° C, preferably at 35 to 70° C, particularly preferably at 40 to 60° C.
  • the drying conditions are preferably selected such that drying continues until there is a drying loss of less than 4 %, preferably less than 3 %, particularly preferably less than 2 %.
  • the granulating in step (b2) may be performed by means of dry granulation, especially by means of compacting.
  • the compacting is preferably carried out in a roll granulator.
  • the rolling force is preferably 5 to 70 kN/cm, preferably 10 to 60 kN/cm, more preferably 15 to 50 kN/cm.
  • the gap width of the roll granulator is, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1.5 to 3 mm, especially 1.8 to 2.8 mm.
  • the compacted material is usually granulated.
  • the granulating can be performed with processes known in the state of the art.
  • the granulating is performed in a screen mill.
  • the mesh width of the screen insert is usually 0.1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, especially 0.8 to 1.8 mm.
  • a Comill ® U5 apparatus (Quadro Engineering, USA), for example, is used for granulating, preferably followed by screening.
  • the compacting can be performed in a compactor, wherein the compacted material is granulated through an integrated screen.
  • the granulation conditions are selected such that the resulting particles (granules) have a volume-average particle size ((D 0 ) value) of 50 to 800 ⁇ , more preferably 1 10 to 650 ⁇ , even more preferably 160 to 450 ⁇ , especially 190 to 350 ⁇ .
  • the granulation conditions are preferably selected such that the resulting granules have a bulk density of 0.2 to 0.85 g/ml, more preferably 0.3 to 0.8 g/ml, especially 0.4 to 0.7 g/ml.
  • the Hausner factor is usually in the range from 1.02 to 1.3, more preferably from 1.04 to 1.20 and especially from 1.1 to 1.25.
  • the "Hausner factor" in this context means the ratio of tapped density to bulk density.
  • the tapped and bulk densities are preferably determined in accordance with Ph. Eur 6.0. 2.9.15.
  • the resulting granules are preferably mixed with the second phase (step c2).
  • the mixing process is as defined above.
  • the resulting mixture is converted into a suitable dosage form, preferably compressed (step d2).
  • the process of compression (d2) is performed as already described above under (dl).
  • the second phase is also granulated.
  • the first granulated phase is first produced in steps (a2) to (c2), and then the second granulated phase is produced in analogous steps.
  • the two granulated phases are mixed and then compressed jointly in step (d2).
  • the tableting conditions are preferably selected such that the resulting tablets have a diameter of 2 to 17 mm, preferably 7 to 15 mm, particularly preferably 9 to 13 mm.
  • the tablets resulting from both the alternative embodiments described above preferably have a hardness of 50 to 200 N, preferably 60 to 180 N, particularly preferably 80 to 120 N.
  • the hardness is determined in accordance with Ph. Eur. 6.0, section 2.9.8.
  • the resulting tablets preferably have a friability of less than 3 %, particularly preferably less than 2 %, especially less than 1 %.
  • the friability is determined in accordance with Ph. Eur. 6.0, section 2.9.7.
  • the tablets of the invention usually have a "content uniformity" of 95 to 105 % of the average content, preferably 98 to 102 %, especially 99 to 101 %. (This means that all the tablets have a content of active agent of between 95 and 105 %, preferably between 98 and 102 %, especially between 99 and 101 % of the average content.
  • the "content uniformity” is determined in accordance with Ph. Eur. 6.0, section 2.9.6.
  • the resulting tablets preferably have a mass of 100 to 700 mg, preferably 200 to 600 mg, particularly preferably 300 to 500 mg, based on the total weight the non-film-coated tablet.
  • the preferred tablets of the invention may also be coated with a film layer.
  • the methods of film-coating tablets which are standard in the state of the art may be employed.
  • macromolecular substances are preferably used, such as modified celluloses, polymethacrylates, polyvinyl pyrrolidone, polyvinyl acetate phthal- ate, zein and/or shellack.
  • HPMC is preferably used, especially HPMC with a weight-average molecular weight of 10,000 to 150,000 g/mol and/or an average degree of substitution of -OCH3 groups of 1.2 to 2.0.
  • the thickness of the coating is preferably 5 to 100 ⁇ , more preferably 10 to 80 ⁇ ⁇ . It should, however, be noted that all the statements regarding the weight of the active agents and excipients in this application always refer to the non-film-coated tablet.
  • the oral dosage forms of the invention can preferably serve as dosage forms with immediate release (or "H?" for short).
  • the release profile of the oral dosage forms of the invention according to the USP method after 10 minutes usually indicates a content of active agent released of at least 30 %, preferably at least 60 %, particularly preferably at least 90 %.
  • the active agent release is determined here by means of the USP method at 75 r.p.m. in 0.1 N HC1 at 37° C with a paddle apparatus.
  • the oral dosage form of the invention preferably the single-phase dosage form of the invention, especially the single-phase tablet of the invention, preferably comprises:
  • C) filler in an amount of 20 to 90 % by weight, preferably 50 to 85 % by weight, particularly preferably 60 to 80 % by weight,
  • the individual statements of percentages refer to the content in the tablet without any film layer.
  • the oral dosage form of the invention comprises a first phase, containing A) dimebolin in an amount of 2 to 30 % by weight, preferably 7 to 22 % by weight, particularly preferably 10 to 18 % by weight,
  • C) filler in an amount of 0 to 30 % by weight, preferably 5 to 25 % by weight, particularly preferably 10 to 20 % by weight,
  • F) binder in an amount of 0 to 5 % by weight, preferably 0.5 to 3, particularly preferably 0.8 to 2 % by weight,
  • C) filler in an amount of 20 to 70 % by weight, preferably 30 to 65 % by weight, particularly preferably 35 to 60 % by weight,
  • the individual statements of percentages refer to the content in the tablet without any film layer.
  • dimebolin refers here to the amount of active agent in the form of the (anhydrous) free base.
  • the amount of donepezil specified refers to the amount of donepezil monohydrochloride.
  • Example 1 Tablet with single-phase structure
  • Dimebolin in the form of a dihydrochloride
  • MMC microcrystalline cellulose
  • pregelatinised starch was passed through a screen (# 0.8 mm) and mixed in a Turbula ® Tl 0B for 15 min.
  • Donepezil in the form of the monohydrochloride
  • pregelatinised starch MCC
  • lactose monohydrate were screened into a separate mixing vessel and mixed in the Turbula ® for 15 min. After mixing, the mixture was passed through a 0.8 mm screen.
  • the dimebolin premix was then added to the donepezil premix.
  • the mixture was mixed in the Turbula ® for 15 min, and then magnesium stearate was added through a screen (0.8 mm) and mixed in the Turbula ® for 5 min.
  • the finished mixture was pressed into tablets of 11 mm diameter each, hardness 80-120 N using a Korsch ® EK0.
  • Dimebolin in the form of a dihydrochloride
  • calcium hydrogen phosphate and Kollidon ® VA 64 were passed through a screen (mesh width 0.8 mm) and mixed in the Turbula ® for 15 min.
  • Donepezil in the form of the monohydrochloride
  • Kollidon ® VA 64 and calcium hydrogen phosphate were screened into a separate mixing vessel and mixed in the Turbula ® for 15 min. After mixing, the mixture was passed through a 0.8 mm screen. The dimebolin premix was then added to the donepezil premix. The mixture was mixed in the Turbula ® for 15 min.
  • PVP polyvinyl pyrrolidone
  • CaH phosphate calcium hydrogen phosphate
  • Aerosil ® 200 were added through a screen (mesh width 0.8 mm) and mixed in the Turbula ® for 10 min.
  • Magnesium stearate was added through a screen (mesh width 0.8 mm) and mixed in the Turbula ® for 3 min.
  • the finished mixture was pressed into tablets of 1 1 mm diameter each, hardness 80-120 N.
  • Example 3 Tablet with a first and second phase, wet granulation
  • Dimebolin in the form of a dihydrochloride
  • MCC and pregelatinised starch were passed through a screen (mesh width 0.8 mm) and mixed in a Diosna ® for 2 min.
  • the mixture was granulated with an 8 % aqueous solution of polyvinyl pyrrolidone (Mw 25,000) and then dried in a drying cabinet at 40° C - 60° C until there was a drying loss of less than 2 %.
  • Donepezil in the form of the monohydrochloride
  • pregelatinised starch MCC
  • lactose monohydrate from the second phase were screened into a separate mixing vessel and mixed in the Turbula ® for 15 min. After mixing, the mixture was passed through a screen (mesh width 0.8 mm).
  • Dimebolin in the form of a dihydrochloride
  • MCC pregelatinised starch
  • cross- linked polyvinyl pyrrolidone were passed through a screen (mesh width 0.8 mm) and mixed in the Turbula ® for 10 min.
  • the mixture was compacted using a Gerteis Macro- Pactor and passed through a screen (mesh width 0.8 mm).
  • Donepezil in the form of the monohydrochloride
  • pregelatinised starch, MCC, 50 % lactose-monohydrate and cross- linked polyvinyl pyrrolidone for the outer phase were screened into a separate mixing vessel and mixed in the Turbula ® for 10 min.
  • the mixture was compacted and passed through a screen (mesh width 0.8 mm).
  • the screened premixes were combined and mixed in the Turbula ® for 15 min.
  • magnesium stearate was added through a screen (mesh width 0.8mm) and mixed in the Turbula ® for 5 min.
  • the finished mixture was pressed into tablets of 1 1 mm diameter each, hardness 80-120 N.

Abstract

La présente invention concerne des formes pharmaceutiques orales comportant la diméboline et le donézépil ainsi que leurs procédés de production.
PCT/EP2011/003925 2010-08-06 2011-08-04 Forme pharmaceutique orale comportant la diméboline et le donézépil WO2012016708A1 (fr)

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