Induction regime for the administration of 2-(2-chlorphenyl)-2-(methylamino) cyclohexan-1-one

Abstract

The present invention relates to administration regimes of 2-(2-Chlorphenyl)-2- (methylamino) cyclohexan-1-one, also known as ketamine, or derivatives thereof, for the use in treating depression, in particular treatment resistant depression.

Description

[0001] Induction regime for the administration of 2-(2-Chlorphenyl)-2-(methylamino) cyclohexan- 1-one

[0002] The present invention relates to administration regimes of 2-(2-Chlorphenyl)-2- ( methylamino) cyclohexan-l-one, also known as ketamine, for the use in treating depression, in particular treatment resistant depression. In particular it relates to ketamine or a derivative thereof for oral administration for use in the treatment of depression in a patient, wherein said treatment comprises a first treatment phase and at least one further treatment phase, wherein in said first treatment phase said patient receives a treatment with an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, and wherein in said at least one further treatment phase, the patient receives a further treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often. The invention further relates to ketamine or a derivative thereof for oral administration for use in the treatment of depression in a patient, wherein said patient had received an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, and wherein said patient receives a further treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often.

[0003] Background of the Invention

[0004] 2-(2-Chlorphenyl)-2-(methylamino) cyclohexan-l-one, also known as ketamine, is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression, a pain management tool, and as a recreational drug.

[0005] Ketamine was initially developed in the 1970’ as a short acting anaesthetic agent (Moaddel et al., 2016, Journal of Pharmaceutical and Biomedical Analysis, 127, 3-8). Ketamine acts as a non-competitive, glutamatergic NMDAR-antagonist. Additionally, it has been shown that a single intravenous administration in form of a 40-minute infusion (0.5 mg / kg) of the ketamine hydrochloride results in rapid improvement in patients with major depressive disorder and bipolar depression lasting one week (Zarate et al., 2012, Biol. Psychiatry, 72(4): 331-338). Different types of ketamine administrations have been tested over the last decades in the field of depression, for example, intravenous administration of ketamine has demonstrated for the first time an anti-depressive effect in MDD in (Berman et al. 2000) and later in treatment resistant depression (Zarate et al. 2006), however this treatment is not approved and occurs off label, mostly in clinics.

[0006] WO 2015 / 158854 Al discloses an oral dosage form for administration of ketamine and a method of preparing an oral dosage form for administration of ketamine.

[0007] WO 2018 / 234568 A2 discloses hydroxynorketamine for the use in the treatment of depression, wherein hydroxynorketamine is administered in form of at least one prodrug, and wherein the at least one prodrug is orally administered in a modified-release dosage form.

[0008] Major depressive disorder affects millions of adults in the United States, and women are affected at twice the rate of men. Approximately 30% of individuals may continue to experience depression symptoms despite treatment with oral antidepressants. (Nurs Womens Health. 2020 Jun;24(3):228-232.). In this context the U.S. Food and Drug Administration granted fast track and breakthrough therapy designations to intranasal esketamine (Spravato) which was then approved in March 2019 in conjunction with an oral antidepressant, for the treatment of treatment resistant depression (TRD) in adults and for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior (https: / / www.ema.europa.eu / en / medicines / human / EPAR / spravato, Bahr, R. P T. 2019 Jun; 44(6): 340-342, 344-346, 375).

[0009] Ketamine-based pharmacological therapies represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder and introduce novel therapeutic options for the affected population. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders (McIntyre, R. S. Am J Psychiatry. 2021 May l;178(5):383-399).

[0010] Regarding safety and tolerability, so far ketamine administration has been associated with

[0011] • psychotomimetic effects, such as dissociation

[0012] • a risk of induction of psychosis, especially in individuals with a pre-existing vulnerability,

[0013] • dizziness, drowsiness, and light-headedness, and

[0014] • increases in systolic and diastolic blood pressure,

[0015] • increased heart rate and

[0016] • bladder related symptoms.

[0017] Noteworthy, a dose-response relationship (i.e. increased incidence correlated with an increased dose) is reported for some of the above listed adverse events (e.g. such as the probability of experiencing lower urinary tract symptoms, elevation in blood pressure, dissociation) (McIntyre, R. S. Am J Psychiatry. 2021 May 1 ;178(5):383-399).

[0018] As a conclusion, clinicians prescribing ketamine should be aware of the greater propensity to adverse events and potential safety concerns when relatively higher doses of intravenous ketamine are administered (McIntyre, R. S. Am J Psychiatry. 2021 May 1 ; 178(5):383-399).

[0019] For intranasal administration of esketamine, a less frequent dosing was evaluated. Improvement in depressive symptoms appeared to be sustained despite reduced dosing frequency in the openlabel phase. Nevertheless, for most patients, ketamine administration on reduced dosing was accompanied with transient elevations in blood pressure and dissociative symptoms. (Daly, E. J. et al. JAMA psychiatry. 2018; 75(2): 139-148.)

[0020] Therefore, there is still an unmet need for additional pharmacological treatments for depression, which are fast acting, safe, well tolerated, and convenient to patients.

[0021] The present invention surprisingly revealed that combining a conventional antidepressant with a slow-release formulation of ketamine at high doses for a limited time period, results in a fast onset of the antidepressant effect which is also maintained. The treatment is safe, convenient and comes at a reduced cost. In particular, the treatment exerts no acute negative effects on alertness and daytime sleepiness, while repeated administration is not associated with a negative effect on sleep quality. The combination with a conventional antidepressant is particularly suitable as ketamine can act as a booster until the conventional antidepressant therapy provides full effect.

[0022] Summary of the Invention

[0023] In a first aspect, the present invention relates to ketamine or a derivative thereof for oral administration for use in the treatment of depression in a patient, wherein said treatment comprises a first treatment phase and at least one further treatment phase, wherein a) in said first treatment phase said patient receives a treatment with an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, and b) wherein in said at least one further treatment phase, the patient receives a further treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often. In a second aspect, the present invention provides ketamine or a derivative thereof for oral administration for use in the treatment of depression in a patient, wherein said patient had received an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, and wherein the patient receives a further treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often.

[0024] Description of the Figures

[0025] In the following, the content of the Figures comprised in this specification is described. In this context, it is also referred to the detailed description of the invention above and / or below.

[0026] Figure 1: Study design of the phase II study of the slow-release oral dosage form

[0027] Figure 2: Graph depicting the least Squares Means MADRS Score Change from Baseline.

[0028] MADRS: Montgomery-Asberg Depression Rating Scale; *: statistically significant at 5% level.

[0029] Figure 3: Bar charts depicting in A) the Proportion of Responders (>50% reduction in

[0030] MADRS from baseline) at day 1, 4, 7, 14, 21 and 49, and B) the proportion of sustained responders at Day 49 among responders at Day 21.

[0031] Figure 4: Bar charts depicting in A) the Proportion of Remitters (subjects with a MADRS total score < 10) at day 1, 4, 7, 14, 21 and 49, and B) the Proportion of sustained remitters at Day 49 among remitters at Day 21.

[0032] Figure 5: Bar charts depicting in A) Least Squares Means HAM-D17 Score Changer from

[0033] Baseline (HAM-D17: Hamilton Rating Scale for Depression, 17-item Version) and in B) Least Squares Means CGLS Score Changer from Baseline (CGLS: Clinical Global Impression Scale - Severity of Illness).

[0034] Figure 6: Bar chart depicting the mean CADSS scores at the different time points. CADSS:

[0035] Clinician- Administered Dissociative States Scales; hrs: hours after investigational product intake; bars ± whiskers indicate mean ± standard deviation.

[0036] Figure 7: Bar charts depicting the different vital Signs measured during the clinical study with-(A) Mean values of Systolic Blood Pressure (mmHg) (B) Diastolic Blood Pressure (mmHg).

[0037] Figure 8: Bar charts depicting the Heart Rate (bpm) as one of the vital signs measured during the clinical study.

[0038] Figure 9: Bar chart depicting the mean concentrations of Ketamine, Norketamine and

[0039] Hydroxynorketamine at Day 1, 7 h post treatment administration.

[0040] Figure 10: Study design of the Head-to-Head Comparison of slow release dosage form (SR) versus SPRAY ATO® Figure 11: Graph depicting the maximum CADSS scores at pre- and post- administration assessments until 24 hours after dosing (all subjects).

[0041] Figure 12: Graph depicting the incidence of dissociative symptoms (Esketamine (SPRAVATO®) versus slow release dosage form (SR))

[0042] Figure 13: Diastolic blood pressure mean values, 10 h after Investigational Product (IP) administration.

[0043] Figure 14: Systolic blood pressure mean values, 10 h after IP administration.

[0044] Figure 15: Heart rate (Pulse) mean values, 10 h after IP administration.

[0045] Figure 16: Bar chart depicting Pittsburgh Sleep Quality Index (PSQI) score mean changes from baseline on Day 21 and at the end of follow-up on day 49.

[0046] Figure 17: Bar chart depicting Karolinska Sleepiness Scale (KSS) mean changes from baseline on day 1 at Ih, 4h, and 7h and on days 4, 7, 14, and 21.

[0047] Figure 18: Bar chart depicting Modified Observer’s Assessment of Alertness / Sedation (MOAA / S) score mean of maximum changes from baseline for slow release dosage form (SR)) versus Esketamine (SPRAVATO®).

[0048] Figure 19: Bar chart depicting Karolinska Sleepiness Scale (KSS) mean of maximum increases from baseline for slow release dosage form (SR) versus Esketamine (SPRAVATO®).

[0049] Figure 20: Bar chart depicting Bond-Lader Visual Analogue Mood Scale (BL-VAS) mean change from baseline at C iax for slow release dosage form (SR) versus Esketamine (SPRAVATO®).

[0050] Detailed Description of the Invention

[0051] Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0052] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0053] In the following, the elements of the present invention will be described. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0054] Definitions and Embodiments of the Invention:

[0055] In the following, some definitions of terms frequently used in this specification and preferred embodiments are provided. These terms will, in each instance of its use, in the remainder of the specification have the respectively defined meaning and preferred meanings.

[0056] Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Kdlbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[0057] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents, unless the content clearly dictates otherwise.

[0058] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, are to be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step.

[0059] The active ingredient:

[0060] The active ingredient used according to the present invention is ketamine or a derivative thereof. Preferably, the derivative is a pharmaceutically acceptable salt, solvate, prodrug, or metabolite of ketamine, in particular the metabolites as disclosed below.

[0061] "Ketamine" as used herein is understood to comprise the compound of formula (I) having the IUPAC name 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-l-one. Accordingly, ketamine comprises the R and S enantiomers as well as pharmaceutically acceptable salts or solvates thereof. In one embodiment, ketamine is (R)-ketamine or pharmaceutically acceptable salts or solvates thereof. In another embodiment, ketamine is (S)-ketamine or pharmaceutically acceptable salts or solvates thereof. In a further, preferred embodiment, ketamine is a racemate of (S)-ketamine and (R)-ketamine or pharmaceutically acceptable salts or solvates thereof, or any mixture of (S)-ketamine and (R)-ketamine or pharmaceutically acceptable salts or solvates thereof.

[0062] Ketamine or the derivatives thereof, in particular the metabolites, can preferably comprise the pharmaceutically acceptable acid addition salts thereof. The acids which are used to prepare the pharmaceutically acceptable acid addition salts are preferably those which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, (D,L)- and L- tartrate, 5 (D,L)- and L-malate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate and benzoate. A preferred salt is the hydrochloride of ketamine or the derivatives thereof.

[0063] Ketamine as used herein can also comprise or substantially consist of one or more of its metabolites. The metabolites may be one or more of norketamine, dehydronorketamine, or hydroxynorketamine, preferably norketamine or hydroxynorketamine, more preferably hydroxynorketamine.

[0064] Norketamine has the IUPAC name 2-amino-2-(2-chlorophenyl)cyclohexan-l-one of formula (II) and is obtained from ketamine through N-demethylation. Norketamine can be provided as (R)- norketamine or pharmaceutically acceptable salts or solvates thereof, or (S)-norketamine or pharmaceutically acceptable salts or solvates thereof, racemate of (S)-norketamine and (R)- norketamine or pharmaceutically acceptable salts or solvates thereof, or any mixture of (S)- norketamine and (R)-norketamine or pharmaceutically acceptable salts or solvates thereof.

[0065] Dehydronorketamine has the IUPAC name 6-amino-6-(2-chlorophenyl)cyclohex-2-en-l- one of formula (III)

[0066] Dehydronorketamine can be provided as (R)-dehydronorketamine or pharmaceutically acceptable salts or solvates thereof, or (S)-dehydronorketamine or pharmaceutically acceptable salts or solvates thereof, racemate of (S)-dehydronorketamine and (R)-dehydronorketamine or pharmaceutically acceptable salts or solvates thereof, or any mixture of (S)-dehydronorketamine and (R)-dehydronorketamine or pharmaceutically acceptable salts or solvates thereof. Norketamine and dehydronorketamine can preferably comprise the pharmaceutically acceptable acid addition salts thereof. The acids which are used to prepare the pharmaceutically acceptable acid addition salts are preferably those which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, (D,L)- and L-tartrate, (D,L)- and L- malate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate and benzoate. A preferred salt is the hydrochloride salt.

[0067] Hydroxynorketamine is a further metabolite of ketamine. While the major metabolite of ketamine is norketamine, norketamine is secondarily converted into 4-, 5-, and 6- hydroxynorketamines, mainly HNK (6-hydroxynorketamine).

[0068] In one preferred embodiment of the invention, the slow release dosage form comprises (R,S)-ketamine, preferably (R,S) -ketamine hydrochloride. It has been found that administration of (R,S) -ketamine hydrochloride as a prodrug for hydroxynorketamine, and in an oral slow release dosage form, said ketamine generates surprisingly much higher plasma concentration levels of hydroxynorketamine compared to intravenous and oral administered ketamine in an immediate- release dosage form. In particular, it was found that administration of (R,S) -ketamine in a slow release dosage form according to the present invention results in a ratio of AUCK / HNK (AUCKetamine: AUCuydroxynorketamine) between 1:7 and 1:25 depending on the dose, preferably between 1:15 and 1:25. In contrast, intravenous administration of (R,S) -ketamine merely led to an AUCK / HNK of 1:0.3. Beyond that, from the Rao et al., 2016, it is known that immediate oral administration (R,S)-Ketamine results in an AUCK / HNK between 1:3.8 and 1:5 (Rao et al., Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance, Anesthesiology, 2016, V 125, No. 6, p. 1103-1112). In addition, the plasma concentration levels of (R,S) -ketamine administered with the slow release dosage of the invention are so low that the usual ketamine- induced side effects, such as dizziness, abuse liability etc., are avoided. These plasma concentration levels show that administration of (R,S) -ketamine in a slow release dosage form according to the present invention allows significant metabolization of (R,S) -ketamine into hydroxynorketamine, which is advantageous for the treatment of depression, in particular in the treatment regime of the present invention.

[0069] In a particular preferred embodiment of the present invention, the oral administration of the slow release dosage form comprising ketamine or a derivative thereof, such as (R,S)-ketamine, for example when administered as a single dose and under fasting conditions, results in plasma concentration profiles exhibiting a ratio of AUCK / HNK between 1:7 and 1:30, preferably 1:10 and 1:30, more preferably 1:15 and 1:30 and most preferably 1:18 and 1:28 . Optionally, the oral administration of the slow release dosage form comprising ketamine or a derivative thereof, such as (R,S)-ketamine, for example when administered as a single dose and under fasting conditions, results in plasma concentration profiles exhibiting a ratio of AUCK / \K of between 1:2 and 1:20, preferably between 1:4 and 1:15 and most preferably between 1:6 and 1:12.

[0070] "Pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia (United States Pharmacopeia-33 / National Formulary-28 Reissue, published by the United States Pharmacopeia Convention, Inc., Rockville Md., publication date: April 2010) or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0071] In addition to salt forms, according to the present invention, ketamine or the derivative thereof can be used as prodrug, i.e. in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide ketamine or the derivative thereof, and especially ketamine. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound used in this invention following administration of the prodrug to a patient. Additionally, prodrugs can be converted to the compounds used in the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a dose form together with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson L.A. and Tunek A. (1988) Drug Metabolism Reviews 19(2): 165-194 and Bundgaard H. “Design of Prodrugs”, Elsevier Science Ltd. (1985). E.g. amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard H. et al. (1989) J. Med. Chem. 32(12): 2503-2507). Examples of prodrugs of ketamine have been described in the art for example in WO2020143198, WO2019137381, or WO2022225868.

[0072] The active ingredient used according to the present invention, i.e. ketamine or a derivative thereof, may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds (for example2H (i.e. deuterium, D) in place of1Hias described for example in W02008134525 Al). The compounds may also be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine- 125 (125I) or carbon- 14 (14C). All isotopic variations of the active ingredient used according to the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0073] The dosage form:

[0074] The ketamine (which term is used herein as including ketamine and derivatives thereof, in particular its metabolites) used according to the present invention is for oral administration, i.e. suitable for oral administration. Preferably, the ketamine is present in a pharmaceutical composition for oral use. According to the invention, the ketamine is used in a slow release oral dosage form, in particular as described in the following.

[0075] The oral dosage form of the present invention is a slow release oral dosage form. The term “slow release” dosage form is a modified release dosage form, in which the rate or place of release of the active ingredient is slowed compared to that of an immediate release dosage form when administered by the same route. Modified release dosage forms can include delayed-, extended-, prolonged-, sustained-, controlled-, programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release systems including, but not limited to, matrix controlled release systems, osmotic controlled release devices, multiparticulate controlled release systems, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.

[0076] In one embodiment of the invention, the slow release oral dosage form is a matrix controlled release dosage form. A matrix system can be either a diffusion-controlled or an erosion- controlled release system.

[0077] In one embodiment, the matrix controlled release dosage form comprises a matrix system, which preferably is swellable, non- swellable, erodible or non-erodible, and preferably comprises polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins. In a further embodiment, the dosage form comprises a non- erodible matrix system. Ketamine or its metabolites can be dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Preferred materials for forming a matrix system comprise chitin, chitosan, dextran, and pullulan, gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan, starches, such as dextrin and maltodextrin, hydrophilic colloids, such as pectin, phosphatides, such as lecithin, alginates, propylene glycol alginate, gelatin, collagen, and cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethylcellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMC AT), and ethylhydroxy ethylcellulose (EHEC), polyethyleneoxide (PEO), polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ), poly(2-hydroxyethyl- methacrylate), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, degradable lactic acid-glycolic acid copolymers, poly-D-(-)-3-hydroxybutyric acid, and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

[0078] A particularly preferred material for forming a matrix system is polyethyleno xide (PEO). The molecular weight of the polyethylene oxide used in the matrix is preferably from about 100,000 to about 10,000,000, more preferably about 300,000 to 3,000,000. In one embodiment, the molecular weight of the polyethylene oxide used in the matrix is at least about 4,000,000, at least about 5,000,000, at least about 6,000,000, at least about 7,000,000, more preferably from about 1,000,000 to about 10,000,000, more preferably from about 4,000,000 to 10,000,000, more preferably from 4,000,000 to 7,000,000. The weight average molecular weight is preferably determined by rheological measurements. Suitable PEOs are commercially available, e.g. under the tradename POLYOX™.

[0079] Additional materials for forming a matrix system comprise plastics (polyolefin based polymers), such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinylacetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides such as hydrogenated castor oil. In a preferred embodiment the matrix forming material is hydrogenated castor oil. In another preferred embodiment the matrix forming material is HPMC.

[0080] The matrix forming material is preferably present in the dosage form of the invention in a concentration of between 10 and 95 wt.-%, more preferably 20 to 90 wt.-%, in particular 30 to wt.- 85 %, e.g. 40 to 80 wt.-%, based on the total weight of the dosage form.

[0081] In one embodiment, when the molecular weight of the polyethylene oxide used in the matrix is at least about 4,000,000, at least about 5,000,000, at least about 6,000,000, at least about 7,000,000, more preferably from about 1,000,000 to about 10,000,000, more preferably from about 4,000,000 to 10,000,000, more preferably from 4,000,000 to 7,000,000, the polyethylene oxide is present in an amount of at least about 30 wt.-% , such as 50 to 85 wt.-%.

[0082] The dosage form comprising a matrix system may further comprise excipients such as lubricants, fillers, glidants, binders, stabilizers. Regarding preferred embodiments of said excipients it is referred to explanations given below.

[0083] In a preferred embodiment the dosage form comprises

[0084] 10 and 95 wt.-%, more preferably 20 to 75 %, in particular 30 to 65 % matrix forming material,

[0085] 0 to 90 wt.-%, preferably 5 to 70 wt.%, more preferably 10 to 50 wt.%, in particular 15 to 30 wt.-% fillers, optionally 0 to 25 wt.-%, preferably 1 to 20 wt.%, more preferably 5 to 15 % binders,

[0086] 0 to 5 wt.-%, preferably 0.1 to 4 wt.%, more preferably 0.5 to 3 % glidants,

[0087] 0 to 5 wt.-%, preferably 0.1 to 3 wt.%, more preferably 0.3 to 2 % lubricants, based on the total weight of the dosage form.

[0088] The matrix controlled release dosage form can be prepared by direct-compression, wetgranulation or dry-granulation. Direct compression is a preferred embodiment. For more detailed explanations about the compression step it is referred to WO 2015 / 158854 Al.

[0089] In one preferred embodiment, the slow release oral dosage form comprising ketamine shows a specific in vitro release of ketamine. Preferably, the slow release oral dosage form provides an in vitro release of ketamine of 0 to 45% after 2 hours, of 10 to 70% after 4 hours, of 30 to 85% after 6 hours, and of 45 to 100% after 8 hours, when measured according to the USP Basket Method I in 0. IM HC1 at 100 rpm and 37°C. More preferably, the slow release oral dosage form provides an in vitro release of ketamine of 0 to 40% after 2 hours, of 10 to 70% after 4 hours, of 30 to 85% after 6 hours and of 45 to 100% after 8 hours, when measured according to the USP Basket Method I in 0. IM HC1 at 100 rpm and 37°C.

[0090] In a further preferred embodiment, the in vitro release of ketamine is 5 to 30%, preferably 8 to 25% after 2 hours, 20 to 60% after 4 hours, 45 to 80% after 6 hours and 60 to 99% after 8 hours, when measured according to the USP Basket Method I in 0.1M HC1 at 100 rpm and 37°C.

[0091] In one embodiment, the ratio of the amount of ketamine released after 1 hour of in-vitro dissolution of the dosage form at 37°C in a aqueous solution containing 20% by volume of ethanol (0.1M HCl / EtOH 80:20 (v / v)) to the amount of ketamine released after 1 hour of in-vitro dissolution of the dosage form at 37°C in an ethanol- free aqueous solution is less than about 2:1, preferably less than 1.7:1, more preferably less than 1.5:1, most preferably less than 1.2:1, when measured according to the USP 1 Basket Method in 0.1M HC1 at 100 rpm.

[0092] As used herein for all in vitro release measurements, the USP Basket Method I is carried out in 500 ml liquid for ketamine amounts of less than or equal to 10 mg and in 1000 ml liquid for ketamine amounts of more than 10 mg. If ketamine is used as free base, the amount of 10 mg refers to the weight of the free base. If ketamine is used in the form of a pharmaceutical acceptable salt or solvate, the amount of 10 mg refers to the weight of the salt or solvate. The dissolution profiles were measured using the USP 1 Basket Method at 37°C, 500ml / 1000 ml 100 rpm in 0.1M HC1 and 0.1M HCl / EtOH 80:20, respectively.

[0093] In a further embodiment of the invention, the dosage form of the invention can be present in form of an osmotic controlled release device, including one-chamber system (elementary osmotic pump), two-chamber system (push-pull systems), asymmetric membrane technology (AMT), and extruding core system (ECS). Osmotic controlled release devices should comprise cores, for example tablets, comprising ketamine, which are enveloped by a semipermeable membrane which preferably has at least one orifice. The water-permeable membrane is impermeable to the components of the core but permits water to enter the system from outside by osmosis. The water which penetrates in then, through the osmotic pressure produced, releases the active ingredient in dissolved or suspended form from the orifice(s) in the membrane. The total active ingredient release and the release rate can substantially be controlled via the thickness and porosity of the semipermeable membrane, the composition of the core and the number and size of the orifice(s). In addition to the ketamine, the core of the osmotic device optionally includes an osmotic agent which preferably creates a driving force for transport of water from the environment of use into the core of the device.

[0094] In the osmotic two-chamber system, the core consists of two layers, one active ingredient layer and one osmosis layer. The active ingredient layer preferably comprises 1 to 70% ketamine, 30 to 95% of one or more osmopolymers. The osmosis layer preferably comprises 30 to 90% of one or more osmopolymers, 10 to 60% of an osmogen, where the difference from 100% in the individual layers is formed in each case independently of one another by one or more additional ingredients in the form of pharmaceutically usual excipients. The osmogens and osmopolymers used in the core of the osmotic two-chamber system may be as described in the following paragraphs.

[0095] In one embodiment, the osmotic agents are water- swellable polymers, which are also referred to as "osmopolymers" and "hydrogels," including hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0096] In a second embodiment, the osmotic agents are osmo gens which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Preferred osmogens comprise water-soluble salts of inorganic or organic acids or nonionic organic substances with a high solubility in water, such as for example carbohydrates, especially sugars, sugar alcohols or amino acids. For example, the osmogens are selected from inorganic salts such as chlorides, sulphates, carbonates and bicarbonates of alkali metals or alkaline earth metals, such as lithium, sodium, potassium, magnesium, calcium, and phosphates, hydrogen phosphates or dihydrogen phosphates, acetates, succinates, benzoates, citrates or ascorbates thereof. It is furthermore possible to use pentoses such as arabinose, ribose or xylose, hexoses such as glucose, fructose, galactose or mannose, disaccharides such as sucrose, maltose or lactose or trisaccharides such as raffinose. The water-soluble amino acids include glycine, leucine, alanine or methionine. Sodium chloride is particularly preferably used according to the invention. The osmogens are preferably present in an amount of 10 to 30% based on the total mass of the core ingredients.

[0097] In one embodiment, a combination of osmo gens and osmopolymers is used in the osmotic controlled release device.

[0098] The core further comprises pharmaceutically acceptable excipients comprising buffer substances such as sodium bicarbonate, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose and / or polyvinylpyrrolidone, lubricants such as magnesium stearate, wetting agents such as sodiumlauryl sulphate and / or flow regulators such as colloidal silicon dioxide.

[0099] Materials for forming the semipermeable membrane of the osmotic controlled release device include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Preferably, the material for forming the semipermeable membrane comprises plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CA phthalate, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CAp-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly- ( methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural and synthetic waxes.

[0100] In a further embodiment, the semipermeable membrane may also be a hydrophobic microporous membrane which is permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119. Hydrophobic polymers for forming hydrophobic but water-permeable membranes comprise polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural and synthetic waxes.

[0101] The delivery port(s) on the semipermeable membrane are formed post-coating by mechanical or laser drilling. Alternatively, delivery port(s) are formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. Yet further, delivery ports are formed during the coating process, as in the case of asymmetric membrane coatings.

[0102] The osmotic controlled release dosage form can be prepared according to conventional methods and techniques known to those skilled in the art (see Santus and Baker, J Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695- 708; Verma et al., J Controlled Release 2002, 79, 7-27).

[0103] As described above, the dosage form disclosed herein can be an AMT controlled release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising ketamine and other pharmaceutically acceptable excipients or carriers. (See U.S. Pat. No. 5,612,059 and WO 2002 / 17918.) The AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.

[0104] In further embodiments, the dosage form disclosed herein is formulated as ECS controlled release dosage form, which comprises an osmotic membrane that coats a core comprising ketamine, hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

[0105] In a preferred embodiment of the invention, the oral dosage form is a multi particulate dosage form and comprises a multitude of particles. Particles may be pellets, granules, spheroids, microtablets. Preferably, particles are pellets which contain a core comprising ketamine, its metabolites, or a pharmaceutically acceptable salt or solvate thereof. Preferably, the pellets contain a core comprising ketamine and a release control layer coated upon the core. Preferably, the release control layer is (physically) separated from the ketamine containing core. The ketamine containing core may be a core which contains ketamine and excipients. In those embodiments, the excipients preferably do not substantially retard or delay the release of the ketamine.

[0106] Preferably, the core comprises a layer of ketamine or its derivatives, in particular its metabolites on an inert core. The inert core (also referred to as seed core or neutral bead) may be granules or beads, preferably spherical, and further preferably made from sugar or cellulose or other suitable materials. By way of example, spherical inert cores based on saccharose, such as those commercially available under the trade name Suglets® or those based on cellulose, such as those commercially available under the trade name Celphere® or Cellets® may be mentioned. Saccharose-based inert cores are particularly preferred. Inert cores may preferably have a particle size in the range of 100 to 500 pm and more preferably in the range of 200 to 400 pm, with the particle size range indicating the size range for 90% of the particles as determined by sieve analysis. Preferably, ketamine is provided by coating a ketamine-containing layer directly onto the inert cores. The ketamine-containing layer preferably does not delay release of ketamine, i.e. is an immediate-release layer.

[0107] In one embodiment, each pellet contains a core comprising ketamine and a release control layer coated upon the core. In an alternative embodiment, pellets containing ketamine cores and a release control layer coated upon the cores can be mixed to other pellets.

[0108] In an embodiment of the invention, the core does not comprise a neutral bead as described above, but a bead comprising ketamine (or a derivative thereof) and optionally at least one pharmaceutically acceptable excipient. The ketamine containing bead can be formed by dry granulation, wet granulation, spray granulation or extrusion.

[0109] Preferably, a suitable ketamine-containing core comprises

[0110] 10 to 50 wt.%, preferably 15 to 40 wt.%, more preferably 20 to 30 wt.% inert core (neutral bead),

[0111] 20 to 90 wt.%, preferably 35 to 80 wt.%, more preferably 50 to 70 wt.% ketamine (or a derivative thereof), in particular ketamine hydrochloride,

[0112] 0.1 to 20 wt.%, preferably 1 to 15 wt.%, more preferably 3 to 10 wt.% binder, and optionally

[0113] 0 to 20 wt.% , preferably 1 to 15 wt.%, more preferably 3 to 10 wt.% glidant, based on the total weight of the ketamine containing core.

[0114] Binders generally serve to enhance the integrity and stability of tablets. In addition, they may improve the suitability of pharmaceutical compositions for granulation. Binders are commonly also used for the preparation of films, such as active agent containing layers, around an inert core. Exemplary binders include synthetic polymers, such as polyvinyl pyrrolidone (PVP), vinyl pyrrolidone- vinyl acetate-copolymer, modified celluloses, such as hydroxy alkyl celluloses and mixtures thereof. A binder is typically used in an amount of 0 to 25% by weight, preferably 0.1 to 15% by weight and in further embodiments 1 to 10% by weight of the controlled release oral dosage form. Preferably, hypromellose (HPMC) or PVP is used as binder in the ketaminecontaining core, more preferably HPMC. Preferably, said HPMC has a methoxy content of 20% to 40%, more preferably 25% to 35%. Further, preferably said HPMC has a hydroxypropoxy content of about 5% to 15%, more preferably 7% to 12%. Preferably, a 2% by weight (aqueous) solution of said HPMC has a viscosity of 0.5 to 100 mPa*s, preferably 1 to 50 mPa*s, more preferably 2 to 10 mPa*s, measured at 20°C, preferably by means of a BrookfieldSynchro-Lectric LVF viscosimeter. Preferably, the PVP has an average molecular weight of 1,000 to 2,500,000, preferably 5,000 to 2,000,000, more preferably 10,000 to 1,500,000. Generally, glidants such as disperse silica, such as Aerosil ®, or talc can be used. In particular, talc is used as glidant in the ketamine-containing core.

[0115] In one embodiment, the ketamine-containing core does not comprise a glidant.

[0116] The release control layer may be disposed in direct vicinity, i.e. in immediate contact with and surrounding the ketamine containing core, which is preferred. In other exemplary embodiments, an intermediate layer may be disposed between the ketamine containing core and the release control layer. This intermediate layer may further control the release of ketamine from the core. However, it is preferred that, if present, the intermediate layer does not substantially influence the release from the core.

[0117] The release control layer comprises a release control substance for controlling the release of ketamine from the pellets. The release control substance may be any substance known in the art as suitable to control the release of an active substance. Exemplary embodiments of suitable control release substances include cellulose esters, such as cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, polyvinyl chloride, nylon, polyamide, polyethylene oxide, polylactide-co-glycolide and mixtures thereof. Further suitable polymers include those selected from alkylcelluloses, in particular cellulose ethers, polymers and copolymers based on acrylate or methacrylate, polymers and copolymers based on acrylic or methacrylic esters and mixtures thereof. Preferably, the release control substance is a water insoluble polymer, preferably an alkyl cellulose. More preferably, the alkyl cellulose is ethyl cellulose.

[0118] In exemplary embodiments of the present invention wherein the release control substance is a polymer, said polymer has a weight average molecular weight of 5,000 to 500,0000 g / mol, preferably of 50,000 to 900,000 g / mol, more preferably of 100,000 to 400,000 g / mol, for instance of 140,000 to 300,000 g / mol. The weight average molecular weight is preferably determined by gel permeation chromatography.

[0119] In further embodiments, and in addition or in the alternative to one or more of the properties mentioned above, the release control substance, and in particular the polymer, preferably has a solubility in water of less than 20 mg / 1, preferably less than 15 mg / 1, preferably between 0.001 to 10.0 mg / 1. The solubility in water is preferably determined in accordance with European Regulation RL67-548 EWG, Annex V, Chapter A6 (German version referred to and referenced herein).

[0120] In further embodiments where a polymer is used as or as part of the release control substance, and in addition or in the alternative to one or more of the properties mentioned above, the polymer has a glass transition temperature of 20 to 220°C, for instance 60 to 150°C or 90 to 140°C. The glass transition temperature is preferably measured by means of differential scanning calorimetry DSC, preferably using a Mettler Toledo instrument and a preferably applying a heating / cooling rate of 10°C per minute.

[0121] In a particularly preferred embodiment, the release-control substance is ethylcellulose having an ethoxyl content of about 30 to 70%, more preferred of about 40 to 60%. Preferably, a 2% by weight (aqueous) solution of ethylcellulose has a viscosity of 5 to 500 mPa*s, preferably 10 to 100 mPa*s, measured at 25°C, preferably by means of a Brookfield-Synchro-Lectric LVF viscosimeter.

[0122] In exemplary embodiments, the release control substance is contained in an amount of 0.1 to 80% by weight of the total weight of the pellets in the dosage form, more preferably in amounts of 0.5 to 60% by weight, 10 to 50% by weight, 15 to 40% by weight, of the total weight of the pellets in the dosage form.

[0123] Control of the release rate can be adapted by appropriate selection of the control release substance or mixture of such substances, its / their amount, coating thickness, inclusion of further excipients, such as pore formers and / or plasticizers or others.

[0124] Further to the release control substance, one or more additional excipients may be used, in particular in a release control layer. A preferred excipient for use with the release control substance, in particular a polymeric release control substance, is a plasticizer and / or a pore builder and / or glidants.

[0125] A plasticizer, as the term is used herein, is a substance that typically lowers the glass transition temperature of the polymer it is used in admixture with by at least 2°C, preferably at least 5°C, for instance between 5 and 30°C, as compared to the polymer alone. Preferably, the plasticizer is triethyl citrate or propylene glycol.

[0126] A pore former usually is a substance having a water- solubility which is higher than the water solubility of the release-control substance. Preferably, the pore former has a solubility in water of more than 20 mg / 1, preferably 50 mg / 1 to 5000 mg / 1, more preferably 100 to 1000 mg / 1. The solubility in water is preferably determined as described above. In particular, hydroxypropyl cellulose (HPC) is used as pore former.

[0127] In a preferred embodiment, the release control layer comprises

[0128] 20 to 95 wt.%, preferably 40 to 80 wt.%, more preferably 50 to 70 wt.% release control substance, preferably as described above,

[0129] 0.1 to 30 wt.%, preferably 1 to 25 wt.%, more preferably 5 to 20 wt.% pore builder, preferably as described above, 0.1 to 30 wt.%, preferably 1 to 25 wt.%, more preferably 5 to 20 wt.% plasticizer, preferably as described above, and optionally

[0130] 0 to 40 wt.% , preferably 2 to 30 wt.%, more preferably 5 to 20 wt.% glidant, preferably as described above, based on the total weight of the release control layer.

[0131] The release control layer may be a single layer or a plurality of layers. For ease of fabrication, embodiments with a single release control layer are preferred.

[0132] The pellets may be used as a pharmaceutical formulation, for instance, without any further processing. For this kind of administration, the pellets are preferably filled into sachets. In the alternative, they may be incorporated into capsules, optionally together with one or more excipients, or into other suitable ingestible pharmaceutical dosage forms.

[0133] Most preferably, the pellets are contained in an external phase of at least one pharmaceutically acceptable excipient. Furthermore, the controlled release oral dosage form is preferably a tablet.

[0134] As evident from what has been set out before, most preferably, the oral dosage form according to the present invention does not contain any ketamine (or a derivative thereof) in immediate-release form, i.e. does not contain ketamine, the release of which is not controlled by the release-control substance(s). For instance, a tablet comprising the plurality of controlled release ketamine pellets does not comprise any further ketamine in the external phase or as top-coating on the tablet.

[0135] In particularly preferred embodiments, the pellets are mixed to a so-called “external phase” in order to be compressed into tablets. The external phase should ensure the stability of the pellets during the compression and is usually composed of one or more pharmaceutically acceptable excipients, such as fillers, binders, disintegrants, glidants and lubricants.

[0136] Fillers are normally used to dilute a pharmaceutical composition and provide bulk. Examples for preferred fillers include lactose, starch, calcium phosphate, calcium carbonate, saccharose, sugar alcohols such as mannitol, sorbitol, xylitol, and celluloses and derivatives. Microcrystalline cellulose is particularly preferred.

[0137] In a preferred embodiment a filler mixture comprising sodium carboxymethyl cellulose and microcrystalline cellulose, preferably in a weight ratio of 5:1 to 1:5, more preferably 3:1 to 1 :3 is used. A filler or mixture of fillers may be used in an amount of 0 to 80% by weight, preferably 1 to 70% by weight, based on the total weight of the controlled release oral dosage form, preferably the tablet. Binders generally serve to enhance the integrity and stability of tablets. In addition, they may improve the suitability of pharmaceutical compositions for granulation. Binders are commonly also used for the preparation of films, such as active agent containing layers, around an inert core. Exemplary binders include synthetic polymers, such as polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate-copolymer, modified celluloses, such as hydroxy alkyl celluloses and mixtures thereof. A binder is typically used in an amount of 0 to 30% by weight, preferably 0.1 to 15% by weight and in further embodiments 1 to 10% by weight of the controlled release oral dosage form. Preferably hypromellose (HPMC) is used as binder.

[0138] A disintegrant enhances the disintegration of a dosage form, in particular a tablet, after its immersion in water or gastric juices. Suitable disintegrants include carrageenan, starch, croscarmellose, crospovidone, and mixtures thereof. Disintegrants may be used in amounts of 0 to 25% by weight, preferably 1 to 20% by weight and in further embodiments 3 to 15% by weight of the controlled release oral dosage form, preferably the tablet.

[0139] The oral dosage forms may further include a glidant, such as disperse silica, such as Aerosil®, or talc. A glidant (or mixture thereof) may be comprised in an amount of 0 to 5% by weight, for instance 0.1 to 4% by weight of the controlled release oral dosage form, preferably the tablet.

[0140] The oral controlled release dosage form may further comprise a lubricant, in particular in tablets prepared by compression. Suitable lubricants include stearic acid, magnesium stearate, adipic acid and sodium stearyl fumarate (Pruv®).

[0141] Preferably, the amount of pellets in the controlled release oral dosage form ranges from 1% to 100% by weight, based on the total weight of the controlled release dosage form. In preferred embodiments, the pellets are comprised in an amount of 20% to 90% by weight, more preferably 25% to 80% by weight, based on the total weight of the controlled release dosage form.

[0142] In a preferred embodiment the external phase (without coated cores) comprises

[0143] 85 to 99.9%, preferably 90 to 98% by weight filler,

[0144] 0 to 5%, preferably 0.1 to 1.0% by weight lubricant and

[0145] 0.1 to 10%, preferably 1.0 to 5% by weight glidant, based on the total weight of the external phase.

[0146] Optionally, the oral dosage form according to the present invention, particularly when present in the form of a tablet, can comprise an external film for improved ease of swallowing, for protection, for colouring, for taste-masking or other purposes. Preferably, this external film does not influence the release of ketamine to any significant extent. The external film may comprise the usual excipients known in this art for this purpose. A combination of hypromellose, talc, a colouring agent, such as titanium dioxide, and / or a polymer, such as polyethylene glycol is a preferred embodiment herein. Preferably, ready to use products like Opadry® based on hypromellose or polyvinyl alcohol are used for the film coating. This optional film is not counted towards the total weight of the controlled release oral dosage form herein. Expressed differently, any amount of an ingredient expressed as weight percent herein refers to the controlled release oral dosage form without this optional external film. As evident from the above, the external film is most preferably free of ketamine in any form.

[0147] The oral dosage form according to the present invention has the advantage that it may be divided into two or more units without impairing the slow release of ketamine. The slow release oral dosage form, and in particular the tablet, may therefore comprise means facilitating its division into two or more units, such as a break-line, each of said units providing controlled release of ketamine. The dosage form according to the present invention therefore provides for the possibility to adjust the dosage, for instance halve the dosage by breaking the tablet in two.

[0148] In preferred embodiments according to the present invention, the ketamine salt is ketamine hydrochloride. The dosage form, in particular the slow release oral dosage form of the further treatment, may contain ketamine (or a derivative thereof) in amounts of 5 to 400 mg, preferably 120 to 400 mg, more preferably 200 to 320 mg. If ketamine is used as free base, the amount of 5 to 400 mg refers to the weight of the free base. If ketamine is used in the form of a pharmaceutical acceptable salt, the amount of 5 to 400 mg refers to the weight of the salt. Preferably, the dosage form of the present invention comprises 10 mg ketamine, 20 mg ketamine, 40 mg ketamine, 80 mg ketamine, 100 mg ketamine, 120 mg ketamine, 140 mg ketamine, 160 mg ketamine, 180 mg ketamine, 200 mg ketamine, 220 mg ketamine, 240 mg ketamine, 260 mg ketamine, 280 mg ketamine, 300 mg ketamine, 320 mg ketamine, 340 mg ketamine, 360 mg ketamine, 380 mg ketamine, more preferably 10 mg ketamine hydrochloride, 20 mg ketamine hydrochloride, 40 mg ketamine hydrochloride, 80 mg ketamine hydrochloride, 100 mg ketamine hydrochloride, 120 mg ketamine hydrochloride, 140 mg ketamine hydrochloride, 160 mg ketamine hydrochloride, 180 mg ketamine hydrochloride, 200 mg ketamine hydrochloride, 220 mg ketamine hydrochloride, 240 mg ketamine hydrochloride, 260 mg ketamine hydrochloride, 280 mg ketamine hydrochloride, 300 mg ketamine hydrochloride, 320 mg ketamine hydrochloride, 340 mg ketamine hydrochloride, 360 mg ketamine hydrochloride, 380 mg ketamine hydrochloride, in particular 40 mg ketamine hydrochloride or 80 mg ketamine hydrochloride.

[0149] It is further preferred that the dosage form of the present invention comprises: i) ketamine-containing cores comprising

[0150] 1 to 30 wt.%, preferably 2 to 20 wt.%, more preferably 3 to 10 wt.% inert cores,

[0151] 1 to 40 wt.%, preferably 5 to 20 wt.%, more preferably 10 to 15 wt.% ketamine, in particular ketamine hydrochloride,

[0152] 0.01 to 10 wt.%, preferably 0.1 to 5 wt.%, more preferably 0.5 to 3 wt.% binder, and

[0153] 0 to 10 wt.%, preferably 0.1 to 5 wt.%, more preferably 0.5 to 3 wt.% glidant, ii) a release-control layer coated on each ketamine-containing core, comprising

[0154] 1 to 40 wt.%, preferably 3 to 20 wt.%, more preferably 7 to 15 wt.% release-control substance,

[0155] 0.01 to 10 wt.%, preferably 0.1 to 6 wt.%, more preferably 1 to 4 wt.% pore builder,

[0156] 0 to 10 wt.%, preferably 0.1 to 6 wt.%, more preferably 1 to 4 wt.% plasticizer, 0 to 15 wt.%, preferably 0.1 to 10 wt.%, more preferably 0.5 to 5 wt.% glidant, and iii) an external phase comprising

[0157] 20 to 85%, preferably 40 to 75%, more preferably 50 to 65% filler,

[0158] 0 to 3 wt.%, preferably 0.001 to 2.0 wt.%, more preferably 0.1 to 0.5 wt.% lubricant and 0 to 5 wt.%, preferably 0.1 to 5 wt.%, more preferably 0.5 to 2.0 wt.% glidant, wherein all wt.% are based on the total weight of the tablet (without film coating).

[0159] The tablets of the present invention preferably have a tablet height of 2 to 8 mm, more preferably 3 to 5 mm, and a length of 3 to 22 mm, preferably 5 to 17 mm. Preferably, the tablets have a hardness of 40 to 300 N, more preferably of 50 to 200 N.

[0160] In a further embodiment of the invention, the administration of a single slow release oral dosage form leads in-vivo to a Cmaxof ketamine of 1 to 150 ng / ml, preferably 2 to 120 ng / ml, more preferably 3 to 100 ng / ml, still more preferably 4 to 70 ng / ml, further more preferably 5 to 40 ng / ml, and to a AUCo-oo of ketamine of 5 to 1000 h- ng / ml, preferably 10 to 750 h- ng / ml, more preferably 50 to 600 h- ng / ml, still more preferably 100 to 400 h- ng / ml.

[0161] In a further embodiment, the administration of a single slow release oral dosage form leads in-vivo to a Cmaxof norketamine of 5 to 750 ng / ml, preferably 10 to 600 ng / ml, more preferably 15 to 500 ng / ml, still more preferably 20 to 400 ng / ml, further more preferably 25 to 300 ng / ml, and to a AUCo-oo of norketamine of 100 to 8000 h- ng / ml, preferably 150 to 6000 h- ng / ml, more preferably 500 to 4000 h- ng / ml. “Crnax” means the peak concentration of ketamine in the plasma, e.g. determined as described below. “AUCo-00” describes ketamine bio availability and is measured by calculating the area under curve (AUC) of the plasma drug concentration time profile from time zero extrapolated to infinity.

[0162] In a further preferred embodiment of the invention, the administration of a single slow release oral dosage form leads in-vivo to a Tmaxof ketamine of 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 7 h, most preferably 5 to 7 h.

[0163] In a further preferred embodiment of the invention, the administration of a single slow release oral dosage form leads in-vivo to a Tmaxof norketamine of 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 7 h, most preferably 5 to 7 h.

[0164] “Tmax” means the time from administration to reach Cmax.

[0165] Typically, Cmax, AUCO -co and Tmax as referred to herein correspond to the mean values of the respective agent and / or metabolite in a patient group and therefore can be understood as mean Cmax, mean AUCO-co and mean Tmax, respectively, as known in the art. These values are typically determined after administration on an empty stomach, typically in the morning, as known and usual in the art.

[0166] In a further embodiment of the invention, the single administration of the slow release oral dosage form at a total dose of 120 mg of ketamine leads in-vivo to a Cmax of ketamine of 1 to 150 ng / ml, preferably 2 to 120 ng / ml, more preferably 3 to 100 ng / ml, still more preferably 4 to 70 ng / ml, further more preferably 10 to 50 ng / ml, such as 20 to 45 ng / ml, and to a AUCo-oo of ketamine 5 to 1000 h- ng / ml, preferably 10 to 750 h- ng / ml, more preferably 50 to 600 h- ng / ml, still more preferably 100 to 500 h- ng / ml, and a Tmax of ketamine which is 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 7 h, most preferably 5 to 7 h, and / or

[0167] Cmax of norketamine of 5 to 750 ng / ml, preferably 10 to 600 ng / ml, more preferably 50 to 500 ng / ml, still more preferably 50 to 400 ng / ml, further more preferably 100 to 400 ng / ml, and to a AUCo-oo of norketamine of 100 to 8000 h- ng / ml, preferably 500 to 6000 h- ng / ml, more preferably 2000 to 5000 h- ng / ml, and a Tmax of norketamine is 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 7 h, most preferably 5 to 7 h, and / or

[0168] Cmax of hydroxynorketamine of 5 to 900 ng / ml, preferably 50 to 800 ng / ml, more preferably 100 to 600 ng / ml, still more preferably 100 to 400 ng / ml, further more preferably 200 to 400 ng / ml, and to a AUCo-oo of hydroxynorketamine of 1000 to 12000 h- ng / ml, preferably 3000 to 12000 h- ng / ml, more preferably 6000 to 10000 h- ng / ml, and a Tmax of hydroxynorketamine is 3 to 17 h, preferably 5 to 17 h, more preferably 8 to 15 h, most preferably 9 to 13h.

[0169] In a further embodiment of the invention, the single administration of a slow release oral dosage form at a total dose of 240 mg of ketamine leads in-vivo to a Cmax of ketamine of 1 to 200 ng / ml, preferably 20 to 180 ng / ml, more preferably 20 to 150 ng / ml, still more preferably 20 to 120 ng / ml, and to a AUG) ® of ketamine 5 to 1200 h- ng / ml, preferably 100 to 1000 h- ng / ml, more preferably 300 to 950 h- ng / ml, still more preferably 500 to 900 h- ng / ml, and a Tmax of ketamine which is 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 7 h, most preferably 5 to 7 h, and / or

[0170] Cmax of norketamine of 5 to 1200 ng / ml, preferably 50 to 1000 ng / ml, more preferably 100 to 900 ng / ml, still more preferably 150 to 700 ng / ml, further more preferably 150 to 60000 ng / ml, and to a AUCo-oo of norketamine of 100 to 12000 h- ng / ml, preferably 1000 to 10000 h- ng / ml, more preferably 5000 to 10000 h- ng / ml, and a Tmax of norketamine is 3 to 9 h, preferably 3 to 8 h, more preferably 4 to 8 h, most preferably 5 to 8 h, and / or

[0171] Cmax of hydroxynorketamine of 5 to 1500 ng / ml, preferably 100 to 1000 ng / ml, more preferably 100 to 800 ng / ml, still more preferably 100 to 700 ng / ml, and to a AUCo-oo of hydroxynorketamine of 1000 to 25000 h- ng / ml, preferably 7000 to 20000 h- ng / ml, more preferably 12000 to 20000 h- ng / ml, and a Tmax of hydroxynorketamine is 3 to 17 h, preferably 5 to 17 h, more preferably 8 to 15 h, most preferably 9 to 13.

[0172] In these embodiments, the total doses, e.g. the total dose of 120 mg or 240 mg, respectively, may refer to a single unit dose, e.g. one tablet, or refer to several unit doses, e.g. several tablets, e.g. a 80 mg tablet and a 40 mg tablet for the total dose of 120 mg, and 3 times a 80 mg tablet for the 240 mg total dose, respectively.

[0173] In a further preferred embodiment of the invention, the oral dosage form has a Fabs of 5 to 25 %, preferably 7 to 20%, more preferably 9 to 18 %. “Fabs” is the absolute bio availability. Absolute bio availability compares the bioavailability of the active drug in systemic circulation following non- intravenous administration (i.e., after oral administration in the present case), with the bio availability of the same drug following intravenous administration. It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The absolute bio availability is the dose-corrected area under curve (AUC) non-intravenous (oral) divided by AUC intravenous. For example, the formula for calculating Fabs for a drug administered by the oral route is given below:

[0174] Fabs — AUCoral / AUCiv X doSCiv / doSCoral

[0175] In a further preferred embodiment of the invention, the oral dosage form used does not significantly (preferably below ± 15 mmHg) increase blood pressure, (mean systolic blood pressure and / or mean diastolic blood pressure) upon administration, preferably within two hours after administration.

[0176] The slow release oral dosage form of used in the present invention is preferably administered once or twice daily, preferably twice daily.

[0177] The oral dosage form used according to the present invention can be prepared and is preferably obtained by the methods disclosed in WO 2015 / 158854 Al.

[0178] A typical method for preparing an oral dosage form as described above comprises the steps of: a) coating each inert core with a layer comprising ketamine or a pharmaceutically acceptable salt or solvent thereof, b) coating each coated inert core with a release control layer comprising a release control substance for controlling the release of ketamine, thus forming pellets, c) mixing the pellets with at least one pharmaceutically acceptable excipient, d) forming a tablet from the mixture comprising the pellets and the at least one pharmaceutically acceptable excipient.

[0179] For preferred embodiments of inert cores, preferred ketamine forms, release controlling substances, further excipients, the pellets etc., it is referred to the explanations concerning embodiments of the dosage forms above, which equally apply to the method for preparing a controlled release dosage form according to the present invention. Step a) may further include dissolving or suspending ketamine or a salt thereof in a suitable solvent or solvent mixture, optionally together with a binder, such as a hydroxyalkyl cellulose, such as hydroxy propylmethyl cellulose. The solvent is preferably water, an alcohol, such as ethanol, or mixtures thereof.

[0180] Preferably, the inert cores are sugar spheres. Preferably, ketamine hydrochloride is used. Further preferably, the coating step a) is a coating step in a fluid bed processor wherein preferably a solution or suspension (in particular solution) of ketamine hydrochloride and one or more excipients, such as hypromellose, is sprayed onto the inert cores. The coating solution or suspension usually comprises respectively consists of water and / or an alcohol. Preferably, the process temperature is between 30 and 60°C.

[0181] Preferably, step b) involves coating by spraying a coating solution containing the release control substance onto the coated inert cores from step a). The spraying step is preferably performed in a fluid bed processor. The fluid bed processor is preferably suitable for coating powders, particles, inert spheres, beads and tablets, and / or simultaneous drying. Preferably, the process temperature is between 30 and 60°C.

[0182] The solvent of the coating solution or suspension from step b) predominantly contains alcohol, i.e. the solvent used for dissolving the release controlling agent and optional further excipients contains preferably 60% or more by weight, more preferably 70% or more by weight of alcohol. A mixture of ethanol and water is particularly preferred. Furthermore, preferably ethylcellulose is used as the release controlling agent. Additional excipients may include hydroxypropyl cellulose, talc, triethyl citrate and other pharmaceutically suitable excipients.

[0183] The pellets preferably have a weight average particle diameter (dso) of 50 to 1000 pm, in preferred embodiments 100 to 800 pm, in further embodiments 150 to 600 pm, as measured by sieve analysis, such as by means of a Retsch Siebmaschine AS 300 control. The thickness of the release control layer is preferably in a range of 0.1 to 200 pm, preferably 0.5 to 100 pm.

[0184] Tablets with a combination of several of the above features have been found to be particularly advantageous: they provide good clinical efficacy, not least due to providing an advantageous dissolution profile without the need to include an immediate release portion of ketamine. They can be broken or divided without affecting the release of drug from the tablet.

[0185] The treatment regimen:

[0186] The present invention relates to ketamine or a derivative thereof for oral administration for use in the treatment of depression in a patient, wherein said treatment comprises a first treatment phase and at least one further treatment phase. In the first treatment phase, the patient receives (or received) a treatment with an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less.

[0187] The ketamine used in the first treatment phase can be any ketamine or derivative thereof as defined above, in particular the metabolites of ketamine as described above, e.g. norketamine, dehydronorketamine, hydroxynorketamine, or suitable prodrugs thereof as known in the art. In one embodiment, ketamine is (R)-ketamine or pharmaceutically acceptable salts or solvates thereof. In another embodiment, ketamine is (S)-ketamine or pharmaceutically acceptable salts or solvates thereof. In a further, preferred embodiment, ketamine is a racemate of (S)-ketamine and (R)- ketamine or pharmaceutically acceptable salts or solvates thereof, or any mixture of (S)-ketamine and (R)-ketamine or pharmaceutically acceptable salts or solvates thereof.

[0188] The ketamine or a derivative thereof used in the first treatment phase is administered by oral administration of the slow release oral dosage form as described above. The antidepressant other than ketamine or a derivative thereof can also be administered orally, but also by every other suitable way of administration known in the art. While the Preferably, the antidepressant and the ketamine or a derivative thereof could be combined in the same dosage form, preferably these are administered in separate dosage forms, e.g. as separate tablets or in different ways of administration.

[0189] In the first treatment phase, the patient preferably demonstrates / has demonstrated a clinical meaningful response to said first treatment. “A clinical meaningful response” as used in accordance with the present invention preferably means an improvement (decline of the baseline score) of at least 35%, preferably at least 40%, more preferably at least 50% in a typically used scale of severity such as MADRS score, HAM-D score, and / or CGI-S score. Preferably, a clinical meaningful response means a reduction in the MADRS score of at least 6 points, which substantially corresponds to a CGI-S score reduction of 1 point (also known in the art as “clinical meaningful change”), or a reduction in the MADRS score of at least 12 points, which substantially corresponds to a CGI-S score reduction of 2 points (also known in the art as “clinical substantial change”).

[0190] MADRS score and HAM-D score are discussed in more detail below. The CGI scale (CGI- S) was developed for use in NIMH- sponsored clinical trials to provide a brief, stand-alone assessment of the clinician’s view of the patient’s global functioning prior to and after initiating a study medication. The CGI provides an overall clinician-determined summary measure that takes into account all available information, including a knowledge of the patient’s history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient’s ability to function (Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007 Jul;4(7):28-37. PMID: 20526405; PMCID: PMC2880930).

[0191] In a preferred embodiment, in response to said first treatment phase, in said first treatment phase and / or in said further treatment phase, the patient achieved a remission, which preferably corresponds to a MADRS score <12, most preferably <10.

[0192] In a preferred embodiment, the MADRS score, HAM-D score, and / or CGI-S score reduction obtained by the patient in the first treatment phase is at least substantially maintained in the further treatment phase. That is, the clinical meaningful response to said first treatment is maintained, or the MADRS score, HAM-D score, and / or CGI-S score are even further reduced in the further treatment phase.

[0193] As it will be understood by the skilled in the art any score reduction herein referred to will not be obtained by all patients, but potentially only a subgroup of patients. That is, the present invention in particular addresses this subgroup of patents. Thus, in one embodiment, the patient has responded to a ketamine based therapy, in particular with a clinical meaningful response ass defined above.

[0194] According to the present invention, the first treatment phase, i.e. the combined administration of an antidepressant other than ketamine or a derivative thereof with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, lasts for one or two weeks, or less. In one preferred embodiment, the first treatment phase has / had a duration of about 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In one preferred embodiment, the first treatment phase has / had a duration of about two weeks at most, most preferably about one week at most, e.g. about one week.

[0195] In one embodiment, the first treatment phase ends and the further treatment phase in accordance with the present invention starts, i.e. the first dose of the further treatment is administered, 1 day, 2 days, 3, days, 4, days, 5, days, 6 days, 7 days, such as one week, such as 2 weeks, preferably 1 day, after the last dose of the first treatment has been administered.

[0196] According to the present invention, in the first treatment phase, in the combined administration of an antidepressant other than ketamine or a derivative thereof with a first treatment with ketamine or a derivative thereof, the ketamine or a derivative thereof is administered using a slow release oral dosage form (as described above), wherein total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week. The total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg, preferably about 180 mg to 360 mg, more preferably about 200 mg to 360 mg, most preferred about 240 mg to 360 mg, such as 240 mg to 320 mg, such as 240 mg. In these embodiments, the total doses, e.g. the total dose of 120 mg or 240 mg, respectively, may refer to a single unit dose, e.g. one tablet, or refer to several unit doses, e.g. several tablets, e.g. a 80 mg tablet and a 40 mg tablet for the total dose of 120 mg, 3 times a 80 mg tablet for the 240 mg total dose, and 4 times a 80 mg tablet for the 320 mg total dose, respectively.

[0197] According to the present invention, in the first treatment phase, in the combined administration of an antidepressant other than ketamine or a derivative thereof with a first treatment with ketamine or a derivative thereof, the ketamine or a derivative thereof is administered using a slow release oral dosage form (as described above), the total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week. Preferably, the total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg (preferably 240 mg to 360 mg) are administered 3 to 7 times a week, e.g. 3 times, 4 times, 5 times, 6 times, or 7 times (daily) a week. More preferably, total single doses of ketamine or a derivative thereof of about 200 mg to 320 mg or 200 mg to 280 mg are administered 3 to 7 times a week, e.g.

[0198] 3 times, 4 times, 5 times, 6 times, or 7 times a week. Even more preferred, total single doses of ketamine or a derivative thereof of about 240 mg are administered 3 to 7 times a week, e.g. 3 times,

[0199] 4 times, 5 times, 6 times, or 7 times a week.

[0200] According to the present invention, in the first treatment phase, a first treatment with ketamine or a derivative thereof is combined with an antidepressant other than ketamine or a derivative thereof with, i.e. the ketamine or the derivative thereof as a slow release oral dosage form is used as an addon therapy, i.e. with the other antidepressant. Suitable antidepressant are those listed under ATC codes N06A (antidepressiva), N05A (antipsychotica), and N05B (anxiolytics), preferably N06A (antidepressiva) (ATC version as valid November 1, 2023). Preferably, the antidepressant is selected from the group consisting of mono-amine oxidase inhibitors (MAOI), tricyclic antidepressants (TCA), serotonin specific reuptake inhibitors (SSRI), serotonin noradrenergic reuptake inhibitors (SNRI), noradrenaline reuptake inhibitor (NRI), "natural products" (such as Kava-Kava, St. John's Wort), dietary supplement (such as s- adenosylmethionine) and others. Specific antidepressants are desipramine, imipramine, imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine, dibenzepin, amitriptyline, nortriptyline, protriptyline, doxepin, iprindole, melitracen, butriptyline, dosulepin, amoxapine, dimetacrine, amineptine, maprotiline, quinupramine, zimelidine, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidone, escitalopram, isocarboxazid, nialamide, phenelzine, tranylcypromine, iproniazide, iproclozide, moclobemide, toloxatone, oxitriptan, tryptophan, mianserin, nomifensine, trazodone, nefazodone, minaprine, bifemelane, viloxazine, oxaflozane, mirtazapine, bupropion, medifoxamine, tianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, gepirone, duloxetine, agomelatine, desvenlafaxine, vilazodone, hyperici herba, vortioxetine, levomilnacipran, brexanolone, and selegiline.

[0201] More specifically, the antidepressants include, but are not limited to, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, citalopram, escitalopram, sertraline, paroxetine, tianeptine, agomelatine, nefazadone, venlafaxine, desvenlafaxine, vilazodone, vortioxetine, duloxetine, reboxetine, mirtazapine, mianserin, phenelzine, tranylcypromine, and / or moclobemide.

[0202] In one preferred embodiment, in said first treatment phase said patient receives a treatment with an antidepressant other than ketamine or a derivative thereof, which is a serotonin specific reuptake inhibitor (SSRI) and / or a serotonin noradrenergic reuptake inhibitor (SNRI).

[0203] Suitable modes of administration, total dosages, and dosage regimens of the antidepressant other than ketamine or a derivative thereof are as known in the art and described for example in the Maudsley Prescribing Guidelines in Psychiatry (David M. Taylor, Thomas R. E. Barnes, Allan H. Young, 14th Edition, Wiley-Blackwell, July 2021) or Prescriber's Guide Stahl's Essential Psychopharmacology (Stephen M. Stahl, Cambridge University Press, 19 October 2021).

[0204] In the further treatment phase, the patient receives a further treatment with ketamine using a slow release oral dosage form. Preferably, the slow release oral dosage form is as described herein, and in particular provides the PK values, such as Tmax, AUC, and Cmax as described above. Preferably, the slow release oral dosage form used in the further treatment phase is the one used in the first treatment phase. The ketamine used in the further treatment phase can be any ketamine or derivative thereof, in particular the metabolites of ketamine as described above, e.g. norketamine, dehydronorketamine, hydroxynorketamine, or suitable prodrugs thereof as known in the art. In one embodiment, ketamine is (R)-ketamine or pharmaceutically acceptable salts or solvates thereof. In another embodiment, ketamine is (S)-ketamine or pharmaceutically acceptable salts or solvates thereof. In a further, preferred embodiment, ketamine is a racemate of (S)- ketamine and (R)-ketamine or pharmaceutically acceptable salts or solvates thereof, or any mixture of (S)-ketamine and (R)-ketamine or pharmaceutically acceptable salts or solvates thereof.

[0205] In the further treatment phase, the patient receives a further treatment with ketamine using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often. That is, total single doses comprising about 240 mg to 360 mg of ketamine or a derivative thereof are administered. The total doses, e.g. the total dose of 240 mg or 360 mg, respectively, may refer to a single unit dose, e.g. one tablet, or refer to several unit doses, e.g. several tablets, e.g. 3 times a 80 mg tablet for the 240 mg total dose, and 4 times a 80 mg tablet for the 320 mg total dose, respectively. As regards the frequency of administration, these doses are administered 3 times a week, resulting in a total weekly dose of about 720 mg to 1080 mg, or less often. Preferably, the total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 2 times a week, or less often, e.g. between 2 times a week and once a week, more preferably once a week, or once every two weeks, or less often. As regards the amount of ketamine or the derivative thereof, total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered (preferably 240 mg to 320 mg), e.g. about 240 mg, about 320 mg, or about 360 mg.

[0206] Typically, when referring to the amounts of ketamine or a derivative thereof herein, the amount relates to the amounts of ketamine or the corresponding derivative, respectively. E.g. if ketamine is used as free base, the amount refers to the weight of the free base. If ketamine is used in the form of a pharmaceutical acceptable salt or solvate, the amount refers to the weight of the salt or solvate. If a metabolite of ketamine is used, the amount refers to the weight of the metabolite, respectively.

[0207] In one preferred embodiment, in said one further treatment phase, the clinical meaningful response preferably obtained in the first treatment phase is at least substantially maintained in the further treatment phase, preferably the MADRS score, HAM-D score, and / or CGI-S score reduction obtained by the patient in the first treatment phase is at least substantially maintained in the further treatment phase.

[0208] Substantially maintained as used herein means that the MADRS score, HAM-D score, and / or CGI-S score reduction obtained by the patient in the first treatment phase is at least maintained in the further treatment phase. That is, the clinical meaningful response to said first treatment is maintained or even a stronger response is obtained, i.e. the MADRS score, HAM-D score, and / or CGI-S score are even further reduced in the further treatment phase compared to the clinical meaningful response obtained in the first treatment phase. “Substantially” in this regard means that no significant difference occurs of worsening the response obtained in the first treatment phase. Preferably, when relating to a numerical value, MADRS score, HAM-D score, and / or CGI-S score reduction obtained by the patient in the first treatment phase, substantially maintained means an increase of these scores, i.e. a worsening of symptoms, of 10%, preferably of 5% is still considered as substantially maintained. Preferably, the MADRS score, HAM-D score, and / or CGI-S score reduction obtained by the patient in the first treatment phase is at least maintained during at least the first two to four weeks, more preferably for at least 3 to 6 months, most preferably for the duration of the further treatment phase, i.e. throughout the further treatment phase.

[0209] In one embodiment, the further treatment phase with ketamine or the derivative thereof using a slow release oral dosage form comprises administration the slow release dosage form for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 2 months, at least about

[0210] 3 months, at least about 6 months, or at least one year, or more than one year.

[0211] In one preferred embodiment, the further treatment phase has a duration of two months or less, about 6 weeks or less, about 5 weeks or less, about 4 weeks, or less. Preferably, the further treatment phase has a duration of about 1 to 7 weeks, more preferably 2 to 5 weeks, for example

[0212] 4 to 5 weeks.

[0213] In one embodiment, the further treatment phase comprises two treatment phases differing in the dosing frequency, one, preferably the first phase, as described above, and one additional treatment phase with a reduced frequency of administration, wherein the patient receives a further treatment with ketamine or a derivative thereof using the slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered once a week or less often, such as once every two weeks, for 1 to 4 weeks, preferably 2 weeks.

[0214] In some embodiments, the additional treatment phase comprises an administration for at least about 2 months, at least about 3 months, at least about 6 months, or at least one year, or more than one year.

[0215] In one particular embodiment of the invention, the treatment of depression, in particular the further treatment phase or the continuous treatment phase, is a long-term treatment, e.g. preferably more than four months (preferred), more than six months, more than one year, or more than two years.

[0216] In one particular embodiment of the invention, the treatment of depression, in particular the further treatment phase, is a short-term treatment, e.g. preferably less than 6 or less than 4 weeks and / or the continuous treatment phase, is a long-term treatment, e.g. preferably more than four months (preferred), more than six months, more than one year, or more than two years.

[0217] In one embodiment of the invention, in the treatment of depression, after the first and the further treatment phases, the patient receives a treatment with an antidepressant other than ketamine or a derivative thereof. The kind, dose and way of administration of said antidepressant other than ketamine or a derivative thereof is as defined above for the first treatment phase. Such treatment phase after the first and the further treatment phases may be a long-term treatment, e.g. preferably more than four months (preferrred), more than six months, more than one year, or more than two years.

[0218] In one embodiment of the invention, in the treatment of depression, after the first and the further treatment phases, the patient receives a continuous treatment with an antidepressant other than ketamine or a derivative thereof and no treatment with ketamine or a derivative thereof. In this embodiment, ketamine or a derivative thereof for oral administration is for use in the treatment of depression in a patient, wherein said treatment comprises a first treatment phase and at least one further treatment phase, followed by a continuous treatment phase, wherein a) in said first treatment phase said patient receives a treatment with an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, and b) in said at least one further treatment phase, the patient receives a treatment with the antidepressant other than ketamine or a derivative thereof in combination with a further treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often, for about 4 to 7 weeks, wherein the total administered dose of ketamine per week in the further treatment phase is equal to or lower, preferably lower, compared to the first treatment phase, and c) in said continuous treatment phase, the patient receives a treatment with the antidepressant other than ketamine and no treatment with ketamine or a derivative thereof.

[0219] In this embodiment, the preferred embodiments of the kinds, doses and way of administration of ketamine or a derivative thereof in the first treatment phase and the further treatment phase, are as described above for the first treatment phase and the further treatment phase, respectively. In said continuous treatment phase, the patient receives a treatment with an antidepressant other than ketamine and no treatment with ketamine or a derivative thereof. The kinds, doses and way of administration of the antidepressant other than ketamine are as described above.

[0220] In a preferred embodiment of the invention, the antidepressant other than ketamine in said first treatment phase and in said at least one further treatment phase is the same. In a further preferred embodiment the antidepressant other than ketamine of said continuous treatment phase is the same antidepressant as said first treatment phase and in said at least one further treatment phase.

[0221] In a most preferred embodiment, in the first treatment phase and / or in the further treatment phase, the total single doses of ketamine or a derivative thereof is 240 mg.

[0222] In one preferred embodiment, in the first treatment phase the first treatment with ketamine or a derivative thereof is administration of the slow release oral dosage form as described above, wherein total doses of ketamine or a derivative thereof of about 120 mg to 360 mg, preferably about 240 mg, are administered on days 1, 3, 5, and 7, and more preferably the first treatment phase lasts one week.

[0223] In one preferred embodiment, the further treatment phase a) comprises administration of the slow release oral dosage form, wherein the total single doses are about 120 mg to 360 mg, preferably about 240 mg, which dose is administered twice weekly for at least 1, 2, 3, 4, 5 weeks, preferably 5, preferably less than 4 weeks; and / or b) comprises administration of the slow release oral dosage form, wherein the total single doses are about 120 mg to 360 mg, preferably about 240 mg, which dose is administered once weekly for at least 1, 2, 3, 4, 5 weeks, preferably 1, 2, 3 weeks, most preferably 2 weeks.

[0224] In one embodiment, in the first treatment phase and / or in the further treatment phase, the slow release oral dosage form is administered in the morning or the evening, preferably in the evening.

[0225] As used herein, a “patient” means any mammal or bird that may benefit from a treatment with the compounds described herein. Preferably, a “patient” is selected from the group consisting of laboratory animals, domestic animals, or primates including chimpanzees and human beings. It is particularly preferred that the “patient” is a human being, more preferably an adult human being. Preferably, the patient suffers from major depression disorder (MDD), preferably severe MDD, with suicidal ideation, with history of self-harm and / or treatment resistant depression (TRD).

[0226] In a preferred embodiment, the depression patient to be treated has relapsed, e.g. had received a treatment of the depression, which previously may have led to a sufficient clinical reduction of symptoms, but symptoms reoccurred or worsened to such extend that additional or alternative treatment is necessary.

[0227] In one preferred embodiment, the depression patient to be treated refrained from a previous treatment of the depression, in particular treatment with ketamine, or treatment with antidepressant therapy other than ketamine, such as serotonin specific reuptake inhibitors (SSRI) or any serotonin noradrenergic reuptake inhibitors (SNRI), due to adverse events. Such adverse events in particular include one or more of headache, dizziness, dissociation, anxiety, fatigue and / or hypertension. In one preferred embodiment, the patient a) is treatment naive with regard to antidepressant therapy (meaning as known in the art that the patient has not yet received antidepressant therapy); b) did not receive any serotonin specific reuptake inhibitors (SSRI) or any serotonin noradrenergic reuptake inhibitors (SNRI) (as antidepressant therapy) before; c) did not receive the antidepressant therapy used in said first treatment phase, preferably did not receive serotonin specific reuptake inhibitors (SSRI) or serotonin noradrenergic reuptake inhibitors (SNRI); d) has received the antidepressant therapy in said first treatment phase; or e) relapsed upon, did not respond to, or refrained due to adverse events from using the antidepressant therapy in said first treatment phase, preferably the serotonin specific reuptake inhibitors (SSRI) or serotonin noradrenergic reuptake inhibitors (SNRI) used in said first treatment phase.

[0228] In one embodiment, during the further treatment phase, ketamine or the derivative thereof is used as a monotherapy, that is, ketamine or the derivative thereof in the slow release oral dosage form is the only active ingredient administered to the patient for treating the depression.

[0229] In an alternative embodiment, during the further treatment phase, ketamine or the derivative thereof in the slow release oral dosage form is used as a combination (addon) therapy, e.g. with a second antidepressant. Suitable antidepressant are those listed above, e.g. listed under ATC codes N06A (antidepressiva), N05A (antip sychotica), and N05B (anxiolytics), preferably N06A (antidepressiva) (ATC version as valid November 1, 2023).

[0230] As used herein, "treat", "treating" or “treatment”, or ameliorating, respectively, of a disease or disorder means accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s).

[0231] As used herein, “prevent”, “preventing”, “prevention”, or “prophylaxis” of a disease or disorder means preventing that a disorder occurs in a subject for a certain amount of time. For example, if a compound described herein is administered to a subject with the aim of preventing a disease or disorder, said disease or disorder is prevented from occurring at least on the day of administration and preferably also on one or more days (e.g. on 1 to 30 days; or on 2 to 28 days; or on 3 to 21 days; or on 4 to 14 days; or on 5 to 10 days) following the day of administration. A “pharmaceutical composition” according to the invention may be present in the form of a composition, wherein one or more active ingredient and one or more diluents and / or carriers are admixed with each other, or may take the form of a combined preparation, where active ingredients are present in partially or totally distinct form. An example for such a combination or combined preparation is a kit-of-parts.

[0232] An “effective amount” is an amount of a therapeutic agent sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal to receive the therapeutic agent, and the purpose of the administration. The effective amount in each individual case may be determined empirically by a skilled artisan according to established methods in the art.

[0233] The term “carrier”, as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatine, malt, rice flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. The compounds of the invention can be formulated as neutral or salt forms. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0234] The term “depression” is a clinical symptom including persistent feelings of sadness, hopelessness and / or the lose interest in activities. The term “depression” as use herein is considered to encompass major depressive disorder (MDD), bipolar depression (BPD), treatment resistant depression (TRD), and anxiety, in particular treatment resistant generalized anxiety disorder (GAD), preferably major depressive disorder (MDD), bipolar depression (BPD)and treatment resistant depression (TRD). To be diagnosed with depression symptoms persist for at least two weeks without treatment. Symptoms of major depression are typically measured using a rating scale such as the Hamilton rating scale for depression (HAM-D, also known in the art as HRSD, typically used as the 17-item version (HAM-D17); see Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery & Psychiatry, 23, 56-62), or the Montgomery Asberg depression rating scale (MADRS) (Montgomery, S., & Asberg, M. (1979); A New Depression Scale Designed to be Sensitive to Change. The British Journal of Psychiatry, 134(4), 382-389. doi: 10.1192 / bjp.134.4.382). The MADRS and the HAMD are a clinician-reported outcome (ClinRO) scale designed to measure depression severity and are responsive to changes due to AD treatment. The MADRS consists of ten items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. Items are as follows: Item 1 — Reported sadness; Item 2 — Apparent sadness; Item 3 — Inner tension; Item 4 — Reduced sleep; Item 5 — Reduced appetite; Item 6 — Concentration difficulties; Item 7 — Lassitude; Item 8 — Inability to feel; Item 9 — Pessimistic thoughts; and Item 10 — Suicidal thoughts.

[0235] Major depression may also be associated with anxiety symptoms, which may be measured using a rating scale, such as the Hamilton anxiety rating Scale (HAM- A). Depression may be classified as major depressive disorder (MDD) or bipolar depression (BPD) and can be diagnosed using the criteria described in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5-TR) published by the American Psychiatric Association, which also provides additional description of psychiatric disorders or may be diagnosed according to standards described in the International classification of diseases 11 (ICD-11). Preferably, the depression as treated in accordance with the present invention is MDD or bipolar depression (bipolar disorder, depressive episodes), more preferably the MDD is TRD. Typically, the term “treatment resistant depression” (TRD) refers to patients who have not responded to antidepressants, in particular to patients who have not responded to at least two antidepressant therapies, wherein preferably these antidepressant therapies relate to two distinct antidepressants. In one embodiment, MDD is TRD. In one embodiment, TRD is defined as less than 50% improvement in at least 2 different optimised antidepressant treatment periods (each for at least 6 weeks) within the current episode and before Visit 1 as confirmed by the Treatment-Resistant Depression Checklist (TRD-C).

[0236] The term “anxiety” or "anxiety disorder" refers to a state of anxiety, uncertainty, and / or fear that may arise from the expectations of an event and / or situation. Anxiety can be diagnosed using the criteria described in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5-TR) published by the American Psychiatric Association, which also provides additional description of psychiatric disorders or may be diagnosed according to standards described in the international classification of diseases 11 (ICD-11).

[0237] In one further aspect, the present invention relates to a method of treating depression in a patient in need thereof, wherein said treatment comprises a first treatment phase and at least one further treatment phase, wherein a) in said first treatment phase said patient receives / is administered a treatment with an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, and b) wherein in said at least one further treatment phase, the patient receives / is administered a further treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often.

[0238] The preferred embodiments of this method, in particular of the patient, of the first treatment phase, of the further treatment phase, of the slow release oral dosage form, and all other features are as described above.

[0239] In a further preferred embodiment of this method, the treatment does not exert adverse effects, in particular no acute negative effects, e.g. on alertness and / or daytime sleepiness, and / or repeated administration is not associated with adverse effects, e.g. a negative effect on sleep quality, such as after 1, 2 or 3 weeks.

[0240] The patient group:

[0241] The present invention further relates to ketamine or a derivative thereof for oral administration for use in the treatment of depression in a particular patient group, namely wherein said patient had received an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less. According to the invention, said patient receives a further treatment with ketamine using a slow release oral dosage form, wherein total doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often. In an embodiment, the patient changed antidepressant therapy, and preferably for setting in or getting used to the medication, receives a first treatment and at least one further treatment, followed by a continuous treatment, wherein in said first treatment, said patient receives a treatment with an antidepressant other than ketamine or a derivative thereof (which preferably the patient has not received before) in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, and in said at least one further treatment, the patient receives a treatment with the antidepressant other than ketamine or a derivative thereof in combination with a further treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often, for about 4 to 7 weeks, wherein the total administered dose of ketamine per week in the further treatment is equal to or lower, preferably lower, compared to the first treatment, and in said continuous treatment, the patient receives a further treatment with the antidepressant other than ketamine and no treatment with ketamine or a derivative thereof. In these embodiments of the invention, i.e., the treatment of a patient group, the preferred embodiments of the first treatment phase, of the further treatment phase, of the continuous treatment phase, of the slow release oral dosage form, and of all other aspects of the treatment, and of the results thereof, are as described above for the treatment regimen.

[0242] Examples

[0243] The following examples are for illustrative purposes only and do not limit the invention described above in any way.

[0244] The compounds and compositions as disclosed herein, in particular ketamine and slow release oral dosage forms, can be prepared by methods known to one of skill in the art and routine modifications thereof, and / or following procedures similar to those described in the art and routine modifications thereof, and / or procedures found in WO 2015 / 158854 Al and routine modifications thereof, which are hereby incorporated in their entirety, and references cited therein and routine modifications thereof.

[0245] Example 1: Phase II Study

[0246] Study Design

[0247] The phase II study of the slow-release oral dosage form (SR-tablets, or sometimes only referred to as “SR” herein) in accordance with the invention was a multicentre, proof-of-concept clinical trial in subjects > 18 and < 65 years of age with TRD. The clinical trial consisted of a screening period of up to 14 days, a 3-week double-blind treatment period, and a follow-up period of 4 weeks. Subjects could be inpatient during screening but had to be outpatient at the baseline visit to continue in the clinical trial. Baseline assessments were performed at Day -1 and before IP intake at Day 1. In case eligibility was confirmed at Day 1 , subjects were randomised ( 1 : 1 : 1 ) to treatment with 120 mg SR-tablets, 240 mg SR-tablets, or placebo once daily in addition to their current antidepressant treatment. Treatment with agreed ongoing antidepressant medication(s) had to be continued and to be kept at a stable dose throughout the trial. The subjects came for subsequent visits at Day 4 (±1), Day 7 (±1), Day 14 (±2) and Day 21 (±2, end-of-treatment visit). A follow-up visit (FU) was performed 28 (±2) days after the end-of-treatment visit or an early discontinuation visit (EDV) (see Figure 1).

[0248] Diagnosis and main criteria for inclusion and exclusion

[0249] Subjects aged > 18 and < 65 years with major depressive disorder (MDD), with a current moderate (single or recurrent) or severe depressive episode (single or recurrent, without psychotic features) were included in this trial. In Czech Republic only subjects with a current moderate (single or recurrent) depressive episode were allowed to be included. In addition, subjects had to fulfil the criteria for TRD, defined as less than 50% improvement in at least 2 different optimised antidepressant treatment periods (each for at least 6 weeks) within the current episode and before Visit 1 as confirmed by the Treatment-Resistant Depression Checklist (TRD-C). Subjects had to be on a stable antidepressant treatment (without change of treatment) for at least 6 weeks before Visit 1 until FU visit and had to have a Hamilton Depression Rating Scale 17-item (HAM-D17) score > 19 at Visit 1 and Visit 2a. Subjects with MDD with severe episode with psychotic features; schizophrenia spectrum and other psychotic disorders; bipolar disorder, other mental disorder due to known physiological condition, paranoid or schizoid personality disorder; antisocial, borderline, histrionic or narcissistic personality disorder or moderate to severe intellectual disability / mental retardation, e.g. due to neurodevelopmental disorders, neurocognitive or neurodegenerative disorders or autism spectrum disorder were not eligible for the trial. Subjects with first-degree relatives with psychotic or bipolar disorders were also not considered eligible.

[0250] Trial Objectives

[0251] Primary Objective: To explore the efficacy of slow-release oral dosage form (SR-tablets) (120 mg or 240 mg) administered once daily (OD) as add-on therapy to standard treatment compared to placebo with respect to improvement of depressive symptoms assessed by change in Montgomery- Asberg Depression Rating Scale (MADRS) total score in subjects with MDD, fulfilling criteria for TRD.

[0252] Secondary Objectives: To investigate the efficacy, safety and tolerability of add-on slow-release oral dosage form (SR-tablets) treatment (120 mg OD or 240 mg OD) compared to placebo in subjects with TRD. To evaluate population pharmacokinetics of ketamine and its metabolites (norketamine and hydroxynorketamine).

[0253] Demographics

[0254] The subjects’ age ranged from 19 to 65 years and the mean (SD) age was 40.3 (11.44) years. The median age of all randomised subjects was 41.0 years and more subjects 67 (54.9%) were below or equal to the median age of all randomised subjects. Out of 122 subjects, 121 (99.2%) were in the age group between 18 and 64 years. Between the treatment arms the age ranges were comparable. All subjects were white (122 subjects, 100%). Female subjects slightly prevailed in this study (72 subjects, 59.0%). Out of the 72 female subjects, 53 (73.6%) females were of childbearing potential. Between the treatment arms the distribution of male and females, as well as females of childbearing potential was comparable. Baseline characteristics were balanced between the trial arms (Table 1).

[0255] Table 1. Patients' baseline characteristics in the study

[0256] SR SR , ... , . r B,ase .li.ne c.haract.eri.st .i.cs 240 mg / day 120 mg / ,d.ay P ,lace . bo to1tal .

[0257] (n=40) (n=42)((n-IZZ)

[0258] Age in years, median (range) 40 (21-64) 41 (19-65) 40 (19-58) 41 (19-65)

[0259] Female, n (%) 24 (60.0) 27 (64.3) 21 (52.5) 72 (59.0)

[0260] Male, n (%) 16 (40.0) 15 (35.7) 19 (47.5) 50 (41.0)

[0261] Childbearing potential, n (%) 17 (70.8) 20 (74.1) 16 (76.2) 53 (73.6)

[0262] MDD characteristics

[0263] Number of previous major depression episodes, 2 (1-12) 2 (1-8) 3 (1-8) 2 (1-12) median (range)

[0264] Time since onset of the first episode in months, 68.3 (3.1- 62.2 (3.8- 70.0 (5.3- 63.6 (3.1- median (range) 387.3) 520.3) 349.5) 520.3)

[0265] Time since onset of the current episode in months, 9.8 (3.1- 10.8 (3.5- 11.0 (4.1- 10.6 (3.1- median (range) 26.8) 22.7) 23.9) 26.8)

[0266] Number of antidepressant treatments of current 1 (1-4) 1 (1-4) 2 (1-3) 1 (1-4) episode, median (range)

[0267] Concomitant antidepressant medication, N (%)

[0268] Selective serotonin reuptake inhibitors 11 (27.5) 11 (26.2) 10 (25.0) 32 (26.2)

[0269] Benzodiazepine derivatives 3 (7.5) 3 (7.1) 4 (10.0) 10 (8.2)

[0270] Diazepines, oxazepines, thiazepines, and oxepines 3 (7.5) 4 (9.5) 3 (7.5) 10 (8.2)

[0271] Other antidepressants 32 (80.0) 37 (88.1) 31 (77.5) 100 (82.0)

[0272] Results

[0273] Primary Endpoint (Efficacy): MADRS Total Score LS Mean Change From Baseline on Day 21 (& Other Timepoints)

[0274] Patients with TRD received adjunctive treatment for 21 days. For the highest dose group,

[0275] 240 mg / day SR-tablets, a rapid improvement in depressive severity on the MADRS was observed, achieving clinically relevant and statistically significant separation from placebo at Day 4 (AMADRS -3.66, p=0.0199) and Day 7 (AMADRS -3.95, p=0.0416). The improvement was maintained during the 3-week period on active treatment. For both the placebo treatment arm and the low-dose 120 mg / day treatment arm, there was a gradual improvement over time until Week

[0276] 3. After 3 weeks, at the primary endpoint (Day 21), the separation between the 240 mg / day SR- tablets treatment arm and the placebo arm was -1.82 points (non- significant) (see Figure 2). This data confirms that combining an antidepressant therapy with a slow release form of ketamine administered at high doses for a limited time provides anti depressive treatment with a fast onset of the antidepressant effect that is then maintained, wherein the treatment is safe, convenient and comes at a reduced cost (compared to a supervised administration). In particular, the slow release oral dosage form used according to the present invention is very suitable to support the fast onset and to maintain the clinical meaningful response obtained after a first treatment with ketamine for an extended period of time (e.g. shown here for day 21 to day 49). This maintenance of therapeutic effect during the follow up period after discontinuation of administration of API is a new and surprising finding not reported so far.

[0277] Secondary Endpoint (Efficacy): Response

[0278] Responders were subjects with at least 50% reduction of the MADRS total score compared to the baseline value. At all post-baseline visits, the highest responder rates occurred in the SR240 arm. At Day 1 (7[+l] hours after IP intake), Day 7 and Day 21 (end-of- treatment) or an early discontinuation visit, the second-best responder rate occurred in the placebo arm, whereas at Day

[0279] 4, Day 14 and Day 49 (Follow up (FU) visit), the second-best responder rate was calculated for the SR120 arm. At the end of the treatment period at Day 21 or the early discontinuation visit, the highest responder rate was seen in the SR- 240 arm (19 subjects, 47.5%), followed by the placebo arm (15 subjects, 37.5%) and the SR-120 arm (14 subjects, 34.1%) (see Figure 3A).

[0280] Sustained responders were defined subjects achieving response at week 3 and at FU visit. As it can be seen from Figure 3B a sustained remission was similar in the two treatment arms, and lower in the placebo arm. For example, around 60% of the responders detected on day 21 in the 120 and 240 arm had a sustained response on day 49 and were therefore still responders. This data also confirms that the slow release oral dosage form used according to the present invention is very suitable to maintain the clinical meaningful response obtained after a first treatment with ketamine for an extended period of time (e.g. shown here for day 21 to day 49). Secondary Endpoint (Efficacy): Remission

[0281] Remitters were subjects with a MADRS total score < 10. At each post-baseline visit, the highest remitter rates occurred in the SR- 240 arm. The second-best remitter rate was always calculated for the SR- 120 arm, except at Day 21 (end-of-treatment) or EDV, when the placebo arm had the second-best remitter rate. At the end of the treatment period at Day 21 / EDV, the remitter rate in the SR- 240 arm was 40.0% (16 subjects), in contrast to 24.4% (10 subjects) in the SR-120 arm and 25.0% (10 subjects) in the placebo arm (Figure 4A).

[0282] Sustainer remitters were defined subjects achieving remission at week 3 and at FU visit. Sustained remission was higher in the 120mg treatment arm, compared to the 240mg treatment arm, and lower at the placebo arm. (Figure 4B)

[0283] Secondary Endpoint (Efficacy): HAM-D17

[0284] The Hamilton Depression Rating Scale 17-item version (HAM-D17) is a widely used depression rating scale containing 17 items pertaining to symptoms of depression experienced over the past week. In all treatment arms, the mean HAM-D17 total scores decreased, which corresponds to an improvement in depression symptoms. The highest change in HAM-D17 total score from baseline to Day 21 / EDV was observed in the SR- 240 arm with a mean (SD) change of -11.2 (8.09), followed by the SR-120 arm with -10.9 (7.74). The smallest improvement occurred in the placebo arm with a mean (SD) change of -8.8 (7.06). The mean (SD) change in HAM-D17 total score from baseline to FU visit was highest in the SR-120 arm with -10.4 (7.89), followed by the SR- 240 arm with -10.1 (7.35). The smallest improvement occurred in the placebo arm with a mean (SD) change of -7.6 (6.91). (see Figure 5A)

[0285] Secondary Endpoint (Endpoint): CGI-S

[0286] The Clinical Global Impression Scale - Severity of Illness (CGI-S) required the investigator to assess how mentally ill the subject was at the specific timepoint. In all treatment arms, the mean CGI-S decreased, which corresponds to an improvement in illness severity. The highest change from baseline to Day 21 / EDV in CGI-S was observed in the SR -240 arm with a mean (SD) of - 1.3 (1.28), followed by -1.2 (1.29) in the SR -120 arm and -1.0 (1.25) in the placebo arm. The mean (SD) change in CGI-S from baseline to FU visit was highest in the SR -240 arm with -1.2 (1.06), followed by the SR -120 arm with -1.1 (1.30). The smallest change occurred in the placebo arm with a mean (SD) change of -0.9 (1.17) (see Figure 5B). Secondary Endpoint (Endpoint): Generalized Anxiety Disorder 7-item (GAD-7)

[0287] The GAD-7 is a 7-item self-report scale to assess the symptoms of a generalized anxiety disorder, with higher scores indicating more severe anxiety symptoms. At Day 4, Day 7, Day 14 and Day 21, negative mean and median changes from baseline, which correspond to improvements in anxiety symptoms, were seen in all treatment arms. The best improvements were seen in the -240 arm at each of these visits. At Day 4, Day 7, Day 14 the changes from baseline in the -120 and in the placebo arm were comparable.

[0288] Secondary Endpoint (Safety): CADSS

[0289] The Clinician- Administered Dissociative States Scale (CADSS) is an established instrument to measure dissociation, that was used in prior regulatory submissions. The range of the scale is 0 to 92, and a score >4 is of potential clinical significance. For the patients treated with 120 mg / day SR or 240 mg / day SR, all mean scores were <1. The incidence of a CADSS total score >4 and change>0 (reflecting potential clinical significance) was 10% in patients treated with placebo, 12% in patients treated with 120 mg / day SR, and 15% in patients treated with 240 mg / day SR. To provide context, the corresponding values from the SPRAVATO®, program (short-term study displayed in the US label) were 5% for placebo, 61% for patients treated with 56 mg Spravato, and 69% for patients treated with 84 mg Spravato (see Figure 6)

[0290] Secondary Endpoint (Safety): Vital Signs

[0291] No relevant differences between the treatment arms or changes over time were observed in mean values for body systolic blood pressure, diastolic blood pressure or heart rate (see Figure 7A, B and 8).

[0292] Secondary Endpoint (Safety): Frequent TEAEs (>5%)

[0293] The most common Treatment-Emergent Adverse Events (TEAEs) for patients treated with SR (240mg) were dizziness, headache, dissociation, and hepatic enzyme increases. The most common TEAEs for patients treated with SR (120mg) were headache and dizziness. The most common TEAE for patients treated with placebo was headache.

[0294] Table 2: Frequent TEAEs >5%; E: Number of events; N: Number of subjects in the safety set; n: Number of subjects with at least one TEAE; TEAE: adverse events with the first onset or worsening after the first IP intake and not more than 14 days after the last IP intake; %: Percentage based on N.

[0295] Pharmacokinetics on Day 1

[0296] Oral slow release (prolonged-release) ketamine has a different metabolite profile than systemically administered ketamine. During the first day of study medication, participants were monitored on site, and assessments of dissociation (CADSS), heart rate, and blood pressure were performed before (baseline) and 1, 4, and 7 hours after dosing. Seven hours after dosing on the first day of study medication, at the anticipated Cmax for ketamine, concentrations of norketamine and hydroxynorketamine were higher than the concentration of ketamine, suggesting substantial metabolism of the parent compound ketamine. Seven hours after dosing on the first day of study medication, at the anticipated Cmax for ketamine, depressive severity measured by the MADRS in the 240mg treatment arm had decreased from baseline by -7.65 points, and the difference versus placebo was -2.22 points (p=0.1423). (Figure 9)

[0297] Table 3: Mean concentrations (ng / mg) of Ketamine, Norketamine and Hydro xynroketamine at Day 1, 7 h post treatment administration.

[0298] Sleep quality and daytime sleepiness / sedation during treatment

[0299] Oral slow release (prolonged-release) ketamine administered at 240mg and 120mg daily did not induce disturbances to sleep quality or increased daytime sleepiness compared to placebo. Furthermore, improvements from baseline in sleep quality were seen in the SR- 240 arm at the end of treatment on day 21 (Pittsburgh Sleep Quality Index (PSQI) change from baseline (CFB) = -3.2; SD = 3.6; p < .001) and at the end of follow-up on day 49 (PSQI CFB = -2.1; SD = 3.99; p = .002; Figure 16). Daytime sleepiness decreased already at 1 h after SR treatment, with the largest reduction on day 4 in the SR- 240 arm (Karolinska Sleepiness Scale (KSS) CFB = -1.4; SD = 1.89; p < .001; Figure 17).

[0300] The PSQI is as described in Buysse DJ et al. (The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2): 193-213. doi: 10.1016 / 0165-1781(89)90047-4. PMID: 2748771) and KSS is described in Akerstedt, T. and Gillberg, M. ((1990). Subjective and Objective Sleepiness in the Active Individual. International Journal of Neuroscience, 52(1-2), 29-37) and Baulk SD et al. (Driver sleepiness— evaluation of reaction time measurement as a secondary task. Sleep. 2001 Sep 15;24(6):695-8)

[0301] Conclusion

[0302] In conclusion, the data presented herein demonstrate that the oral slow release (prolonged-release) ketamine used according to the present invention has a rapid, clinically relevant reduction of depressive symptoms (statistically significant separation vs placebo on day 4 and 7) with good tolerability and only minimal signs of dissociative symptoms.

[0303] The relative absence of dissociate symptoms was noted and contrasted with other routes and administration regimes of ketamine. This data also confirms that the slow release oral dosage form used according to the present invention is very suitable to maintain the clinical meaningful response obtained after a first treatment with ketamine for an extended period of time.

[0304] Furthermore, the data demonstrate that the slow release oral dosage form used according to the present invention surprisingly does not induce disturbances to sleep quality or increased daytime sleepiness compared to placebo and is thus devoid of sleep related side effects.

[0305] Example 2: Head-to-Head Comparison of SR (slow release) versus SPRAVATO®

[0306] Study Design

[0307] SR-03 was a single-center phase I study to assess the tolerability, safety and pharmacokinetics of SR compared to intranasal esketamine in healthy male participants. Each participant received two single doses of

[0308] • SR oral tablet (240mg) orally and placebo intranasal solution

[0309] • Intranasal esketamine (84mg) and placebo oral tablet

[0310] The doses were administered in a sequence-balanced, blinded mode, with a 2- to 4- week washout between doses. 26 subjects were randomized, and 25 patients received both doses. The study was conducted between Jul 2023 and Aug 2023. No serious adverse effects (SAEs) were reported (see Figure 10).

[0311] Primary Endpoint: CADSS Scores Over Time: SR versus SPRAVATO®

[0312] CADSS score were obtained up until 24 h after administration of the study IMP, either SPRAVATO® or SR. After administration of SPRAVATO®, subjects were rated substantially higher in CADSS compared to after administration of SR. Note that the highest rating observed after administration of SR was 7 and the majority of ratings were equal to 0 (see Figure 11).

[0313] Secondary Endpoint: Incidence of dissociative symptoms

[0314] Dissociative symptoms were defined as those corresponding to a CADSS total score > 4 and change > 0 from baseline to any time after IMP administration within the study period. The incidence of dissociative symptoms observed after administration of SPRAVATO® (0.96 CI 0.88 -1.00) was substantially higher than this observed after administration of SR (0.04 CI 0.00-0.11) (see Figure 12).

[0315] Early Increases in Pulse Rate and Blood Pressure after SPRAVATO® Treatment

[0316] After administration of SPRAVATO®, peak plasma concentrations of ketamine were generally achieved after approximately 40 minutes; clinically relevant and statistically significant increases in heart rate and blood pressure were observed at that time point. Increases in heart rate and blood pressure after SPRAVATO® administration were transient, normalized after 4 hours.

[0317] After administration of SR, there was no increase in heart rate or blood pressure at the time points corresponding to peak ketamine concentration (after about 6.5 hours). The small variability in heart rate or blood pressure seen after SR treatment closely paralleled the changes seen after SPRAVATO® treatment, and most likely represented natural diurnal variations (see Figure 13, 14 and 15).

[0318] Pharmacokinetics

[0319] Pharmacokinetic analysis in the SR-03 trial revealed a similar overall exposure to the parent molecules, with an AUCO-Tlast of 348.0 ng-h / ml for ketamine after administration of 240 mg SR and 369.9 ng-h / ml for esketamine after administration of 84 mg intranasal esketamine. Cmax was lower for SR than intranasal esketamine, with 39.1 ng / ml (at 7 hours 15 min) vs. 104.1 ng / ml (at 40 min). However, exposure to the metabolites norketamine and hydroxynorketamine after SR was 2.6 and 3.4 times higher than the exposure to (S)-norketamine and (S)-hydroxynorketamine after intranasal esketamine, respectively.

[0320] More detailed data are provided in Tables 4- 1 to 4-4 below

[0321] Table 4-1: Summarized PK parameters of ketamine and esketamine after the administration of either 240 mg SR or 84 mg Esketamine (Spravato®)

[0322] *For parameters which require the termination slope the respective subject concentration curve must have had at least three measurements after Cmax to be included into the analysis. Otherwise, the respective parameter of a subject was set to “missing”.

[0323] Table 4-2: Summarized PK parameters of norketamine and esnorketamine after the administration of either 240 mg SR or 84 mg Esketamine (Spravato®)

[0324] *For parameters which require the termination slope the respective subject concentration curve must have had at least three measurements after Cmax to be included into the analysis. Otherwise, the respective parameter of a subject was set to “missing”.

[0325] Table 4-3: Summarized PK parameters of hydroxynorketamine and eshydroxynorketamine after the administration of either 240 mg SR or 84 mg Esketamine (Spravato®)

[0326] *For parameters which require the termination slope the respective subject concentration curve must have had at least three measurements after Cmax to be included into the analysis. Otherwise, the respective parameter of a subject was set to “missing”.

[0327] Table 4-4: Summarized PK parameters of dehydronorketamine and esdehydronorketamine after the administration of either 240 mg SR or 84 mg Esketamine (Spravato®)

[0328] *For parameters which require the termination slope the respective subject concentration curve must have had at least three measurements after Cmax to be included into the analysis. Otherwise, the respective parameter of a subject was set to “missing”. Sleep quality and daytime sleepiness / sedation during treatment

[0329] No effect on daytime sleepiness was observed after a single administration of SR (mean of maximum KSS score increases from baseline, increase from base line (IFB) max = 0.54; SD = 1.82; p = .143; Figure 18). The SR administration had no influence on alertness / sedation (Modified Observer’s Assessment of Alertness / Sedation (MOAA / S score) mean of maximum changes from baseline, CFBmax = 0; SD = 0; p: n.a.; Figure 19), nor on drowsiness (Bond-Lader Visual Analogue Mood Scale (BL-VAS) score mean changes from baseline at maximum plasma concentration, CFB at Cmax = 3.73; SD = 28.53; p = .511; Cmax at 6 h 30 min; Figure 20). These observations for the SR were contrasted with those made after a single administration of Spravato®): daytime sleepiness deteriorated (KSS IFBmax = 2.24; SD = 2.31, p < .001; Figure 18), alertness showed a small but significant decrease (MOAA / S CFBmax = -0.88; SD = 0.33; p < .001; Figure 19); drowsiness also deteriorated at Cmax (BL-VAS CFB at Cmax = 21.52; SD = 28.55; p < .001; Cmax at 40min; Figure 20).

[0330] Thus, one single administration of up to 240mg of SR exerts no acute negative effects on alertness and daytime sleepiness while repeated administration is not associated with a negative effect on sleep quality after 3 weeks.

[0331] The BL-VAP score is as described in Bond A and Lader M (The use of analogue scales in rating subjective feelings. Br. J. med. Psychol. 1974, 47,211-218).

[0332] The MOAA / S scale is as described in Chernik DA et al. (Validity and reliability of the Observer's Assessment of Alertness / Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990 Aug;10(4):244-51.)

[0333] In conclusion, the oral slow release (prolonged-release) ketamine used according to the invention appears better tolerated than intranasal esketamine in terms of daytime sleepiness / drowsiness. Obtained data support the oral slow release (prolonged-release) ketamine used according to the invention to be devoid of negative effects on sleep quality, daytime sleepiness and drowsiness.

[0334] Example 3: Comparative example

[0335] As summarized in the Clinical Review Report on Esketamine Hydrochloride (Spravato®) provided by the Canadian Agency for Drugs and Technologies in health (2021 Apr. Clinical Evidence as available from: https: / / www.ncbi.nlm.nih.gov / books / NBK572276 / on October 21, 2023) there were 3 double-blind, randomized, controlled induction studies that evaluated the safety and efficacy of intranasal esketamine plus oral antidepressant versus intranasal placebo plus oral antidepressant, in patients with MDD who had shown inadequate response to at least 2 prior antidepressant therapies of adequate dose and duration. The primary outcome in all 3 trials was the change from baseline to week 4 in physician-assessed depression symptom severity measured using the MADRS. The trials (TRD3001, TRD3002, and TRD3005) used a similar study design that included a 4- week screening period, a 4- week double-blind induction period, and up to a 24- week follow-up period.

[0336] During the screening period, patients continued current antidepressant medications, and those who were adherent and had documented nonresponse (< 25% improvement in MADRS total score) were eligible for randomization to receive intranasal esketamine or placebo plus a newly initiated open- label SSRI (escitalopram or sertraline) or SNRI (duloxetine or venlafaxine XR) administered daily. In all 3 trials, patients were allocated to treatments through an interactive web response system and the computer-generated randomization code was stratified by country and class of antidepressant (SSRI or SNRI), with permuted blocks of 4 (TRD3002 and TRD3003) or 6 (TRD3001).

[0337] In Study TRD3001, 346 adults who were 18 to 64 years of age were randomized 1:1:1 to intranasal esketamine 56 mg, esketamine 84 mg, or placebo administered twice weekly, in addition to a newly initiated open-label oral antidepressant.

[0338] Study TRD3002 enrolled 227 adults ( 18 to 64 years of age) who were randomized 1 : 1 to intranasal esketamine (flexible dose: 56 mg or 84 mg) or placebo twice weekly, plus a newly initiated openlabel oral antidepressant.

[0339] In Study TRD3005, 137 patients 65 years of age or older were randomized 1:1 to intranasal esketamine 28 mg, 56 mg, or 84 mg (flexible dosing) or intranasal placebo twice weekly plus a newly initiated open-label SSRI or SNRI antidepressant.

[0340] The harms reported in the review protocol for those studies are as it follows in Table 5. Table 5: Summary of Most Common Adverse Events for Induction Studies with ESK = esketamine; NR = not reported, a Safety population and b Frequency of 5% or greater in at least 1 treatment group among the induction studies. When comparing the Treatment-Emergent Adverse Events (>5%) obtained for the slow release formulation with the most common adverse events observed for Spravato, data suggest that adverse events such as dizziness, Paresthesia, dissociation, anxiety, nausea, fatigue and blood pressure are less often observed for the slow release formulation than for esketamine.

Claims

Claims1. Ketamine or a derivative thereof for oral administration for use in the treatment of depression in a patient, wherein said treatment comprises a first treatment phase and at least one further treatment phase, wherein a) in said first treatment phase said patient receives a treatment with an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, and b) characterized in that in said at least one further treatment phase, the patient receives a further treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often.

2. Ketamine or a derivative thereof for oral administration for use in the treatment of depression in a patient, wherein said patient had received an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using a slow release oral dosage form, wherein total doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, characterized in that the patient receives a further treatment with ketamine using a slow release oral dosage form, wherein total doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often.

3. Ketamine or a derivative thereof for oral administration for use according to claim 1 or 2, wherein in said first treatment phase the patient has demonstrated a clinical meaningful response to said first treatment, preferably wherein in said one further treatment phase the clinical meaningful response obtained in the first treatment phase is at least substantially maintained in the further treatment phase, preferably the MADRS score, HAM-D score, and / or CGI-S score reduction obtained by the patient in the first treatment phase is at least substantially maintained in the further treatment phase.

4. Ketamine or a derivative thereof for oral administration for use according to claim 3, wherein the clinical meaningful response in said first treatment phase means an improvement of at least 35%, preferably at least 40%, more preferably at least 50% in a typically used scale of severity such as MADRS score , HAM-D score, and / or CGI-S score, preferably a CGI-S score reduction obtained by the patient in the first treatment phase of about 1 point, preferably of about 2 points.

5. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein in said first treatment phase and / or in said further treatment phase, the patient achieves a remission, which preferably corresponds to a MADRS score <12, most preferably <10.

6. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein in the first treatment the antidepressant other than ketamine or a derivative thereof is selected from the group consisting of those listed under ATC codes N06A (antidepressiva) and N05A (antip sychotica) (ATC version as valid November 1, 2023).

7. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein in the first treatment the antidepressant other than ketamine or a derivative thereof is selected from the group consisting of serotonin specific reuptake inhibitors (SSRI) and serotonin noradrenergic reuptake inhibitors (SNRI).

8. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein the patient a) is treatment naive with regard to antidepressant therapy b) did not receive any serotonin specific reuptake inhibitors (SSRI) or any serotonin noradrenergic reuptake inhibitors (SNRI) before; c) did not receive the antidepressant therapy used in said first treatment phase, preferably did not receive serotonin specific reuptake inhibitors (SSRI) or serotonin noradrenergic reuptake inhibitors (SNRI); d) has received the antidepressant therapy in said first treatment phase; or e) relapsed upon, did not respond to, or refrained due to adverse events from usingthe antidepressant therapy in said first treatment phase, preferably the serotonin specific reuptake inhibitors (SSRI) or serotonin noradrenergic reuptake inhibitors (SNRI) used in said first treatment phase.

9. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein said treatment comprises a first treatment phase and at least one further treatment phase, followed by a continuous treatment phase, wherein a) in said first treatment phase said patient receives a treatment with an antidepressant other than ketamine or a derivative thereof in combination with a first treatment with ketamine or a derivative thereof using the slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 120 mg to 360 mg are administered 2 to 7 times a week for one or two weeks, or less, b) in said at least one further treatment phase, the patient receives a treatment with the antidepressant other than ketamine or a derivative thereof in combination with a further treatment with ketamine or a derivative thereof using the slow release oral dosage form, wherein total single doses of ketamine or a derivative thereof of about 240 mg to 360 mg are administered 3 times a week or less often, for about 4 to 7 weeks, wherein the total administered dose of ketamine per week in the further treatment phase is lower compared to the first treatment phase, and c) in said continuous treatment phase, the patient receives a treatment with the antidepressant other than ketamine and no treatment with ketamine or a derivative thereof.

10. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein in the first treatment phase and / or in the further treatment phase, the total single doses of ketamine or a derivative thereof is 240 mg.

11. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein the first treatment phase has a duration of about less than 2 weeks, preferably about 10 days or less, more preferably about one week, or less.

12. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein in the first treatment phase the first treatment with ketamine or a derivative thereof is administration of a slow release oral dosage form, wherein totaldoses of ketamine or a derivative thereof of 240 mg are administered on days 1, 3, 5, and 7, and preferably the first treatment phase lasts one week.

13. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein the further treatment phase a) comprises administration of the slow release oral dosage form, wherein the total single doses are 240mg, which dose is administered twice weekly for at least 1, 2, 3, 4, 5 weeks, preferably 5, preferably less than 4 weeks; and / or b) comprises administration of the slow release oral dosage form, wherein the total single doses are 240 mg, which dose is administered once weekly for at least 1, 2, 3, 4, 5 weeks, preferably 1, 2, 3 weeks, most preferably 2 weeks.

14. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein the slow release oral dosage form is a form provides an in vitro release of ketamine of 0 to 45% after 2 hours, of 10 to 70% after 4 hours, of 30 to 85% after 6 hours and of 45 to 100% after 8 hours, when measured according to the USP Basket Method I in 0.1M HC1 at 100 rpm and 37°C, and / or wherein the slow release oral dosage form is a modified release oral dosage form, wherein the ratio of the amount of ketamine released after 1 hour of in-vitro dissolution of the dosage form at 37°C in a aqueous solution containing 20% by volume of ethanol to the amount of ketamine released after 1 hour of in-vitro dissolution of the dosage form at 37°C in an ethanol-free aqueous solution is less than 2: 1, preferably less than 1. 7: 1, more preferably less than 1.5:1, most preferably less than 1.2:1, when measured according to the USP 1 Basket Method in 0.1M HC1 at 100 rpm.

15. Ketamine or a derivative thereof for oral administration for use according to any one of the preceding claims, wherein said depression is MDD, preferably TRD, or bipolar depression.

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