WO2024013062A1 - Forme pharmaceutique orale solide comprenant de la vortioxétine et de la vitamine d - Google Patents

Forme pharmaceutique orale solide comprenant de la vortioxétine et de la vitamine d Download PDF

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Publication number
WO2024013062A1
WO2024013062A1 PCT/EP2023/068993 EP2023068993W WO2024013062A1 WO 2024013062 A1 WO2024013062 A1 WO 2024013062A1 EP 2023068993 W EP2023068993 W EP 2023068993W WO 2024013062 A1 WO2024013062 A1 WO 2024013062A1
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Prior art keywords
vitamin
vortioxetine
oral dosage
dosage form
pharmaceutically acceptable
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PCT/EP2023/068993
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English (en)
Inventor
Yuan DING
Ralph SCHNEITER
Zdravka MISIC
Anne-Cecile V. Bayne
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Dsm Ip Assets B.V.
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Publication of WO2024013062A1 publication Critical patent/WO2024013062A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • 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
    • A61P25/24—Antidepressants

Definitions

  • Solid oral dosage form comprising vortioxetine and vitamin D
  • the present invention relates to the treatment of patients suffering from major depressive disorder (MDD). It also relates to personalized medicine.
  • MDD major depressive disorder
  • Trintellix® is an FDA approved medical drug comprising vortioxetine hydrobromide.
  • Commercially available Trintellix® tablets comprise 5 mg, 10 mg, 15 mg, or 20 mg vortioxetine (as hydrobromide).
  • Trintellix® is mostly used for treatment of depression. In some European countries, a corresponding product is or was available as Brintellix®. Similar to Trintellix®, Brintellix® can only be obtained with a prescription and is available as tablets (5, 10, 15 and 20 mg) and oral drops (20 mg/ml). The most common side effects reported with vortioxetine are nausea, diarrhea, dry mouth, constipation, vomiting, flatulence, dizziness and sexual dysfunction.
  • the forced swim test measures the presence of or reduction in positive coping skills in rats and mice.
  • FST forced swim test
  • animals When animals are treated with an effective anti-depressant prior to the test, they show reduced immobility and more climbing, suggesting that the animals do not give up, while untreated animals show increased immobility and will float more in the water. Therefore, reduced immobility and more climbing is thought to be an anti-depressive, positive coping phenotype in the FST.
  • Guilloux et al. (2013) have found that vortioxetine (2.5-5 mg/kg) increased mobility in the FST [see Guilloux, J. P.
  • the German G-BA (“Gemeinsamer Bundesauschuss”) evaluates the additional benefit of drugs with new active ingredients compared to a comparative therapy.
  • Such benefit assessment is done in accordance with Section 35a of the German Social Code, Book V (known as the AMNOG procedure).
  • the result of this benefit assessment is the starting point for price negotiations between the National Association of Statutory Health Insurance Funds (“GKV- Spitzenval”) and the pharmaceutical manufacturer. At the end of the negotiations, it is determined how much the statutory health insurance will pay for the drug in the future.
  • the benefit assessment of vortioxetine has been rather negative. As a result, the originator company appears to have withdrawn Brintellix® from the German market.
  • vortioxetine therapy is improved by taking into consideration the vitamin D level of the patient to be treated.
  • vortioxetine requires a certain level of vitamin D in the body of the patient.
  • the inventors have unveiled that patients who lack vitamin D are more likely to not sufficiently respond to a vortioxetine treatment.
  • the present invention relates to a fixed-dose combination (FDC) that is suitable to improve the vortioxetine treatment of patients who lack vitamin D.
  • the preferred fixed-dose combination of the invention is a solid oral dosage form which comprises - in addition to vortioxetine - also vitamin D.
  • the solid oral dosage form of the invention is similar to the commercially available vortioxetine tablet (Brintellix®).
  • the solid oral dosage form of the invention is preferably a compressed tablet that comprises 5 mg, 10 mg, or 20 mg vortioxetine hydrobromide.
  • a 10 mg Brintellix® tablet has an in vitro disintegration time of less than 1 minute.
  • disintegration time of a Brintellix® tablet was significantly increased when adding vitamin D. This is disadvantageous, as there is a linear relationship between disintegration of the tablet and dissolution of the drug; disintegration testing is an appropriate drug product quality control method for evaluating drug release from this dosage form (Nickerson et al., “Correlation of dissolution and disintegration results for an immediate-release tablet”, Journal of Pharmaceutical and Biomedical Analysis 150 (2016), page 339, left column, section “4. Conclusions”).
  • One embodiment of the invention relates to a vortioxetine tablet comprising calcifediol instead of vitamin D3.
  • calcifediol is commercially available under the tradename ampli-D® at DSM® Nutritional Products (Switzerland).
  • Calcifediol is also available as Rayladee® (OPKO Health, Miami, FL) and as Hidroferol® oral solution (Faes Farma, S.A., Spain).
  • One embodiment of the invention relates to a method of manufacturing a solid oral dosage form, wherein vitamin D3 and/or calcifediol are added to vortioxetine granules before compressing the obtained blend into tablets.
  • vitamin D3 and/or calcifediol are added to vortioxetine granules before compressing the obtained blend into tablets.
  • extra-granular addition also reduces the unwanted increase of the tablet's disintegration time.
  • the use of granules comprising both, vortioxetine and vitamin D, for manufacturing tablets is not preferred.
  • Figures 1 and 2 relate to Example 1 (vide infra).
  • Figure 1 shows a lack of effects of acute vortioxetine treatment in the forced swim test (FST) in male Balb/cJ mice that were vitamin D deficient.
  • Vortioxetine was dosed at 5 mg/kg bw at 24, 6 and 1 hours before the FST.
  • the immobility time in seconds [s] is shown and is expressed as means ⁇ SE (standard error). The experiment duration was 6 minutes.
  • a vehicle was applied.
  • vortioxetine had no positive effect in vitamin D deficient mice.
  • immobility time was about as long as in the control group.
  • FIG 2 shows the effects of vitamin D supplementation in the forced swim test (FST) in male Balb/cJ mice that were treated with vortioxetine.
  • Vortioxetine (5 mg/kg bw) alone or in combination with vitamin D at 0.05 (low) or 0.10 (high) mg/kg bw was given at 24, 6 and 1 hours prior to the FST.
  • the immobility time was recorded and the data in seconds [s] is expressed as means ⁇ SE (standard error).
  • the experiment duration was 6 minutes. Significance (*) of p ⁇ 0.05 was tested using one-way RM ANOVA with Tukey’s post-hoc analysis.
  • Figure 2 shows that in vitamin D deficient mice, vortioxetine shows positive effect only if vitamin D is coadministered.
  • Figures 3 and 4 relate to Example 2 (vide infra).
  • FIG 3 shows a lack of effects of acute vortioxetine treatment on cerebral blood flow (CBF) in male Balb/cJ mice that were vitamin D deficient.
  • Vortioxetine was dosed at 5 mg/kg bw at 24, 6 and 1 hours before the CBF. In the control group, a vehicle was applied. The mean percentage above baseline ⁇ SE (standard error) is shown. Trial time post dipyridamole injection lasted for 10 minutes. It is surprising that vortioxetine has no effect on CBF in vitamin D deficient mice.
  • Figure 4 shows effects of acute vortioxetine treatment in combination with different doses of vitamin D on cerebral blood flow (CBF) in male Balb/cJ mice that were vitamin D deficient.
  • Vortioxetine (5 mg/kg bw) alone or in combination with vitamin D at 0.05 (low) or 0.10 (high) mg/kg bw was given at 24, 6 and 1 hours priorto the CBF measurement.
  • the mean percentage above baseline ⁇ SE (standard error) is shown.
  • Trial time post dipyridamole injection lasted for 10 minutes. Significance (*) of p ⁇ 0.05 was tested using one-way RM ANOVA with Tukey’s post- hoc analysis.
  • Figure 4 shows that in vitamin D deficient mice, vortioxetine has an effect on CBF if vitamin D is co-administered.
  • Figure 5 relates to Example 3 (vide infra) and shows effects of acute vortioxetine treatment in the forced swim test (FST) in male Balb/cJ mice that were vitamin D deficient.
  • Vortioxetine (5 mg/kg bw) alone or in combination with calcifediol at 0.025 mg/kg bw was given at 24, 6 and 1 hours prior to the FST.
  • the immobility time was recorded and the data in seconds [s] is expressed as means ⁇ SE (standard error).
  • the experiment duration was 6 minutes. Significance (*) of p ⁇ 0.05 was tested using one-way RM ANOVA with Tukey’s post-hoc analysis.
  • a comparison of Figure 5 with Figure 2 shows that a low dosage of the selected vitamin D metabolite (calcifediol) is as effective as a high dosage of vitamin D3.
  • Figure 6 relates to Example 3 (vide infra) and shows effects of acute vortioxetine treatment in combination with different doses of vitamin D on cerebral blood flow (CBF) in male Balb/cJ mice that were vitamin D deficient.
  • Vortioxetine (5 mg/kg bw) alone or in combination with vitamin D at 0.05 or 0.10 mg/kg bw, or in combination with calcifediol at 0.025 or 0.050 mg/kg bw, was given at 24, 6 and 1 hours prior to the CBF measurement.
  • the mean percentage above baseline ⁇ SE (standard error) is shown.
  • Trial time post dipyridamole injection lasted for 10 minutes. Significance (*) of p ⁇ 0.05 was tested using one-way RM ANOVA with Tukey’s post-hoc analysis.
  • the inventors have unveiled a reason for poor response to vortioxetine treatment: lack of vitamin D.
  • the surprising interaction of vitamin D and vortioxetine allows to improve various aspects of the current vortioxetine treatment.
  • Direct compression is the shortest, most effective and least complex way to produce tablets.
  • the manufacturer can compress a blend of the drug with excipients. No additional processing steps are required.
  • some powders are difficult to compress even if a readily compactable binder/adhesive is included in the blend.
  • granules of the same powders are often more easily compressed.
  • tablette excipients are critical and often essential components of a modern drug product. In many products, excipients make up the bulk of the total dosage form.
  • a “tableting excipient” is a pharmaceutical excipient that is useful when compressing a tablet.
  • Exemplary tableting excipients are, amongst others, diluents, fillers, binders, disintegrants, lubricants, coloring agents and preservatives.
  • Granules are formed by granulation. Granulation is the process of forming granules and involves agglomeration of fine particles into larger granules. Wet granulation and dry granulation are two types of granulation technologies. The granules of the present invention are preferably formed by wet granulation. Wet granulation requires a processing solvent. In the context of the present invention, water is the preferred processing solvent. For agglomeration of fine particles into larger granules, a binder might be necessary. When doing wet granulation, the binder must be adapted to the chosen processing solvent.
  • the granules of the present invention are preferably formed by wet granulation, wherein water is used as processing solvent and wherein a binder suitable for aqueous wet granulation is used.
  • binders are soluble in water.
  • Preferred binders are PVP (polyvinylpyrrolidone, also commonly called polyvidone or povidone) and HPMC (hydroxypropyl methylcellulose; short: hydromellose).
  • a particular compound When manufacturing a solid pharmaceutical dosage form, a particular compound may be blended with other ingredients prior to granulation and is thus incorporated within the obtained granules. This is referred to as “intra-granular addition”.
  • a particular compound or a mixture of compounds
  • the obtained blend can then be further processed (e.g. can be compressed into tablets or can be filled into sachets).
  • an “extra-granular” compound is not part of a granule (i.e. is outside of a granule) whereas an “intra-granular” compound is part of a granule.
  • intra-granular composition is a composition obtained by a granulation process.
  • An example of an intra-granular composition are the granules described herein.
  • vortioxetine refers to vortioxetine or a pharmaceutically acceptable salt thereof.
  • vortioxetine is to be understood in a broad manner.
  • vortioxetine refers to a pharmaceutically acceptable salt of vortioxetine.
  • vortioxetine refers to vortioxetine hydrobromide.
  • vitamin D refers to any kind of vitamin D, including all vitamers of vitamin D and also including metabolites of all vitamers of vitamin D.
  • a vitamin D metabolite is thereby a molecule that is either a precursor, an intermediate or the final, physiologically modified product of the vitamin D pathway in the human body.
  • vitamin D is to be understood in a very broad manner.
  • vitamin D refers to D3 (cholecalciferol), vitamin D2 (ergocalciferol), to a vitamin D metabolite or a mixture thereof.
  • vitamin D refers to vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol) or a mixture thereof.
  • the most preferred vitamin D metabolite is calcifediol (25-hydroxyvitamin D3, also referred to as "25-OH D3").
  • vitamin D refers to calcifediol.
  • Alternative vitamin D metabolites are 1 -alpha, 25-vitamin D3 and 1 -alpha, 25-vitamin D2.
  • Patent claims relating to a “pharmaceutical combination” are product claims.
  • a “pharmaceutical combination for simultaneous administration” is a combination that is suitable for simultaneous administration.
  • simultaneous administration it is meant that vitamin D and vortioxetine are administered on the same day. Said two active ingredients can be administered at the same time (for fixed combinations) or one at a time (for free combinations).
  • a “fixed combination” is a pharmaceutical combination that delivers both actives (i.e. vitamin D and vortioxetine) at the same time to a patient.
  • a solid oral dosage form e.g. a tablet
  • a liquid oral dosage form e.g. oral drops
  • a “free combination” is a pharmaceutical combination that allows to administer both actives (i.e. vitamin D and vortioxetine) separately, i.e. one at a time. Treatment regimens in which vortioxetine and vitamin D are not administered by the same route of administration and/or are not administered at the same time require free combinations.
  • kits are a set of articles or equipment needed for a specific purpose.
  • the preferred kit of the invention comprises the herein described free combination and optionally means for measuring the vitamin D level of a patient.
  • An alternative kit of the invention comprises the herein described fixed combination and means for measuring the vitamin D level of a patient.
  • a “pharmaceutical combination for sequential administration” is a combination that is suitable for sequential administration.
  • sequential administration it is meant that during a period of two or more days of continuous treatment, only one of vortioxetine and vitamin D is administered on any given day.
  • a patient's vitamin D deficiency may be treated first (i.e. before initiating the vortioxetine treatment).
  • Vortioxetine treatment then starts afterwards.
  • Sequential administration requires a free combination.
  • separate administration it is meant that vitamin D and vortioxetine are administered one at a time.
  • separate administration can referto both, sequential administration and - when referring to the administration of both actives on the same day but one at a time - also to simultaneous administration.
  • a “patient” is a human subject who is in need of medical advice and/or is suffering from a disease.
  • a “patient” is preferably a human subject that is in need of pharmaceutical drug. More preferably, it is a human subject that is in need of vortioxetine or a pharmaceutically acceptable salt thereof.
  • vitamin D is essential. In that sense, everybody needs vitamin D. However, this is not what is meant by the expression “in need of vitamin D”.
  • a patient who is “in need of vitamin D” is a patient whose vitamin D level is below the recommendation limit of a governmental or non-governmental medical organization.
  • the recommendation limit of the Institute of Medicine (IOM) is 50 nmol calcifediol per liter blood.
  • the recommendation limit the medical ‘Endocrine Society’ association is 75 nmol calcifediol per liter blood.
  • a patient who is “in need of vitamin D” is preferably a patient whose calcifediol blood concentration is lower than 75 nmol/L or is lower than 50 nmol/L.
  • vitamin D supplementation e.g. oral vitamin D supplementation
  • a patient whose vitamin D level is in a healthy range is not in need of vitamin D supplementation.
  • a patient whose calcifediol blood concentration is 75 nmol/L or more is not in need of vitamin D supplementation.
  • a patient who is “vitamin D insufficient” has a calcifediol blood concentration preferably lower than 50 nmol/L.
  • a patient who is “vitamin D deficient” has a calcifediol blood concentration preferably lower than 30 nmol/L. In case of a calcifediol blood concentration lower than 10 nmol/L, the patient is severely vitamin D deficient.
  • Vortioxetine non-responder is a patient who is in need of antidepressant treatment but shows no positive response to the vortioxetine treatment.
  • no positive response to vortioxetine treatment means that a daily dosage of 20 mg vortioxetine (as hydrobromide) does not relieve the patient's symptoms.
  • Vortioxetine low-responder is a patient who is in need of antidepressant treatment but shows poor response to the vortioxetine treatment.
  • “poor response to vortioxetine treatment” means that a daily dosage of 10 mg or 15 mg vortioxetine (as hydrobromide) does not relieve the patient's symptoms.
  • Vortioxetine non-responders may also be considered as vortioxetine low-responders.
  • Vortioxetine non-responders may also be considered as vortioxetine low-responders.
  • not every vortioxetine low-responder is necessarily also a vortioxetine non-responder.
  • a not sufficient vitamin D level is believed to be a reason for being a vortioxetine non-responder or a vortioxetine low-responder.
  • the herein disclosed pharmaceutical combination comprises vitamin D.
  • vitamins Several kinds (vitamers) of vitamin D exist.
  • the two major vitamers are vitamin D3 and vitamin D2.
  • a preferred pharmaceutical combination of the present invention comprises vitamin D3, vitamin D2 or a mixture thereof.
  • the pharmaceutical combination of the present invention comprises either vitamin D3 or vitamin D2, but not a mixture thereof.
  • Calcifediol is a vitamin D metabolite, more specifically a vitamin D3 metabolite. In the human body, calcifediol is the most abundant metabolite of vitamin D. When determining a patient's vitamin D status (i.e. vitamin D level), it is common to directly or indirectly measure the concentration of calcifediol in a sample of the patient's blood. When orally administered, calcifediol has excellent bioavailability and hence, is very well absorbed by the body. This helps reaching optimal vitamin D levels faster.
  • the pharmaceutical combination of the present invention comprises at least one vitamin D metabolite, preferably at least one vitamin D3 metabolite and most preferably calcifediol.
  • Calcifediol for human consumption is commercially available as ampli-D® (DSM® Nutritional Products, Switzerland). Without wishing to be bound by theory, it is believed that calcifediol is improving vortioxetine treatment more effectively because a metabolic step can be skipped in the patient's body: whereas most kinds of vitamin D first need to be hydroxylated in the liver at position 25, this is not needed if calcifediol is administered. Although there is no need to do so, a mixture comprising vitamin D and a metabolite thereof could be used.
  • an alternative embodiment of the present invention relates to a pharmaceutical combination comprising vitamin D3 and at least one vitamin D metabolite, or vitamin D2 and at least one vitamin D metabolite, or vitamin D3, vitamin D2 and at least one vitamin D metabolite.
  • calcifediol is the preferred vitamin D metabolite.
  • the herein disclosed pharmaceutical combination comprises vortioxetine.
  • vortioxetine Several kinds of vortioxetine exist, including pharmaceutically acceptable salts of vortioxetine. Most if not all commercially available products comprise a pharmaceutically acceptable salt of vortioxetine. Commercially available, solid mono-preparations comprise vortioxetine hydrobromide.
  • the purpose of the present invention is to improve existing vortioxetine treatments.
  • pharmaceutically acceptable salts of vortioxetine are preferred.
  • Vortioxetine hydrobromide is the most preferred pharmaceutically acceptable salt of vortioxetine.
  • vortioxetine (D.L)-lactate is the preferred pharmaceutically acceptable salt of vortioxetine.
  • the pharmaceutical combination of the present invention comprises vortioxetine and vitamin D.
  • vortioxetine and vitamin D the above-mentioned preferences apply.
  • the herein disclosed pharmaceutical combination comprises preferably a pharmaceutically acceptable salt of vortioxetine, wherein said pharmaceutically acceptable salt of vortioxetine is more preferably vortioxetine hydrobromide (with the proviso that it is not a liquid oral dosage from).
  • a preferred pharmaceutical combination of the present invention comprises a pharmaceutically acceptable salt of vortioxetine and vitamin D3, wherein said pharmaceutically acceptable salt of vortioxetine is preferably vortioxetine hydrobromide.
  • An also preferred pharmaceutical combination of the present invention comprises a pharmaceutically acceptable salt of vortioxetine and calcifediol, wherein said pharmaceutically acceptable salt of vortioxetine is preferably vortioxetine hydrobromide.
  • An alternative pharmaceutical combination of the present invention comprises a pharmaceutically acceptable salt of vortioxetine and vitamin D2, wherein said pharmaceutically acceptable salt of vortioxetine is preferably vortioxetine hydrobromide.
  • the alternative pharmaceutical combination of the present invention comprises vortioxetine and a mixture of various kinds of vitamin D such as a mixture comprising vitamin D2 and D3, or a mixture comprising vitamin D2 and calcifediol, or a mixture comprising vitamin D3 and calcifediol.
  • pharmaceutical combinations comprising vortioxetine base instead of a pharmaceutically acceptable salt of vortioxetine.
  • a preferred kit of the invention comprises means for vitamin D injection (e.g. a prefilled syringe or a vial) and at least one oral dosage form, said at least one oral dosage form comprising a pharmaceutically acceptable salt of vortioxetine being preferably vortioxetine hydrobromide.
  • such kit may further comprise means facilitating the ex vivo measurement of calcifediol in a blood sample.
  • Free combinations comprising means for a vitamin D injection and at least one oral dosage form that comprises vortioxetine (or a pharmaceutically acceptable salt thereof) can be administered simultaneously or sequentially. If it is recommended to administer the injection and the oral dosage form on the same day, said free combination is for simultaneous administration. If it is recommended to administer the injection and the oral dosage form on different days, said free combination is for sequential administration.
  • Such recommendations can be found e.g. in a package leaflet, in a Summary of Product Characteristics (SmPC) or in guidelines for practitioners/ pharmacists. It is also possible that said free combination is either for simultaneous or for sequential administration (i.e. the practitioner and/or pharmacist can deicide).
  • a more general embodiment of the present invention relates to a free combination for simultaneous administration or preferably for sequential administration.
  • a preferred embodiment of the present invention relates to a free combination comprising vitamin D3 and vortioxetine hydrobromide and to kit comprising such free combination.
  • An also preferred embodiment of the present invention relates to a free combination comprising calcifediol and vortioxetine hydrobromide and to kit comprising such free combination.
  • a preferred kit comprises at least one oral dosage form, wherein said at least one oral dosage form is a solid or liquid oral dosage form that comprises vortioxetine hydrobromide.
  • An alternative embodiment of the present invention relates to a free combination comprising vitamin D3 and vortioxetine hydrobromide and to kit comprising such free combination.
  • Oral dosage forms comprising vitamin D may be liquid or solid.
  • Oral dosage forms comprising vortioxetine may also be liquid or solid. Whereas it is possible to combine two liquid oral dosage forms into one combined liquid oral dosage form, it is difficult or even impossible to combine a liquid oral dosage form with a solid oral dosage form. In this situation, a free combination is preferred.
  • One embodiment of the present invention relates to the herein described pharmaceutical combination, wherein said pharmaceutical combination is a free combination that comprises at least one solid oral dosage form and at least one liquid oral dosage form.
  • a preferred embodiment of the present invention relates to a pharmaceutical combination comprising at least one solid oral dosage form and at least one liquid oral dosage form, wherein said at least one solid oral dosage form comprises vitamin D3 and wherein said at least one liquid oral dosage form comprises a pharmaceutically acceptable salt of vortioxetine (or vice versa).
  • An also preferred embodiment of the present invention relates to a pharmaceutical combination comprising at least one solid oral dosage form and at least one liquid oral dosage form, wherein said at least one solid oral dosage form comprises calcifediol and wherein said at least one liquid oral dosage form comprises a pharmaceutically acceptable salt of vortioxetine (or vice versa).
  • An alternative embodiment of the present invention relates to a pharmaceutical combination comprising at least one solid oral dosage form and at least one liquid oral dosage form, wherein said at least one solid oral dosage form comprises vitamin D2 and wherein said at least one liquid oral dosage form comprises a pharmaceutically acceptable salt of vortioxetine (or vice versa).
  • Such pharmaceutical combinations are free combinations for simultaneous and/or sequential administration.
  • Brintellix® solution oral drops, 20 mg/ml is a commercially available liquid oral dosage form of vortioxetine. Each drop contains vortioxetine (D.L)-lactate equivalent to 1 mg vortioxetine.
  • vortioxetine (D.L)-lactate is the preferred pharmaceutically acceptable salt of vortioxetine.
  • kits comprising such free combinations for simultaneous and/or sequential administration.
  • kits may further comprise means facilitating the ex vivo measurement of calcifediol in a blood sample.
  • free combinations are more versatile than fixed combinations.
  • free combinations also have some downsides such as higher manufacturing cost, increased complexity of supply chain and/or reduced patient compliance. Therefore, there are situations where fixed combinations are the better option.
  • fixed combinations For simultaneous administration, fixed combinations often increase patient compliance.
  • One embodiment of the present invention relates to the herein described pharmaceutical combination, wherein said pharmaceutical combination is for simultaneous administration, and wherein said pharmaceutical combination is preferably a fixed combination, and wherein said pharmaceutical combination is more preferably a solid or liquid oral dosage form, and wherein said pharmaceutical combination is most preferably a solid oral dosage form.
  • a preferred embodiment of the present invention relates to a solid or liquid oral dosage form comprising vitamin D3, a pharmaceutically acceptable salt of vortioxetine and at least one pharmaceutically acceptable excipient, wherein said at least one pharmaceutically acceptable excipient is preferably a pharmaceutically acceptable carrier.
  • An also preferred embodiment of the present invention relates to a solid or liquid oral dosage form comprising calcifediol, a pharmaceutically acceptable salt of vortioxetine and at least one pharmaceutically acceptable excipient, wherein said at least one pharmaceutically acceptable excipient is preferably a pharmaceutically acceptable carrier.
  • An alternative embodiment of the present invention relates to a solid or liquid oral dosage form comprising vitamin D2, a pharmaceutically acceptable salt of vortioxetine and at least one pharmaceutically acceptable excipient, wherein said at least one pharmaceutically acceptable excipient is preferably a pharmaceutically acceptable carrier.
  • a preferred kit of the invention comprises such solid or liquid oral dosage form and means facilitating the ex vivo measurement of calcifediol in a blood sample.
  • liquid carriers such as water, ethanol, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol and phosphate buffer solutions
  • sugars such as lactose, glucose and sucrose
  • starches such as corn starch and potato starch
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate
  • powdered tragacanth malt, gelatin, talc
  • fat and oils such as cocoa butter, waxes, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil
  • glycols such as propylene glycol
  • polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar such as water, ethanol, pyrogen-free water, isotonic s
  • the dosage of one active ingredient depends on the dosage of the other active ingredient. In the context of the present invention, this is typically not the case: the amount of vitamin D that needs to be administered to a given patient does usually not depend on the amount of vortioxetine that is administered to the patient.
  • the required vitamin D dosage rather depends on the vitamin D level of the patient and on the chosen vitamin D vitamer. If the vitamin D status (i.e. vitamin D level) of a patient is very low, often a relatively high amount of vitamin D needs to be administered. Similarly, if the vitamin D level of a patient is almost sufficient, often a relatively small amount of vitamin D will suffice.
  • the inventors have found that calcifediol is more effective than other vitamin D vitamers such that a relatively low amount of calcifediol may be sufficient to bring the vitamin D level of the patient back to normal.
  • the herein described pharmaceutical combination is preferably a fixed combination that comprises preferably from 10 pg to 2000 pg cholecalciferol or from 5 pg to 100 pg calcifediol, and that comprises more preferably from 10 pg to 1000 pg cholecalciferol or from 5 pg to 80 pg calcifediol, and that comprises most preferably from 15 pg to 100 pg cholecalciferol or from 5 pg to 35 pg calcifediol.
  • a further embodiment of the invention relates to a solid oral dosage form, wherein said solid oral dosage form comprises (in addition to vortioxetine hydrobromide) preferably from 10 pg to 2000 pg cholecalciferol or from 5 pg to 100 pg calcifediol, more preferably from 10 pg to 1000 pg cholecalciferol or from 5 pg to 80 pg calcifediol, and most preferably from 15 pg to 100 pg cholecalciferol or from 5 pg to 35 pg calcifediol.
  • said solid oral dosage form comprises (in addition to vortioxetine hydrobromide) preferably from 10 pg to 2000 pg cholecalciferol or from 5 pg to 100 pg calcifediol, more preferably from 10 pg to 1000 pg cholecalciferol or from 5 pg to 80 pg
  • kits comprising a free combination as herein described, wherein said kit comprises at least one solid oral dosage form, and wherein said at least one solid oral dosage form comprises preferably from 10 pg to 2000 pg cholecalciferol or from 5 pg to 100 pg calcifediol, and that comprises more preferably from 10 pg to 1000 pg cholecalciferol or from 5 pg to 80 pg calcifediol, and that comprises most preferably from 15 pg to 100 pg cholecalciferol or from 5 pg to 35 pg calcifediol.
  • the purpose of the present invention is to improve existing vortioxetine treatments.
  • Commercially available solid mono-preparations comprise 5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide or 20 mg vortioxetine hydrobromide. Therefore, the herein described solid fixed combination preferably also comprises 5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide or 20 mg vortioxetine hydrobromide.
  • a preferred embodiment of the invention relates to the herein described pharmaceutical combination, wherein said pharmaceutical combination is a solid oral dosage form comprising: 5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide or 20 mg vortioxetine hydrobromide; and from 10 pg to 2000 pg cholecalciferol or from 5 pg to 100 pg calcifediol; and at least one pharmaceutically acceptable excipient.
  • Such solid oral dosage form may be part of a kit and is not suitable for separate administration.
  • An alternative embodiment of the invention relates to the herein described pharmaceutical combination, wherein said pharmaceutical combination is a free combination comprising at least one solid oral dosage form, said solid oral dosage form comprising 5 mg vortioxetine hydrobromide or 10 mg vortioxetine hydrobromide or 15 mg vortioxetine hydrobromide; or said solid oral dosage form comprising 20 mg vortioxetine hydrobromide, or from 10 pg to 2000 pg cholecalciferol or from 5 pg to 100 pg calcifediol, and said solid oral dosage form further comprising at least one pharmaceutically acceptable excipient.
  • Solid oral dosage forms of this alternative embodiment comprise vitamin D or vortioxetine, but not both. They are therefore suitable for sequential administration.
  • the above-mentioned materials can serve as the at least one pharmaceutically acceptable excipient.
  • the current vortioxetine treatment there is no need to improve the current vortioxetine treatment.
  • a patient turns out to be a vortioxetine low-responder or (even worse) a vortioxetine non-responder.
  • a reason for a sub-optimal response maybe a lack of vitamin D. If this is the case, vortioxetine treatment can be relatively easy improved by raising the patient's vitamin D level. It is therefore meaningful to measure the vitamin D status of patients that are in need of vortioxetine.
  • the vitamin D level of a vortioxetine low-responder or of a vortioxetine non-responder is measured.
  • the patient's current vortioxetine medication is preferably switched to the herein described pharmaceutical combination.
  • the vitamin D level of a patient is measured before initiating a vortioxetine treatment.
  • the herein described free combination may be used (e.g. to raise the patient's vitamin D level before initiating the vortioxetine treatment). In either case, it is meaningful to measure the vitamin D level of a patient that is in need of vortioxetine.
  • Measurement devices suitable for measuring the vitamin D levels are well known and commercially available. In the context of the present invention, such measurement devices are used for assessing the benefit of the herein described pharmaceutical combination for a predetermined patient. Such approach is particularly meaningful if vortioxetine treatment of said predetermined patient has not yet been initiated or if said predetermined patient is a vortioxetine low-responder or a vortioxetine non-responder.
  • the patient's calcifediol blood concentration is measured (directly or indirectly) the patient's calcifediol blood concentration.
  • said measurement is done ex vivo in a blood sample of the patient.
  • One embodiment of the present invention relates to the use of a measurement device for assessing the benefit of the herein described pharmaceutical combination, wherein the benefit for a predetermined patient is assessed and wherein said measurement device is suitable for measuring ex vivo the concentration of calcifediol in a blood sample of said predetermined patient, and wherein said predetermined patient is preferably a vortioxetine low-responder or a vortioxetine non-responder.
  • a preferred embodiment of the present invention relates to the use of a measurement device for assessing the benefit of the herein described pharmaceutical combination, wherein the benefit for a predetermined patient is assessed and wherein said measurement device is suitable for measuring ex vivo the concentration of calcifediol in a blood sample of said predetermined patient, and wherein vortioxetine treatment of said predetermined patient preferably has not yet been initiated. Also disclosed is a method of identifying patients that are likely to benefit from the pharmaceutical combination of the invention, characterized in that a device is used which is suitable for measuring ex vivo the concentration of calcifediol in a blood sample.
  • kits comprising means facilitating the ex vivo measurement of calcifediol in a blood sample, wherein said means is preferably a device for measuring ex vivo the concentration of calcifediol in a blood sample.
  • said means is preferably a device for measuring ex vivo the concentration of calcifediol in a blood sample.
  • a preferred kit of the invention comprises means facilitating the ex vivo measurement of calcifediol in a blood sample, wherein said means are preferably expendable materials that are consumed when running a device for measuring ex vivo the concentration of calcifediol in a blood sample.
  • the present invention also relates to a pharmaceutical combination for use as a medicament, wherein said pharmaceutical combination comprises i) vitamin D, and ii) vortioxetine or a pharmaceutically acceptable salt thereof, and wherein i) vitamin D and ii) vortioxetine or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.
  • vortioxetine is preferably vortioxetine hydrobromide
  • vitamin D is preferably vitamin D3, vitamin D2, at least one vitamin D metabolite or a mixture thereof.
  • one embodiment of the present invention relates to the herein described pharmaceutical combination for use in the treatment of a vortioxetine non-responder and/or in the treatment of a vortioxetine low-responder.
  • the positive effects of vortioxetine may be enhanced by replacing a low-responder's daily oral dosage of e.g. 10 mg vortioxetine hydrobromide with a daily oral dosage of 10 mg vortioxetine hydrobromide plus a suitable amount of vitamin D.
  • a low-responder's daily oral dosage of e.g. 10 mg vortioxetine hydrobromide with a daily oral dosage of 10 mg vortioxetine hydrobromide plus a suitable amount of vitamin D.
  • One embodiment of the invention relates to the herein described pharmaceutical combination for use in the treatment of a patient that is suffering from depression, anxiety and/or chronic pain, wherein the patient's medical symptoms remain at least partially despite that said patient is being treated with vortioxetine medication, characterized in that the patient's vortioxetine medication
  • • is preferably free of vitamin D and metabolites thereof.
  • a low-responder's daily oral dosage of e.g. 10 mg vortioxetine hydrobromide may be replaced by a daily dosage of 5 mg vortioxetine hydrobromide plus a suitable amount of vitamin D. Replacement of a high dosage with a lower dosage will reduce many, most or even all dose-dependent side-effects of vortioxetine.
  • One embodiment of the invention relates to the herein described pharmaceutical combination for use in the treatment of a patient who’s previous vortioxetine treatment has been stopped due to vortioxetine induced side effects, wherein the patient's previous vortioxetine medication
  • the patient to be treated is a vortioxetine non-responder.
  • a patient who has so far not benefited from the positive effects of vortioxetine is now treated by use of the pharmaceutical combination of the present invention.
  • the pharmaceutical combination of the present invention is also useful if vortioxetine treatment has not yet been initiated (i.e. before a patient's response to the vortioxetine treatment is known).
  • One embodiment of the present invention relates to the herein disclosed pharmaceutical combination for use in the treatment of a patient who is in need of vortioxetine or a pharmaceutically acceptable salt thereof. Such treatment is of particular benefit if the patient to be treated is also in need of vitamin D.
  • a preferred embodiment of the present invention relates to the use of the herein disclosed pharmaceutical combination for use in the treatment of a patient who is in need of vortioxetine or a pharmaceutically acceptable salt thereof, wherein said patient is vitamin D deficient or insufficient, and/or wherein said patient has a calcifediol blood concentration that is lower than 75 nmol/L, preferably lower than 50 nmol/L, more preferably lower than 30 nmol/L, yet more preferably lower than 25 nmol/L, even more preferably lower than 20 nmol/L and most preferably lower than 12 nmol/L.
  • calcifediol blood concentrations are preferably concentrations that have been measured before initiating oral administration of vitamin D, or that have been measured less than 3 days or preferably less than 2 days after initiating oral administration of vitamin D.
  • the present invention also relates to a pharmaceutical combination for use in the treatment of a patient is suffering from depression, anxiety and/or chronic pain, wherein said pharmaceutical combination comprises i) vitamin D, and ii) vortioxetine or a pharmaceutically acceptable salt thereof, and wherein i) vitamin D and ii) vortioxetine or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially, and wherein said patient is vitamin D deficient and/or has a calcifediol blood concentration that is lower than 75 nmol/L, preferably lower than 50 nmol/L, more preferably lower than 30 nmol/L, yet more preferably lower than 25 nmol/L, even more preferably lower than 20 nmol/L and most preferably lower than 12 nmol/L.
  • the pharmaceutical combination is preferably a fixed combination, is more preferably a solid or liquid oral dosage form, and is most preferably a solid oral dosage form.
  • a particularly preferred embodiment of the invention relates to the herein described a solid or liquid oral dosage form for use in the treatment of a patient who
  • (b) has a calcifediol blood concentration that is lower than 75 nmol/L, preferably lower than 50 nmol/L, more preferably lower than 30 nmol/L, yet more preferably lower than 25 nmol/L, even more preferably lower than 20 nmol/L and most preferably lower than 12 nmol/L, and wherein said solid or liquid oral dosage form is preferably a solid oral dosage form, and wherein said solid oral dosage form preferably comprises:
  • (b) has a calcifediol blood concentration that is lower than 75 nmol/L, preferably lower than 50 nmol/L, more preferably lower than 30 nmol/L, yet more preferably lower than 25 nmol/L, even more preferably lower than 20 nmol/L and most preferably lower than 12 nmol/L, and wherein said liquid oral dosage form comprises vortioxetine (D,L)-lactate, vitamin D and at least one pharmaceutically acceptable excipient, wherein said at least one pharmaceutically acceptable excipient is preferably a pharmaceutically acceptable liquid carrier, and wherein said vitamin D is preferably vitamin D3, vitamin D2, at least one vitamin D metabolite or a mixture thereof, and is more preferably vitamin D3 or calcifediol.
  • said liquid oral dosage form comprises vortioxetine (D,L)-lactate, vitamin D and at least one pharmaceutically acceptable excipient, wherein said at least one pharmaceutically acceptable excipient is preferably a pharmaceutically acceptable
  • the pharmaceutical combination is preferably a kit comprising the herein described free combination.
  • a free combination for use as a medicament or for use in the treatment of a patient who is suffering from depression, anxiety and/or chronic pain
  • said free combination comprises i) vitamin D, and ii) vortioxetine or a pharmaceutically acceptable salt thereof
  • said patient is vitamin D deficient and/or has a calcifediol blood concentration that lower than 75 nmol/L, preferably lower than 50 nmol/L, more preferably lower than 30 nmol/L, yet more preferably lower than 25 nmol/L even more preferably lower than 20 nmol/L and most preferably lower than 12 nmol/L.
  • Cerebral blood flow is the blood supply to the brain in a given period of time. In a human adult, CBF is typically 750 millilitres per minute or 15% of the cardiac output. Cerebral blood flow is determined by a number of factors, such as viscosity of blood, how dilated blood vessels are, and the net pressure of the flow of blood into the brain, known as cerebral perfusion pressure, which is determined by the body's blood pressure.
  • cerebral perfusion pressure which is determined by the body's blood pressure.
  • cerebral perfusion pressure which is determined by the body's blood pressure.
  • the patient's cerebral blood flow (CBF) is increased. This suggests that abnormal cerebral blood flow is associated with a patient's lower or poor responsiveness to a vortioxetine treatment. Therefore, one embodiment of the present invention relates to the pharmaceutical combination of the present invention for use in the treatment of a patient suffering from major depressive disorder (MDD), wherein said patient has a suboptimal cerebral blood flow.
  • MDD major depressive disorder
  • a suboptimal cerebral blood flow is associated with several cerebrovascular diseases such as cerebrovascular atherosclerosis.
  • depression and cerebrovascular atherosclerosis often occur in comorbidity showing neuropsychological impairment and poor response to antidepressant treatment. Therefore, one embodiment of the present invention relates to the pharmaceutical combination of the present invention for use in the treatment of depression that is associated with a cerebrovascular disease.
  • a further embodiment of the present invention relates to the herein described pharmaceutical combination for use in the treatment of a patient who is suffering from depression and from at least one cerebrovascular disease, and is preferably for use in the treatment of a patient who is suffering from depression that is associated with cerebrovascular atherosclerosis.
  • ROVIMIX® Hy-D® 1.25% is a formulation comprising 1.25 weight-% 25-Hydroxy-vitamin D3, based on the total weight of the formulation.
  • Vortioxetine (Advanced Chemblock Inc., Cat. P50895, CAS 960203-27-4, Batch 19394) was prepared in for PO (per os) dosing at 10 mL/kg in vehicle.
  • the purchased vortioxetine is vortioxetine hydrobromide.
  • vortioxetine refers to vortioxetine hydrobromide.
  • the vehicle for mock PO dosing of the test articles was sterile saline.
  • Dipyridamole was used for induction of vasodilation during the assays of cerebral blood flow. Dipyridamole (Millipore-Sigma, catalog No. D9766; Lot No. BCCB0805) was prepared fresh in a 20% b-cyclodextrin solution in sterile water (VetOne, lot No. A1806022) on study days 64 through 67 for intraperitoneal (IP) injection at 1 mL/kg.
  • IP intraperitoneal
  • mice were housed either in shoebox cages (static airflow, approximately 0.045 m2 floor space) with filter tops or in individually ventilated pie cages (passive airflow, approximately 0.045-0.048 m2 floor space).
  • An attending veterinarian was on site or on call during the live phase of the study. No concurrent medications were given.
  • the animals were acclimated for 7 days prior to being placed in the study. During the acclimation and study periods, the animals were housed in a laboratory environment with temperatures ranging 19°C to 25°C and relative humidity of 30% to 70%. Automatic timers provided 12 hours of light and 12 hours of dark. Animals were allowed access ad libitum to Envigo Teklad 8640 diet or vitamin D-deficient diet and fresh municipal tap water.
  • mice were given immediate ad libitum access to water and standard rodent chow and acclimated to the facility for 7 days prior to any further intervention. After 7 days of acclimatization, the animals were randomized by weight, placed on chow deficient in vitamin D, and subjected to mock oral gavage on a twice-weekly basis for 6 weeks. For behavioral testing the study was divided into 4 cohorts of 24 animals each (3 mice/group per cohort) with dosing and testing of each cohort proceeding on successive days. The mice were dosed by oral gavage 24, 6, and 1 hour prior to behavioral testing.
  • Example 1 Vortioxetine alone is not effective in vitamin D deficient animals. A combination of vitamin D and vortioxetine is needed for anti-depressive effects in the forced swim test.
  • the forced swim test is a test centered on a rodent’s response to unescapable stress. Results of this test have been interpreted as a measure of susceptibility to negative mood. It is used to measure the effectiveness of antidepressants. Forced swim tests were performed in groups of 12 mice, per treatment. We provided the substances to the animals per gavage at 24, 6 and 1 hours before the FST. The animals were acclimated to the testing room for 1 hour prior to testing. Four animals were tested simultaneously. The animals were each placed in a plexiglass cylindrical container (45 cm x 20 cm; Stoelting Co., Wood Dale, IL) filled with fresh water (25- 27°C) to 30 cm above the bottom.
  • a plexiglass cylindrical container 45 cm x 20 cm; Stoelting Co., Wood Dale, IL
  • mice remained in the containers for 6 minutes and were monitored by a computer program with tracking software (Ethovision, Noldus). The mice were observed constantly to mitigate the outside chance that an animal drowned or began to drown (i.e., spent more than 5 seconds completely submerged). After 6 minutes, the animals were removed, towel-dried, and returned to their holding cages. The chambers were drained and cleaned with 70% ethanol then refilled between tests. The animals were returned to their home cage and room after all of the animals in the cohort were tested. All videos were checked and threshold-ed post-hoc by an experimenter blind to the group assignments. Total time swimming or immobile was then acquired via computer-driven video analysis.
  • Example 1 shows the benefit of administering vortioxetine together with vitamin D when treating vitamin D deficient subjects.
  • CBF cerebral blood flow
  • the animals were anesthetized one hour after the last test article administration using 2% isoflurane (VetOne, catalogue No. 502017), and each animal's skull was exposed by a midline scalp incision. The scalp was removed to visualize the brain without disturbing the overlying skull.
  • the animals were then injected (IP) with dipyridamole (DP; 10 mg/kg) and placed in the prone position under the laser Doppler device (MoorLDI2; Moor Instruments, Wilmington, DE). Body temperature was maintained at approximately 30°C with a heating pad, and anesthesia and immobility were maintained with 1 .5% isoflurane.
  • the surface of the brain was diffusely illuminated by a 785-nm laser light.
  • the scattered light was filtered and detected by a digital camera positioned above the animal's head.
  • Raw speckle images were used to compute the speckle contrast, which is a measure related to the number and velocity of moving particles (i.e., CBF).
  • CBF moving particles
  • Example 3 The combination of vortioxetine and calcifediol, a metabolite of vitamin D3, relieved the depressive mood in mice in the forced swim test (FST).
  • Vortioxetine alone was not effective in ameliorating depressive mood in vitamin D deficient Balb/cJ mice in the forced swim test (cf. Example 1).
  • calcifediol 25-hydroxy vitamin D3, 25D3 co-administration was tested in the FST.
  • a low dose of calcifediol 0.025 mg/kg bw
  • Figure 5 shows that the combination of calcifediol with vortioxetine effectively improves the anti-depressive behavior of vitamin D deficient mice in the FST as seen by reducing the immobility per minute.
  • Example 4 Both combinations, ‘vortioxetine and vitamin D’ and ‘vortioxetine and calcifediol’, improved cerebral blood flow in a dose-dependent manner.
  • Example 4 shows a dose-effect relationship for both, vitamin D and calcifediol.
  • Example 5a Mono-therapy; comparison with comparator therapy.
  • Example 5a vortioxetine is compared with another therapy (“comparator therapy”) to assess its added benefit.
  • component therapy another therapy
  • Both drugs are approved for patient treatment by the drug authorities. They have a positive benefit-risk ratio, i.e. both are effective and safe.
  • a first group is treated with a vortioxetine, whereas a second group is treated with a comparator therapy.
  • Patient-relevant endpoints (“positive effects”) from which the additional benefit is to be derived are defined.
  • An additional benefit is attested if, for example, a significant improvement of disease symptoms or an avoidance of side effects can be shown compared to the comparative therapy.
  • Example 5a shows that vortioxetine has little added benefit.
  • Example 5b Mono-therapy; subjects with low vitamin D level are excluded.
  • Example 5b the assessment of Example 5a is repeated. However, to participate in the assessment, patients must have a healthy vitamin D level (i.e. low vitamin D level is an exclusion criterion).
  • Example 5a 100 patients that have a calcifediol blood concentration of more than 50 nmol/L are split into two groups. A first group is treated with vortioxetine, whereas a second group is treated with a comparator therapy. The same patient-relevant endpoints (“positive effects") as in Example 5a are applied. The duration of the assessment is as long as in Example 5a, but at least 6 months.
  • a comparison of Examples 5a and 5b shows the relevance of a healthy vitamin D level when treating a patient with vortioxetine: to unfold the full potential of vortioxetine, the patient to be treated should have a healthy vitamin D level.
  • Example 5c Combination therapy; low vitamin D subjects receive vitamin D supplementation.
  • Example 5c the assessment of Example 5a is repeated. However, to participate in the assessment, patients must have a low vitamin D level (i.e. normal vitamin D level is an exclusion criterion).
  • Example 5a 100 patients that have a calcifediol blood concentration of less than 30 nmol/L are split into two groups.
  • a first group is treated with a fixed combination (namely with a solid oral dosage form comprising vortioxetine and calcifediol), whereas a second group is treated with a comparator therapy.
  • the same patient-relevant endpoints (“positive effects") as in Example 5a are applied.
  • the duration of the assessment is as long as in Example 5a, but at least 6 months.
  • Example 5c the combination therapy (vortioxetine + calcifediol) has a significant added benefit.
  • Examples 5c shows that a low vitamin D level of a patient does not need to be a show-stopper. Oral supplementation of vitamin D (via fixed combination) brings the patient's vitamin D level back to normal and thus, makes vortioxetine treatment successful.
  • Example 6a In the presence of vortioxetine, adding Vitamin D3 increases disintegration time of the tablet.
  • Example 6a vitamin D3 has been added intra-granularly.
  • the materials were first blended and then granulated in a high shear granulation device (Diosna P 1/6 mixer). An aqueous suspension of Klucel (6 w/w %) and water were sprayed on the blend. The speed of impeller: 900rpm; the speed of chopper: l OOOrpm. The suspension was manually added at a constant speed through the syringe for binding with the powder blend. Then, the water was added for wetting. The granulates were dried overnight at around 22-25°C, RH 24- 27%.
  • the resulting granules were sieved manually with the fraction range of 600 pm - 150 pm. LOD of granules determined with HR73 Halogen Moisture Analyzer (Mettler). Moisture content in the trial was between 0.6 - 1 %. After blending with the rest of the excipients for 7minutes at 23 rotations/minute in a Turbula mixer, the mixture was used for tableting. A Korsch XP-1 single punch press equipped with a 7mm round curved punch was used for tableting. The blend was compressed into tablets at 8kN compression force.
  • Disintegration time of the obtained tablets was measured using a disintegration apparatus (Sotax DT50, Sotax AG, Switzerland). According to the European Pharmacopeia guidelines, the disintegration time of 6 tablets in one batch was measured simultaneously in distilled water (800 mL) at 37 °C. The mean value of the 6 tablets was considered the disintegration time of one sample (European Directorate for the Quality of Medicines. "Healthcare. Council of Europe Disintegration of tablets and capsules (monograph 2.9. 1).” European Pharmacopeia; Council of Europe: France (2019): 323-325).
  • Disintegration time can be adjusted by adding a disintegrant such as sodium starch glycolate (Desai et al., “Review of Disintegrants and the disintegration Phenomena”, Journal of Pharmaceutical Sciences 105 (2016) 2545-2555).
  • a disintegrant such as sodium starch glycolate
  • Table 1 Comparison of disintegration times for a tablet comprising vortioxetine alone (VXT), or vortioxetine in combination with vitamin D3 (VXT + Vit.D3)
  • Example 6a shows that disintegration time increases massively (from 30 seconds to more than 7 minutes) when adding vitamin D3 intra-granularly.
  • Example 6b In the absence of vortioxetine, the effect of vitamin D3 on the tablet's disintegration time is less severe.
  • Example 6b vitamin D3 has also been added intra-granularly. However, to better understand the issue unveiled in Example 6a, further tablets with vitamin D3 but without vortioxetine were produced.
  • Table 2 Comparison of disintegration times for a tablet comprising vortioxetine alone (VXT), vortioxetine in combination with vitamin D3 (VXT + Vit.D3), or vitamin D3 alone (Vit.D3)
  • Example 6b shows that the negative effect of vitamin D3 addition on disintegration time of the obtained tablet is less pronounced in the absence of vortioxetine (increase to only 4'47" instead of increase to more than 7 minutes).
  • this interaction is unwanted (i.e. unwanted synergistic effect).
  • Example 7 Increase of disintegration time of the tablet can be reduced by adding vitamin D3 extra-granularly instead of intra-granularly.
  • Example 7 the trial of Example 6a is repeated. However, in contrast to the method of Example 6a, vitamin D3 is added extra-granularly.
  • Table 3 Comparison of disintegration times for a tablet comprising vortioxetine alone (VXT), or vortioxetine in combination with vitamin D3 (VXT + Vit.D3) which was added intra- or extra- granularly
  • Example 7 shows that the negative effect of vitamin D3 addition on disintegration time of the obtained tablet is less pronounced if vitamin D3 is added extra granularly instead of intra granularly.
  • the increase of the disintergration time is approx. 3 minutes instead of more than 7 minutes (intra granular addition).
  • Example 8a Increase of disintegration time of the tablet can be reduced by adding calcifediol instead of vitamin D3
  • Example 8a the trial of Example 6a is repeated. However, in contrast to Example 6a, calcifediol was added instead of vitamin D3. Both kinds of vitamin D were added intra-granularly. Calcifediol increases the vitamin D blood level of a patients much more efficient. In terms of patient benefit, 8.67 mg Vitamin D3 correspond to 2.89 mg Calcifediol. Table 4: Comparison of disintegration times for a tablet comprising vortioxetine alone (VXT), or vortioxetine in combination with vitamin D3 (VXT + Vit.D3) or calcifediol (VXT + AmpliD) which was added intra-granularly
  • Example 8a shows that the negative effect of vitamin D3 addition on disintegration time of the obtained tablet is less pronounced if calcifediol instead of vitamin D3 is added.
  • the increase of the disintergration time is approx. 2 minutes instead of more than 7 minutes (intra granular addition).
  • Example 8b the increase of disintegration time due to the addition of calcifediol can be reduced by extra-granular addition instead of intra-granular addition
  • Example 8b the trial of Example 8a was repeated. However, in contrast to the method of Example 8a, calcifediol has been added extra-granularly.
  • Table 5 Comparison of disintegration times for a tablet comprising vortioxetine alone (VXT), or vortioxetine in combination with calcifediol (VXT + AmpliD) which was added intra- or extra- granularly
  • Example 8b shows that the negative effect of calcifediol addition on disintegration time of the obtained tablet is less pronounced if calcifediol is added extra granularly instead of intra granularly.
  • disintergration time is approx. 2 minutes.
  • disintergration time is approx. 1 minutes. This is roughly the same disintegration time as Brintellix® tablet, considering the resting time of a Brintellix® tablet in the patient's stomach and also considering that Brintellix® tablet is a immediate release formulation.
  • Example 9 In the absence of vortioxetine, calcifediol increases of the tablet's disintegration time is less than vitamin D3.
  • Example 9 the effect of calcifediol vs. vitamin D3 on disintegration time are compared.
  • Table 6 Comparison of disintegration times for a tablet comprising vortioxetine alone (VXT), vitamin D3 alone (Vit.D3), or calcifediol alone (AmpliD), the vitamin being added intra- or extra- granularly
  • Example 9 shows that intra granular addition of vitamin D increases disintegration time of the tablet more than extra granular addition of vitamin D, regardless whether vitamin D3 or calcifediol is added. However, if vitamin D3 is replaced by a corresponding amount of calcifediol, the increase in disintegration time is 3-4 times smaller.
  • the examples show that adding vitamin D increases disintegration time of the tablet, regardless whether vortioxetine is present or not. However, if vitamin D3 is replaced by a corresponding amount of calcifediol, the increase in disintegration time is 3-4 times smaller.

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Abstract

Un manque de vitamine D est une cause possible d'une mauvaise réponse à un traitement par vortioxétine. De nombreux mauvais répondeurs à la vortioxétine et de non-répondeurs à la vortioxétine bénéficient d'une supplémentation en vitamine D. La combinaison pharmaceutique de l'invention est une combinaison pharmaceutique pour une administration simultanée ou séquentielle comprenant de la vitamine D et de la vortioxétine. Ainsi, la vitamine D est de préférence le cholécalciférol ou le calcifédiol. La vortioxétine préférée est le bromhydrate de vortioxétine.
PCT/EP2023/068993 2022-07-11 2023-07-10 Forme pharmaceutique orale solide comprenant de la vortioxétine et de la vitamine d WO2024013062A1 (fr)

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US202263359919P 2022-07-11 2022-07-11
US63/359,919 2022-07-11
EP22190819.7 2022-08-17
EP22190819 2022-08-17

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