WO2024110577A1 - Composition comprenant du zuclopenthixol - Google Patents

Composition comprenant du zuclopenthixol Download PDF

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Publication number
WO2024110577A1
WO2024110577A1 PCT/EP2023/082831 EP2023082831W WO2024110577A1 WO 2024110577 A1 WO2024110577 A1 WO 2024110577A1 EP 2023082831 W EP2023082831 W EP 2023082831W WO 2024110577 A1 WO2024110577 A1 WO 2024110577A1
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WIPO (PCT)
Prior art keywords
cyclodextrin
zuclopenthixol
pharmaceutical composition
formulation
range
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PCT/EP2023/082831
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English (en)
Inventor
Jesper Tungelund LARSEN
Birgit CHRISTENSEN
Gudrun Lasskogen
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H. Lundbeck A/S
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Publication of WO2024110577A1 publication Critical patent/WO2024110577A1/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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to a pharmaceutical composition comprising zuclopenthixol, or a pharmaceutically acceptable salt thereof, and a cyclodextrin, as well as to preparation of and use of said pharmaceutical composition.
  • Zuclopenthixol is a first-generation antipsychotic drug which is marketed as a medicament and used for treatment of schizophrenia, psychoses, or mania. Zuclopenthixol is marketed since 1976 across the world under tradenames such as cisordinol or clopixol. Zuclopenthixol is a thioxanthene and is the cis-isomer of clopenthixol.
  • Zuclopenthixol has a chemical structure according to formula (I) Zuclopenthixol is marketed in different formulations, one of which is an aqueous composition formulation which is used for administration by oral drop comprising the active substance at a concentration of 20 mg/mL and further comprising 12% (w/v) ethanol at pH 2.
  • zuclopenthixol examples include two different solutions for injection (comprising zuclopenthixol acetate or zuclopenthixol decanoate, respectively), with the decanoate ester formulation being a long-acting formulation (LAI).
  • LAI long-acting formulation
  • the inventors of the present inventions have identified that Zuclopenthixol in aqueous compositions is prone to degradation with formation of degradation products wherein e.g. the alkene of zuclopenthixol is either hydrolyzed, partially or fully oxidized, or wherein the stereochemistry of the alkene is converted to the trans-isomer.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable cyclodextrin.
  • the present invention relates to a pharmaceutical composition as described herein for use in the treatment of a CNS disorder, such as psychosis.
  • the present invention relates to a method for preparing a pharmaceutical composition as described herein, the method comprising the steps of: a. dissolving the pharmaceutically acceptable cyclodextrin in water, b. adding zuclopenthixol to the composition formed in step a. and stirring until dissolved, and c. adjusting pH of the composition by addition of sodium hydroxide.
  • Figures 1 A-D shows the amounts of degradations products, 2-CTX(A), Sordinol Carbinol(B), Sordinol Dicarbinol(C), and unknown total(D), in formulations at varying pH (2.0, 4.0 or 6.0) and in the presence (H3PO4 or AcOH) or absence (pH) of buffer systems.
  • Figures 2 A-D shows the amounts of degradations products, 2-CTX(A), Sordinol Carbinol(B), Sordinol Dicarbinol(C), and unknown total(D), in formulations at pH 4.0 and comprising either AcOH buffer or cyclodextrins (kleptose or captisol).
  • Figures 3 A-D shows the amounts of degradations products, 2-CTX(A), Sordinol Carbinol(B), Sordinol Dicarbinol(C), and unknown total(D), in formulations comprising 2-hydroxypropyl- ⁇ -cyclodextrin (Kleptose) and at varying pH (3, 4, 5, 6, 7).
  • Figures 4 A-B shows the absorbance measured at 410 nm (A) and 440 nm (B) for formulations comprising 2-hydroxypropyl- ⁇ -cyclodextrin (Kleptose) and at varying pH (3, 4, 5, 6, 7).
  • Figures 5 A-D shows the amounts of degradations products, 2-CTX(A), Sordinol Carbinol(B), Sordinol Dicarbinol(C), and unknown total(D), in formulations comprising Sulfobutylether- ⁇ -cyclodextrin Sodium (Captisol) and at varying pH (2, 4, 6).
  • Figure 6 shows the amounts of degradations products, 2-CTX, Sordinol Carbinol, Sordinol Dicarbinol, and Trans(E)-clopenthixol, in formulations comprising zuclopenthixol at pH 2 (dark grey), or comprising zuclopenthixol and 2-hydroxypropyl- ⁇ -cyclodextrin (Kleptose) at pH 5 (middle grey) or pH 6 (light grey).
  • the % content of the degradation products were analyzed after 12 weeks (pH2 formulation without cyclodextrin) or after 19 weeks (cyclodextrin containing formulations) of storage at 40 °C/75%RH.
  • the present invention relates to a formulation of zuclopenthixol, wherein degradation of the compound is prevented or decreased, and thus, wherein the stability of zuclopenthixol is increased.
  • the stability of zuclopenthixol is increased in a formulation comprising a cyclodextrin, such as comprising 2-hydroxypropyl- ⁇ -cyclodextrin, whereby degradation of zuclopenthixol, such as via alkene hydrolysis or oxidation is prevented or decreased.
  • the formulation of the present disclosure also demonstrates a low propensity to isomerization of the alkene of zuclopenthixol upon storage.
  • the present invention relates to a pharmaceutical formulation comprising a compound of formula (I) Formula (I), or a pharmaceutically acceptable salt thereof, which compound is also referred to herein as zuclopenthixol.
  • the present disclosure provides a pharmaceutical formulation comprising zuclopenthixol, or a pharmaceutically acceptable salt thereof, and 2-hydroxypropyl- ⁇ -cyclodextrin. In aqueous solutions, zuclopenthixol is prone to degradation with formation of degradation products.
  • Examples of degradation products of zuclopenthixol include compounds wherein the alkene of zuclopenthixol is either hydrolyzed, partially or fully oxidized, or wherein the stereochemistry of the alkene is converted from the cis-isomer to the trans-isomer.
  • the pharmaceutical composition of the present disclosure provides an increased stability of zuclopenthixol.
  • Examples of degradation products of zuclopenthixol include but are not limited to compounds of formula (II), (III), (IV) and (V).
  • the pharmaceutical composition of the present disclosure prevents or decreases degradation of zuclopenthixol to the compound of formula (II) formula (II), which is also referred to herein as sordinol carbinol or carbinol.
  • the compound of formula (II) is formed by hydrolysis of zuclopenthixol.
  • the pharmaceutical composition of the present disclosure prevents or decreases degradation of zuclopenthixol to the compound of formula (III) formula (III), which is also referred to herein as sordinol dicarbinol or dicarbinol.
  • the pharmaceutical composition of the present disclosure prevents or decreases degradation of zuclopenthixol to the compound of formula (IV) formula (IV), which is also referred to herein as 2-CTX.
  • the pharmaceutical composition of the present disclosure provides a low level of degradation of zuclopenthixol to the compound of formula (V) formula (V), which is also referred to herein as trans-ordinol or trans(E)- clopenthixol. Degradation of zuclopenthixol to form trans-clopenthixol may be a result of light exposure of the formulation.
  • the pharmaceutical composition of the present disclosure prevents or decreases degradation of zuclopenthixol, such as prevents or decreases degradation of zuclopenthixol to any one of the compounds of formula (II), (III), and (IV), or any combination of the compounds of formula (II), (III), and (IV).
  • the pharmaceutical composition of the present disclosure provides such decreased degradation of zuclopenthixol by formation of a complex of zuclopenthixol with the pharmaceutically acceptable cyclodextrin in the composition, such as by formation of an inclusion complex, whereby the alkene of zuclopenthixol is protected from degradation, such as protected from hydrolysis and/or from oxidative degradation.
  • the pharmaceutical composition provides a low level of isomerization, such as provides a low level of conversion of the cis-alkene to the trans-alkene.
  • Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits. Cyclodextrins are composed of 5 or more ⁇ -D-glucopyranoside units linked by ⁇ -1,4 glycosidic bonds. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape.
  • ⁇ (alpha)-cyclodextrins contain 6 glucose subunits
  • ⁇ (beta)- cyclodextrins contain 7 glucose subunits
  • ⁇ (gamma)-cyclodextrins contain 8 glucose subunits in the ring.
  • Cyclodextrins have a toroidal shape, with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively. Because of this arrangement, the interior of the cyclodextrin toroid is less hydrophilic than the aqueous environment and thus able to host e.g. hydrophobic molecules by formation of an inclusion complex.
  • the exterior of the cyclodextrin toroid is sufficiently hydrophilic to impart cyclodextrins (or their inclusion complexes) water solubility.
  • Inclusion complex formation does not take place with any compound, and an inclusion complex may form only if the compound has e.g. the required physicochemical properties and size, and if the correct match between cyclodextrin or cyclodextrin derivative and compound is found, with the correct properties of the solution.
  • complex formation requires addition of heat to drive the complex formation. Given the potential of cyclodextrins to form inclusion complexes, these have been used for increasing the solubility of hydrophobic molecules.
  • Formation of inclusion complexes between a cyclodextrin and a molecule has also been used for masking of odour and/or taste of the molecule. Formation of inclusion complexes between a cyclodextrin and a molecule may also confer protection of the molecule from the exterior environment of the solution. However, the ability of cyclodextrins to stabilize a given molecule cannot be predicted and as described above, not all molecules are capable of forming such inclusion complexes. Formation of the inclusion complex is a dynamic process, wherein the equilibrium of the inclusion complex depends on various factors such as the type of CD, pH of the medium, and the presence of any additives.
  • zuclopenthixol is capable of forming a complex with cyclodextrins, such as capable of forming an inclusion complex with a cyclodextrin, such as 2-hydroxypropyl- ⁇ -cyclodextrin, and that such complex provides protection of zuclopenthixol from degradation. More specifically it has been found that the complex provides protection of the alkene of zuclopenthixol from degradation such as hydrolysis and/or oxidative degradation. Furthermore, a low amount of conversion of the cis-alkene to the trans-alkene was observed for the pharmaceutical composition of the present disclosure.
  • cyclodextrin refers to a cyclodextrin which is physiologically tolerable and thus safe to include in a pharmaceutical formulation, such as cyclodextrins causing no known adverse events when administered to a mammal, such as a human.
  • a pharmaceutically acceptable cyclodextrins may also for example be a cyclodextrin approved by the regulatory authorities or listed in generally recognized pharmacopeia, such as the U.S. pharmacopeia, for use in mammals, more particularly in humans.
  • cyclodextrins include but are not limited to randomly methylated ⁇ -cyclodextrin, 2-O-methyl- ⁇ - cyclodextrin, heptakis-(2,6-di-O-methyl)- ⁇ -cyclodextrin, (dimethyl- ⁇ -cyclodextrin), acetylated dimethyl- ⁇ -cyclodextrin, heptakis-(2,3,6-tri-O-methyl)- ⁇ -cycIodextrin, trimethyl- ⁇ -cyclodextrin, 2- hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin sulphate, ⁇ -cyclodextrin phosphate, and 2- hydroxypropyl-gamma-cyclodextrin.
  • the pharmaceutically acceptable cyclodextrin is selected from the group consisting of randomly methylated ⁇ -cyclodextrin, 2-O-methyl- ⁇ -cyclodextrin, heptakis-(2,6-di-O- methyl)- ⁇ -cyclodextrin, (dimethyl- ⁇ -cyclodextrin), acetylated dimethyl- ⁇ -cyclodextrin, heptakis- (2,3,6-tri-O-methyl)- ⁇ -cycIodextrin, trimethyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, ⁇ - cyclodextrin sulphate, ⁇ -cyclodextrin phosphate, and 2-hydroxypropyl-gamma-cyclodextrin.
  • the pharmaceutically acceptable cyclodextrin is 2-hydroxypropyl- ⁇ - cyclodextrin (also referred to herein as 2-HP- ⁇ -CD).
  • Cyclodextrins may be substituted, derivatized or modified to varying degrees, which may be indicated by the degree of substitution (DS).
  • DS indicates the average number of substituted hydroxyl groups per anhydroglucose unit of the cyclodextrin.
  • DS of the 2-hydroxypropyl- ⁇ - cyclodextrin of the present invention include amorphous, randomly substituted 2-hydroxypropyl- ⁇ - cyclodextrin having a DS in the range of 0.4 to 1.2, such as in the range of 0.4 to 1.0, such as in the range of 0.4 to 0.7, such as in the range of 0.5 to 0.7, such as in the range of 0.6 to 0.7.
  • the DS of the 2-hydroxypropyl- ⁇ -cyclodextrin is at least 0.5, such as at least 0.6, for example 0.62.
  • Suitable 2-hydroxypropyl- ⁇ -cyclodextrin is Kleptose, such as Kleptose having a degree of substitution of about 0.6, such as about 0.62.
  • the degree of substitution may be determined by methods known by the skilled person, such as by e.g. gas chromatography (GC), nuclear magnetic resonance (NMR), and plasma desorption fast atom bombardment mass spectrometry (FAB-MS).
  • the pharmaceutical composition of the present invention comprises a complex formed between zuclopenthixol and the cyclodextrin, such as an inclusion complex formed between zuclopenthixol and the cyclodextrin.
  • the complex or inclusion complex has an equilibrium constant K of at least 700 M -1 .
  • the equilibrium constant is at least 700 M -1 when measured at pH 4.
  • the equilibrium constant may be measured according to the method as described in example 5 of the present disclosure or by other methods known to the person skilled in the art.
  • Pharmaceutical composition relates to a pharmaceutical composition comprising a compound of formula (I) Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable cyclodextrin.
  • the pharmaceutical composition is an aqueous liquid composition, such as an oral drop formulation.
  • the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the range from about 1 mg/mL to about 100 mg/mL, such as in the range of about 1 mg/mL to about 75 mg/mL, such as in the range of about 1 mg/mL to about 50 mg/mL, such as in the range of about 1 mg/mL to about 40 mg/mL, such as in the range of about 1 mg/mL to about 30 mg/mL, such as in the range of about 1 mg/mL to about 25 mg/mL, such as in the range of about 1 mg/mL to about 20 mg/mL.
  • the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the range from about 1 mg/mL to about 100 mg/mL, such as in the range of about 5 mg/mL to about 100 mg/mL, such as in the range of about 10 mg/mL to about 100 mg/mL, such as in the range of about 15 mg/mL to about 100 mg/mL, such as in the range of about 16 mg/mL to about 100 mg/mL, such as in the range of about 18 mg/mL to about 100 mg/mL, such as in the range of about 20 mg/mL to about 100 mg/mL.
  • the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the range from about 1 mg/mL to about 100 mg/mL, such as in the range of about 5 mg/mL to about 75 mg/mL, such as in the range of about 10 mg/mL to about 50 mg/mL, such as in the range of about 10 mg/mL to about 40 mg/mL, such as in the range of about 10 mg/mL to about 30 mg/mL, such as in the range of about 15 mg/mL to about 25 mg/mL, such as in the range of about 18 mg/mL to about 22 mg/mL.
  • the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 20 mg/mL.
  • the compound of formula (I) is in the form of a salt, such as a hydrochloride salt, hydrobromide salt, dihydrobromide salt, or dihydrochloride salt.
  • the compound of formula (I) is in the form of a dihydrochloride salt.
  • the molar ratio of the cyclodextrin to the compound of formula (I) is in the range of about 0.1:1 to about 100:1, such as in the range of about 0.5:1 to about 100:1, such as in the range of about 1:1 to about 100:1, such as in the range of about 2:1 to about 100:1, such as in the range of about 5:1 to about 100:1.
  • the molar ratio of the cyclodextrin to the compound of formula (I) is in the range of about 0.1:1 to about 100:1, such as in the range of about 0.5:1 to about 50:1, such as in the range of about 0.5:1 to about 20:1, such as in the range of about 0.5:1 to about 10:1, such as in the range of about 0.8:1 to about 5:1, such as in the range of about 0.8:1 to about 2:1, such as in the range of about 0.9:1 to about 1.5:1.
  • the molar ratio of the cyclodextrin to the compound of formula (I) is about 1:1.
  • the composition comprises 2-hydroxypropyl- ⁇ -cyclodextrin in an amount above the stoichiometric amount as compared to zuclopenthixol, such as having a molar ratio of the cyclodextrin to the compound of formula (I) of about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1.1:1, or about 1.05:1.
  • a molar ratio of the cyclodextrin to the compound of formula (I) of about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1.1:1, or about 1.05:1.
  • Such slight excess of cyclodextrin may be advantageous to ensure full protection of the zuclopenthixol.
  • the cyclodextrin is present in an amount from about 5% to about 20% (w/v), such as in an amount from about 5% to about 15% (w/v), such as in an amount from about 5% to about 12% (w/v), preferably the cyclodextrin is present in an amount from about 5% to about 10% (w/v). In one embodiment, the cyclodextrin is present in an amount of at least 12% (w/v), preferably in an amount of at least 10% (w/v).
  • the cyclodextrin is present in an amount of about 15% (w/v), about 14% (w/v), about 13% (w/v), about 12% (w/v), about 11% (w/v), about 10% (w/v), about 9% (w/v), or about 8% (w/v).
  • the pH of the composition is above 3 and below 7, such as in the range of 4-6, such as in the range of 5-6, for example 5, for example 6. In a preferred embodiment, the pH of the composition is about 5, such as 5.
  • the pH of the composition is in the range of 4 to 7, such as in the range of 4 to 6, such as in the range of 4.5 to 6.5, such as in the range of 4.8 to 5.2, such as in the range of 4.5 to 5.5, such as in the range of 5 to 6, preferably the pH is about 5, such as 5.
  • the pH of the composition may be adjusted by addition of sodium hydroxide (NaOH) to the composition after dissolving zuclopenthixol and the cyclodextrin in the aqueous solution.
  • no additional buffering agent is needed for maintaining a stable pH during storage, since zuclopenthixol may function as a buffering agent in the composition.
  • the composition does not contain an additional buffering agent.
  • the pharmaceutical composition of the present invention may further comprise ethanol (EtOH).
  • EtOH ethanol
  • the presence of ethanol in the composition may prevent bacterial growth in the composition during storage.
  • the pharmaceutical composition further comprises ethanol.
  • the ethanol content of the pharmaceutical composition is in the range of 0 % to 20 (w/v), such as in the range of 0 % to 15 (w/v), such as in the range of 5 % to 15 (w/v).
  • the ethanol content of the pharmaceutical composition is about 12% (w/v).
  • the pharmaceutical composition of the present disclosure may be used as an oral drop formulation, whereby zuclopenthixol as the active pharmaceutical ingredient (API) of the composition is administered by oral drop.
  • the present invention provides a pharmaceutical composition for use as an oral drop formulation comprising a compound of formula (I) Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable cyclodextrin.
  • the pharmaceutical composition of the present disclosure is an oral drop formulation.
  • the pharmaceutical composition of the present disclosure is stable during storage, such as provides a stable drop measure, stable drop rate, and stable uniformity of dose during storage.
  • the pharmaceutical composition of the present disclosure comprises a compound according to formula (I), or a pharmaceutically acceptable salt thereof, 2-hydroxypropyl- ⁇ - cyclodextrin and ethanol, wherein a.
  • the concentration of the compound of formula (I) is in the range of 15 to 25 mg/mL, preferably 20 mg/mL; b. the concentration of 2-hydroxypropyl- ⁇ -cyclodextrin is present in an amount from about 5% to about 12% (w/v), preferably 10% (w/v); c. the ethanol content is in the range of 5% to 15% (w/v), preferably 12% (w/v); and d. the pH is in the range of 4.5 to 5.5, preferably 5.
  • the pharmaceutical composition of the present disclosure comprises zuclopenthixol dihydrochloride, 2-hydroxypropyl- ⁇ -cyclodextrin and ethanol, wherein a.
  • the concentration of zuclopenthixol dihydrochloride is in the range of 15 to 25 mg/mL, preferably about 23.6 mg/mL; b. the concentration of 2-hydroxypropyl- ⁇ -cyclodextrin is present in an amount from about 5% to about 12% (w/v), preferably 10% (w/v); c. the ethanol content is in the range of 5% to 15% (w/v), preferably 12% (w/v); and d. the pH is in the range of 4.5 to 5.5, preferably 5.
  • the present invention provides a method of preparing a pharmaceutical composition as disclosed herein, the method comprising the steps of: a. dissolving the pharmaceutically acceptable cyclodextrin in water, b. adding zuclopenthixol to the composition formed in step a.
  • step b. comprises stirring for less than 1 h, such as for less than 50 min, 40min, 30, or 20 min.
  • the method further comprises an additional step of addition of ethanol to the composition formed in step a. prior to addition of zuclopenthixol.
  • pH is adjusted by addition of sodium hydroxide, such as 5N sodium hydroxide, under vigorous stirring of the composition.
  • the method further comprises a step d. of addition of water to obtain the desired concentration of zuclopenthixol in the composition, such as obtaining a concentration of about 20 mg/mL of zuclopenthixol.
  • the composition is protected from light during the method of preparation. Stability of composition
  • the pharmaceutical composition of the present invention provides a high stability formulation of zuclopenthixol, displaying an amount of degradation products which is well within and below the specification limits of the zuclopenthixol formulation. Furthermore, the pharmaceutical composition of the present invention displays a very stable color of solution, also falling within the specification of the zuclopenthixol formulation.
  • the pharmaceutical composition as disclosed herein comprises less than 1 w/w% of the carbinol degradation product (formula II) after storage for 24 months at 25 °C.
  • the pharmaceutical composition as disclosed herein comprises less than 0.1%w/w, such as less than 0.05 %w/w of the carbinol degradation product (formula II) after storage for 18 months at 25°C/60% RH. In one embodiment, the pharmaceutical composition as disclosed herein comprises less than 0.5 w/w%, such as less than 0.1 w/w%, such as less than 0.05 w/w%, such as less than 0.02 w/w% of the carbinol degradation product (formula II) after 6 months of storage at 40°C/75% RH. In one embodiment, the pharmaceutical composition as disclosed herein comprises less than 1 w/w% of the dicarbinol degradation product (formula III) after storage for 24 months at 25 °C.
  • the pharmaceutical composition as disclosed herein comprises less than 0.1%w/w, such as less than 0.05 %w/w of the dicarbinol degradation product (formula III) after storage for 18 months at 25°C/60% RH. In one embodiment, the pharmaceutical composition as disclosed herein comprises less than 0.5 w/w%, such as less than 0.2 w/w%, such as less than 0.1 w/w% of the dicarbinol degradation product (formula III) after 6 months of storage at 40°C/75% RH. In one embodiment, the pharmaceutical composition as disclosed herein comprises less than 0.2 w/w% of the 2-CTX degradation product (formula IV) after storage for 24 months at 25 °C.
  • the pharmaceutical composition as disclosed herein comprises less than 0.1%w/w, such as less than 0.05 %w/w of the 2-CTX degradation product (formula IV) after storage for 18 months at 25°C/60% RH.
  • the present invention provides a pharmaceutical composition wherein less than less than 0.2 w/w%, such as less than 0.1 w/w%, such as less than 0.05 w/w% of the 2-CTX degradation product (formula IV) after 6 months of storage at 40°C/75% RH.
  • the pharmaceutical composition as disclosed herein comprises less than 2 w/w% of the trans(E)-clopenthixol degradation product (formula V) after storage for 24 months at 25 °C.
  • the pharmaceutical composition as disclosed herein comprises less than 0.2%w/w, such as less than 0.1 %w/w of the trans(E)-clopenthixol degradation product (formula V) after storage for 18 months at 25°C/60% RH.
  • the present invention provides a pharmaceutical composition wherein less than less than 1 w/w%, such as less than 0.5 w/w%, such as less than 0.2 w/w% of the trans(E)-clopenthixol degradation product (formula V) after 6 months of storage at 40°C/75% RH.
  • the pharmaceutical composition as disclosed herein comprises less than 0.25 w/w% of unknown degradation products after storage for 24 months at 25 °C.
  • the pharmaceutical composition as disclosed herein comprises less than 0.1%w/w, such as less than 0.05 %w/w of unknown degradation products after storage for 18 months at 25°C/60% RH. In one embodiment, the pharmaceutical composition as disclosed herein comprises less than 0.2 w/w%, such as less than 0.1 w/w%, such as less than 0.05 w/w%, of unknown degradation products after 6 months of storage at 40°C/75% RH. In one embodiment, the color of solution of the pharmaceutical composition of the present invention is equal to or less than GY5, such as equal to or less than GY6, such as less than equal to or less than GY7 after storage for 24 months at 25 °C.
  • the color of solution of the pharmaceutical composition of the present invention is equal to or less than GY5, such as equal to or less than GY6, such as less than equal to or less than GY7 after storage for 18 months at 25°C/60% RH. In one embodiment, the color of solution of the pharmaceutical composition of the present invention is equal to or less GY7 after 6 months of storage at 40°C/75% RH.
  • GY refers to the color of the formulation, as compared to standard solution as described in European Pharmacopoeia Chapter 2.2.2 (10 th edition).
  • the pharmaceutical composition of the present invention may be stored in any suitable container, such as a glass container or a suitable plastic container, such as polypropylene or polyethylene.
  • the pharmaceutical composition is stored in a Type III glass bottle.
  • Method of treatment by administering composition The pharmaceutical composition of the present invention comprising zuclopenthixol may be used in treatment of a CNS disorder, such as for example in the treatment of schizophrenia, psychoses, or mania.
  • said CNS disorder is acute or chronic.
  • the CNS disorder is acute psychosis, such as in a patient suffering from schizophrenia or mania.
  • the CNS disorder is acute schizophrenia, acute psychosis, or mania.
  • the CNS disorder is chronic schizophrenia or other psychoses.
  • the CNS disorder is acute and chronic schizophrenia or other psychoses, especially with symptoms such as hallucinations, delusions, thought disturbances as well as agitation, restlessness, hostility and/or aggressiveness.
  • the present invention provides a pharmaceutical composition according to the present disclosure for use in the treatment of a CNS disorder.
  • the present invention provides a method of treatment of a CNS disorder, the method comprising administration of a pharmaceutical composition according to the present disclosure.
  • the present invention provides use of a pharmaceutical composition according to the present disclosure for the manufacture of a medicament for use in the treatment of a CNS disorder.
  • the present invention provides use of a pharmaceutical composition according to the present disclosure for the treatment of a CNS disorder.
  • the CNS disorder is psychosis.
  • the patient being treated for psychosis is suffering from schizophrenia or mania.
  • the pharmaceutical composition according to the present invention is administered orally, such as by oral drop.
  • Items 1 A pharmaceutical composition comprising a compound of formula (I) Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable cyclodextrin. 2. The pharmaceutical composition according to item 1, wherein the composition is an aqueous liquid composition. 3.
  • composition according to any one of the preceding items, wherein the pharmaceutically acceptable cyclodextrin is selected from pharmaceutically acceptable, water- soluble, native or derivatized cyclodextrins, such as selected from the group consisting of randomly methylated ⁇ -cyclodextrin, 2-O-methyl- ⁇ -cyclodextrin, heptakis-(2,6-di-O-methyl)- ⁇ - cyclodextrin, (dimethyl- ⁇ -cyclodextrin), acetylated dimethyl- ⁇ -cyclodextrin, heptakis-(2,3,6-tri- O-methyl)- ⁇ -cycIodextrin, trimethyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, ⁇ - cyclodextrin sulphate, ⁇ -cyclodextrin phosphate, and 2-hydroxypropyl-gamma-cyclodextrin.
  • composition according to any one of the preceding items wherein the pharmaceutically acceptable cyclodextrin is 2-hydroxypropyl- ⁇ -cyclodextrin.
  • pharmaceutically acceptable cyclodextrin is 2-hydroxypropyl- ⁇ -cyclodextrin having a degree of substitution of at least 0.6, such as at least 0.62. 6.
  • composition according to any one of the preceding items, wherein the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the range from about 1 mg/mL to about 100 mg/mL, such as in the range of about 1 mg/mL to about 75 mg/mL, such as in the range of about 1 mg/mL to about 50 mg/mL, such as in the range of about 1 mg/mL to about 40 mg/mL, such as in the range of about 1 mg/mL to about 30 mg/mL, such as in the range of about 1 mg/mL to about 25 mg/mL, such as in the range of about 1 mg/mL to about 20 mg/mL. 7.
  • composition according to any one of the preceding items, wherein the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the range from about 1 mg/mL to about 100 mg/mL, such as in the range of about 5 mg/mL to about 100 mg/mL, such as in the range of about 10 mg/mL to about 100 mg/mL, such as in the range of about 15 mg/mL to about 100 mg/mL, such as in the range of about 16 mg/mL to about 100 mg/mL, such as in the range of about 18 mg/mL to about 100 mg/mL, such as in the range of about 20 mg/mL to about 100 mg/mL.
  • concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the range from about 1 mg/mL to about 100 mg/mL, such as in the range of about 5 mg/mL to about 100 mg/mL, such as in the range of about 10 mg/mL to about 100 mg/mL, such as in the range of
  • the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the range from about 1 mg/mL to about 100 mg/mL, such as in the range of about 5 mg/mL to about 75 mg/mL, such as in the range of about 10 mg/mL to about 50 mg/mL, such as in the range of about 10 mg/mL to about 40 mg/mL, such as in the range of about 10 mg/mL to about 30 mg/mL, such as in the range of about 15 mg/mL to about 25 mg/mL, such as in the range of about 18 mg/mL to about 22 mg/mL, preferably the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 20 mg/mL.
  • the pharmaceutical composition according to any one of the preceding items wherein the compound of formula (I) is in the form of a salt, such as a hydrochloride salt, hydrobromide salt, dihydrobromide salt, or dihydrochloride salt.
  • the molar ratio of the cyclodextrin to the compound of formula (I) is in the range of about 0.1:1 to about 100:1, such as in the range of about 0.5:1 to about 100:1, such as in the range of about 1:1 to about 100:1, such as in the range of about 2:1 to about 100:1, such as in the range of about 5:1 to about 100:1.
  • the molar ratio of the cyclodextrin to the compound of formula (I) is in the range of about 0.1:1 to about 100:1, such as in the range of about 0.5:1 to about 50:1, such as in the range of about 0.5:1 to about 20:1, such as in the range of about 0.5:1 to about 10:1, such as in the range of about 0.8:1 to about 5:1, such as in the range of about 0.8:1 to about 2:1, such as in the range of about 0.9:1 to about 1.5:1, preferably the molar ratio of the cyclodextrin to the compound of formula (I) is about 1:1. 12.
  • the pharmaceutical composition according to any one of the preceding items wherein the cyclodextrin is present in an amount from about 5% to about 20% (w/v), such as in an amount from about 5% to about 15% (w/v), such as in an amount from about 5% to about 12% (w/v), preferably the cyclodextrin is present in an amount from about 5% to about 10% (w/v). 13.
  • the pharmaceutical composition according to any one of the preceding items wherein the pH of the composition is above 3 and below 7, such as in the range of 4-6, such as in the range of 5-6, for example 5, for example 6, preferably 5. 15.
  • the pharmaceutical composition according to any one of the preceding items, wherein the composition further comprises EtOH. 17.
  • the pharmaceutical composition according to any one of the preceding items wherein the EtOH content is in the range of 0 % to 20 (w/v), such as in the range of 0 % to 15 (w/v), such as in the range of 5 % to 15 (w/v), preferably the ethanol content is 12% (w/v). 18.
  • the pharmaceutical composition according to any one of the preceding items, wherein the composition is an oral drop formulation.
  • a pharmaceutical composition comprising a compound according to formula (I), or a pharmaceutically acceptable salt thereof, 2-hydroxypropyl- ⁇ -cyclodextrin and ethanol, wherein a.
  • the concentration of the compound of formula (I) is in the range of 15 to 25 mg/mL, preferably 20 mg/mL
  • the concentration of 2-O-hydroxypropyl- ⁇ -cyclodextrin is present in an amount from about 5% to about 12% (w/v), preferably 10 % (w/v).
  • the ethanol content is in the range of 5% to 15% (w/v), preferably 12% (w/v), and d.
  • the pH is in the range of 4.5 to 5.5, preferably 5.
  • 24. A method of preparing a pharmaceutical composition according to any one of items 1 to 20, the method comprising the steps of: a. dissolving the pharmaceutically acceptable cyclodextrin in water, b. adding zuclopenthixol to the composition formed in step a. and stirring until dissolved, and c. adjusting pH of the composition by addition of sodium hydroxide.
  • the pharmaceutical composition of the present invention may be prepared as outlined in the present example.
  • Example 2 Stabilizing formulation – Screening for stabilizing factors
  • the aim of this examples was to investigate different factors for their ability to stabilize Zuclopenthixol in the formulation and to prevent degradation of zuclopenthixol in the formulation, such as prevent degradation by hydrolysis and/or oxidative degradation as described above.
  • Formulation 1 To a 100 ml volumetric flask was added 2.9 g Zuclopenthixol 2HCl and 70 mL ELGA water. pH measured to 2.0 with no addition of 5 M NaOH. The volume was adjusted to 100 mL with ELGA water before transfer of the solution to suitable utensil and addition of 25.0 mL Ethanol 96%.
  • Formulation 2 To a 100 ml volumetric flask was added 2.9 g Zuclopenthixol 2HCl and 70 mL ELGA water. pH was adjusted to 4.0 by addition of 5 M NaOH.
  • Formulation 4 To a 100 ml volumetric flask was added 2.9 g Zuclopenthixol 2HCl, 70 mL ELGA water, and 750 ⁇ L glacial acetic acid. pH was adjusted to 4.0 by addition of 5 M NaOH. The volume was adjusted to 100 mL with ELGA water before transfer of the solution to suitable utensil and addition of 25.0 mL Ethanol 96%.
  • Formulation 5 To a 100 ml volumetric flask was added 2.9 g Zuclopenthixol 2HCl, 70 mL ELGA water, and 750 ⁇ L glacial acetic acid. pH was adjusted to 6.0 by addition of 5 M NaOH.
  • Formulation 7 To a 100 ml volumetric flask was added 2.9 g Zuclopenthixol 2HCl, 70 mL ELGA water, and 630 ⁇ L phosphoric acid. pH was adjusted to 6.0 by addition of 5 M NaOH. The volume was adjusted to 100 mL with ELGA water before transfer of the solution to suitable utensil and addition of 25.0 mL Ethanol 96%.
  • Formulation 8 To a 100 ml volumetric flask was added 2.9 g Zuclopenthixol 2HCl and 70 mL ELGA water. pH was adjusted to 4.0 by addition of 5 M NaOH.
  • formulation 10 Due to low solubility of ⁇ -CD, formulation 10 was discarded prior to the stability study. Stability study: 10 mL of each of the test formulations prepared according to the above method was transferred to laboratory glassware bottles which were sealed and stored at 40 °C, 75%RH for 4 weeks with protection from light throughout the experiment. Samples were withdrawn after 0, 17 and 36 days and analyzed according to the methods below. pH of the withdrawn samples was measured using a Metrohm 780 pH meter.
  • Amount of degradation products To measure the content of degradation products, the withdrawn samples were analyzed by HPLC, using a Symmetry Shield RP18, 50 x 2.1 mm ID, 3.5 ⁇ m column, mobile phases A: 0.04% TFA in water, B: 0.04% TFA in MeCN, C: methanol. The flow was 0.6 ml/min with a temperature of 40 °C. The injection volume was 10 ⁇ L and detection was UV at 270 nm.
  • the degradation product is also formed in higher amount at lower pH ( Figure 1C).
  • 2-CTX The results show a higher amount of the 2-CTX degradation product (Formula (IV)) at pH 2.0 and 4.0 as compared to the formulations of higher pH 6.0 ( Figure 1A).
  • Table 6 displays the amount of unknown degradation products in the different formulations of the example.
  • Formulations having a higher pH of 6.0 show less degradation products in general.
  • the formulation of pH 6.0 was, however, found to develop a yellow colour over time. Addition of a buffer to the composition was found to provide a more stable pH over a 5 week period, however, the stable pH was found to have no positive impact on the stability of zuclopenthixol in the formulation.
  • the stability of zuclopenthixol was found to be lower than for the formulation comprising no buffer.
  • formulations at pH 4.0 comprising no buffer, AcOH buffer, 2-hydroxypropyl- ⁇ - cyclodextrin, or sulfobutylether- ⁇ -cyclodextrin Sodium it is clear that the presence of 2- hydroxypropyl- ⁇ -cyclodextrin in the formulation provides a markedly higher stability of zuclopenthixol in the formulation, as demonstrated by the lower amounts of degradation products.
  • the same effect was not found in formulations comprising sulfobutylether- ⁇ -cyclodextrin sodium, wherein especially a high content of dicarbinol was observed.
  • Example 3 Influence of pH in formulations comprising cyclodextrins
  • the aim of this examples was to study the impact of pH on the stability of Zuclopenthixol in a formulation comprising cyclodextrin, specifically comprising 2-hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ cyclodextrin sodium.
  • the example was performed in order to identify the optimal pH for a pharmaceutical formulation comprising zuclopenthixol and cyclodextrin, and to test whether different pH would result in complex formation between zuclopenthixol and different cyclodextrins.
  • Materials and methods The influence of different parameters on Zuclopenthixol stability and degradation was studied by preparation of different formulations 9-19, table 7: Table 7: Overview of formulations tested Preparation of samples: The test formulations were prepared in a batch size of 150 mL, as described below for each formulation. In general, a fresh bottle of ethanol was used in order to decrease the risk of peroxide content in ethanol thereby lowering the risk of oxidation due to peroxide content.
  • Stock formulation A To a 500 mL volumetric flask was added 23 g Zuclopenthixol 2HCl and 100 g 2-hydroxypropyl- ⁇ - cyclodextrin (Kleptose, degree of substitution of 0.62). ELGA water was added to the flask and the volume adjusted to 500 mL.
  • Formulation 11 To a glass beaker was added 75 mL of stock formulation A and pH was adjusted to 3.0 by addition of 5 M NaOH. The solution was transferred to a 150 mL volumetric flask and the volume was adjusted to 150 mL with ELGA water.
  • Formulation 12 To a glass beaker was added 75 mL of stock formulation A and pH was adjusted to 4.0 by addition of 5 M NaOH.
  • Formulation 13 To a glass beaker was added 75 mL of stock formulation A and pH was adjusted to 5.0 by addition of 5 M NaOH. The solution was transferred to a 150 mL volumetric flask and the volume was adjusted to 150 mL with ELGA water.
  • Formulation 14 To a glass beaker was added 75 mL of stock formulation A and pH was adjusted to 6.0 by addition of 5 M NaOH. The solution was transferred to a 150 mL volumetric flask and the volume was adjusted to 150 mL with ELGA water.
  • Formulation 15 To a glass beaker was added 75 mL of stock formulation A and pH was adjusted to 7.0 by addition of 5 M NaOH. The solution was transferred to a 150 mL volumetric flask and the volume was adjusted to 150 mL with ELGA water.
  • Formulation 16 Weigh out 2.9 g Zuclopenthixol 2HCl to a 100 ml volumetric flask. Add 70 mL ELGA water. Adjust pH to 2.0 with 5 M NaOH. Add 12.5 g Captisol. The volume was adjusted to 100 mL with ELGA water before transfer of the solution to suitable utensil and addition of 25.0 mL Ethanol 96%. Formulation 9 was prepared as described in example 2.
  • Formulation 17 Weigh out 2.9 g Zuclopenthixol 2HCl to a 100 ml volumetric flask. Add 70 mL ELGA water. Adjust pH to 6.0 with 5 M NaOH. Add 12.5 g Captisol. The volume was adjusted to 100 mL with ELGA water before transfer of the solution to suitable utensil and addition of 25.0 mL Ethanol 96%.
  • Formulation 10, 18 and 19 Due to low solubility of ⁇ -CD, formulations 10, 18 and 19 were discarded prior to the stability study.
  • the injection volume was 10 ⁇ L and detection was UV at 270 nm.
  • the gradient was linear with the points 0 min: 82% A, 18% B, 0% C to 8 min: 82% A, 18% B, 0% C to 17 min: 5% A, 10% B, 85% C to 19 min: 5% A, 10% B, 85% C to 30 min: 82% A, 18% B, 0% C.
  • pH of the withdrawn samples was measured using a Metrohm 780 pH meter. Absorbance of the withdrawn sample was measured using an Agilent Cary 60 UV spectrophotometer.
  • Carbinol The amount of carbinol degradation product (Formula (II)) was found to be low for all samples tested, with the only exception being the Kleptose pH 3.0 formulation which showed 0.021% carbinol after 19 weeks of storage ( Figures 3B and 5B).
  • Dicarbinol The amount of dicarbinol degradation product (Formula (III)) was found to be lowest at higher pH, with the kleptose comprising formulations having a pH of 5, 6, and 7 showing the lowest amount ( Figure 3C).
  • the stability was also found to be highest at higher pH 6.0 ( Figure 5C), however, even after only 36 d of storage, the dicarbinol content was higher than for the kleptose formulations at pH 5, 6, and 7, after 19 weeks of storage.
  • Table 9 displays the amount of dicarbinol in the different formulations of the example.
  • 2-CTX The amount of the 2-CTX degradation product (Formula (IV)) was found to be low in kleptose containing formulations, with the formulations as higher pH 5, 6, and 7 showing the lowest amount ( Figure 3A).
  • the stability was also found to be highest at higher pH 6.0 ( Figure 5A), however, even after only 36 days of storage, the 2-CTX content was higher than for the kleptose formulations at pH 5, 6, and 7, after 19 weeks of storage.
  • Table 10 displays the amount of 2-CTX in the different formulations of the example.
  • the colour, appearance and pH of the formulations Colour and appearance of the sample comprising kleptose was analyzed by visual appearance and by measuring absorbance at 410 nm and 440 nm.
  • the samples were analyzed at timepoints 2 weeks, 4 weeks and 19 weeks.
  • the formulation with pH 6 was found to be the most stable formulation, closely followed by the formulation with pH 5 and pH 7. All three formulations were clear and colourless at all timepoints measured ( Figures 4 A and B).
  • a larger change in colour and absorbance at 410 and 440 nm was observed when lowering pH of the formulation (pH 4 and pH 3). pH of the formulations
  • pH of all kleptose comprising formulations appeared stable over time, despite the absence of a buffering agent. See further in below table 12.
  • Table 12 pH of the formulations at timepoints 0, 2 weeks, 4 weeks, and 19 weeks. Comparative stability The stability of Zuclopenthixol in the best performing formulations 13 and 14 was compared to a formulation comprising 20 mg/mL zuclopenthixol at pH 2 comprising no cyclodextrin and wherein no adjustment of the pH is performed. The 19 weeks timepoint data of formulations 13 and 14 was compared to data of the pH 2.0 no CD formulation after 12 weeks storage at 40 °C and 75%RH. The level of degradation was found to be significantly lower for the optimized formulations 13 and 14 ( Figure 6), when compared to the pH 2.0 no Cd formulation.
  • Example 4 Stress stability study of zuclopenthixol composition comprising 2-hydroxypropyl- ⁇ - cyclodextrin
  • the aim of the present example was to test the stability and pharmaceutical applicability of the composition of the present invention, by analyzing the composition on various parameters, including degradation, drop rate, drop measure, uniformity of dose, and absorbance.
  • Materials and methods Experimental design The pharmaceutical composition tested comprises Zuclopenthixol 20 mg/mL, 10% 2-hydroxypropyl- ⁇ - cyclodextrin, 12% ethanol (w/v, 96%), pH adjusted to 5.0 with 1 M NaOH.
  • the composition was prepared according to the method as described in example 1.
  • the injection volume was 30 ⁇ L and detection was UV at 270 nm.
  • pH of the withdrawn samples was measured using a Metrohm 780 pH meter. Absorbance of the withdrawn sample was measured using an Agilent Cary 60 UV spectrophotometer. Colour and clarity was evaluated by visual inspection of the samples as described in Ph.Eur. (European pharmacopeia, 10 th edition). Dropping speed was measured by placing a flask in a vertical position and count the number of drops delivered in 10 seconds. The test was repeated three times and an average was calculated. Uniformity of Dose was determined as described in Ph.Eur. (European pharmacopeia, 10 th edition) (liquid preparations for oral use).
  • the optimized pharmaceutical formulation was analyzed on various parameters as listed in below tables 15-17. Stability and pharmaceutical applicability of formulation The formulation was found to provide a stable pharmaceutical formulation having a stable density and pH of the formulation of the period of the 6 months storage time (Table 13). Also, the drop measure and drop rate was found to be stable over the time course of the experiment. Furthermore, it was found that the API content of zuclopenthixol was stable of the time course of the experiment, resulting in a good uniformity of dose. The observed stability of the formulation in these parameters is important for the applicability of the formulation as a pharmaceutical formulation, specifically for the applicability of the formulation as an oral drop formulation.
  • Table 13 Stability and pharmaceutical applicability of formulation as measured over the time course of 6 months Color and appearance of the formulation The formulation was found to have a high stability in color and appearance with the color being equal to or below GY7 and the solution being clear during the time course of the experiment (Table 14). Also, the absorbance of the solution as measured at 410, 440, and 600 nm was low during the time course of the experiment.
  • Stock solution A Weigh out 11.85 g zuclopenthixol 2HCl to a 250 mL volumetric flask. Dissolve in ELGA water and adjust volume to 250 mL by addition of ELGA water.
  • Stock solution B Weigh out 50 g 2-hydroxypropyl- ⁇ -cyclodextrin (Kleptose, degree of substitution of 0.62) to a 250 mL volumetric flask. Dissolve in ELGA water and adjust volume to 250 mL by addition of ELGA water.
  • Stock solution C Measure out 100 mg trimethylsilylpropanesulfonic acid sodium salt (DSS) to a 5 mL volumetric flask.
  • DSS trimethylsilylpropanesulfonic acid sodium salt
  • Stock solution D Measure 25.0 mL stock solution A to a suitable utensil. Adjust pH to 4.0 by addition of 5 M NaOH and transfer the solution to a 50 mL volumetric flask using several volumes of ELGA water and adjust volume to 50 mL by addition of ELGA water.
  • Samples 4A-J To 10 suitable containers (A-J) was added: 1.0 mL stock D + 200 ⁇ L stock C To the respective samples was then added: Sample 4A: 0 mL stock B + 3.8 mL ELGA water Sample 4B: 0.1 mL stock B + 3.7 mL ELGA water Sample 4C: 0.2 mL stock B + 3.6 mL ELGA water Sample 4D: 0.3 mL stock B + 3.5 mL ELGA water Sample 4E: 0.4 mL stock B + 3.4 mL ELGA water Sample 4F: 0.5 mL stock B + 3.3 mL ELGA water Sample 4G: 0.6 mL stock B + 3.2 mL ELGA water Sample 4H: 0.8 mL stock B + 3.0 mL ELGA water Sample 4I: 1.2 mL stock B + 2.6 mL ELGA water Sample 4J: 3.8 mL stock B + 0 mL ELGA water DSS was found
  • ⁇ rel.acetone which is the chemical shift of vinyl proton of zuclopenthixol when the NMR-spectrum is calibrated to that of the acetone chemical shift reference, was determined for each sample 4A-J. Data were fitted relative to molar concentrations using an expression of the form: ⁇ ⁇ + ⁇ ( ⁇ ) + 1 ⁇ ⁇ ⁇ ⁇ ⁇ 0.0025 + ⁇ ( ⁇ ) + 1 ⁇ ⁇ ⁇ ⁇ 0.0025 2 Wherein ddmax was the theoretical maximum of the ⁇ value, c(CD) was the concentration of 2- hydroxypropyl- ⁇ -cyclodextrin of the respective sample, and K was the equilibrium constant for the formation of a 1:1 API:CD complex.
  • Example 6 Microbiological tests of sample The aim of this study was to test whether the pharmaceutical composition of the present disclosure was pharmaceutically applicable, specifically related to microbial growth in the sample. Materials and methods The pharmaceutical composition was prepared according to the method described in example 1. In a first sample, the composition was stored in brown type III glass bottles with a drop aggregate inserted and closed with a screw cap.
  • microbiological quality The test for microbiological quality (Microbial enumeration test and Escherichia Coli test) was carried out according to Ph.Eur.2.6.12 (USP ⁇ 61>) and Ph.Eur 2.6.13 (USP ⁇ 62>).
  • Ph.Eur.2.6.12 USP ⁇ 61>
  • Ph.Eur 2.6.13 USP ⁇ 62>
  • antimicrobial capacity test was performed with reference to Ph.Eur.5.1.3. The study was designed to confirm the efficacy of antimicrobial preservation of the formulation.
  • test organisms used were: Candida albicans, Aspergillus brasiliensis, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli.
  • Start levels of organisms in the challenge were (Table 17): Table 17: Start level of Candida albicans, Aspergillus brasiliensis, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli.
  • Table 18 Microbiological quality TAMC: total aerobic microbial count; TYMC: total combined yeasts/moulds count The microbial growth in the second sample is listed in below table 19.
  • Table 19 Microbial growth Conclusion This example demonstrates that the pharmaceutical composition of the present disclosure, comprising ethanol, satisfies the requirements of pharmaceutical applications with respect to microbiological quality and antimicrobial preservation.
  • Example 7 Stability study of zuclopenthixol composition comprising 2-hydroxypropyl- ⁇ - cyclodextrin The aim of the present example was to test the stability and pharmaceutical applicability of the composition of the present invention during storage at 25°C/60% RH, by analyzing the composition on various parameters, including degradation, appearance and API content.
  • the pharmaceutical composition tested comprised Zuclopenthixol 20 mg/mL, 10% 2-hydroxypropyl- ⁇ -cyclodextrin, 12% ethanol (w/v, 96%), pH adjusted to 5.0 with 5 M NaOH.
  • the composition was prepared according to the method as described in example 1. To a 25 mL drop bottle of glass type III was added 22 mL of the pharmaceutical composition and the bottle was fitted with a drop aggregate and closed with a cap. Stability study: The sample was placed in stability at 25°C/60% RH. Samples were withdrawn and analyzed after 3, 6, 9, 12 and 18 months.
  • Amount of degradation products To measure the content of degradation products, the withdrawn samples were analyzed by HPLC, using a X-Bridge phenyl, 75 mm x 4.6 mm (ID) x 2.5 ⁇ m column, mobile phase Acetate buffer 25mM pH 5.2/Acetonitrile (70/30), using isocratic elution. The flow was 1.1 ml/min with a temperature of 40 °C. The injection volume was 30 ⁇ L and detection was UV at 270 nm. pH of the withdrawn samples was measured using a Metrohm 780 pH meter. Colour and clarity was evaluated by visual inspection of the samples as described in Ph.Eur (European pharmacopeia, 10 th edition).
  • the optimized pharmaceutical formulation was analyzed on various parameters as listed in below tables 20-21. Stability and pharmaceutical applicability of formulation The formulation was found to provide a stable pharmaceutical formulation having a stable pH of the formulation of the period of the 18 months storage time (Table 20). Furthermore, it was found that the API content of zuclopenthixol was stable over the time course of the experiment. The formulation was found to have a high stability in color and appearance with the color being equal to or below GY7 and the solution being clear during the time course of the experiment (Table 20).
  • Example 8 Stability study of Flupentixol composition comprising 2-hydroxypropyl- ⁇ -cyclodextrin
  • the aim of this examples was to investigate the ability of 2-hydroxypropyl- ⁇ -cyclodextrin to stabilize Flupentixol in a formulation and to prevent degradation of Flupentixol in the formulation, such as prevent degradation by hydrolysis and/or oxidative degradation as described in this example.
  • Flupentixol is disclosed below according to formula (VI). Flupentixol is found as a mixture of the Z and the E isomer.
  • Table 22 Formulation 20 was prepared with same pH, ethanol content and stoichiometric ratio between active ingredient and 2-hydroxypropyl- ⁇ -cyclodextrin as for the optimized zuclopenthixol formulations of the previous examples 4 and 7.
  • Table 22 Overview of formulations tested Preparation of samples: The test formulations were prepared as described below for each formulation. All formulations were prepared with protection from light.
  • Formulation 20 To a 500 ml volumetric flask was added 100 g of 2-hydroxypropyl- ⁇ -cyclodextrin and 150 mL Purified water. Upon stirring was added 60 g of ethanol 96% and subsequently 23.36 g of Flupentixol 2HCl. When all solids were dissolved, pH was adjusted to 5.0 by addition of 5 M NaOH. The volume was adjusted to 500 mL with ELGA water before transfer of the solution to suitable utensil for stability, as described below.
  • Formulation 21 To a 500 ml volumetric flask was added 100 g of 2-hydroxypropyl- ⁇ -cyclodextrin and 150 mL Purified water. Upon stirring was added 100 g of ethanol 96% and subsequently 23.36 g of Flupentixol 2HCl. When all solids were dissolved, pH was adjusted to 5.0 by addition of 5 M NaOH. The volume was adjusted to 500 mL with ELGA water before transfer of the solution to suitable utensil for stability, as described below.
  • Formulation 22 To a 500 ml volumetric flask was added 100 g of 2-hydroxypropyl- ⁇ -cyclodextrin and 150 mL Purified water.
  • Amount of degradation products To measure the content of degradation products, the withdrawn samples were analyzed by HPLC, using a X-Bridge phenyl 75 x 4.6 mm (ID), 2.5 ⁇ m column, mobile phase: A: Ammonium Acetate buffer pH 6.5 with 0.5 % TEA, B: Acetonitrile (gradient A/B: 65/35). The flow was 1.1 mL/min with a temperature of 40 °C and runtime of 30 min. The injection volume was 30 ⁇ L and detection was UV at 270 nm. Results: Upon degradation of Flupentixol, the following degradation products are observed: Formula (VII), also referred to herein as Sulfoxide-F.
  • pH and Flupentixol content The pH and Flupentixol content of the formulations were measured during the time course of the experiment. pH was found to be stable, whereas a small decrease in Flupentixol content was observed over time for all formulations (table 23).

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Abstract

La présente invention concerne une composition pharmaceutique comprenant du zuclopenthixol, ou un sel pharmaceutiquement acceptable de celui-ci, et une cyclodextrine, la composition présentant une stabilité chimique accrue du zuclopenthixol. La composition pharmaceutique trouve une application particulière dans le traitement d'un trouble du SNC, tel que dans le traitement de la schizophrénie, de la psychose ou de la manie.
PCT/EP2023/082831 2022-11-24 2023-11-23 Composition comprenant du zuclopenthixol WO2024110577A1 (fr)

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