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WO2013087808A1 - Composition pharmaceutique comprenant une pyrazolopyrimidine et une cyclodextrine - Google Patents

Composition pharmaceutique comprenant une pyrazolopyrimidine et une cyclodextrine Download PDF

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Publication number
WO2013087808A1
WO2013087808A1 PCT/EP2012/075480 EP2012075480W WO2013087808A1 WO 2013087808 A1 WO2013087808 A1 WO 2013087808A1 EP 2012075480 W EP2012075480 W EP 2012075480W WO 2013087808 A1 WO2013087808 A1 WO 2013087808A1
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WO
WIPO (PCT)
Prior art keywords
pyrazolo
cyclodextrin
pyrimidin
methyl
methanone
Prior art date
Application number
PCT/EP2012/075480
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English (en)
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WO2013087808A8 (fr
Inventor
Bernhard Hauptmeier
Kevin Kiehm
Patrick Plitt
Alda Szlak-Freier
Original Assignee
Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2013087808A1 publication Critical patent/WO2013087808A1/fr
Publication of WO2013087808A8 publication Critical patent/WO2013087808A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • composition comprising a Pyrazolopyrimidine and Cyclodextrin
  • the present invention relates to pharmaceutical compositions containing at least one pyrazolopyrimidine derivative and at least one cyclodextrin.
  • the invention also deals with a process for the preparation of a pharmaceutical composition containing at least one pyrazolopyrimidine derivative and at least one cyclodextrin.
  • the invention also relates to different medical uses of these pharmaceutical compositions.
  • pyrazolopyrimidine derivatives have been described in the literature.
  • different types of substituted pyrazolopyrimidine compounds have been disclosed in WO 2008/015269, WO 2008/015270, WO 2008/015271, WO 2009/095253, WO 2009/095254 and WO2007/006530, wherein the pyrazolo[l,5-a]pyrimidines disclosed are negative modulators of the known receptor 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
  • WO 2004/089471 the use of substituted pyrazolo[l,5-a]pyrimidines for the treatment of diseases is described where it is desirable to inhibit the enzyme 1 lBHSDl .
  • pyrazolopyrimidine compounds are described as inhibitors of ion-channels in human cells.
  • WO 2003/101993 several types of pyrazolopyrimidine compounds and their use for the treatment of hepatitis infections are disclosed.
  • pyrazolopyrimidine derivatives which have a NADPH-oxidase inhibitor activity are described.
  • US 2010/249138 discloses pyrazolopyrimidines of general formula (GK1) and pharmaceutical compositions for the treatment of syndromes after cessation of compulsive behaviours.
  • US 2006/0189633 describes the pyrazolopyrimidine derivate drug Indiplon, which contains a polar acetamido-group and is having the following structure.
  • This compound can be formulated as powder, tablet or oral solution.
  • Various carriers for the compound are described in US 2006/0189633, e.g. selected from the large group of claim 13, encompassing polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), lactose, starches, mannitol, methylcellulose, hydroxylmethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxylpropylmethylcellulose (HPMC), a-cyclodextrin, ⁇ -cyclodextrin and hydroxylpropyl-a-cyclodextrin.
  • PEG polyethylene glycol
  • PVP polyvinylpyrrolidone
  • lactose lactose
  • starches mannitol
  • methylcellulose methylcellulose
  • ethylcellulose hydroxyethylcellulose
  • HPMC hydroxylpropylcellulose
  • HPMC hydroxylpropylmethylcellulose
  • co-crystals of 6-bromo-pyrazolo[l,5-a]pyrimidin-2-yl)-(l-methyl- 3,4-dihydro-lH-isoquinolin-2-yl)-methanone are described, which can be used for CNS- disorders.
  • the co-crystals can be formulated as pharmaceutical formulations such as tablets, capsules and powder formulations.
  • pyrazolo[l,5-a]pyrimidine derivatives are disclosed, which are linked to a heterocyclic amine and which are potent modulators of the receptor mGluR5.
  • Many pyrazolo[l,5-a]pyrimidine derivatives have a low solubility in water, e. g. lower than 0.1 mg per ml of water.
  • the wettability of many pyrazolo[l,5-a]pyrimidine derivatives is very low (measured by contact angles theta » 90°), so that the preparation of aqueous compositions is difficult.
  • the pyrazolo[l,5-a]pyrimidines often exhibit an octanol/water partition coefficient log P greater than 1, in particular from 2 to 5.
  • the lipophilicity of a compound can in general be expressed by the logP or logD value, which is a high value for lipophilic compounds and very low value for hydrophilic compounds.
  • the octanol/water partition coefficient (logP) of the compounds tested according to this invention can be determined by accepted standard methods, such as OECD (1995), Test No. 107: Partition Coefficient (n-octanol/water): Shake Flask Method, OECD Guidelines for the Testing of Chemicals, Section 1 : Physical-Chemical properties, OECD Publishing.
  • the logP value may be determined according to the Draft OECD guideline OECD (2000), OECD Draft guideline for the Testing of Chemicals: 122 Partition Coefficient (n- Octanol/Water): pH-Metric Method for Ionisable Substances.
  • compositions containing pyrazolo[l,5-a]pyrimidine derivatives often are difficult to prepare and/or not stable during storage, in particular when formulated as aqueous preparations. Furthermore, for many pharmaceutical applications, the amount of pyrazolo[l,5-a]pyrimidine derivative needed at the specific site of action is higher than conventional pharmaceutical formulations can provide with.
  • substituted pyrazolo[l,5-a]pyrimidine derivatives such as those mentioned in WO 2008/015269, are molecules with a very low aqueous solubility of e. g. only 2 to 50 microgram per milliliter. The solubility in aqueous media can often not be improved by the adjustment of pH-value, as many pyrazolo[l,5-a]pyrimidine derivatives have no relevant basic or acidic groups.
  • Solvents such as water
  • co-solvents such as DMSO or glycerol
  • solubility is the use of surfactants to design aqueous based solutions for oral applications. This can also lead to an improvement of the solubility of pyrazolopyrimidines.
  • the toxicological acceptance of surfactants in preclinical studies and in human used drug products for acute and chronic use is often limited, the challenges and limitations are similar to those of co-solvent based approaches.
  • compositions should provide with pharmacologically active and well tolerated concentrations of the pyrazolo[l,5-a]-pyrimidine compounds.
  • the low solubility in aqueous media also limits the drug product design space and poses a challenge for preclinical studies and the clinical testing phases and may limit the development options for the marketed drug products.
  • the hydrophobic small molecules of the substituted pyrazolo[l,5-a]pyrimidine derivatives (P) were found to be solubilised by the use of cyclodextrin derivatives (C), e.g. via the formation of van-der-Waals complexes.
  • the pharmaceutical composition of this invention often comprises a pyrazolo[l,5-a]pyrimidine derivative which has a molecular weight between 200 and 800 g/mol, such as those mentioned in WO 2008/015269.
  • the composition also contains, as an additional component, together with the active compound (P), a cyclodextrin derivative (C).
  • Cyclodextrins (C) are known to be cyclic oligosaccharides with a hydrophilic outer surface and a hydrophobic cavity. Typical examples of cyclodextrins are alpha-cyclodextrins, beta-cyclodextrins and gamma- cyclodextrins. They differ in the size of the cavity formed by the sugar-units. For the purpose of this invention, beta-cyclodextrins and gamma-cyclodextrins are preferably used. In particular, non-native cyclodextrins are used, in particular cyclodextrins that have been chemically modified, e. g. by hydroxyalkylation. These can be used with poorly soluble pyrazolo[l,5-a]pyrimidine derivatives (P), such as those mentioned in WO 2008/ 015269.
  • P poorly soluble pyrazolo[l,5-a]pyrimidine derivatives
  • formulations can be prepared, which increase the solubility of a pyrazolo[l,5-a]pyrimidine derivative into the milligram/ml range.
  • the formation of complexes of a pyrazolo[l,5-a]pyrimidine derivative (P), such as those mentioned in WO 2008/ 015269, and a cyclodextrin derivative (C) can occur with and without heating and in the absence of further excipients (e. g. co-solvent or emulsifier).
  • the invention therefore relates to pharmaceutical compositions comprising at least one pyrazolo-[l,5-a]pyrimidine compound (P) or a pharmaceutically acceptable salt (or a co- crystal) or a stereoisomeric form (or a polymorphic form) thereof and at least one pharmaceutically acceptable cyclodextrin compound (C) and optionally one or more further components (F).
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one pyrazolo[l,5-a]pyrimidine compound (P) of formula (I)
  • 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_ 3 alkyl, C 3 - 6 cycloalkyl or trifluoromethyl;
  • R 4 and R 5 each independently represent hydrogen, Ci_ 3 alkyl, C 3 - 6 cycloalkyl or trifluoromethyl;
  • R 6 and R 7 independently represent hydrogen, Ci_3-alkyl, C 3 - 6 cycloalkyl or trifluoromethyl;
  • R 10 and R 11 independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, Ci-C3alkyl, Ci-C3alkyloxy, cyclohexyl, phenyl, or a ring system radical from the group: furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrazolyl, benzofuryl, benzothieny
  • R 10 and R 11 together with the two carbon atoms carying them represent a heteroaryl having 5 or 6 ring members or a heterocyclyl group having 5 or 6 ring members, which can be substituted by one of the following groups: halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, Ci_3alkyl and Ci_3alkoxy;
  • the groups Y 1 to Y 4 in formula (I) often all denote a carbon atom, in some embodiments of the invention, three or four of the groups Y 1 to Y 4 denote carbon atoms.
  • the invention also relates to a pharmaceutical composition, comprising at least one pyrazolo[l ,5-a]pyrimidine compound of formula (I) in which the radicals denote:
  • R 10 and R 1 1 independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, Ci-C 3 alkyl, Ci-C 3 alkyloxy, cyclohexyl, phenyl, or a ring system from the group: thiophene, pyrrole, furane, pyrazole, tetrazole, oxazole, isoxazole, thiazole, pyridine, pyrimidine and morpholino, or a pharmaceutically acceptable salt or a stereoisomeric form thereof. Often, R 10 and R 1 1 both represent hydrogen.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one pyrazolo[l ,5-a]pyrimidine compound of formula (I) in which:
  • R 2 , R 3 , R 4 and R 5 independently represent hydrogen, methyl, ethyl or trifluoromethyl
  • R 6 and R 7 independently represent hydrogen or methyl
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one pyrazolo[l ,5-a]pyrimidine compound of formula (I) in which:
  • R 2 and R 3 represents methyl, ethyl or trifluoromethyl and the remaining of R 2 and R 3 represents hydrogen, or a pharmaceutically acceptable salt or a stereoisomeric form thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pyrazolo[l ,5- ajpyrimidine compound of formula (I) in which:
  • R 1 denotes bromo
  • one of R 2 and R 3 represents methyl, ethyl or trifluoromethyl and the remaining of R 2 and R 3 represents hydrogen, or a pharmaceutically acceptable salt or a stereoisomeric form thereof.
  • the invention also relates to a pharmaceutical composition comprising at least one pyrazolo[l ,5-a]pyrimidine compound of formula (I), wherein:
  • R 1 denotes bromo
  • R 2 represents methyl or ethyl
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 10 and R 1 1 all represent hydrogen and which has at least one chiral carbon atom in the R-configuration, or a pharmaceutically acceptable salt or a stereoisomeric form thereof.
  • the chiral carbon atom of the compounds of formula (I) is preferably in the bicyclic amine-part of the amide-molecule, e. g. in the isoquinoline ring system.
  • the invention also relates to a pharmaceutical composition comprising at least one pyrazolo[l,5-a]pyrimidine compound of formula (I), wherein R 1 denotes bromo, or a pharmaceutically acceptable salt or a stereoisomeric form thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one pyrazolo[l,5-a]pyrimidine compound of formula (I), which has an octanol/water partition coefficient of log P value greater than 1, in particular from 2 to 5 and often from 2.1 to 4.5.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as pyrazolo[l,5- ajpyrimidine compound (P) the following compound of formula (A)
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (A) and a cyclodextrin derivative (C) selected from beta-cyclodextrins and gamma-cyclodextrins.
  • the cyclodextrin compound (C) is selected from the group consisting of randomly alkylated beta-cyclodextrins and hydroxyalkyl-substituted beta-cyclodextrins.
  • the further active ingredients (B) can e. g. be a known drug compound for the treatment of CNS-diseases, such as Alzheimer-drugs marketed.
  • the further components (F) of the composition (F) are e.g.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pyrazolopyrimidine, such as those mentioned in WO 2008/015269, wherein the at least one cyclodextrin compound (C) is selected from the group of cyclodextrin-derivatives consisting of: alpha-cyclodextrin, beta-cyclodextrin, alkylated beta-cyclodextrin, 2-O-methyl-beta- cyclodextrin, heptakis-(2,6-di-0-methyl)-beta-cyclodextrin (dimethyl-beta-cyclo-dextrin), acetylated dimethyl-beta-cyclodextrin, heptakis-(2,3,6-tri-0-methyl)-beta-cyclodextrin- (trimethyl-beta-cyclo
  • the cyclodextrin compound (C) is selected from the group consisting of beta-cyclodextrins, alkylated beta-cyclodextrins and 2-hydroxypropyl- beta-cyclo-dextrins.
  • the cyclodextrin compound (C) is selected from the group consisting of gamma-cyclodextrins, alkylated gamma- cyclodextrins and 2-hydroxypropyl-gamma-cyclo-dextrins.
  • cyclodextrin-derivatives are used which are modified (in view of native cylodextrins) by introduction of additional hydroxyl-groups.
  • methyl-beta-cyclodextrines such as Crysmeb (of Roquette Pharma) can advantageously be used.
  • cyclodextrin derivatives C
  • alpha-, beta- and gamma-cyclodextrins comprising 6, 7 and 8 glucopyranose units
  • the beta- and gamma-cyclodextrins are preferably used, in particular in chemically modified (non-native) forms.
  • Many chemically modified cyclodextrins can be used to increase the water solubility of the pyrazolopyrimidine compounds (P).
  • modified beta- cyclodextrin-derivatives are of particular interest for the compositions according to the invention.
  • the term "cyclodextrin-derivatives" includes such modified versions of the native cyclodextrins.
  • a typical example of a suitable grade of hydroxyalkyl-beta- cyclodextrin is amorphous, often randomly substituted hydroxypropyl-beta-cyclodextrin, such as Kleptose.
  • This hydroxyalkyl-beta-cyclodextrin derivative often has a "Degree of Substitution” (DS) in the range of about 4.5, i.e. between approx. 4 and 5, such as the product marketed as Kleptose HPB (by Roquette). It is noted that the DS value, as used herein, defines the average number of substituted hydroxyl groups per anhydro-glucose unit, not per cyclodextrin molecule.
  • Other examples of useful grades are (e.g.
  • hydroxypropyl-beta- cyclodextrin with a degree of substitution (DS) in the range of about 5.6, or in the range of 2 to 4, or in the range of 5, or in the range of 6.5, respectively.
  • DS degree of substitution
  • An example of a suitable grade of hydroxypropyl-gamma-cyclodextrin is the product marketed as Cavasol W8 HP (by Wacker Chemie, Germany).
  • the invention also relates to a pharmaceutical composition wherein the molar ratio of the pyrazolo[l,5-a]pyrimidine compound (P), such as those of formula (I), and the cyclodextrin derivative (C) is in the range from 1 :20 to 1 :0.5; in particular from 1 : 10 to 1 : 1; often from 1 : 10 to 1 : 1.8.
  • the invention also relates to a pharmaceutical composition wherein the composition is a liquid composition, a semi- so lid composition or a solid composition, comprising (in the dosage form) an amount of the pyrazolo[l,5-a]pyrimidine compound (P) in the range from 0.1 to 1000 mg, preferably from 1 to 500 mg, often from 10 to 250 mg.
  • P pyrazolo[l,5-a]pyrimidine compound
  • the invention also relates to a pharmaceutical composition
  • the composition is an aqueous liquid composition, comprising at least 70 % by weight of water and a concentration of the pyrazolo[l,5-a]pyrimidine compound (P) in the range from 1 to 50 mg/ml.
  • the composition also comprises a cyclodextrin derivative (C) (e.g. in the range from 10 to 500 mg/ml) and may comprise as further component (F) one or several co- solvents, in particular one co-solvent.
  • Typical co-solvents are dimethyl sulfoxide (DMSO), l,3-dimethyl-2-imidazolinone (DMI), dimethyl acetamide (DMA), pyrrolidone (Soluphor P), ethanol, glycerol, PEG 200, PEG 300, PEG 400, propylene glycol and N-methyl-2- pyrrolidone (NMP).
  • DMSO dimethyl sulfoxide
  • DMI dimethyl acetamide
  • DMA dimethyl acetamide
  • Soluphor P Soluphor P
  • ethanol glycerol
  • PEG 200, PEG 300, PEG 400 propylene glycol
  • NMP N-methyl-2- pyrrolidone
  • the co-solvent often is used in an amount of less than 2 percent by weight, in particular less than 1 percent by weight of the total pharmaceutical composition.
  • the invention also relates to a pharmaceutical composition, wherein the composition is an aqueous liquid composition, comprising at least 75 % by weight of water and a concentration of the pyrazolo[l,5-a]pyrimidine compound (A) in the range from 1 to 20 mg/ml, and which comprises as one further component (F) a co-solvent from the group of DMSO, DMI, DMA, Soluphor P, ethanol glycerol, PEG 200, PEG 300, PEG 400, propylene glycol and NMP.
  • the invention also relates to a pharmaceutical composition as described above for the treatment of a disorder or a disease of the central nervous system, in particular of those CNS-diseases described below.
  • a further aspect of the invention deals with a process for preparation of a pharmaceutical composition as described above, comprising the steps of mixing together at least one pyrazolo[l,5-a]pyrimidine compound (P) or a pharmaceutically acceptable salt or a stereoisomeric form (or a polymorphic form) thereof, and at least one pharmaceutically acceptable cyclodextrin derivative (C) and optionally one or several further components (F).
  • This mixing can be done in a liquid, such as water, at room temperature or at elevated temperature (e.g. 21 to 70° C).
  • the use of high energy mixers can be advantageous.
  • This mixing together can be done without water being present, at room temperature or at elevated temperature (e.g. 21 to 70° C). It is possible to use a co-solvent during this mixing process to facilitate the process.
  • the complexes can be formed by using different molar ratios of pyrazolo[l,5-a]pyrimidine derivative (P) and cyclodextrin derivative (C).
  • the complexes formed often show a molar ratio of about 1 :1 to 10: 1, but often the molar amount of cyclodextrin derivative (C) used in the formulation is higher than the molar amount of pyrazolo[l,5-a]pyrimidine derivative (P).
  • HPBCD hydroxypropyl-beta-cyclodexrin
  • the quantification of the molar ratios in the complexes formed between the pyrazolo[l,5- ajpyrimidine derivative (P), such as compound (A), and the cyclodextrin derivative ( C), such as beta cyclodexrin, can be measured by proton nuclear magnetic resonance (in mixtures of D 2 0 and d 6 -DMSO; with 500 or 800 MHz spectrometer). It is possible to measure the ratios e.g. by integration of the known proton NMR-signals of the pyrazolopyrimidine (e.g.
  • Typical complexes of beta cyclodextrin (C) and compound (A) were prepared from molar ratios from 4: 1 to 10: 1, with no free signals from compound (A) found.
  • Typical complexes of hydroxypropyl-beta cyclodextrin (HPBCD) and compound (A) were prepared from molar ratios from 1 : 1 to 10: 1, in particular ratios from 5: 1 to 10: 1. Two different conformations were found for compound (A) in solution, which both form complexes with HPBCD. The aromatic part of compound (A) seems to dock with the narrow end of the HPBCD-molecules. By integration of the NMR-signals, the molar ratios between the cyclodextrins and compound (A) are in general between 4: 1 and 10: 1.
  • cyclodextrins can be used in pharmaceutical compositions.
  • One technical problem is that cyclodextrin-containing formulations are difficult to be combined with standard excipients (such as classical preservatives), since the excipients are often bound and complexed by the cyclodextrin.
  • a preservative may be inactivated by the use of cyclodextrins.
  • cyclodextrins Typical uses of cyclodextrins are mentioned e. g. in US 4,596,795, describing a tablet containing progesterone and a cyclodextrin.
  • WO 2009/156160 the CNS-compound neramexane is mentioned with a cyclodextrin-derivative.
  • indole derivates are disclosed, which can be used in combination with fatty acids for pharmaceutical compositions, which also can contain stabilizers such as phospholipids, sugar lipids, proteins or cyclodextrins.
  • compositions for treatment of ophthalmic hypertension which contain a bicyclic active ingredient, such as dorzolamid, which can be formulated in aqueous solutions together with a cyclodextrin.
  • a bicyclic active ingredient such as dorzolamid
  • One further goal of the present invention is to provide new pharmaceutical compositions which can easily be prepared, based on low-cost active ingredients, which compositions are easily applicable to humans and animals, and are well tolerated and have an acceptable long-term stability (in particular for several months).
  • the compositions described above can be e. g. in the form of a solid composition (e.g. powder, tablet), a semi-solid composition (e.g. gel) or a liquid composition (e.g. solution, suspension).
  • the invention also relates to a pharmaceutical composition, wherein the molar ratio of the pyrazolo[l,5-a]pyrimidine compound (P), in particular compound (A), and the beta cyclodextrin (BCD) or hydroxypropyl-beta-cyclodexrin (HPBCD) or gamma cyclodextrin (GCD) or hydroxypropyl-gamma-cyclodexrin (HPGCD) is in the range from 1 :20 to 1 :0.5; in particular from 1 : 10 to 1 : 1, often from 1 : 10 to 1 :4.
  • BCD beta cyclodextrin
  • HPBCD hydroxypropyl-beta-cyclodexrin
  • GCD gamma cyclodextrin
  • HPGCD hydroxypropyl-gamma-cyclodexrin
  • composition is an aqueous liquid composition comprising at least 70 % by weight of water and wherein the concentration of the compound of formula (I), in particular of formula (A), is in the range from 1 mg/ml to 50 mg/ml.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a beta cyclodextrine compound, for example in a concentration of at least 10 mg/ml, for example from 10 to 500 mg/ml, such as from 50 to 180 mg/ml.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a hydrophobic (lipophilic) pyrazolopyrimidine compound (P).
  • the hydrophilicity and hydrophobicity can be determined by the octanol/water partition coefficient (logP), for example according to the standard methods mentioned herein.
  • a compound having an octanol/water partition coefficient of logP ⁇ l will be considered hydrophilic.
  • a compound having an octanol/water partition coefficient of logP>l will be considered hydrophobic.
  • the pharmaceutical composition can as further component (F) also contain a pH-regulator, e. g. to improve the stability. Typical examples are selected from the group consisting of physiologically acceptable acids, bases (such as NaOH), and acidic and alkaline salts.
  • the invention also relates to a pharmaceutical composition, such as an aqueous composition, comprising as further component (F) a co-solvent, and/or an emulsifier and/or a preservative.
  • a pharmaceutical composition such as an aqueous composition
  • co-solvents are DMSO and glycerol.
  • water-miscible, organic co-solvents may be incorporated (in small amounts) in order to solubilise the poorly water-soluble, lipophilic pyrazolopyrimidine compound (P).
  • liquid composition or formulation includes liquid solutions and dispersions, such as emulsions and suspensions.
  • the invention also relates in general to a composition
  • a composition comprising as component (F) a preservative, e. g. in a concentration from 0.1 to 0.0001 % by weight, for example from 0.01 to 0.001 % by weight (of the total formulation).
  • the invention also relates to a pharmaceutical composition as described above for the treatment of a disorder or a disease of the central nervous system, such as the following diseases: Alzheimer's disease, Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE), diseases involving ⁇ -amyloid and/or tauopathy, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, postoperative cognitive deficit (POCD), systemic lupus erythematosus, systemic clerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular
  • the invention also relates to a process for preparation of a pharmaceutical composition comprising the steps of mixing together at least one pharmaceutically acceptable compound of formula (I) and at least one pharmaceutically acceptable cyclodextrin derivative (C) and if necessary further pharmaceutically acceptable components (F).
  • the invention also relates to the use of a cyclodextrin compound (C), in particular of a beta-cyclodextrin, for the preparation of a pharmaceutical composition comprising a pyrazolopyrimidine compound (P) for the treatment of a disease, in particular a CNS- disease
  • the invention further relates to such a use, wherein the composition is an aqueous liquid composition comprising as further component (F) a co-solvent and/or a preservative.
  • the invention also relates to such a use wherein the concentration of the cyclodextrin- compound (C) is at least 10 mg/ml, for example 10 to 500 mg/ml, often from 20 to 180 mg/ml.
  • the compounds of the invention are usually named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hours, and “rt” for room temperature).
  • the term “analog” or “derivative” is used herein in the conventional pharmaceutical sense referring to a molecule that structurally resembles a reference molecule, but has been modified in a controlled manner to replace one or more specific substituent(s) of the molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule.
  • composition according to the invention may comprise the compound of formula (I) and/or a "pharmaceutically acceptable salt” and/or a “derivative” and/or a “polymorphic form” and/or one or several "stereoisomeric forms” of a compound of formula (I).
  • pharmaceutically acceptable refers to ingredients of the compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (such as a human).
  • pharmaceutically acceptable means approved by a European or US-regulatory agency or listed in a recognized pharmacopeia for use in mammals.
  • the compounds of the present invention may be in the form of pharmaceutically acceptable salts, but often they do not form 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 nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • the compounds of the present invention may be in the form of co-crystals with other pharmaceutically acceptable small molecules.
  • the compounds of the invention having at least one chiral center may exist in and be isolated in optically active (such as R- or S-isomers) and racemic forms.
  • optically active such as R- or S-isomers
  • the compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically active, polymorphic, tautomeric or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein.
  • composition of the invention comprises at least one compound of formula (I) and/or a pharmaceutically acceptable salt thereof and also comprises at least one pharmaceutically acceptable cyclodextrin derivative (C), and optionally one or several further components (F).
  • the pharmaceutically acceptable salts of the compound (I) can be prepared by known methods. These salts include e. g. acid addition salts, such as salts made with hydrochloric, methylsulfonic, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, tartaric, citric, benzoic, carbonic, cinnamic, mandelic, methanesulfonic, ethane-sulfonic, hydroxyl- ethanesulfonic, benezenesulfonic, p-toluenesulfonic, cyclohexane-sulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic or 2-acetoxybenzoic acid.
  • acid addition salts such as salts made with hydrochloric, methylsulfonic, hydro
  • Pharmaceutically acceptable salts also include base addition salts, e.g. using cations such as Na, K, Mg, Ca, alkyl- ammonium or choline. All of these salts may be prepared by conventional means. The nature of the salt is not particularly critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • the invention in particular relates to aqueous liquid compositions containing a compound (I). These are liquid preparations wherein the major liquid component is water.
  • compositions normally contain at least 70% by weight, often at least 80 % by weight (w/w of the total composition) of water, but these aqueous liquid compositions may further comprise other liquid components, such as one or several pharmaceutically acceptable, organic co-solvents.
  • the invention also relates to semi-solid compositions.
  • This term means a composition with low viscosity whose major liquid component is water.
  • the semi-solid composition may comprise further components (F), such as pharmaceutically acceptable organic co- solvents, viscosity regulation polymers, pH-regulators, preservatives and emulsifiers. Examples of such further components are ethanol, glycerol, propylene glycol, and polyethylene glycol. Such water-miscible organic solvents (such as glycerol) may be incorporated for example in order to solubilise an insufficiently water-soluble ingredient, such as the pyrazolopyrimidine.
  • the term semi-solid composition includes in particular gels, but also creams and ointments. In comparison to a liquid composition these formulations have an increased viscosity, compared to aqueous solutions. The viscosity of semi-solid compositions can be controlled by using one or several polymeric components or a combination of polymers.
  • polymorphic form of a compound of formula (I) means a particular crystalline or non-crystalline form of a particular compound (I) which has particular physical properties (such as particular X-ray structure) with differ from the properties of a compound having the same chemical formula.
  • stereoisomeric form of compound (I) is used herein in the conventional chemical sense to refer to a molecule that has the same summarizing chemical formula but differs in the structure. Typical examples are enantiomers, diastereoisomers and racemates.
  • heteroaryl means an aromatic heterocyclic system, in particular having 5 or 6 membered ring systems, which contain at least one atom which is not a carbon atom, such as e.g. N, S, O. Typical examples are pyridine, pyrimidine, thiophene, etc.
  • heterocyclyl means a non-aromatic heterocyclic system, in particular having 5 or 6 membered ring systems, which contain at least one atom which is not a carbon atom, such as e.g. N, S, O. Typical examples are piperidine, pyrolidine, etc.
  • complexes of the pyrazolopyrimidine compounds (P) and the cyclodextrins (C) takes e. g. place in solution and typically is an equilibrium process. Complexes may also occur in solid state.
  • An inclusion complex is a structure wherein a guest molecule is either partially or completely contained within a cavity of a larger host molecule. E.g. the compound (A) can be included in one or several molecules of the cyclodextrin derivative.
  • the amount of the compound of formula (I) in the pharmaceutical composition may be decided taking into account the desired pharmaceutical use (e.g. for oral or parenteral CNS-formulations), the type of the active ingredient of formula (I) and the concentrations of the other ingredients.
  • the concentration of the active ingredient of formula (I) may be e. g. at least 0.5 mg/ml. If the active ingredient is a compound of formula (I), the concentration in a (liquid) formulation often is in the range from 0.1 to 100 mg/ml, for example 1 to 50 mg/ml, and often from 1 to 30 mg/ml.
  • the amount of cyclodextrin-derivative (C) in the composition may be selected taking into account the type of cyclodextrin (C) and the concentration of the active compound (I) and the pharmaceutical use.
  • the concentration of the cyclodextrin-derivative (C) in the composition often is at least 5 mg/ml, for example 10 to 250 mg/ml.
  • a concentration of 0.1 to 100 mg/ml of a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be formulated in such a composition.
  • liquid or semi solid compositions may be prepared with a molar ratio of a compound of formula (I) to cyclodextrin-derivative (C) of from 1 : 20 to 1 : 0.5.
  • Another embodiment of the invention may comprise a molar ratio of a compound of formula (I) to cyclodextrin-derivative (C) of from 1 : 10 to 1 : 1. It was found that such molar ratios may lead to a remarkably degree of taste masking, which may be associated with the spontaneous formation of a soluble complex between the cyclodextrin molecule and the drug of formula (I). After oral or topic (e.g. into the eye) administration, the compound of formula (I) is rapidly absorbed from the composition and becomes bioavailable.
  • the composition of the invention may further comprise, besides the pyrazolopyrimidine compound (P) at least one further active ingredient (B), such as a further drug compound useful for the treatment of CNS-diseases.
  • Typical examples are the commercial products for treatment of Alzheimer's and Parkinson disease.
  • one or more sweeteners may be incorporated into the composition.
  • one or more flavours, flavour enhancers, and taste masking agents may be used.
  • Typical sweeteners are natural or synthetic compounds which have a sweet taste and are physiologically acceptable. Examples of natural sweeteners include common sugars and sugar alcohols such as sucrose, glucose, fructose, maltose, maltitol, xylitol, lactitol, mannitol, and sorbitol.
  • a sugar alcohol may be used to improve the flavour of the composition of the invention, for example sorbitol.
  • a useful concentration range for sorbitol or other sugars and sugar alcohols is from about 5 % (w/v) to about 25 % (w/v).
  • Useful artificial sweeteners include saccharin-sodium, Saccharin, sodium cyclamate, acesulfame K, neohesperidine dihydrochalcone, and aspartame, as well as any other sweeteners whose safety in human use is established. Appropriate concentrations depend on the individual sweetener which is selected, but also on the specific cyclodextrin which is chosen.
  • hydroxypropyl-beta- cyclodextrin already provides for a rather sweet taste, so that the addition of a sweetening agent may not increase the palatability of the formulation any further.
  • Suitable flavors which may further improve the taste of cyclodextrin-containing aqueous compositions of compounds of formula (I) include grape, orange, peppermint, spearmint, cherry, liquorice, and aniseed.
  • peppermint flavours are physicochemically and organoleptically well- compatible with the key components of the composition of the invention and may lead to palatable formulations.
  • the preservation of the active compound of formula (I) can be important. It is possible to formulate the composition without any additional preservative.
  • the composition of the invention is substantially free of preservatives.
  • the term "substantially” means that preservatives are not detectable in the composition, or only in concentrations which are generally considered irrelevant with regard to any preservation effects.
  • the pharmaceutical composition may optionally comprise as further component (F) at least one preservative. Whether a composition is effectively preserved may be determined according to tests known in the art.
  • the pharmaceutical composition can also contain as further component (F) a preservative such as benzalkonium chloride, cetylpyridium chloride, cetrimide, cetyl trimethyl-ammonium bromide, benzethonium chloride, chlorhexidine gluconate, ethanol, isopro-panol, propylen glycol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid, benzoic acid, thiomersal, organomercury components, chlorobutanol and/or benzyl alcohol.
  • a preservative such as benzalkonium chloride, cetylpyridium chloride, cetrimide, cetyl trimethyl-ammonium bromide, benzethonium chloride, chlorhexidine gluconate, ethanol, isopro-panol, propylen glycol, butylparaben, ethylparaben, methylpara
  • the preparation of the composition comprising the pyrazolopyrimidine (P) according to the invention is technically easy, quick and cost-efficient.
  • the components are e. g. weighed and the compound of formula (I) is combined (mixed) with measured amounts of the cyclodextrin-derivative (C) and water and optionally further components (F), optionally followed by stirring until dissolution occurs.
  • the mixture may be agitated, sonicated and/or heated for some time, e. g. from 2 minutes to 64 hours.
  • the solution may be further processed by filtration or centrifugation to remove residual particles. If a solid formulation is desired, the solution may be dried, such as by tray drying, spray drying or freeze drying.
  • 6-Bromo-pyrazolo[l,5-a]pyrimidin- ⁇ 2yl)-((S)-3-methyl-3,4-dihydro-lH- soquino lin-2-yl)-methanone 6-Chloro-pyrazolo [ 1 ,5-a]pyrimidin-2-yl)-( 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2- yl)-methanone
  • This compound (A) is the R-enantiomer, but both isomers (R and S) were prepared by classical chemical synthesis.
  • the compound (A) was tested in various compositions (formulations) inter alia for CNS- applications.
  • the compound (A) is a small molecule having a molecular weight of about 360 g/mol, but is very little soluble in aqueous media (about 0.001 to 0.01 mg/ml).
  • the compound (A) can be formulated as aqueous based, liquid solutions with over 100- fold higher concentrations of the drug substance avoiding the use of larger amounts of excipients, such as co-solvents. These pharmaceutical solutions can be easily applied to different animal species and human beings via nearly all application routes like the oral, buccal, dermal, nasal, rectal, vaginal, pulmonary, ocular and parenteral route.
  • the compound (A) is a lipophilic compound with limited wettability and solubility in aqueous media. The lipophilicity can be expressed by the logP value, which is approximately 3 for compound (A).
  • GCD Gamma-cyclodextrin
  • ⁇ -CD Gamma-cyclodextrin
  • HPBCD Hydroxypropyl-beta-cyclodextrin
  • MBCD Methylbeta-cyclodextrin
  • compositions were prepared by using as cyclodextrin component (C) different amounts of a suitable grade of the above mentioned beta- and gamma- cyclodextrins.
  • HPBCD is e. g. an amorphous, randomly substituted hydroxypropyl-beta- cyclodextrin, having a "Degree of Substitution” (DS) in the range between 4 and 5.
  • the commercial product Kleptose HPB (marketed by Roquette) was used.
  • An aqueous solution comprising 16 % by weight of hydroxypropyl-beta-cyclodextrin (HPBCD) was prepared. At a temperature of 50° C, 5 mg of compound (A) can be solved in 1 ml of the HPBCD-solution, a stable complex was formed.
  • pyrazolopyrimidine component (6-Bromo-pyrazolo[l,5-a]-pyrimidine-2-yl)-(l(R)- methyl-3,4-dihydro-lH-isoquinoline-2-yl)-methanone, compound (A) was used, which is very poorly soluble in aqueous media. However it can be formulated as aqueous based, liquid solutions with over 100-fold higher concentrations of the drug substance using low amounts of specific cyclodextrines (HPBCD). These solutions can be easily applied to different animal species and human beings via nearly all application routes like the oral, dermal, nasal, rectal and parenteral route.
  • HPBCD specific cyclodextrines
  • compositions were prepared by mixing the respective cyclodextrine compound (C) and the Compound (A) with distilled water at 37° C for 64 hours, followed by filtration (PTFE-filter) and then analysis by High Performance Liquid Chromatography (Agilent 1100; Water/ Acetonitrile/Perchloric acid): a) 1 ml water + 450 mg cyclodextrin + 10 mg Compound (A)
  • the solubility of Compound (A) in water was increased about 500-times, leading e. g. to the solubility at pH 7 at 20°C of more than 5 mg/ml, which is very useful for oral or parenteral formulations of the drug.
  • the solubility of Compound (A) can be increased. Not only the solubility was increased, but also the time for preparing the solutions can be reduced.
  • the solutions obtained were used for preparing pharmaceutical formulations, e. g. by adding further excipients to the solution and/or by freeze-drying the solutions. The solutions were further used for pharmacological testing.
  • the products obtained after freeze-drying of the solutions or obtained by crystallization and the pyrazolopyrimidin-CD-complexes formed can be analysed by classical methods, such as X-ray Powder Diffraction, Polarized Light Microscopy, Differential Scanning Calorimetry, IR-Spectroscopy, NMR-Spectroscopy and HPLC. With BCD and GCD, crystallites were obtained and characterized. By NMR-spectroscopy, the complexes formed between compound (A) and different cyclodextrin derivatives can be characterized.
  • compound (A) (6-Bromo-pyrazolo[l,5-a]-pyrimidine-2-yl)-(l(R)-methyl-3,4-dihydro- lH-isoquinoline-2-yl)-methanone, compound (A) was used, which is very poorly soluble in aqueous media. It can be formulated as aqueous based, liquid solution with over 100- fold higher concentrations of the drug substance using small amounts of HPBCD and very low amounts of excipients, such as the co-solvent DMSO.
  • compositions of pyrazolopyrimidines of formula (I) can be easily prepared by using cyclodextrin derivatives (C) in combination to a co-solvent, such as DMSO.
  • pyrazolopyrimidine component (6-Bromo-pyrazolo[l,5-a]pyrimidin-2-yl)-(3,4- dihydro-lH-isoquinolin-2-yl)-methanone was used, which is very poorly soluble in aqueous media. However it can be formulated as aqueous based, liquid solutions with much higher concentrations of the drug substance using low amounts of specific cyclodextrins, such as hydroxypropyl-beta-cyclodextrins (HPBCD), e.g. Kleptose HPB.
  • HPBCD hydroxypropyl-beta-cyclodextrins
  • compositions were prepared by mixing the pyrazolo[l,5-a]pyrimidin compound and the HPBCD with destilled water (and in further experiments with different co- solvents) at 37° C for several hours, followed by filtration (PTFE-filter) and then analysis by High Performance Liquid Chromatography.
  • pyrazolopyrimidine component 2-[(6-Bromopyrazolo[l,5-a]-pyrimidin-2-yl)carbonyl]- 7-methoxy-l-methyl-l,2,3,4-tetrahydro-6-isoquinolin-ol was used, which is poorly soluble in aqueous media.
  • it can be formulated as aqueous based, liquid solutions with much higher concentrations of the drug substance using low amounts of specific cyclodextrins, such as hydroxypropyl-beta-cyclodextrins (HPBCD), e.g. Kleptose HPB.
  • HPBCD hydroxypropyl-beta-cyclodextrins
  • compositions were prepared by mixing the pyrazolo[l,5-a]pyrimidin compound and the HPBCD with distilled water (and in further experiments with different co-solvents) at 37° C for several hours, followed by filtration (PTFE-filter) and then analysis by High Performance Liquid Chromatography.
  • PTFE-filter filtration-filter
  • HPBCD High Performance Liquid Chromatography
  • the pyrazolo[l,5-a]pyrimidin compound was found to be considerably solubilised (5.3 mg/ml) by the use of 0.2 ml of DMSO in combination with 0.4 ml of PEG400 and 0.4 ml of an aqueous solution of HPBCD (30 % w/w).
  • the solution obtained was stable and can be used for preparing pharmaceutical formulations, e. g. by freeze-drying the solutions.
  • pyrazolopyrimidine component (6-Chloro-pyrazolo[l,5-a]pyrimidin-2-yl)-((R)-l- methyl-3,4-dihydro-lH-isoquinolin-2-yl)-methanone was used, which is poorly soluble in aqueous media. However it can be formulated as aqueous based, liquid solutions with much higher concentrations of the drug substance using low amounts of specific cyclodextrins, such as hydroxypropyl-beta-cyclodextrins (HPBCD), e.g. Kleptose HPB.
  • HPBCD hydroxypropyl-beta-cyclodextrins
  • compositions were prepared by mixing the pyrazolo[l,5-a]pyrimidin compound and the HPBCD with distilled water (and in further experiments with different co-solvents) at 37° C for several hours, followed by filtration (PTFE-filter) and then analysis by High Performance Liquid Chromatography.
  • PTFE-filter filtration-filter
  • HPBCD High Performance Liquid Chromatography
  • the pyrazolo[l,5-a]pyrimidin compound was found to be considerably solubilised (4.8 mg/ml) by the use of 0.2 ml of DMSO in combination with 0.8 ml of an aqueous solution of HPBCD (30 % w/w).
  • the solution obtained was stable at room temperature and can be used for preparing pharmaceutical formulations, e. g. by freeze-drying the solutions.
  • the compound (6-Bromo-pyrazolo[l,5-a]-pyrimidine-2-yl)-(l(R)-methyl-3,4-dihydro-lH- isoquinoline-2-yl)-methanone can also be formulated without aqueous media by mixing the compound with the cyclodextrin compound (e.g. HPBCD) as dry composition.
  • the cyclodextrin compound e.g. HPBCD
  • the formation of complexes can be observed, even without water being present as solvent. It can be helpful to use small amounts of organic solvents (such as DMSO or alcohols).

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Abstract

L'invention porte sur des compositions pharmaceutiques comprenant au moins un composé pyrazolo[1,5-a]pyrimidine substitué (P) ou un sel pharmaceutiquement acceptable de celui-ci ou une forme stéréoisomère de celui-ci et au moins un dérivé de cyclodextrine pharmaceutiquement acceptable (C), et éventuellement un ou plusieurs autres composants (F), tels qu'un cosolvant, ayant des stabilités inattendues.
PCT/EP2012/075480 2011-12-15 2012-12-14 Composition pharmaceutique comprenant une pyrazolopyrimidine et une cyclodextrine WO2013087808A1 (fr)

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US9181249B2 (en) 2013-12-20 2015-11-10 Takeda Pharmaceutical Company Limited Substituted pyrido[3,4-b]pyrazines as GPR6 modulators
EP3373920A4 (fr) * 2015-11-13 2019-07-17 Pietro Paolo Sanna Méthodes et compositions pour le traitement de maladies liées à la consommation d'alcool

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US10077266B2 (en) 2013-12-20 2018-09-18 Takeda Pharmaceutical Company Limited Substituted pyrido[3,4-b]pyrazines as GPR6 modulators
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