WO2023139142A1

WO2023139142A1 - A pharmaceutical composition comprising ketanserin and uses thereof

Info

Publication number: WO2023139142A1
Application number: PCT/EP2023/051165
Authority: WO
Inventors: Fredrik Von Kieseritzky; Gabriella SMEDFORS; Ulf Bremberg
Original assignee: Amidea Sweden Ab
Priority date: 2022-01-20
Filing date: 2023-01-19
Publication date: 2023-07-27
Also published as: SE2250051A1

Abstract

The disclosure relates to an aqueous pharmaceutical composition for intranasal administration, said aqueous pharmaceutical composition comprising: (a) a compound of Formula (I) or pharmaceutically acceptable salt thereof, (b) Lauroyl Macrogol-32 glycerides, and (c) optionally an intranasal penetration enhancer. The disclosure the aqueous pharmaceutical composition for use in the treatment and/or prevention of psychedelic effects associated with a psychedelic drug.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING KETANSERIN AND USES THEREOF

Technical field

The present disclosure relates to the pharmaceutical drug ketanserin, a pharmaceutical composition comprising ketanserin and uses thereof. More specifically, the present disclosure relates to an aqueous pharmaceutical composition for intranasal administration of ketanserin to treat and/or prevent psychedelic effects provided by a psychedelic drug.

Background

Psychedelic drugs, or psychedelics, are a class of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness via serotonin 2A receptor agonism, which is known as psychedelic experiences or "trips". This causes specific psychological, visual and auditory changes, and often a substantially altered state of consciousness. The so-called classical psychedelics drugs having the largest scientific and cultural influence include mescaline, lysergic acid diethyl amide (LSD), psilocybin, and dimethyltryptamine (DMT).

Most psychedelic drugs fall into one of the three families of chemical compounds: tryptamines, phenethylamines, or lysergamides. These chemicals all bind to serotonin 5-HT2A receptors, which modulate the activity of key circuits in the brain involved with sensory perception and cognition, however the exact nature of how psychedelics induce changes in perception and cognition via the 5-HT2A receptor is still unknown, although reduced default mode network activity is likely a primary mechanism of action. The psychedelic experience is often compared to non-ordinary forms of consciousness such as those experienced in meditation, mystical experiences, and near-death experiences. The phenomenon of ego dissolution is often described as a key feature of the psychedelic experience.

Many psychedelic drugs are illegal worldwide under the United Nations (UN) conventions, with occasional exceptions for religious use or research contexts. Despite these controls, recreational use of psychedelics is common. Legal barriers have made the scientific study of psychedelics more difficult. Research has been conducted, however, and studies show that psychedelics are physiologically safe and do not lead to addiction. Studies conducted using psilocybin in a psychotherapeutic setting revealed that psychedelic drugs may assist with treating depression, anxiety, alcohol addiction, nicotine addiction. Psilocybin has also been effective as preventative treatment against severe hedache such as cluster headache and migraine in clinical trials. Although further research is needed, existing results show that psychedelics may be useful for treating certain forms of pathology that cannot currently be satisfactorily treated. However, this will require that there are safe, controlled and preferably also easy ways of reducing and/or terminating psychedelic side effects associated with administration of the psychedelic drugs.

WO 2019/081764 Al discloses a combination product for the treatment of neurological and/or psychiatric disorders. The combination product comprises (i) a compound which promotes neurogenesis and has hallucinogenic and/or psychedelic side effects, and (ii) a 5-HT2A receptor antagonist which alleviates and/or removes the hallucinogenic and/or psychedelic side effects caused by the first compound. It is mentioned that the 5-HT2A receptor antagonist may be selected from the group consisting of Methiothepin, Ritanserin, Ketanserin, Flibanserin, Methysergide, Trazodone, Nefazodone, Cinitapride, Cyproheptadine, Brexpiprazole, Cariprazine, Agomelatine, Pimavanserin, Eplivanserin, Volinanserin, Altanserin, Setoperone, LY-367,265, 1-(1-Naphthyl)piperazine, SB 206553, Pirenperone, SB-215505, Metergoline, Deramciclane, Amperozide, Glemanserin, 5-MeO-NBpBrT, Adatanserin, AM DA, Cinanserin, Fananserin, Iferanserin, AC-90179, LY86057, GSK-215083, Cyamemazine, Mesulergine, BF-1, LY215840, Sergolexole, Spiramide, LY53857, Amesergide, LY108742, Pipamperone, LY314228 and 5-1- 91 150. Further, it is described that the combination product is prepared for oral, sublingual, buccal, intranasal, intravenous, intramuscular, subcutaneous, rectal, transdermal, topical and/or inhalation-mediated administration.

Thus, ketanserin is a pharmaceutical drug mentioned in the context of termination of a hallucinogenic experience, and disentangling the specific cognitive effects of 5-HT2A receptor activation. However, a disadvantage associated with ketanserin is its low solubility in water which is a problem in the context of liquid formulations required for many applications such as nasal administration.

Thus, there is a need for a liquid pharmaceutical composition comprising ketanserin in an amount allowing for termination, or at least significantly reducing, a psychedelic experience such as termination of a psychedelic experience. Further, there is a need for a pharmaceutical composition comprising ketanserin allowing for easy administration such as administration to a subject in need thereof.

It is an object of the present disclosure to provide a liquid pharmaceutical composition comprising ketanserin that overcomes or at least mitigates one or more disadvantages associated with the use of ketanserin such as described above and/or fulfils the aforementioned need. Further, it is an object of the present disclosure to provide advantages and/or aspects not provided by hitherto known techniques. Summary

The present disclosure provides an aqueous pharmaceutical composition for intranasal administration, said aqueous pharmaceutical composition comprising :

(a) a compound of Formula I:

or pharmaceutically acceptable salt thereof,

(b) Lauroyl Macrogol-32 glycerides, and

(c) optionally an intranasal penetration enhancer.

Further, the present disclosure provides a kit of parts comprising :

(i) an aqueous pharmaceutical composition as described herein,

(ii) a psychedelic drug, and

(iii) optionally instructions for use.

There is also provided an aqueous pharmaceutical composition as described herein or a kit of parts as described herein for use as a medicament.

Further, there is provided an aqueous pharmaceutical composition as described herein or a kit of parts as described herein for use in the treatment and/or prevention of psychedelic effects associated with a psychedelic drug.

There is also provided a use of an aqueous pharmaceutical composition or a kit of parts as described herein for the manufacture of a medicament for use in the treatment and/or prevention of psychedelic effects associated with a psychedelic drug.

There is also provided a method for treatment and/or prevention of psychedelic effects associated with a psychedelic drug, said method comprising administering to a mammal such as a human, in need thereof, an effective amount such as a therapeutically effective amount of the aqueous pharmaceutical composition or a kit of parts as described herein. Brief description of the drawings

Figure 1 shows the chemical structure of the compound CIMBI-36.

Figure 2 shows efficacy of intranasal ketanserin in stopping or reducing ongoing CIMBI- 36 (25B-NBOME)-induced Wet Body Shakes (WBS) in Male SD Rats.

Description

There is provided an aqueous pharmaceutical composition for intranasal administration, said aqueous pharmaceutical composition comprising or consisting of:

(a) a compound of Formula I:

or pharmaceutically acceptable salt thereof,

(b) Lauroyl Macrogol-32 glycerides, and

(c) optionally an intranasal penetration enhancer.

The present disclosure is based on the unexpected finding that the presence of Lauroyl Macrogol-32 glycerides in an aqueous composition allows for solubilizing the compound of Formula I, which is also known under the name ketanserin or the chemical name 3- (2-(4-(4-fluorobenzoyl)piperidin-l-yl)ethyl)quinazoline-2,4(lH,3H)-dione. Thus, there is provided the use of Lauroyl Macrogol-32 glycerides for solubilizing a compound of Formula I, or pharmaceutically acceptable salt thereof, such as solubilization in water or an aqueous composition. As a result, the compound of Formula I can be provided as a liquid formulation. Further, a higher concentration of the compound of Formula I can be achieved as compared to a corresponding aqueous composition lacking Lauroyl Macrogol-32 glycerides. In this way, the very low water solubility of the compound of Formula I is overcome and the aqueous composition can have a concentration that is high enough to allow for administration, such as intranasal administration, of a therapeutically effective amount of the compound of Formula I. This concentration may be denominated a therapeutically effective concentration.

Thus, there is provided an aqueous pharmaceutical composition comprising the compound of Formula I in a therapeutically effective concentration for intranasal administration. For example, the therapeutically effective concentration for intranasal administration of the compound of Formula I may be from about 25 mg/mL to about 200 mg/mL, such as from about 25 mg/mL to about 100 mg/mL, such as about 50 mg/mL.

It will be appreciated that the compound of Formula I may be provided as a base, i.e. in non/salt form, or as a pharmaceutically acceptable salt such as an acid addition salt. For example, the pharmaceutically acceptable salt may be a combination of the compound of Formula I and an acid such as a combination of the compound of Formula I and the acid in a ratio of 1 : 1 or 2: 1. In particular, the pharmaceutically acceptable salt of the compound of Formula I may be a combination of the compound of the compound of Formula I with HCI taken in a ratio of 1 : 1. Other pharmaceutically acceptable salts of the compound of Formula I include acetate, benzoate, bensylate, citrate, fumarate, gluconate, hydrobromide, isethionate, lauryl sulfate (estolate), malate, mesylate, napsylate, napsylate, oleate, pamoate, phosphate, succinate, sulfate and tartrate salt(s).

The compound of Formula I, or a pharmaceutically acceptable salt thereof, may be amorphous or crystalline. Further, the compound of Formula I may be in the form of a dry and/or frozen formulation. For instance, the compound of Formula I may be spray dried. Additionally or alternatively, the compound of Formula I may be combined with a carrier. Examples of carriers that may be used include silica particles such as mesoporous particles, microspheres such as microspheres comprising or consisting of PLGA (i.e. poly(lactic-co-glycolic acid), chitosan, alginate or any combination thereof, or nano-particulate carriers such as carbon nanotubes and/or lipid nanocarriers.

The Lauroyl Macrogol-32 glycerides of the aqueous pharmaceutical composition comprise a mixture of monoesters, diesters and triesters of glycerols and monoesters and diesters of macrogols. Lauroyl Macrogol-32 glycerides is the name provided in the European Pharmacopoeia for this mixture, with the corresponding USP NF name being Lauroyl polyoxyl-32 glycerides. The Lauroyl Macrogol-32 glycerides may also have the Chemical Abstract service number (CAS number) CAS 121548-04-07.

The macrogols, i.e., polyethylene glycols (PEGs), may have a molecular weight of about 1500. In particular, the aforementioned esters may be PEG esters of lauric acid such as PEG-32 esters of lauric acid. As used herein, PEG-32 is understood to consist of or comprise the chemical structure HO-(CH2CH2O)32-OH. Thus, the PEG-32 may consist or substantially consist of HO-(CH2CH2O)32-OH, or the PEG-32 may contain HO- (CH2CH₂O)32-OH in admixture with further polyethylene glycols. For instance, the Lauroyl Macrogol-32 glycerides may comprise or consist of one or more of the following : glyceryl 1-laurate, glyceryl 2-laurate, glyceryl 1,2-dilaurate, glyceryl 1,3- dilaurate, trilaurin, PEG-32 laurate, PEG-32 dilaurate. Additionally, the Lauroyl Macrogol-32 glycerides may comprise free polyethylene glycol.

It will be appreciated that the Lauroyl Macrogol-32 glycerides may be denominated Lauroyl Polyoxyl-32 glycerides or Lauroyl PEG-32 glycerides, and the aforementioned terms may be used interchangeably.

The Lauroyl Macrogol-32 glycerides of the aqueous pharmaceutical composition may have a melting point of 43-44 °C. Additionally or alternatively, the Lauroyl Macrogol- 32 glycerides may have a broad endotherm from about 10 °C to about 45 °C and/or an onset melting temperature of about 38 °C. Further, the Lauroyl Macrogol-32 glycerides may have a hydrophilic-lipophilic balance (HLB) from 10 to 14 such as 11 or 14. The HLB value may be determined as known in the art. For instance, the HLB value may be determined using Griffin 's method as described in Journal of the Society of Cosmetic Chemists, 1(5) : 311-26. Further, the Lauroyl Macrogol-32 glycerides may be obtained by partial alcoholysis of saturated oils containing triglycerides of lauric acid using macrogoL

The aqueous pharmaceutical composition may comprise a penetration enhancer such as an intranasal penetration enhancer. In this way, the uptake of the aqueous pharmaceutical composition across the mucous membranes may be improved thereby enhancing the therapeutic effect of the administration of the aqueous pharmaceutical composition. For instance, the intranasal penetration enhancer may be selected from the group consisting of chitosan, oleic acid, cyclodextrin and diethylene glycol monoethyl ether. In a further example, the intranasal penetration enhancer may comprise or consist of diethylene glycol monoethyl ether. The compound diethylene glycol monoethyl ether is sold under the registered trademark Transcutol®. Further, the compound diethylene glycol monoethyl ether has the CAS number CAS 111-90-0.

The aqueous pharmaceutical composition may further comprise pH adjuster(s). Additionally or alternatively, the aqueous pharmaceutical composition may comprise or be free from preservative(s).

The aqueous pharmaceutical composition may further comprise one or more of the following components: oil(s) such as castor oil, chlorobutanol, glycerine, phenethyl alcohol, liposome(s). Alternatively, the aqueous pharmaceutical composition may comprise or consist of one or more of the aforementioned components and optionally be free from Lauroyl Macrogol-32 glycerides.

Further, instead of or in addition to the Lauroyl Macrogol-32 glycerides the pharmaceutical composition described herein may comprise a Self Micro Emulsifying Drug Delivery System that is not based on Lauroyl Macrogol-32 glycerides. As used herein, a Self Micro Emulsifying Drug Delivery System is a drug delivery system that uses a microemulsion achieved by chemical rather than mechanical means so that the microemulsion is an intrinsic property of the drug formulation rather than being achieved by mixing and/or handling.

The aqueous pharmaceutical composition may further comprise one or more surfactants. The one or more surfactants may improve the stability and/or the solubility of the components of the composition.

The water content of the aqueous pharmaceutical composition may be from about 50 wt% to about 95 wt%, based on the total weight of the aqueous pharmaceutical composition. For instance, the water content may be about 60 wt% or more, such as about 70 wt% or more, such as about 80 wt% or more, such as about 90 wt% or more, such as about 95 wt%.

The aqueous pharmaceutical composition may be provided as a liquid, which may comprise particles. For instance, the aqueous pharmaceutical composition may be provided as a dispersion. The dispersion may comprise (i) particles comprising the compound of Formula I, Lauroyl Macrogol-32 glycerides and optionally the intranasal penetration enhancer and (ii) a liquid, such as water. The dispersed particles may be distributed throughout the composition, such as evenly distributed throughout the composition.

The aqueous pharmaceutical composition may be enclosed in a dispenser, which may be provided with actuating means or an applicator. For instance, the dispenser may be a nasal spray dispenser or a dispenser for nose drops.

Further, there is provided a kit of parts comprising :

(i) an aqueous pharmaceutical composition as described herein,

(ii) a psychedelic drug, and

(iii) optionally instructions for use. The kit of parts may be provided as a single composition comprising (i) and (ii). Alternatively, the components (i), (ii) and optionally (iii) may be provided separately.

The psychedelic drug(s) described herein may have agonistic action on the serotonin 5-HT2A receptor. For example, the psychedelic drug(s) may comprise or consist of one or more of the following : lysergamide(s), phenethylamine(s), tryptamine(s), or prodrug(s) or analogues(s) thereof. The lysergamide(s), or prodrug(s) or analogues(s) thereof, may be one or more of the following : Lysergic Acid Diethylamide (LSD), lp-LSD, lb-LSD, lcP-LSD, 1-acetyl-LSD (ALD-52), N-ethyl-nor- LSD (ETH-LAD). The phenethylamine(s), or prodrug(s) or analogues(s) thereof, may be one or more of the following : 2, 5-dimethoxyphenetylamines such as mescaline, cacti containing mescaline, 2,5-dimethoxy-4-bromophenethylamine (2C-B), 2-(4- bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25B- NBOMe or CIMBI-36), 2-(4-Iodo-2,5-dimethoxyphenyl)ethan-l-amine (2C-I), 2,5- dimethoxy-4-ethylthiophenethylaminem(2C-T-2), 2-[2,5-Dimethoxy-4- (propylsulfanyl)phenyl]ethan-l-amine (2C-T-7)or 2,5-dimethoxyamphetamine(s) such as 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4- bromoampethamine (DOB), 4-chlorio-2,5-dimethoxy-amphetamine (DOC), 2,5- dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-iodoamphetamine (DOI), 3,4,5-trimethoxyamphetamine (TMA), 2,4,5-trimethoxyamphetamine (TMA-2).The tryptamine(s), or prodrug(s) or analogues(s) thereof, may be one or more of the following : psilocybin, psilocin, dimethyltryptamine (DMT), N,N-dipropyltryptamine (DPT), 4-hydroxy-N-ethyl-N-methyltryptamine (4-HO-MET), O-acetylpsilocin (4-AcO- DMT), 4-acetoxy-N-methyl-N-ethyltryptamine (4-AcO-MET), N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).

There is also provided an aqueous pharmaceutical composition or a kit of parts as described herein for use as a medicament.

Further, there is provided an aqueous pharmaceutical composition or a kit of parts as described herein for use in the treatment and/or prevention of psychedelic effects associated with a psychedelic drug.

There is also provided the use of an aqueous pharmaceutical composition or a kit of parts as described herein for the manufacture of a medicament for use in the treatment and/or prevention of psychedelic effects associated with a psychedelic drug. There is also provided a method for the treatment and/or prevention of psychedelic effects associated with a psychedelic drug, said method comprising administering to a mammal such as a human, in need thereof, an effective amount such as a therapeutically effective amount of the aqueous pharmaceutical composition or a kit of parts as described herein.

The treatment and/or prevention of psychedelic effect(s) associated with a psychedelic drug may involve reduction and/or elimination such as complete or substantially complete elimination of the psychedelic effect(s) associated with the psychedelic drug. Further, the aqueous pharmaceutical composition or a kit of parts for use as described herein may be administered intranasally such as intranasally to a patient such as a human. Of course, it is a significant benefit that the compound of Formula I, i.e. ketanserin, can be administered intranasally in a therapeutically effective amount since this is a simple and effective way of providing the ketanserin to a patient or individual in need thereof. In contrast to administration modes such as parenteral, oral sublingual and/or buccal administration, intranasal administration allows for rapid absorption, high bioavailability and/or direct absorption into the Central Nervous System (CNS). The intranasal administration also allows for providing an appropriate amount of the ketanserin without requiring access to sophisticated equipment or a particular setting such as a hospital. Further, an advantage of intranasal administration is that it is easier to provide to patients or individuals who for whatever reason are uncooperative to take medication. This may be important for e.g. individuals suffering from an overdose of a psychedelic drug who will have to be managed and where a non-invasive and quick delivery of ketanserin to the CNS is desired.

As used herein, intranasal administration intends administration through the nasal cavity of the nose of a patient or individual. In this way, a drug such as ketanserin is transferred across the mucosa of the nasal cavity.

It will be appreciated that the aqueous pharmaceutical composition or a kit of parts may be administered to a patient or individual who is under the influence of psychedelic effect(s) associated with a psychedelic drug. The psychedelic drug may have been administered to the patient or individual intranasally or in one or more of the following ways: orally, sublingually, buccally, intravenously, intramuscularly, subcutaneously, rectally, transdermally, topically and/or by inhalation. Thus, while it is envisaged that the aqueous pharmaceutical composition containing ketanserin is administered intranasally the administration mode of the psychedelic drug(s) may be the same or different. The administration of the aqueous pharmaceutical composition or kit of parts may take place in a hospital setting to e.g. terminate a medical treatment or an overdose involving a psychedelic drug such as a psychedelic drug described herein.

Alternatively, the administration may take place outside a hospital setting in order to e.g. terminate psychedelic effect(s) of a psychedelic drug such as a psychedelic drug described herein.

It will be appreciated that the psychedelic effect(s) described herein may comprise or consist of hallucinogenic effect(s).

There is also provided a method for preparing the aqueous pharmaceutical composition described herein, said method comprising the steps of:

(a) providing a first composition comprising Lauroyl Macrogol-32 glycerides and water,

(b) adding a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, to the first composition thereby providing the aqueous pharmaceutical composition,

(c) optionally adding a penetration enhancer as described herein to step (a) and/or step (b), and

(d) optionally stirring the first composition and/or the aqueous pharmaceutical composition.

It will be appreciated that the method may be performed at a suitable temperature such as room temperature, i.e. at a temperature from about 20 °C to about 25 °C such as about 22 °C. Further, the first composition of the method may comprise from about 5 wt% to about 15 wt% such as about 10 wt% of the Lauroyl Macrogol-32 glycerides and optionally from about 10 to about 20 wt% such as about 15 wt% of the penetration enhancer. The compound of Formula I in step (b) may be added to provide a therapeutic concentration as described herein.

In this document, unless otherwise stated, the naming and the drawing of the chemical compounds have been made using the program ChemDraw Ultra 12.0.2.1076. In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context).

The invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention. Examples

General

Gelucire 48/16, Gelucire 44/14 and Gelucire 50/13 were purchased from Gattefosse. As used herein, transcutol stands for diethylene glycol monoethyl ether.

Abbreviations g grams

HPMC hydroxypropylmethylcellulose h hour(s) kg kilogram(s) mg milligram(s) mL millilitre(s)

SD Sprague Dawley t time

WBS wet body shakes wt% percent by weight pg microgram(s) pL microlitre(s) pm micrometre(s)

Example 1

The solubility of ketanserin was tested in a number of different vehicles as shown in Table 1. The testing was performed by adding the vehicle to ketanserin free base. The study was performed in such a way that at the start there was an excess of solid ketanserin to avoid supersaturation situations. The solubility was judged visually, and ketanserin was considered soluble when no or substantially no solid sediment of ketanserin remained after addition of the vehicle.

Table 1

It was concluded that only the vehicle Gelucire 44/14 provided satisfactory solubility of ketanserin. Microscopic examinations were subsequently performed with systems comprising ketanserin and Gelucire 44/14, and it was found that ketanserin base or ketanserin tartrate could be solubilized in a concentration of 50 mg/mL, wherein the aforementioned concentration refers to the amount of ketanserin base. Example 2

Composition la

A first flask was charged with 15 g Gelucire 44/14 and 135 g purified water was added with stirring at room temperature, until a homogeneous opaque system was obtained. In a second flask, 6.9 g ketanserin tartrate was weighed in. 100 mL mixture from the first flask was added to the second flask, and the resulting mixture was stirred at room temperature until no sediment could be visually identified. After stirring for an additional 5 minutes, the resulting mixture- which was denominated composition la- was transferred to suitable packing containers, and used as such. The composition la had a ketanserin concentration of 50 mg/mL. Further, the composition la appeared to be a microemulsion. It was concluded that an aqueous composition comprising Gelucire 44/14 allows for solubilization of a high concentration of ketanserin such as a ketanserin concentration of 50 mg/mL.

Example 3

Composition lb

A first flask was charged with 15 g Gelucire 44/14 and 112.5 g purified water was added with stirring at room temperature, followed by 22.5 g transcutol, until a homogeneous opaque system was obtained. In a second flask, 6.9 g ketanserin tartrate was weighed in. 100 mL mixture from the first flask was added to the second flask, and the resulting mixture was stirred at room temperature until no sediment could be visually identified. After stirring for an additional 5 minutes, the resulting mixture- which was denominated composition lb- was transferred to suitable packing containers, and used as such. The composition lb had a concentration of 50 mg/mL. Further, the composition la appeared to be a microemulsion. It was concluded that an aqueous composition comprising Gelucire 44/14 and transcutol allows for solubilization of a high concentration of ketanserin such as a ketanserin concentration of 50 mg/mL.

Example 4

Two ketanserin compositions were tested using a Franz diffusion cell in order to assess their suitability for nasal delivery.

The first ketanserin composition was an aqueous composition containing 10 wt% Gelucire 44/14 and ketanserin in a concentration of 50 mg/mL. The second ketanserin composition was an aqueous composition containing 10 wt% Gelucire 44/14, 15 wt% transcutol and ketanserin in a concentration of 50 mg/mL. No pH adjuster was present in the first and second ketanserin compositions. The Franz diffusion cell experiments were performed in order to assess the release of ketanserin from the composition across a membrane. The membrane was provided in order to separate the ketanserin composition from an acceptor. Thus, at the beginning of the experiment the ketanserin composition was placed on one side of the membrane and then the flux of the ketanserin across the membrane into the acceptor side was studied. In this way, the suitability of the composition for intranasal delivery was assessed. If ketanserin flux occurred across the membrane it was considered suitable for intranasal administration. Generally, it is considered that the higher the flux the more suitable the composition is for intranasal administration.

The setup of the Franz cell was as follows.

Acceptor media : Acetate buffer 50 mM, pH 4.0. The solubility of ketanserin free base in this media was found to be approximately 1 mg/mL.

Acceptor volume: 5 mL

Membrane: 0.45 pm PVDF filter, Durapore.

Membrane area: 0.64 cm²

Application: The membrane was first wetted with 100 pL of a solution containing

1 wt% HPMC + 0.1 % Na-docusate. Thereafter, 100 pL of the composition was added, which was considered timepoint to.

Time points: 5, 10, 15, 30 and 60 minutes after tO.

Tests: Duplicate. For the Gelucire 44/14 + Transcutol system only one time point for one of the replicates was performed.

The cumulative release of the ketanserin in the first and second ketanserin compositions were measured, and the flux rates were calculated. The equation (1) below was used for calculating the flux.

Equation (1) :

F = Flux in amount/time unit* membrane surface

A = membrane area accessible for the composition

Y_n = cumulative amount of released ketanserin at the time t_n wherein n is the time after the addition of the composition. For example, n may be the number of minutes after to.

The results for the first and second ketanserin compositions were as shown in Table 2. Table 2

It was concluded that the ketanserin compositions had a satisfactory flux.

Example 5

The efficacy of intranasal ketanserin in stopping or reducing ongoing CIMBI-36 (25B- NBOME)-induced Wet Body Shakes (WBS) in Male SD Rats was tested. The species of rat was chosen based on the findings of Wojtas et al., Neurotox. Res., 2021, 39(2); 305-326. WBS describe abrupt lateral movements, rapid side-to-side rotational head movements and paroxysmal rotational movements of the head (Halberstadt et al., Psychopharmacology (Bert), 2013, 227(4); 727-739).

CIMBI-36 was dissolved in saline to give a concentration of 0.1 mg/mL. The chemical structure of CIMBI-36 is shown in Figure 1. CIMBI-36 may also be denominated 25B-NBOMe, NBOMe-2C-B, Nova or BOM 2-CB or 2-(4-bromo-2,5-dimethoxyphenyl)- /V-[(2-methoxyphenyl)methyl]ethanamine.

Intranasal ketanserin was formulated in a concentration of 50 mg/mL by adding 112.5 g purified water to 15 g Gelucire 44/14, followed by 22.5 g transcutol, whilst stirring at room temperature until a homogeneous opaque system was obtained. 6.9 g ketanserin tartrate was weighed in a second flask, to which 100 mL of the formulation vehicle from the first flask was added. The resulting mixture was stirred at room temperature until no sediment could be visually identified and then stirred for an additional five minutes.

Testing was performed on three groups consisting of six rats each, as shown in Table 3. For Group 1 the treatment was performed as follows: At t=0, the rats were subcutaneously injected with 3 mL/kg of the composition 1A and observed for 15 minutes for the number of spontaneous WBS. At t=15 mins, 80 pL/kg of composition IB was administered intranasally, instilling half of the dose volume into the right nostril and the remaining half into the left nostril under mild gaseous anaesthesia. The rats were then observed for 240 minutes post dose for the number of further spontaneous WBS, noting the time the individual animals woke up from anaesthesia. The WBS responses were counted in bins of 5 minutes. For Groups 2 and 3 the treatment was performed in the same way as described for Group 1 using compositions 2A and 2B for Group 2, and compositions 3A and 3B for Group 3.

Table 3

In this document, s.c. stands for subcutaneous. Further, in this document i.n. stands for intranasal.

The results are shown in Figure 2. A pairwise comparison between the groups was made and the following differences as evidenced by the p value are shown in Table 4. Thus, the CIMBI-36 and ketanserin treated rats in Group 3 demonstrated significantly (p=0.001) less WBS behaviour during five-minute bins than the CIMBI-36 treated controls in Group 2. Table 4

It was also found that the average time for discontinuation of WBS was 163 minutes post treatment, i.e. counted from the injection of the first composition, for the CIMBI- 36 treated rats having received compositions 2A and 2B in Group 2. Further, it was observed that the average time for discontinuation of WBS was 115 minutes post treatment, i.e. counted from the injection of the first composition, for the CIMBI-36 treated rats having received compositions 3A and 3B in Group 3. It was concluded that the aqueous pharmaceutical composition of the present disclosure allows for eliminating psychedelic effects such as psychedelic effects relating to the use of a psychedelic drug.

References

1. WO 2019/081764 Al

2. Journal of the Society of Cosmetic Chemists, 1(5) : 311-26 3. Wojtas et al., Neurotox. Res., 2021, 39(2); 305-326

4. Halberstadt et al., Psychopharmacology (Bert), 2013, 227(4); 727-739

Claims

1. An aqueous pharmaceutical composition for intranasal administration, said aqueous pharmaceutical composition comprising :

(a) a compound of Formula I:

or pharmaceutically acceptable salt thereof,

(b) Lauroyl Macrogol-32 glycerides, and

(c) optionally an intranasal penetration enhancer.

2. The aqueous pharmaceutical composition according to claim 1, wherein the compound of Formula I is provided in a therapeutically effective concentration for intranasal administration.

3. The aqueous pharmaceutical composition according to claim 2, wherein the therapeutically effective concentration for intranasal administration of the compound of Formula I is from 25 mg/mL to 200 mg/mL such as 50 mg/mL.

4. The aqueous pharmaceutical composition according to any one of claims 1-3, wherein the Lauroyl Macrogol-32 glycerides have a peak melting temperature of 43-44 °C.

5. The aqueous pharmaceutical composition according to any one of the preceding claims, wherein the Lauroyl Macrogol-32 glycerides have a hydrophilic-lipophilic balance (HLB) from 10 to 14.

6. The aqueous pharmaceutical composition according to any one of the preceding claims, wherein the Lauroyl Macrogol-32 glycerides comprise one or more of the following : glyceryl 1-laurate, glyceryl 2-laurate, glyceryl 1,2- dilaurate, glyceryl 1,3-dilaurate, trilaurin, PEG-32 laurate, PEG-32 dilaurate.

7. The aqueous pharmaceutical composition according to any one of the preceding claims comprising an intranasal penetration enhancer selected from the group consisting of chitosan, oleic acid, cyclodextrin and diethylene glycol monoethyl ether.

8. The aqueous pharmaceutical composition according to any one of the preceding claims, wherein the intranasal penetration enhancer comprises diethylene glycol monoethyl ether.

9. The aqueous pharmaceutical composition according to any one of the preceding claims, which is provided as a dispersion, such as an emulsion, such as a microemulsion.

10. The aqueous pharmaceutical composition according to claim 9, wherein dispersed particles are evenly distributed throughout the dispersion.

11. The aqueous pharmaceutical composition according to any one of the preceding claims, which is enclosed in a dispenser optionally provided with actuating means or an applicator.

12. A kit of parts comprising :

(i) an aqueous pharmaceutical composition according to any one of claims 1-

11,

(ii) a psychedelic drug, and

(iii) optionally instructions for use.

13. The kit of parts according to claim 12, wherein the psychedelic drug has agonistic action on the serotonin 5-HT2A receptor.

14. The kit of parts according to claim 12 or 13, wherein the psychedelic drug comprises one or more of the following : lysergamide(s), phenethylamine(s), tryptamine(s).

15. The aqueous pharmaceutical composition according to any one of claims 1-11 or the kit of parts according to any one of claims 12-14 for use as a medicament.

16. The aqueous pharmaceutical composition according to any one of claims 1-11 or the kit of parts according to any one of claims 12-14 for use in the treatment and/or prevention of psychedelic effects associated with a psychedelic drug. The aqueous pharmaceutical composition or the kit of parts for use according to claim 16, wherein the treatment and/or prevention involves elimination of psychedelic effects associated with a psychedelic drug. The aqueous pharmaceutical composition or the kit of parts for use according to claim 16 or 17 wherein the aqueous pharmaceutical composition is administered intranasally. The aqueous pharmaceutical composition or the kit of parts for use according to any one of claims 16-18 wherein the aqueous pharmaceutical composition is administered in a hospital setting or outside a hospital setting to a patient who is under the influence of psychedelic effect(s) associated with a psychedelic drug. Use of Lauroyl Macrogol-32 glycerides for solubilization of a compound of Formula I as defined in claim 1.