WO2012139876A1 - Formulations entériques de modulateurs de récepteur de glutamate métabotropique - Google Patents

Formulations entériques de modulateurs de récepteur de glutamate métabotropique Download PDF

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WO2012139876A1
WO2012139876A1 PCT/EP2012/055309 EP2012055309W WO2012139876A1 WO 2012139876 A1 WO2012139876 A1 WO 2012139876A1 EP 2012055309 W EP2012055309 W EP 2012055309W WO 2012139876 A1 WO2012139876 A1 WO 2012139876A1
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pyrazolo
pyrimidin
methanone
isoquinolin
dihydro
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PCT/EP2012/055309
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English (en)
Inventor
Hermann Russ
Andreas BORTA
Cara Heers
Bernhard Hauptmeier
Peter Boderke
Brigitte Purmann
Axel Tardt
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Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2012139876A1 publication Critical patent/WO2012139876A1/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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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Definitions

  • Enteric formulations of metabotropic glutamate receptor modulators The present invention relates to enteric formulations of metabotropic glutamate receptor (mGluR) modulators, methods for the preparation and testing of these formulations and a medicament for use for the treatment of various diseases, such as neurological disorders and in particular Parkinson disease.
  • Neuronal stimuli are transmitted by the central nervous system (CNS) through the interaction of neurotransmitters released by neurons.
  • the neurotransmitters have a specific effect on neuroreceptors of other neurons.
  • L-glutamic acid is a major excitatory neurotransmitter in the mammalian CNS and plays a critical role in a large number of physiological processes. Glutamate-dependent stimulus receptors are divided into two main groups.
  • the first group comprises ligand-controlled ion-channels, the other comprises metabotropic glutamate receptors (mGluR).
  • Metabotropic glutamate receptors are a subfamily of the G-protein-coupled receptors (GPCR). Eight different members of these mGluR are known and various medical applications have been described. On the basis of structural parameters such as sequence homology, the second messenger system utilized by the receptors and their different affinity to low-molecular weight compounds, these eight receptors can be divided into three groups (I, II and III).
  • MGluRl and mGluR5 belong to Group I which are positively coupled to phospholipase C and their activation leads to a mobilization of intracellular calcium ions.
  • MGluR2 and mGluR3 belong to Group II, whereas mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III, both of which are negatively coupled to adenylyl cyclase, as their activation causes a reduction in second messenger cAMP and thus a dampening of neuronal activity.
  • the mGluR5 modulators which are of particular interest for the present invention, have been shown to modulate the effects of the pre-synaptically released neurotransmitter glutamate via postsynaptic mechanisms.
  • the modulators can be positive and/or negative mGluR5 modulators.
  • the modulators may increase or inhibit the effects mediated through these metabotropic glutamate receptors.
  • the invention relates to enteric (coated) formulations, in particular to formulations of different types of negative allosteric modulators of the mGluR5 receptor. Of particular interest are oral formulations of negative mGluR5 modulators. Such modulators decrease the effects mediated through metabotropic glutamate receptors.
  • a variety of patho-physiological processes and disease states affecting the CNS are related to abnormal glutamate neurotransmission.
  • the negative modulators if applied in an appropriate formulation, are therapeutically beneficial in the treatment of several CNS diseases.
  • the present invention relates to a pharmaceutical formulation, comprising at least one negative allosteric modulator of the mGluR5 receptor and at least one layer of enteric coating (or at least one enteric polymer), where the components of the enteric coating (formulation) are specifically chosen that the pharmaceutical formulation releases the negative allosteric modulator of the mGluR5 receptor in the small and/or large intestine.
  • these negative allosteric modulators of the mGluR5 receptor have been described in the literature, e. g. the compounds 2-methyl-6-phenylethynyl-pyridine (MPEP), l-methyl-6-phenyl-l,2,3,6-tetrahydropyridine (MPTP) and several substituted pyrazolopyrimidine derivatives. Some of these heterocyclic compounds are easily dissolvable in water, but often the compounds have a low solubility in water.
  • US 2003/0059471 describe solid formulations comprising a plurality of discrete, flat flakes containing a drug compound.
  • the drug compound can be of various classes. Some CNS- compounds are mentioned, e.g. the drug compound Fenobam.
  • the application routes of negative allosteric modulators of the mGluR5 receptor can be e.g. the pulmonary, rectal, parenteral, nasal, otological, buccal, dermal and/or oral or a combination of several of these application routes. As the treatment with modulators of the mGluR5 receptor for the related diseases often is a long lasting therapy and because often larger amounts of active substance or combinations of substances are used, the oral application route is preferred and has a high compliance and acceptance by patients.
  • the mGluR5 receptor concentration or the distribution of the receptors varies in different parts of the gastro-intestinal tract. Stimulation of these receptors causes interference with the biological movement process of the gastro-intestinal tract and more generally with the digestion process. Negative allosteric modulators of the mGluR5 receptor can e.g. slow down the digestion or lead to a highly variable digestion process.
  • Some modulator compounds also have a limited stability in an acidic environment (e. g. in the stomach) or do not achieve a good level of bioavailability if applied by immediate release oral formulation.
  • bioavailability describes the percentage of an active substance that is adsorbed in a defined period of time in the blood compared with the dose administered via the oral route.
  • Oral administration of a pharmaceutical product often exposes the active substance to a wide range of influences that may alter the compound.
  • the intestinal flora, various enzymes and food components are among the factors which affect the chemical consistency, the gastrointestinal transport rate and/or the absorption rate of the compound applied.
  • the bioavailability is improved by the specific formulation of the modulator compounds.
  • An oral formulation of a modulator of the mGluR5 receptor is transported into the intestine via the stomach, passing through very different physiological environments. For example, the pH value changes from 1 to 3 in the stomach to 5 to 7 in the duodenum and then to 7 to 9 in the ileum. Further, the specific surface area alters from the stomach to the small intestine, where absorption can occur. Before entering the intestine, the pharmaceutical formulation of a modulator of the mGluR5 receptor is exposed to high proton concentration, which can cause hydrolysis, flocculation and precipitation. Furthermore, the time, quantity and type of food consumed and the level of disease of the patient can determine the speed at which the active substance enters and leaves the intestine. The available concentration of the modulator of the mGluR5 receptor in the blood can therefore vary depending on the type of formulation administered.
  • the modulator of the mGluR5 receptor comes in contact with the stomach surface and can elicit effects like slowing down the emptying of the stomach by interaction with local gastric receptors.
  • the release of the active substance can be directed in the small or large intestine.
  • enteric formulations or enteric coated formulations
  • coated tablets or coated capsules are particularly formulation technologies.
  • Enteric formulation in this context means in particular, that a composition (e.g. tablet or capsule) comprising the modulator of the mGluR5 receptor is combined with, e. g. coated, with a material that permits a transit of the active substance through the (acidic) stomach with only limited or without any release of drug substance in the stomach.
  • the active substance is transported into the intestine or into a special part of the intestine before the active substance is released at a pH of 6.8 or higher.
  • enteric means in particular that the release of the active substance is triggered either in the small intestine or in the large intestine or in both compartments. The selection of the optimal release site depends on the type of disease, the intended plasma peak concentrations, the intended plasma time/concentration-profile and the intended time/concentration profile at the target site of action for the respective active substance.
  • capsule encompasses a pharmaceutically acceptable formulation enclosing a dose of one active substance or a combination of active substances and one excipient or a combination of excipients, which is covered by a polymer shell, which e. g. basically consists of gelatine, starch or cellulose or chemical derivatives and combinations of these polymers.
  • a polymer shell which e. g. basically consists of gelatine, starch or cellulose or chemical derivatives and combinations of these polymers.
  • Capsules can be, depending on their consistency, soft or hard capsules. Their content can be solid, semi solid or liquid.
  • excipient defines a pharmaceutically and/or pharmacologically inactive substance, which passes defined characteristics with relevance for the formulation or the drug product.
  • excipient also encompasses a pharmaceutically acceptable, pharmacologically inactive ingredient such as e. g. a binder, a filler, a coating-forming compound, a plasticizers for coatings and a compound which masks odors.
  • a pharmaceutically acceptable, pharmacologically inactive ingredient such as e. g. a binder, a filler, a coating-forming compound, a plasticizers for coatings and a compound which masks odors.
  • optional excipients are pigments, flavors, sweeteners, opacifiers, anti-adhesives, preservatives, glidants, lubricants and sorbents. Suitable substances are known in the art.
  • excipient applied to pharmaceutical formulations of the invention also refers to a diluent or vehicle with which an active substance is administered.
  • Such pharmaceutical excipient can be from animal, vegetable or synthetic origin, see also A.R. Gennaro, 20 th Edition in “Remington: The Science and Practice of Pharmacy”.
  • granule encompasses aggregates of particles, e.g. powder particles, to form a multi-particle entity.
  • a granule encompasses small particles gathered into a larger, permanent aggregate in which the original particles may still be identified. Granules may be obtained in a granulation process in which powder particles adhere to each other by different physical mechanisms.
  • thermoplastic granulation such as thermoplastic granulation, aqueous or organic solvent based pot granulation, granulation in a tumbling mixer, granulation in a fluidized bed granulator, granulation by spray drying or dry granulation by compaction are known in the field of pharmaceutical compositions.
  • immediate release defines a release rate in which at least 80 % of the active substance is released after 30 minutes after oral application of the formulation.
  • Experimental conditions for measuring the release are the conditions as defined in U.S. Pharmacopoeia, e.g. USP 34, or European Pharmacopoeia, e.g. EP 7.
  • the term “delayed release formulation” encompasses a dosage form from which releases an incorporated active substance in a timely delayed and/or controlled way and/orbly or slowly and in a defined part of the gastro intestinal tract over a period of time as defined in detail.
  • This term encompasses a pharmaceutical formulation comprising a therapeutically effective amount of the active substance (or a pharmaceutically acceptable salt, solvate, polymorphic form or isomer thereof), and at least one release delaying excipient.
  • the term encompasses an enteric coating formulation which may be orally administered to a patient in need thereof.
  • multiple unit dosage form encompasses a formulation which consists of at least two units which contain the effective amount of the mGLuR5 modulator.
  • single unit dosage form encompasses a formulation which consists of only one unit which contains the effective amount of the mGLuR5 modulator.
  • granule encompasses aggregates of particles, e.g. powder particles, to form a multi-particle entity.
  • a granule encompasses small particles gathered into a larger, permanent aggregate in which the original particles may still be identified.
  • Granules may be obtained in a granulation process, in which powder particles adhere to each other by different physical mechanisms. Processes such as thermoplastic granulation, aqueous or organic solvent based pot granulation, granulation in a tumbling mixer, granulation in a fluidized bed granulator, granulation by spray drying or dry granulation by compaction are known in the field of pharmaceutical compositions.
  • pellet encompasses a spherical particle typically created by special granulation technologies.
  • a pellet may be produced by layering active material on a starter particle or by extrusion and spheronisation or by pelletizing in a fluidized bed or by thermal melting, forming, cooling processes. Such processes for producing pellets are known in the field of pharmaceutical formulation development.
  • pharmaceutically acceptable in connection with a substance encompasses an ingredient or a substance which does not affect the safety of a human being and/or is well- tolerated by a human being after administration.
  • polymorphic form encompasses an active substance, a pharmaceutically acceptable salt, solvate or isomer thereof forming different crystal structures or lattices.
  • tablette defines any solid pharmaceutical composition comprising the active substance.
  • the term also encompasses compressed and non-compressed formulations.
  • Non compressed tablets can be manufactured e.g. by thermal or melting processes.
  • ⁇ tablets can be coated or bnon-coated.
  • the coating can be functional or non-functional be e.g. controlling the release of the drug substance from the tablet.
  • Tablet may have any shape, which is common in the field of tablets, such as a round shape, a rectangular shape or an oval shape, or a convex shape, or the shape of a disk, or the shape of a bead. The shape may also be irregular.
  • the term tablet also comprises the term "mini- tablet” and "micro-tablet". Such term is known in the field of pharmaceutical compositions.
  • the mini-tablet has a diameter of less than 6 mm, often from 1 to 5.5 mm.
  • a mini-tablet can e.g. have a weight from 10 to 50 mg.
  • a tablet may be made from granules and/or pellets. The processing of granules and or pellets into tablets is known to a person skilled in the art.
  • the invention also relates to pharmaceutical formulations comprising at least one negative allosteric modulator (NAM) of the metabotropic glutamate receptor 5 and at least one excipient for the delayed release for the active substance.
  • NAM negative allosteric modulator
  • These formulations avoid negative effects of the active substances (NAMs) on the gastric system.
  • NAMs active substances
  • the formulations can in particular be used for the treatment of Levodopa-induced dyskinesia (LID)- They have e.g. a beneficial effect on the mobility of Parkinson's disease (PD) patients.
  • LID Levodopa-induced dyskinesia
  • pyrazolopyrimidine compounds have been disclosed in the literature, see in particular WO 2008/015269 but also WO 2008/015270, WO 2008/015271, WO 2009/095253, WO 2009/095254 and WO2007/006530, which pyrazolopyrimidines are negative modulators of mGluR5.
  • WO 2004/087153 various pyrazolopyrimidines are described, which can act as small molecule immune potentiators (SMIP) and which can be used e.g. for cancer treatment.
  • SMIP small molecule immune potentiators
  • mGluR5 negative allosteric modulators As further examples for mGluR5 negative allosteric modulators, several types of tetrahydroquinolinone compounds have been disclosed e.g. in WO 2005/082856 and WO 2009/095253. Further negative modulators of mGluR5 are described having a quinolinon structure, other examples are octahydro-indole derivatives, like those described in WO2007/006530.
  • the enteric coating of an active substance can determine the location within the gastrointestinal system where the formulation can be dissolved and the active compound can be absorbed. Enteric coating prevents the release of the active substance before it reaches the small intestine and is inert or dissolves only slowly at acidic pH but becomes more rapidly dissolving at neutral or alkaline pH level. This issue becomes particularly relevant in Parkinson disease (PD) patients. Gastrointestinal symptoms are a common and burdensome non-motor manifestation of PD. They are due to dysfunction of the autonomic nervous systems and lead to the expression of pooling saliva, pharyngeal or oesophageal dysphagia, delayed gastric emptying, constipation and difficulty defecating. Several studies reported that up to 100% of PD patients show some gastric emptying abnormality during the course of the disease.
  • This invention relates to an enteric formulation to enhance efficacy in particular for the treatment of Levodopa-induced dyskinesia (LID) in PD patients.
  • LID Levodopa-induced dyskinesia
  • a high benefit of the modulators can be reached in PD patients and can prevent a further delay of gastric emptying.
  • the pyrazolopyrimidines of WO 2008/015269 are of particular interest.
  • Some of the common gastrointestinal dysfunctions of PD patients can be treated with medications. Pooling saliva e.g. can be treated with atropine-like drugs and constipation with laxatives. However, for some other gastrointestinal symptoms, such as delayed gastric emptying, an adequate treatment is lacking. The delayed gastric emptying can cause a reduced absorption of orally administered anti-PD medication.
  • Levodopa is taken up mainly in the duodenum.
  • the treatment of PD patients with the specific formulations is a new approach for Levodopa-induced dyskinesia (LID).
  • LID Levodopa-induced dyskinesia
  • these formulations have additional beneficial effects on the primary symptoms of PD.
  • enteric formulation is useful to overcome the problem of delayed gastric emptying and to avoid further side effects regarding to a delay release of e.g. L- Dopa.
  • L- Dopa Based on an enteric formulation, the release of the substance will occur within the small intestine, mainly in the duodenum.
  • the effect on gastric emptying is a local effect, the resorption of the material with the duodenum will no longer effect the stomach and cause no delay of gastric emptying.
  • the invention provides a formulation, such as a tablet, a capsule, a granule and/or a pellet, comprising as an active substance at least one negative allosteric modulator of the mGluR5 receptor and at least one release-controlling excipient, where the pharmaceutical formulation releases the active substance, namely the at least one negative allosteric modulator of the mGluR5, in the small and/or large intestine.
  • a formulation such as a tablet, a capsule, a granule and/or a pellet, comprising as an active substance at least one negative allosteric modulator of the mGluR5 receptor and at least one release-controlling excipient, where the pharmaceutical formulation releases the active substance, namely the at least one negative allosteric modulator of the mGluR5, in the small and/or large intestine.
  • the pharmaceutical formulation comprising the negative allosteric modulator of the mGluR5 receptor and at least one layer of enteric coating, are made in a way (by chosing the components of the enteric coating), so that the pharmaceutical formulation releases the negative allosteric modulator of the mGluR5 receptor in the small and/or large intestine and not into the stomach.
  • the enteric formulation preferably does not release substantial amounts of the active substance, namely the negative allosteric modulator of the mGluR5, into the stomach.
  • the amount of the mGluR5 modulators released into the stomach should be less than 10 % by weight (in particular less than 5%) of the active substance, in particular less than 3%, often less than 1% by weight.
  • the invention in particular provides a formulation, such as a tablet, a capsule, a granule and/or a pellet, comprising as an active substance at least one negative allosteric modulator of the mGluR5 receptor and at least one release-controlling excipient, in particular at least one layer of enteric coating.
  • a pharmaceutical formulation comprising at least one negative allosteric modulator of the mGluR5 receptor and at least one pharmaceutically acceptable excipient, where the pharmaceutical formulation is preferably an enteric tablet or an enteric capsule.
  • the invention relates to a pharmaceutical formulation, comprising 1 to 800 mg, often from 1 to 600 mg of a negative allosteric modulator compound and at least one layer of an enteric polymer coating which is resistant to gastric acids.
  • the weight ratio of enteric polymer coating and modulator compound can be from 500 : 1 to 0.01 : 10, in particular from 50 : 1 to 0.1 : 1.
  • the weight ratio of enteric polymer coating and modulator compound can also be from 500 : 1 to 1 : 10, in particular from 50 : 1 to 3 : 1.
  • One aspect are pharmaceutical formulations, comprising 1 to 800 mg of a negative allosteric modulator compound and at least one layer of an enteric polymer coating which is resistant to gastric acids, wherein the negative allosteric modulator of the mGluR5 receptor is in the form of a multiple unit dosage form (such as a mini tablet).
  • the invention also relates to a pharmaceutical formulation, comprising an enteric tablet or enteric capsule, having an enteric polymer coating with a thickness of 5 to 900 micrometer.
  • the invention relates to a pharmaceutical formulation comprising an enteric polymer coating which is resistant to gastric acids for at least 4 hours, preferably for at least 24 hours, but which allows at least 50 % of the negative allosteric modulator compound to be released from the formulation at a pH of 6.8 or higher within 60 minutes.
  • the invention also relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor a compound from the group comprising pyrazolo[l,5-a]pyrimidines, tetrahydroquinolinones, fused pyridines, ethinyl- substituted fused pyridines, ethinyl- substituted tetrahydro-quinolones or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor a pyrazolo[l,5-a]pyrimidine compound of formula (I) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof,
  • Y 1 represents N or C-
  • Y 2 represents N or C-
  • Y 3 represents N or C-
  • Y 4 represents N or C-
  • R 1 represents chloro or bromo
  • R 2 and R 3 each independently represent hydrogen, Ci- 6 alkyl, C 3 - 7 cycloalkyl or trifluoromethyl; or
  • R 2 and R 3 both together with the carbon atom of the ring represent a carbonyl group
  • R 4 and R 5 each independently represent hydrogen, Ci- 6 alkyl, C 3 - 7 cycloalkyl or trifluoromethyl; or
  • R 4 and R 5 both together with the carbon atom of the ring represent a carbonyl group
  • R 6 and R 7 independently represent hydrogen, Ci-6-alkyl, C 3 - 7 cycloalkyl or trifluoromethyl; or R 6 and R 7 both together with the carbon atom of the ring represent a carbonyl group; R 2 or R 3 together with R 6 and R 7 may also form a bivalent radical from the group
  • R 10 and R 11 independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, Ci- 6 alkyl, C 3 - 7 cycloalkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci- 6 alkoxy, C 3 -7-cycloalkyloxy, C 2 - 6 alkenyloxy, C 2 - 6 alkynyloxy, heteroaryl, heterocyclyl, aryloxy, heteroaryl oxy, heterocyclyloxy, Ci- 6 alkylamino, di-Ci- 6 alkylamino, C3-7-cyclo- alkylamino, di-C 3 -7-cycloalkylamino, Ci- 6 alkyl-C 3 -7-cycloalkylamino, C 2 - 6 alkenylamino, C 2 - 6 alkynylamino, di-C 2 - 6 alkeny
  • the invention also relates to a pharmaceutical formulation, comprising as negative allosteric modulator of the mGluR5 receptor a pyrazolo[l,5-a]pyrimidine compound of formula (Ig) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof,
  • R 1 represents chloro or bromo
  • R 2 , R 6° and R 1 which may be the same or different, each independently represent hydrogen, Ci- 6 alkyl, amino, hydroxy, halogen, or trifluoromethyl;
  • R 8 and R 9 together with the carbon atoms to which they are attached may form an unsaturated cyclic ring system containing 5 to 7 (i.e. 5, 6 or 7) carbon atoms, wherein 0 to 4 (i.e. 0, 1, 2, 3 or 4) of the carbon atoms of the ring system formed by R 8 and R 9 may be replaced by heteroatoms independently selected from nitrogen, oxygen and sulfur and wherein the ring system may be optionally substituted by one or more (e.g., 1, 2, or 3) substituents, which may be the same or different, independently selected from halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, N-Ci_ 6 alkylaminocarbonyl, di-N,N-Ci- 6 alkylaminocarbonyl, Ci- 6 alkyl, hydroxyCi- 6 alkyl, C 2- 6 alkenyl, Ci-6alkoxy, Ci-6alkoxycarbonyl, Ci-6al
  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor a pyrazolo[l,5-a]pyrimidine compound of formula (Ig) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein the radicals denote:
  • R 1 represents chloro or bromo
  • R 2 , R 3 R 4 R 5 , R 6° and R 1 which may be the same or different, each independently represent hydrogen, Ci- 6 alkyl, amino, hydroxy, halogen, or trifluoromethyl;
  • R 8 and R 9 together with the carbon atoms to which they are attached may form an unsaturated cyclic ring system containing 5 to 7 carbon atoms, wherein 0 to 4 of the carbon atoms of the ring system formed by R 8 and R 9 may be replaced by heteroatoms independently selected from nitrogen, oxygen and sulfur and wherein
  • the ring system may be optionally substituted by one or more substituents, which may be the same or different, independently selected from halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, N-Ci- 6 alkylaminocarbonyl, di-N,N-Ci_ 6 alkylaminocarbonyl, Ci- 6 alkyl, hydroxyCi- 6 alkyl, C 2 - 6 alkenyl, Ci- 6 alkoxy, Ci_ 6 alkoxycarbonyl, Ci-6alkylcarbonyloxy, Ci-6alkylamino, di-Ci-6alkylamino, Ci_ 6alkylcarbonylamino, Ci-6alkylenedioxy, aryl, heteroaryl, heterocyclyl, and cycloC3-i 2 alkyl.
  • substituents which may be the same or different, independently selected from halogen, amino, hydroxy, nitro, cyano, trifluoromethyl
  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor a pyrazolo[l,5-a]pyrimidine or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph of the following compounds:
  • the two enantiomers (R and S) of the compound (6-Bromo-pyrazolo[l,5-a]pyrimidin-2- yl)-(l-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-methanone are of particular interest for the specific enteric formulations, in particular the R-isomer.
  • the invention also relates to a pharmaceutical formulation, comprising the compound (6- Bromo-pyrazolo[l,5-a]pyrimidin-2-yl)-(l-R-methyl-3,4-dihydro-lH-isoquinolin-2-yl)- methanone and at least one layer of enteric coating, where the enteric coating comprises one or several of the following copolymers: methyl aciylate/methacrylic acid copolymers, methyl methacrylate/methacrylic acid copolymers and methacrylic acid/ethyl acrylate copolymers.
  • enteric coated mini-tablets comprising 5 to 40 mg of the particular pyrazolopyrimidin and at least one layer of enteric coating.
  • the invention also relates to a pharmaceutical formulation, comprising as negative allosteric modulator of the mGluR5 receptor a pyrazolo[l,5-a]pyrimidine compound of formula (II) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof,
  • Y 1 , Y 2 and Y 3 independantly are CR 10 , CR 11 , CR 10 R U , R 12 , S or O,
  • Y 1 , Y 2 and Y 3 denotes CR 10 ;
  • R 1 represents chloro or bromo
  • R 2 represents hydrogen, Ci- 6 alkyl, C 3 - 7 cycloalkyl or trifluoromethyl
  • R 3 represents hydrogen, Ci- 6 alkyl, C 3 - 7 cycloalkyl or trifluoromethyl
  • R 2 and R 3 together with the carbon atom of the ring represent a carbonyl group
  • R 4 represents hydrogen, Ci_ 6 alkyl, C 3 - 7 cycloalkyl or trifluoromethyl
  • R 5 represents hydrogen, Ci- 6 alkyl, C 3 - 7 cycloalkyl or trifluoromethyl
  • R 4 and R 3 together with the carbon atom of the ring represent a carbonyl group
  • R 6 represents hydrogen, Ci- 6 alkyl, C 3 - 7 cycloalkyl or trifluoromethyl
  • R 7 represents hydrogen, Ci- 6 alkyl, C 3 - 7 cycloalkyl or trifluoromethyl
  • R 6 and R 7 together with the carbon atom of the ring represent a carbonyl group
  • R 2 or R 3 together with R 6 or R 7 may form a bivalent radical of type CH 2 -CH 2 or CH 2 -0;
  • R 10 , R 11 independantly represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, Ci- 6 alkyl, C 3 -7-cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci_ 6 alkoxy, C 3 -7-cycloalkyloxy, Ci- 6 alkenyloxy, C 2-6 alkynyloxy, heteroaryl, heterocyclyl, aryloxy, heteroaryl oxy, heterocyclyloxy, Ci- 6 alkylamino, di-Ci-6alkylamino, C3-7- cycloalkylamino, di-C 3 - 7 -cycloalkylamino, Ci_ 6 alkyl-C3-7-cycloalkylamino, C 2 .
  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor a pyrazolo[l,5-a]pyrimidine compound of formula (III) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof,
  • R 1 represents chloro or bromo
  • R 2 and R 3 each independently represent hydrogen, Ci- 6 alkyl, C3- 7 cycloalkyl or trifluoromethyl; or
  • R 2 and R 3 both together with the carbon atom of the ring represent a carbonyl group
  • R 4 and R 5 each independently represent hydrogen, Ci- 6 alkyl, C3- 7 cycloalkyl or trifluoromethyl; or
  • R 4 and R 5 both together with the carbon atom of the ring represent a carbonyl group
  • R 6 and R 7 independently represent hydrogen, Ci-6-alkyl, C3- 7 cycloalkyl or trifluoromethyl; or R 6 and R 7 both together with the carbon atom of the ring represent a carbonyl group;
  • R 2 or R 3 together with R 6 and R 7 may also form a bivalent radical from the group CH 2 -CH 2 or CH 2 -O;
  • R 8 represents a radical R 9 or a radical R 10 , whereby one of the two radicals R 8 denotes R 9 and the other radical R 8 denotes R 10 ;
  • R 9 represents a cyclic group selected from aryl, heteroaryl or heterocyclyl, wherein the ring system may be optionally substituted by one or two substituents, which may be the same or different and selected independently from halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, Ci- 6 alkyl, hydroxyCi- 6 alkyl and Ci- 6 alkoxy;
  • R 10 represents hydrogen or Ci- 6 alkyl.
  • the preferred compounds of this general formula (III) used in the formulation are described more in detail in WO 2008/015271.
  • the particularly useful compounds of formula (III) are specified in the claims of WO 2008/015271. To the definitions of the radicals made in this document reference is made explicitly.
  • the invention relates to a pharmaceutical formulation, comprising as negative allosteric modulator of the mGluR5 receptor an amino-substituted fused pyrimidine compound of formula (IV) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein
  • Y represents CR 9 R 10 or NR 11 ;
  • R 1 represents H, Ci- 6 alkyl, or F
  • R 2 represents H, Ci- 6 alkyl, or F
  • R 1 and R 2 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkyl, Ci- 6 alkoxy, amino, hydroxy, cyano, acyl, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R 3 represents H, Ci- 6 alkyl, or F
  • R 4 represents H, Ci- 6 alkyl, or F
  • R 3 and R 4 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkyl, Ci- 6 alkoxy, amino, hydroxy, cyano, acyl, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R 5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC 3 - 6 alkyl, and heterocyclyl;
  • R 6 represents H, Ci- 6 alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci_ 6 alkylamino, and di-(Ci- 6 alkyl)amino, or F;
  • R 7 represents Ci- 6 alkyl, which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci_ 6 alkylamino, and di-(Ci- 6 alkyl)amino, cycloC 3 - 6 alkyl, heterocyclyl, or NR 12 R 13 ;
  • R 6 and R 7 together with the carbon atoms to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkyl, Ci- 6 alkoxy, amino, hydroxy, cyano, acyl, Ci- 6 alkylamino, di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R 8 represents Ci- 6 alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci_ 6 alkylamino, and di-(Ci- 6 alkyl)amino, C3- 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, Ci_ 6 alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci_ 6 alkylamino, and di-(Ci- 6 alkyl)amino, C3- 6 cycloalkylcarbonyl, arylcarbonyl, heteroaryl carbonyl, Ci- 6 alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-
  • R 9 represents H, Ci- 6 alkyl, or F
  • R 10 represents H, Ci- 6 alkyl, or F
  • R 9 and R 10 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkyl, Ci- 6 alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
  • R 11 represents Ci- 6 alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci_ 6 alkylamino, and di-(Ci- 6 alkyl)amino, C3- 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, Ci_ 6 alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci_ 6 alkylamino, and di-(Ci- 6 alkyl)amino, C3- 6 cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, Ci- 6 alkoxycarbonyl, which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci
  • R 12 represents H, Ci- 6 alkyl, or C 3 - 6 cycloalkyl
  • R 13 represents H, Ci- 6 alkyl, or C 3 - 6 cycloalkyl
  • R 12 and R 13 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo.
  • substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo.
  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor an amino-substituted fused pyrimidine compound of formula (V) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof,
  • Y represents CR 6 R 7 , R 8 , O or S
  • R 1 represents H, Ci- 6 alkyl, or F
  • R 2 represents H, Ci- 6 alkyl, or F
  • R 1 and R 2 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
  • R 3 represents H, Ci- 6 alkyl, or F
  • R 4 represents H, Ci- 6 alkyl, or F
  • R 3 and R 4 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
  • R 5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC3-6alkyl, and heterocyclyl;
  • R 6 represents H, Ci- 6 alkyl, or F
  • R 7 represents H, Ci- 6 alkyl, or F
  • R 6 and R 7 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
  • R 8 represents H, Ci-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci_ 6 alkylamino, and di-(Ci-6alkyl)amino, C3-6cycloalkyl, Ci-6alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci- 6 alkylamino, and di-(Ci- 6 alkyl)amino, C 3 - 6 cycloalkylcarbonyl, Ci- 6 alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci- 6 alkylamino, and di-(Ci- 6 alkyl)
  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor an ethinyl- substituted fused pyridine compound of formula (VI) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof,
  • Ri represents aryl, heteroaryl, cycloC 3 -i 2 alkyl, cycloCs- ⁇ alkenyl, or heterocyclyl;
  • W represents CH 2 , - CR 2 R 3 CH 2 -, O, S, or R4;
  • X represents CR 2 R 3 or R 5 ;
  • Y represents CH 2 , -CH 2 CH 2 -, or Re
  • R 2 represents hydrogen, fluorine, hydroxy, Ci- 6 alkyl, aryl-Ci- 6 alkyl, or heteroaryl- Ci -6 alkyl;
  • R 3 represents hydrogen or Ci- 6 alkyl; or R 2 and R 3 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci- 6 alkyl, Ci- 6 alkoxy, amino, hydroxy, cyano, acyl, Ci- 6 alkylamino, di- (Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R4 represents hydrogen, Ci- 6 alkyl, or acyl
  • R 5 represents hydrogen, Ci- 6 alkyl, or acyl
  • R6 represents hydrogen, Ci- 6 alkyl, or acyl
  • aryl means phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci- 6 alkyl, hydroxyCi- 6 alkyl, C 2 - 6 alkenyl, Ci- 6 alkoxy, Ci- 6 alkoxyCi.
  • the invention relates to a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor a tetrahydoquinolinone compound of formula (VII) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein R2 represents C26alkyl, cycloC312alkyl, cycloC312alkyl-C16alkyl, C26alkenyl, C26alkynyl, aryl, biaryl, aryl-heteroaryl, heteroaryl- heteroaryl, heteroaryl-aryl, aryf-Ci- eatkyf, aryl-C26alkenyl, aryl- C2-6alkynyl, heteroaryl, heteroaryl-Cl-6alkyl, heteroaryl- C2-6alkenyl, heteroaryl-C2-6alkynyl, 2, 3-dihydro-l H-indenyl, C2-6alkoxy,
  • R12 represents hydrogen, Cl-6alkyl, aryl, heteroaryl, aryl-Cl-6alkyl or heteroaryl-C 1 6alkyl.
  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor an ethinyl- substituted tetrahydo-quinolinone compound of formula (Villa) or (Vlllb) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof,
  • R 1 represents aryl or heteroaryl, which may be optionally substituted by one substituent selected from amino, Ci-6alkyl, hydroxyCi-6alkyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino;
  • R 2 represents hydrogen or Ci- 6 alkyl;
  • R 3 represents hydrogen or Ci- 6 alkyl;
  • R 4 represents hydrogen or Ci- 6 alkyl
  • R 5 represents hydrogen or Ci- 6 alkyl
  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor a phenyl-ethinyl-substituted heterocyclic compound of formula (IX) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof,
  • n 0 or 1
  • A is hydroxy
  • X is hydrogen and
  • Y is hydrogen, or
  • A forms a single bond with X or with Y;
  • R0 is hydrogen, (C 1-4 alkyl, (C 1-4 alkoxy, trifluoromethyl, halogen, cyano, nitro, - COORi wherein Ri is (C 1-4 alkyl or -COR 2 wherein R 2 is hydrogen or (Ci- 4 alkyl, and
  • R is -COR3, -COOR3, -CO R4R5 or -S0 2 R6, wherein R 3 is (C M alkyl, (C 3 .
  • R 4 and R 5 independently, are hydrogen or (C h alky 1 and R6 is (C h alky!, (C3-7)cycloalkyl or optionally substituted phenyl,
  • R' is hydrogen or (Ci- 4 alkyl
  • R" is hydrogen or (Ci- 4 alkyl, or
  • R and R" together form a group -CH 2 -(CH 2 )m- wherein m is 0, 1 or 2, in which case one of n and m is different from 0, with the proviso that Ro is different from hydrogen, trifluoromethyl and methoxy when n is 0, A is hydroxy, X and Y are both hydrogen, R is COOEt and R and R" together form a group -(CH 2 )2-.
  • the compound of formula (IXa), namely (3aR,4S,7aR)-methyl-4-hydroxy-4-(m-tolyl- ethynyl)octahydro-lH-indole-l-carboxylate, can be used in the specific formulations.
  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as negative allosteric modulator of the mGluR5 receptor an ethinyl- substituted bi-cyclic compound of formula (X) or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof,
  • R 1 represents Ci-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci 6alkylamino, and di-(Ci-6alkyl)amino, C3-6cycloalkyl, heterocyclyl, aryl, heteroaryl, Ci_ 6 alkylsulfonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci_
  • R 2 represents aryl, heteroaryl, cycloC3-i 2 alkyl, or heterocyclyl
  • R 3 represents H, F, OH, Ci-6alkoxy
  • R 4 represents Ci-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci_ 6 alkylamino, and di-(Ci-6alkyl)amino, C3-6cycloalkyl, heterocyclyl, Ci-6alkoxy which may be optionally substituted by one or more substituents selected from halogen,
  • R 5 and R 6 which may be the same or different represent H or Ci- 6 alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci_6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, or
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two additional heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, di- (Ci-6alkyl)amino, and oxo;
  • R and R which may be the same or different represent H or Ci- 6 alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci_6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, or R and R together with the nitrogen atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two additional heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, di- (Ci-6alkyl)amino, and oxo.
  • a further aspect of the invention is a process for the preparation of a pharmaceutical formulation as described above, comprising the step of preparing e.g. a tablet or a capsule containing at least one negative allosteric modulator of the mGluR5 receptor and then providing the tablet or capsule with at least one layer of an enteric coating.
  • the invention relates to the use of a formulation as described above for the treatment or prevention of a condition or disease from the following:
  • Alzheimer's disease Parkinson's disease, Parkinson's dementia, mild cognitive impairment, L-dopa-induced dykinesias (LID), L-dopa-induced dykinesias in Parkinson's disease, dyskinesias, drug induced dyskinesias, dopaminomimetic- induced dyskinesias, tremor, anxiety disorders, social anxiety disorder (SAD), dementia, dementia in Alzheimer's disease, major depressive disorder, depression, migraine, movement disorders, pain, chronic pain, neuropathic pain and gastroesophageal reflux disease (GERD).
  • LID L-dopa-induced dykinesias
  • dyskinesias dyskinesias
  • drug induced dyskinesias drug induced dyskinesias
  • dopaminomimetic- induced dyskinesias tremor
  • anxiety disorders social anxiety disorder (SAD)
  • dementia dementia in Alzheimer's disease, major depressive disorder, depression, migraine
  • the invention relates to the use of a formulation for the treatment or prevention of Parkinson's disease, Parkinson's dementia, L-dopa-induced dykinesias (LID), L- dopa-induced dykinesias in Parkinson's disease, dyskinesias, drug induced dyskinesias, dopaminomimetic-induced dyskinesias, tremor, anxiety disorders, depression, migraine, chronic pain, neuropathic pain and gastroesophageal reflux disease (GERD).
  • LID L-dopa-induced dykinesias
  • dyskinesias dyskinesias
  • drug induced dyskinesias drug induced dyskinesias
  • dopaminomimetic-induced dyskinesias tremor
  • anxiety disorders depression, migraine, chronic pain, neuropathic pain and gastroesophageal reflux disease (GERD).
  • GSD gastroesophageal reflux disease
  • indication areas according to the invention are synucleinopathies, alpha-synucleino- pathies, Lewy body dementia, Neurodegeneration with Brain Iron Accumulation, Multiple system atrophy, Parkinson-plus syndrome, Pick's disease progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
  • PSP Pick's disease progressive supranuclear palsy
  • FTDP-17 parkinsonism linked to chromosome 17
  • the invention relates to a pharmaceutical formulation comprising at least two different active substances, which contains at least one a negative allosteric modulator of the mGluR5 receptor and at least one active substance from the group:
  • Levo-Dopa Carbidopa, Benserazid, L-Serine-2-(2,3,4-trihydroxy-benzyl)- hydrazide, L-Tyrosine-2-(2,3,4-trihydroxy-benzyl)-hydrazide and Glycine-2-(2,3, 4-trihydroxy-benzyl)-hydrazide.
  • the invention relates to a pharmaceutical formulation comprising a substituted pyrazolo[l,5-a]pyrimidine compound (in particular a compound of formula (I) or (Ig)) as negative allosteric modulator of the mGluR5 receptor and Levo-Dopa or the compound Carbidopa.
  • a substituted pyrazolo[l,5-a]pyrimidine compound in particular a compound of formula (I) or (Ig)
  • a compound of formula (I) or (Ig) as negative allosteric modulator of the mGluR5 receptor and Levo-Dopa or the compound Carbidopa.
  • a typical tablet, capsule, granule or pellet has a diameter (longest diameter) of from 0.1 to 18 mm, often from 1 to 10 mm, where the measurement of the diameter may be performed by microscopical methods or by a caliper gauge.
  • each tablet, capsule, granule or pellet has a weight ranging from 1 to 1500 mg.
  • the invention also relates to a pharmaceutical formulation comprising the negative allosteric modulator of the mGluR5 receptor in the form of a multiple unit dosage form.
  • Delayed release formulations or dosage forms are known from other active substances, which can be applied e.g. in form of mini-tablets.
  • Mini-tablets comprising a release- controlling excipient are e. g. known from the drug orfiril®, an agent for the treatment of primary (idiopathic) epilepsy.
  • Mini-tablets, small granules and small pellets (in particular enteric coated) have already been described in the literature.
  • the single unit dosage forms usually refer to diffusion-controlled systems where the drug is dissolved or dispersed throughout a solid matrix and the release of the drug is controlled or sustained either by incorporating a suitable filler within the matrix or by coating the matrix with swellable or nonswellable polymer film(s).
  • the former case is known as a monolithic system where the diffusion of a drug through a matrix is the rate-limiting step.
  • the drug release is commonly governed by the swelling rate of the polymer matrix.
  • the diffusion of the drug through the polymer coating or layer of the system is the rate controlling step.
  • mini-tablets are a preferred embodiment of the invention when drug-excipient or drug-drug interactions may occur in a single unit formulation. They are also found to have less variance in transit time through the gastrointestinal tract than single unit dosage forms.
  • the multiple unit dosage forms usually are based on subunits such as granules, pellets, or mini-tablets. They can be delivered in hard gelatin capsules or transformed into tablets that disintegrate immediately in aqueous media of the gastro-intestinal tract, releasing the delayed release units.
  • the multiple unit dosage forms such as mini-tablets, small granules and small pellets (in particular when enteric coated), offer some advantages over the single unit formulation.
  • Multiple unit forms may offer more predictable gastric emptying, gastric emptying less dependent on the state of nutrition, a high degree of dispersion in the digestive tract, less variability of absorption, and a lower risk of dose dumping.
  • their manufacturing is sometimes more complicated, the filling of gelatin capsules is difficult to accomplish especially in the case where different subunits are involved, and the preparation process of mini-tablets necessitates extra care and fine adjustments of tabletting machines.
  • a typical mini-tablet has a diameter of from 0.1 to less than 6 mm.
  • a multiple unit dosage forms of a modulator of the mGluR5 receptor is provided, wherein the unit is in the form of a tablet, granule, or pellet; or a combination of two or more thereof.
  • the diameter of the unit is from 0.1 to 5 mm, or is from 0.2 to 4.5 mm, or is from 0.5 to 2.5 mm.
  • the weight of the unit e.g. mini-tablet is from 0.1 to 100 mg, or from 0.1 to 50 mg, or from 1 to 25 mg, or from 2 to 10 mg.
  • the enteric polymer coating of the tablets and capsules often is in general from 5 to 900 ⁇ , often also from 10 to 600 ⁇ , or from 20 to 100 ⁇ .
  • the coating thickness can be determined microscopically, e.g. via cross-sectioning a tablet.
  • release-controlling and modifying excipient for the enteric coating water-swellable and/or water-insoluble and/or porous polymers are particularly useful. Suitable polymers are generally known to the person skilled in the art.
  • Examples include: Cellulose polymers and their derivatives including, but not limited to, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, carboxymethyl ethylcellulose, cellulose acetate phthalate, cellulose acetate succinate , polysaccharides and their derivatives, polyalkylene oxides, polyoxyethylenoxide polymers polyethylene glycols, chitosan, alginate, carrageen, galactomannan, tragacanth, agar, acacia, gellan, guar gum, gum arabicum, gum tragacanth, locust bean gum, xanthan gum, pectin, shellack, carboxymethyl amylopectin, chitosan, maleic anhydride copolymers, polyacrylate, polymethacrylate,
  • water- swellable and/or water-insoluble and/or porous polymers are preferred which are resistant to gastric fluid, e. g. at pH 1 to 3, often at pH 1 to 5.5.
  • said release-controlling coating is selected such that in application not more than 10 % by weight of said active substance (modulator of the mGluR5 receptor) are released from said tablet within a period of 2 hours.
  • said delayed release formulation is a multiple unit dosage form (such as a mini-tablet).
  • the invention provides a tablet comprising at least two units, preferably at least 10 units, wherein said unit(s) are granules and/or pellets and/or mini-tablets.
  • the invention provides a capsule or stickpack, comprising at least one unit or the delayed release dosage form or a tablet comprising at least two units, wherein said unit is a granule and/or a pellet.
  • a first release-controlling excipient is a polymer selected from: polyacrylate, polymethacrylate and/or ethylcellulose; and at least one second release-controlling excipient is a polymer selected from: methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, carboxymethyl ethylcellulose, polysaccharides and their derivatives, cellulose acetate phthalate, polyalkylene oxides, polyoxyethylenoxide polymers, polyethylene glycols, chitosan, alginate, carrageen, galactomannan, tragacanth, agar, acacia, gellan, guar gum, gum arabicum, gum tragacanth, locust bean gum, xanthan gum, pectin, shellack, carboxymethyl amylopectin,
  • 2-oxazoline poly(ethyleneimine), polyurethane hydrogels, crosslinked polyacrylic acids and their derivatives
  • copolymers of the aforementioned polymers including block copolymers and graft polymers
  • lipids and waxes including, for example, beeswax, natural or synthetic mono-, di- and triglycerides of medium and long chain fatty acids such as hydrogenated vegetable oils, carnauba wax, petroleum wax, microcrystalline wax, long chain fatty acids, long chain fatty alcohols, esters of fatty acids and fatty alcohols; and mixtures of any of these compounds.
  • said at least one first release-controlling excipient is a polymer selected from polyacrylate and/or polymethacrylate.
  • said poly(meth)acrylate is a non-ionic poly(meth)acrylate.
  • said non-ionic poly(meth)acrylate is an ester of poly(meth)acrylate.
  • said second release-controlling excipient is hydroxypropylmethyl- cellulose.
  • said at least one first release-controlling agent is ethylcellulose.
  • said at least one first release-controlling agent is ethylcellulose; and said at least one second release-controlling excipient is a polyvinyl alcohol or a polyvinyl acetate or a polyvinyl alcohol grafted with polyethylene glycol.
  • lipids and waxes including, for example, beeswax, natural or synthetic mono-, di- and triglycerides of medium and long chain fatty acids such as hydrogenated vegetable oils, carnauba wax, petroleum wax, microcrystalline wax, long chain fatty acids, long chain fatty alcohols, esters of fatty acids and fatty alcohols.
  • copolymers of the polymers listed above including block copolymers and graft polymers. Specific examples of copolymers are commercially available polyethylene oxide-polypropylene oxide block copolymers such as known under the trademark Pluronic® and Tectonic® (BASF).
  • Kollidon SR comprises a physical mixture of polyvinyl acetate and polyvinylpyrrolidone. Specifically, Kollidon SR comprises a mixture of 80 % polyvinyl acetate and 19 % polyvinylpyrrolidone. The mixture contains about 0.8 % sodium lauryl sulfate and 0.2 % silica (by weight).
  • Some release-controlling excipients based on polymethacrylate and/or polymethacrylate- copolymers are e.g. commercially available under the trademark Eudragit. Grades are e.g. Eudragit RS 30 D, Eudragit RL 30 D, Eudragit NE 40 D, Eudragit RS PO and Eudragit NE 30 D, or a combination of two or more thereof.
  • Eudragit RS 30 D contains from 6.11 to 8.26 % ammonia methacrylate moieties based on dry substance determined according to Ph. Eur. 2.2.20.
  • Eudragit RL 30 contains from 10.18 to 13.73 % ammonia methacrylate moieties based on dry substance determined according to Ph. Eur. 2.2.20.
  • Eudragit RS PO contains from 4.48 to 6.77 % ammonia methacrylate moieties based on dry substance determined according to Ph. Eur. 2.2.20.
  • Eudragit NE 30 D is a neutral copolymer of ethyl acrylate with methyl methacrylate.
  • copolymers of methacrylic acid and ethyl acrylate such as Eudragit L 100-55, are of particular interest for the coating of pyrazolopyrimidine containing cores.
  • non-ionic polymers such as non-ionic cellulose ether.
  • An example of such polymers is hydroxypropyl methylcellulose (FIPMC), also called hypromellose, which may be used alone or in combination with other polymers.
  • FEPMC hydroxypropyl methylcellulose
  • Different grades of hydroxypropyl methylcellulose according to the invention include commercially available grades such as HPMC 2208, HPMC 2906 and HPMC 2910. These grades differ in their degree of substitution both with regard to the methyl (or methoxyl) and hydroxypropyl (or hydroxypropoxyl) groups.
  • HPMC 2208 which is e.g.
  • the products Eudragit L and Eudragit S are of particular interest, they are easily available.
  • the relative amount of enteric coating needed in the formulation to achieve the desired release characteristics depends, inter alia, on the selected polymer type and grade, the presence or absence of other excipients having impact on release of active substance, and on the desired drug load.
  • the ratio of this enteric polymer to the active substance is typically selected in the range from about 500 : 1 to about 1 : 100, or from about 50 : 1 to about 1 : 50, or from about 5 : 1 to about 1 : 10. In one embodiment, the ratio of enteric polymer to active substance is from 50 : 1 to about 3 : 1 (weight/weight).
  • said delayed release excipients comprise talc or are employed in combination with talc.
  • an active substance can act systemically or locally. In the case of a systemic action, the active substance reaches the target organ in the bloodstream after absorption. In the case of local action, the point of administration and the point of action are the same (e. g. the stomach), no transport of the active substance is needed.
  • the formulation of the negative allosteric modulator of the mGluR5 receptor is preferably administered orally, often as film coated tablet or sugar coated tablet (dragee). This mode of administration is suitable, as the active compound, in particular the substituted pyrazolopyrimidine of formula (I), is not destroyed by the digestive juices produced by the pancreas. Furthermore, as the modulators of the mGluR5 receptor can have a negative side effect on the stomach, the formulations are advantageous. The modulator of the mGluR5 receptor is better absorbed after having passed through the stomach.
  • the negative allosteric modulators of the mGluR5 receptor can be formulated as enteric products.
  • formulations may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit.
  • formulations are preferably administered in the form of an oral pharmaceutical composition, wherein the drug substance (or a combination of more than one drug substance) is present together with one or more pharmaceutically acceptable excipients.
  • the invention deals with a pharmaceutical formulation
  • a pharmaceutical formulation comprising the negative allosteric modulator of the mGluR5 receptor (or optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof), in particular the substituted pyrazolopyrimidine of formula (I) (see WO 2008/015269), and one or more pharmaceutically acceptable excipients, at least one DOPA-Decarboxylase-Inhibitor, such as a compound from the group:
  • the invention relates to a method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission as described above, such method comprising the step of administering to a living animal, including a human, an enteric formulation of a therapeutically effective amount of a compound selected of those of formula (I) described in WO 2008/015269.
  • the invention relates to the use of an enteric formulation of a compound of formula (I) or of formula (la) as defined in WO 2008/015269 or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the treatment of Alzheimer's disease, Parkinson's disease, Parkinson's dementia, L-dopa-induced dykinesias (LID), L-dopa-induced dykinesias in Parkinson's disease, dyskinesias, tremor, anxiety disorders, depression, migraine, chronic pain, neuropathic pain, gastroesophageal reflux disease (GERD) and fragile X syndrome in mammals, including humans.
  • LID L-dopa-induced dykinesias
  • tremor L-dopa-induced dykinesias in Parkinson's disease
  • anxiety disorders depression, migraine, chronic pain, neuropathic pain, gastroesophageal reflux disease (GERD) and fragile X syndrome in mammals, including
  • the invention in particular relates to the use of a enteric formulation, in particular comprising the substituted pyrazolopyrimidine of formula (I), wherein the condition associated with abnormal glutamate neurotransmission is selected from: L-dopa-induced dyskinesias, Parkinson's disease and anxiety disorders.
  • the invention in particular relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising as active ingredient at least one pyrazolopyrimidine-compound of formula (I) as defined in WO 2008/015269 or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, together with one or more other substances exhibiting neurological effects on Parkinson via a different mechanism.
  • the combination of 1-DOPA with the negative mGluR5 -modulator, in particular the substituted pyrazolopyrimidine of formula (I) can be realized in a single enteric pharmaceutical formulation (as principally described in the prior art) comprising the mGluR5 modulator andl-DOPA, in one pharmaceutical formulation.
  • mGluR5 modulator can be administered conjointly (simultaneously or sequentially).
  • the negative mGluR5 modulator of the present invention and the 1-DOPA must be administered separated by a time interval that still permits the resultant beneficial effect in a mammal.
  • the mGluR5 modulator and the 1-DOPA can be administered on the same day (e.g., each - once or twice daily), preferably within an hour of each other, and most preferably simultaneously.
  • These combination products can e.g. be used for the treatment of Parkinson, dopamin-induced dyskinesias and dopaminomimetic-induced dyskinesias.
  • the negative allosteric modulators of the mGluR5 receptor of the present invention may be in the form of pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable.
  • the negative allosteric modulators of the mGluR5 receptor together with one or more excipients are placed into the form of pharmaceutical formulations (and unit dosages thereof), and in such form are employed as coated tablets or coated, filled capsules, all for oral use.
  • Such pharmaceutical formulations may comprise conventional or new ingredients, with or without additional active substances, and such formulations may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Tablets containing 1 to 800 milligrams of active substance or, more broadly, from 0,5 to 1000 milligrams per coated tablet or capsule are suitable representative forms.
  • the negative allosteric modulators of the mGluR5 receptor may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, especially in the form of a pharmaceutical formulation for the oral route.
  • Suitable dosage ranges are from 1 to 2400 milligrams daily, preferably 10 to 1500 milligrams daily, depending as usual upon the exact formulation, the medical indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • the active substance of the formulation may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia,
  • binding agents e.g., prege
  • the tablets containing the negative allosteric modulators of the mGluR5 receptor can be coated by methods well known in the art.
  • the dose of the components in the formulations of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient.
  • a specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease.
  • the appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
  • the potential toxicity and therapeutic efficacy of the formulations of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the NOAEL (No Observed Adverse Effect Level) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio NOAEL/LD 50 .
  • the invention also relates to a process of preparing the formulations, in particular to the preparation of enteric tablets.
  • Tablets may be produced by methods known in the art, e.g. thermal or melting and/or granulation processes and/or by compression processes or by combinations of these processes.
  • the tablet comprises a compressed matrix containing the modulator-compound.
  • the invention also relates to a process for the preparation of a pharmaceutical formulation, comprising the step of preparing a tablet or capsule containing at least one pyrazolopyrimidine compound of formula (I) (which is a negative allosteric modulator of the mGluR5 receptor) and then providing the tablet or capsule with at least one layer of an enteric coating, comprising a copolymer of methyl acrylate and methacrylic acid and/or a copolymer of ethyl acrylate and methacrylic acid.
  • pyrazolopyrimidine compound of formula (I) which is a negative allosteric modulator of the mGluR5 receptor
  • Typical methods for the preparation thereof include the compression of granules prepared by wet or dry or melt granulation, and the direct compression of powder mixtures.
  • Wet granulation involves the weighing of the active substances and the excipients, plus a binder, mixing the ingredients, agglomerating them, screening them damp, drying them, dry screening, lubrication, and compressing the resultant admixture into tablets.
  • Advantages of wet granulation include improvement of the cohesiveness and compressibility of powders, a good particle size distribution suitable for compression, reduction of dust and airborne contamination, and prevention of the segregation of components.
  • dry granulation the ingredients are weighed, mixed and compacted, such as by roller compaction, and subsequently broken up or screened.
  • the screened granules are lubricated and compressed into tablets. Since no liquid binder solution is used for agglomeration, the powder mixture which is granulated in dry form must comprise at least one dry binding agent such as microcrystalline cellulose, polyvinylpyrrolidone, or a co- processed mixture of lactose and microcrystalline cellulose.
  • dry binding agent such as microcrystalline cellulose, polyvinylpyrrolidone, or a co- processed mixture of lactose and microcrystalline cellulose.
  • One of the advantages of dry granulation methods is that they may be suitable for the processing of sensitive materials, such as moisture- or heat-sensitive ingredients, as no water is added during the process and no heating is required for drying the granules.
  • Grades of microcrystalline cellulose are e.g. known under the trademark Avicel® such as Avicel PH 102.
  • said solid matrix comprises one or several binders selected from starches, sugars, cellulose or modified cellulose such as microcrystalline cellulose or other cellulose derivatives, hydroxypropycellulose, lactose, sugar alcohols such as xylitol, sorbitol, matitol. Binders also include gelatin and polyvinylpyrrolidone. In one embodiment, said solid matrix comprises one or several enteric polymers or release modifying or controlling polymers.
  • the formulations may also comprise further ingredients, such as untreated fumed silica.
  • An appropriate grade is known under the trademark CAB-O-SIL®, such as CAB-O-SIL M5.
  • the solid matrix is prepared as a non-compressed matrix, e.g. by thermal or melt processing the ingredients intended to form said matrix. Subsequent to the preparation of the solid matrix comprising said active substance, said solid matrix is coated with said delayed-release excipient to form an enteric coating.
  • said delayed-release excipient in particular for the substituted pyrazolopyrimidine of formula (I), is selected from the group consisting of water-insoluble polymers, and/or water-swellable polymers, and/or porous polymers. It is also possible to combine excipients from different chemical sub-groups.
  • the polymers used as delayed-release excipient may be provided as organic solutions, organic suspension organic dispersion, aqueous solution, aqueous suspension or aqueous dispersions and sprayed onto tablets using conventional coating equipment.
  • the coating solution, suspension or dispersion will also contain one or more plasticizers, such as glycerol, propylene glycol, polyethylene glycol, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triacetin, triethyl citrate, acetyltri ethyl citrate, acetyltributyl citrate, castor oil, mono- and diglycerides etc.
  • the coating provides adhesive properties
  • at least a second layer of a polymer may be applied to said first coating that is capable preventing sticking.
  • This formulation concept is used, if e.g. the active ingredient interacts with excipients in the functional coating layer or the surface properties of the formulation are inappropriate for a direct coating of a functional coating.
  • the delayed-release excipient is based on a polyacrylate or a polymethacrylate or on polyacrylate and/or polymethacrylate-copolymers, which optionally comprising ammonia aciylate moieties and/or ammonia methaciylate moieties.
  • the invention relates to a formulation comprising the active substance (modulator compound) and as delayed-release excipient a polyacrylate or a polymethacrylate or a polyacrylate copolymer and/or polymethacrylate copolymer, which optionally may contain ammonia aciylate moieties and/or ammonia methaciylate moieties, wherein said active agent is embedded or dispersed in a solid matrix, wherein said solid matrix is coated with said excipient.
  • a formulation comprising the active substance (modulator compound) and as delayed-release excipient a polyacrylate or a polymethacrylate or a polyacrylate copolymer and/or polymethacrylate copolymer, which optionally may contain ammonia aciylate moieties and/or ammonia methaciylate moieties, wherein said active agent is embedded or dispersed in a solid matrix, wherein said solid matrix is coated with said excipient.
  • said tablet is coated with ethylcellulose.
  • a Surelease grade such as Surelease E-7-7050 is employed.
  • said tablet is coated with a hydroxypropyl methylcellulose (HPMC). Grades as defined above may be used, such as HPMC 2208, HPMC 2906 and HPMC 2910.
  • HPMC hydroxypropyl methylcellulose
  • said tablet is coated with an ethylcellulose such a Surelease® grade as defined above, such as Surelease® E-7-7050.
  • said tablet is coated with a cellulose acetate.
  • one or two or more of the above mentioned polymers selected from ethylcellulose, hydroxypropyl methylcellulose, polyvinyl acetate/polyvinyl- pyrrolidone and cellulose acetate; may be used for the preparation of the coating.
  • the invention relates to a a pharmaceutical formulation
  • a pharmaceutical formulation comprising an active substance (which is a modulator compound) and as release- controlling excipient one or more of the following: ethylcellulose; hydroxypropyl methylcellulose; polyvinyl acetate/polyvinylpyrrolidone; cellulose acetate.
  • Said active substance often is embedded or dispersed in a solid matrix.
  • Said solid matrix is coated with said delayedrelease excipient.
  • said release-controlling excipient comprises talc or is employed in combination with talc or talcum powder.
  • Enteric coated tablets suitable for oral administration which contain the negative allosteric modulator of the mGluR5 receptor, in particular the substituted pyrazolopyrimidine of formula (I) (and in particular the compound used in Example 1 of this application), may be prepared by conventional tabletting techniques.
  • the following polymers were found to be particularly useful for the enteric coating:
  • PVAP polyvinyl acetate phthalate
  • copolymers of methacrylic acid and ethyl acrylate are of particular interest.
  • Cellulose Acetate Phthalate also called Acetyl phthalyl cellulose; Aquacoat ; CAP; cellacephate; cellulose acetate benzene- 1,2-dicarboxylate; cellulose acetate hydrogen 1,2-benzenedicarboxylate; cellulose acetate hydrogen phthalate; cellulose acetate monophthalate; cellulose acetophthalate; cellulose acetylphthalate.
  • Cellulose acetate phthalate is cellulose in which about half the hydroxyl groups are acetylated, and about a quarter are esterified with one of two acid groups being phthalic acid, where the remaining acid group is free.
  • Polyvinyl Acetate Phthalate (Phthalavin ® enteric coating polymer, PVAP), Sureteric ® , is a specially blended combination of, plasticizers and other ingredients in a completely optimized dry powder formulation. Designed as an alternative to acrylic polymer systems for aqueous enteric coating of solid dosage forms, it provides consistent, reproducible enteric release profiles which ensures excellent product performance.
  • Hypromellose acetate succinate also called cellulose, 2-hydroxypropyl methyl ether, acetate, hydrogen butanedioate, also called HPMC - AS, also called Aqoat, is hypromellose with acetyl and succinoyl groups.
  • excipients are weighed in, sieved, blended and compressed to core tablets.
  • excipients can be fillers, binders, flow promoters, disintergants and glidants.
  • tablets can be made from compound (Example la):
  • tablets can be made from compound (Example lb):
  • the dispersions can be aqueous based or co-solvent based or mixtures of both. If the dispersions are aqueous based, purified water according to pharmacopeial standards is used.
  • Typical cosolvents are ethanol, isopropanol and acetone.
  • the dispersion can also be a mixture of different cosolvents with varying amounts of water.
  • the dispersions can contain further functional excipients like plasticisers and pigments.
  • the functional polymers can also be combinded.
  • a subcoating layer can be applied to the core tablets.
  • the enteric film is prepared, by the excipients Eudragit L 30 D - 55 (anionic methacrylate), Talc, Macrogol 6000 (Polyethylenglykol) and purified water. Depending on the surface of the core tablets and the batch size an enteric film coating layer with a thickness of 10 to 100 micrometer is applied to the core tablets.
  • a fluid bed coater or a pan coater are used.
  • the coating layer can also be applied via hot melt coating.
  • the respective amount of the above mentioned pyrazolopyrimidine and appropriate types and amounts of excipients are weighed in, sieved, blended and filled into hard capsules.
  • excipients can be filler, binder, flow promoter, disintegrants and glidants.
  • the hard capsules consist either of gelatine, starch, carrageenan or cellulose derivatives like hypromellose or mixtures of these polymers or their derivatives.
  • the hard capsules are then coated with a dispersion of an enteric polymer.
  • the dispersions can be aqueous based or cosolvent based or mixtures of both. If the dispersions are aqueous base, purified water according to pharmacopeial standards is used. Typical cosolvents are ethanol, isopropanol and acetone.
  • the dispersion can also be a mixture of different cosolvents with varying amounts of water.
  • the dispersions can contain further functional excipients like plasticisers and pigments.
  • the functional polymers can also be combined.
  • a sub-coating layer can be applied to the hard capsules.
  • the enteric film is prepared, by the commercially available excipients Aqoat (HPMC - AS), Triethyl citrate, Talc, Sodium Lauryl Sulfate and purified water. Depending on the surface of the hard capsules and the batch size, an enteric film coating layer with a thickness of 50 to 250 micrometer is applied to the hard capsules. A standard dispersion composition for such a coating process is described below:
  • the coating layer can also be applied via hot melt coating.
  • Figure 1 shows on the left side the results of oral administration and on the right side the results of intraperitoneral administration.
  • the same specific pyrazolopyrimidine compound (of example 1) administered by the intraperitoneal route (systemic treatment) at a dose of e. g. 2.5 and 5 mg/kg (pharmacologically effective doses) of compound (Exl) had no effect on gastric emptying.
  • the responses of the pyrazolopyrimidine on gastric emptying in the rats were observed by measuring the content of the stomach after single intraperitoneal (i.p.) administration and after single oral (p.o.) administration.
  • Figure 1 shows the effect on gastric emptying in rats after oral and intraperitoneal application of the compound of example 1 and the control substances Atropine (at 10 mg/kg, p.o. and 0.3 mg/kg, i.p.).
  • a significant delay of gastric emptying (increase of stomach content by 99%) can be seen after oral application of the pyrazolopyrimidine compound.
  • This effect is comparable to the effect of the reference substance Atropine.
  • the pyrazolopyrimidine was applied as compound per se, however, for bigger test animals (such as guinea pigs), enteric coated mini-tabletts containing the compound of Example 1 can be used to avoid stomach release and thereby avoid the delay of gastric emptying.
  • a suitable formulation for a capsule containing 50 milligrams of the above mentioned active ingredient is as follows:
  • enteric coated mini-tabletts and bigger test animals By using enteric coated mini-tabletts and bigger test animals, the local effect (in the stomach) can be avoided.
  • This composition is then filled in a 0.8 ml gelatin capsule, which then is coated with a layer of 200 micrometer of acrylic polymer (Eudragit L and/or Eudragit S).
  • enteric coated mini-tablets containing the compound of example 1 can be applied, which do not release the drug compound into the stomach.
  • a large number of mini-tablets each comprising 5 mg of the R-enantiomer of (6-Bromo- pyrazolo[l,5-a]-pyrimidin-2-yl)-(l-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-methanone are prepared from the following ingredients as follows.
  • the 5 mg of the active ingredient, and the amounts of microcrystalline cellulose (Avicel PH 102), sodium carboxymethylcellulose (Ac-Di-Sol) and silica (Cab-O-Sil M5) are weighted and blended. Magnesium stearate is weighed separately and added to the pre-blend.
  • a free fall blender (Bohle PTM 200) can be used.
  • aqueous polymethacrylate dispersion is prepared from the following ingredients:
  • the aqueous polymethacrylate dispersion containing Eudragit® RS 30D-55 is then sprayed onto the small tablets. A thin layer of an enteric film (coating) was obtained.
  • each tablet contains:
  • magnesium stearate 0.3 mg magnesium stearate
  • each coated tablet is 2.1 mm (longest diameter).
  • the tablets are tested with respect to the drug release over time for the modulator of the mGluR5 receptor (6-Bromo- pyrazolo[l,5-a]-pyrimidin-2-yl)-(l-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-methanone in a dissolution tester using the gastric dissolution medium (simulated gastric fluid).
  • a coated tablet containing an amount of 5 mg (or a multitude of coated granules or mini-tabletts) of the pyrazolopyrimidine is suspended in 750 ml of an acidic solution (SGF) at pH 1.2 After stirring with paddles for 2 hours at 100 rpm, not more than 10 %, in particular not more than 5 %, of the active ingredient is released.
  • SGF acidic solution
  • the dissolution medium is adjusted with phosphate buffer to pH 6.8. This pH-change takes about 2 minutes. The further drug release is observed:
  • enteric mini-tablets can be prepared from the pyrazolopyrimidine of Example 1 and the following components. Firstly, the core of the mini-tabletts is prepared which then is enteric coated.
  • enteric mini-tablets can be prepared from the pyrazolopyrimidine of Example 1 and the following components:
  • enteric mini-tablets can be prepared from the pyrazolopyrimidine of Example 1 and the following components:
  • enteric mini-tablets can be prepared from the pyrazolopyrimidine of Example 1 and the following components: Formulation 8d)
  • enteric mini-tablets can be prepared from the pyrazolopyrimidine of Example 1 and the following components:
  • small enteric granules can be prepared from the pyrazolo- pyrimidine of Example 1 and the following components:
  • small enteric granules can be prepared from the pyrazolopyrimidine of Example 1 and the following components: Formulation 9b)
  • small enteric granules can be prepared from the pyrazolopyrimidine of Example 1 and the following components:
  • the pyrazolo-pyrimidine is granulated in a fluid bed or a conventional granulator with the enteric granulation fluid.
  • Example 10 Preparation of pellets
  • small pellets can be prepared from the pyrazolo-pyrimidine of Example 1 and the following components: Formulation 10a)
  • the pyrazolo-pyrimidine is dispersed homogeneously in the Aquaot/excipient dispersion and spayed on the sugar spheres.
  • small pellets can be prepared from the pyrazolo-pyrimidine of Example 1 and the following components:
  • small pellets can be prepared from the pyrazolo-pyrimidine of Example 1 and the following components:
  • the pyrazolo-pyrimidine is dispersed homogeneously in the organic Eudragit dispersion and spayed on the sugar spheres.
  • small pellets can be prepared from the pyrazolo-pyrimidine of Example 1 and the following components: Formulation lOd)
  • the pyrazolo-pyrimidine is dispersed homogeneously in the aqueous FIPMC solution and sprayed onto the cellulose spheres.
  • the organic Eudragit dispersion is sprayed on top as a second layer.
  • enteric mini-particles can be prepared from the pyrazolopyrimidine of Example 1 and the following components:
  • Example 1 5 mg of the active ingredient of Example 1 and the amounts mentioned of the further components are weighted and then blended.
  • the powder is compressed into small mini- tablets.
  • These mini-tablets have a weight of 20 mg each.
  • the mini-tablets are than enteric coated with an aqueous dispersion containing Eudragit L 100-55. In this dispersion the above mentioned further additives are used.
  • the dissolution characteristics of the enteric coated mini-tablets were studied.
  • several of the coated mini-tablets are tested in a dissolution tester with the paddle apparatus for several hours in water (SGF-water, at pH 1.2) at room temperature.
  • mini-tablets comprising the pyrazolopyrimidin compound of example 1 and an enteric coating as described above, the mini-tablets were used in clinical studies performed with 18 healthy human volunteers.
  • mini-tablets containing the enteric coated pyrazolopyrimidin could be applied and swallowed very easily, the mini- tablets were well tolerated and the volunteers after oral application of the mini-tablets showed no delayed emptying of the gastric system.
  • mini-tablets described in example 11 can be filled into small bags or stick packs.
  • the mini- tablets can be filled into small bags which can then be orally applied to the volunteer or patient.

Abstract

La présente invention concerne une formulation pharmaceutique comprenant au moins un modulateur allostérique négatif du récepteur mGluR5 et au moins un excipient pharmaceutiquement acceptable sous la forme d'un comprimé entérique, une capsule entérique ou une forme pharmaceutique unitaire multiple qui a une activité améliorée pour le traitement de la maladie de Parkinson.
PCT/EP2012/055309 2011-04-14 2012-03-26 Formulations entériques de modulateurs de récepteur de glutamate métabotropique WO2012139876A1 (fr)

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WO2014199316A1 (fr) * 2013-06-12 2014-12-18 Novartis Ag Formulation à libération modifiée
CN114366717A (zh) * 2022-01-11 2022-04-19 四川农业大学 一种基于egcg纳米粒的肠溶固体分散体颗粒、制备方法及其应用
US11878001B2 (en) 2017-07-31 2024-01-23 Novartis Ag Use of mavoglurant in the reduction of ***e use or in preventing relapse into ***e use

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WO2014199316A1 (fr) * 2013-06-12 2014-12-18 Novartis Ag Formulation à libération modifiée
KR20160018702A (ko) * 2013-06-12 2016-02-17 노파르티스 아게 변형 방출 제제
JP2016520663A (ja) * 2013-06-12 2016-07-14 ノバルティス アーゲー 調節放出製剤
EA031395B1 (ru) * 2013-06-12 2018-12-28 Новартис Аг Состав с модифицированной кинетикой высвобождения
KR102290249B1 (ko) 2013-06-12 2021-08-17 노파르티스 아게 변형 방출 제제
US11878001B2 (en) 2017-07-31 2024-01-23 Novartis Ag Use of mavoglurant in the reduction of ***e use or in preventing relapse into ***e use
CN114366717A (zh) * 2022-01-11 2022-04-19 四川农业大学 一种基于egcg纳米粒的肠溶固体分散体颗粒、制备方法及其应用

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